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Hydrochlorothiazide use linked to higher skin cancer risk
The common diuretic hydrochlorothiazide is linked to a dose-dependent increased risk of nonmelanoma skin cancer, in particular, squamous cell carcinoma, a case-controlled registry study showed.
This nationwide, case-matched control study examined patients’ cumulative hydrochlorothiazide use between 1995 and 2012 and found a clear dose-response patterns for both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with a more than sevenfold increased risk of SCC for a cumulative use of greater than or equal to 200,000 mg of hydrochlorothiazide (HCTZ).
“Assuming causality, the present results suggest that 1 in 10 SCC cases diagnosed during the study period can be attributed to HCTZ use,” wrote the study authors, who were led by Sidsel Arnspang, MD, of the department of neurology at Odense (Denmark) University Hospital, which is affiliated with the University of Southern Denmark.
The authors noted that they previously had reported a sevenfold increased risk of lip squamous cell carcinoma with hydrochlorothiazide. Furthermore, the International Agency for Research on Cancer recently classified the diuretic and antihypertensive as “possibly carcinogenic to humans.”
“As HCTZ is among the most widely used drugs in the U.S. and Western Europe, a carcinogenic effect of HCTZ would have a considerable impact on public health,” they wrote in their paper, published in the Journal of American Academy of Dermatology.
According to the study authors, the few studies that have investigated a potential link between thiazide use and nonmelanoma skin cancer (NMSC) have reported inconsistent results.
They speculated that this could be because HCTZ often is prescribed in combination with other diuretics, and there may have been difficulties with disentangling its effect from those of the other drugs.
Using data from five nationwide data sources, the research team compared HCTZ use among people diagnosed with SCC or BCC of the skin to use among a matched control group without such cancers. People were excluded from the analysis if they had SCC of the lip because they had been evaluated in the research team’s previous study.
High use of HCTZ was defined as filled prescriptions totaling greater than or equal to 50,000 mg of HCTZ, which corresponds to greater than or equal to 2,000 defined daily doses (for example, approximately 6 years of cumulative use).
Overall, the study population involved 71,533 BCC and 8,629 SCC cases that were matched to 1,430,883 and 172,462 population controls, respectively.
Baseline characteristics of the cases and controls were similar, except BCC cases were slightly more educated than controls. Results showed that high use of hydrochlorothiazide was associated with odds ratios of 1.29 (95% confidence interval, 1.23-1.35) for BCC and 3.98 (95% CI, 3.68-4.31) for SCC.
A clear dose-response relationship was observed with HCTZ use for both BCC and SCC, with the highest ORs observed in the upper exposure category (greater than or equal to 200,000 mg): The OR for BCC in this category was 1.54 (95% CI, 1.38-1.71) and 7.38 for SCC (95% CI, 6.32-8.60).
The researchers observed no associations for BCC or SCC risk with use of other diuretics and other hypertensives, a finding that they said supported a potential causal association between HCTZ and NMSC risk.
Little variation was seen in the association between HCTZ use and BCC or SCC risk in the subgroup analyses, except for notably stronger associations among younger individuals and females.
In analyses stratified according to tumor localization, the authors saw stronger associations for cancers at sun-exposed skin sites, especially the skin of the lower limbs.
“Given the considerable use of HCTZ worldwide and the morbidity associated with NMSC, a causal association between HCTZ use and NMSC risk would have significant public health implications,” Dr. Arnspang and associates concluded. “The use of HCTZ should be carefully considered as several other antihypertensive agents with similar indications and efficiency are available but without known associations with skin cancer.”
The investigators cited several limitations. For example, information on ethnicity and skin type was not available. This information would have been useful in evaluating participants’ photosensitivity as a possible mechanism for a higher skin cancer risk with the use of HCTZ.
The study was funded by a grant from the Danish Cancer Society and the Danish Council of Independent Research. Several of the authors reported receiving grants and or honoraria from pharmaceutical companies.
SOURCE: Arnspang S et al. JAAD. 2017. doi: 10.1016/j.jaad.2017.11.042.
The common diuretic hydrochlorothiazide is linked to a dose-dependent increased risk of nonmelanoma skin cancer, in particular, squamous cell carcinoma, a case-controlled registry study showed.
This nationwide, case-matched control study examined patients’ cumulative hydrochlorothiazide use between 1995 and 2012 and found a clear dose-response patterns for both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with a more than sevenfold increased risk of SCC for a cumulative use of greater than or equal to 200,000 mg of hydrochlorothiazide (HCTZ).
“Assuming causality, the present results suggest that 1 in 10 SCC cases diagnosed during the study period can be attributed to HCTZ use,” wrote the study authors, who were led by Sidsel Arnspang, MD, of the department of neurology at Odense (Denmark) University Hospital, which is affiliated with the University of Southern Denmark.
The authors noted that they previously had reported a sevenfold increased risk of lip squamous cell carcinoma with hydrochlorothiazide. Furthermore, the International Agency for Research on Cancer recently classified the diuretic and antihypertensive as “possibly carcinogenic to humans.”
“As HCTZ is among the most widely used drugs in the U.S. and Western Europe, a carcinogenic effect of HCTZ would have a considerable impact on public health,” they wrote in their paper, published in the Journal of American Academy of Dermatology.
According to the study authors, the few studies that have investigated a potential link between thiazide use and nonmelanoma skin cancer (NMSC) have reported inconsistent results.
They speculated that this could be because HCTZ often is prescribed in combination with other diuretics, and there may have been difficulties with disentangling its effect from those of the other drugs.
Using data from five nationwide data sources, the research team compared HCTZ use among people diagnosed with SCC or BCC of the skin to use among a matched control group without such cancers. People were excluded from the analysis if they had SCC of the lip because they had been evaluated in the research team’s previous study.
High use of HCTZ was defined as filled prescriptions totaling greater than or equal to 50,000 mg of HCTZ, which corresponds to greater than or equal to 2,000 defined daily doses (for example, approximately 6 years of cumulative use).
Overall, the study population involved 71,533 BCC and 8,629 SCC cases that were matched to 1,430,883 and 172,462 population controls, respectively.
Baseline characteristics of the cases and controls were similar, except BCC cases were slightly more educated than controls. Results showed that high use of hydrochlorothiazide was associated with odds ratios of 1.29 (95% confidence interval, 1.23-1.35) for BCC and 3.98 (95% CI, 3.68-4.31) for SCC.
A clear dose-response relationship was observed with HCTZ use for both BCC and SCC, with the highest ORs observed in the upper exposure category (greater than or equal to 200,000 mg): The OR for BCC in this category was 1.54 (95% CI, 1.38-1.71) and 7.38 for SCC (95% CI, 6.32-8.60).
The researchers observed no associations for BCC or SCC risk with use of other diuretics and other hypertensives, a finding that they said supported a potential causal association between HCTZ and NMSC risk.
Little variation was seen in the association between HCTZ use and BCC or SCC risk in the subgroup analyses, except for notably stronger associations among younger individuals and females.
In analyses stratified according to tumor localization, the authors saw stronger associations for cancers at sun-exposed skin sites, especially the skin of the lower limbs.
“Given the considerable use of HCTZ worldwide and the morbidity associated with NMSC, a causal association between HCTZ use and NMSC risk would have significant public health implications,” Dr. Arnspang and associates concluded. “The use of HCTZ should be carefully considered as several other antihypertensive agents with similar indications and efficiency are available but without known associations with skin cancer.”
The investigators cited several limitations. For example, information on ethnicity and skin type was not available. This information would have been useful in evaluating participants’ photosensitivity as a possible mechanism for a higher skin cancer risk with the use of HCTZ.
The study was funded by a grant from the Danish Cancer Society and the Danish Council of Independent Research. Several of the authors reported receiving grants and or honoraria from pharmaceutical companies.
SOURCE: Arnspang S et al. JAAD. 2017. doi: 10.1016/j.jaad.2017.11.042.
The common diuretic hydrochlorothiazide is linked to a dose-dependent increased risk of nonmelanoma skin cancer, in particular, squamous cell carcinoma, a case-controlled registry study showed.
This nationwide, case-matched control study examined patients’ cumulative hydrochlorothiazide use between 1995 and 2012 and found a clear dose-response patterns for both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with a more than sevenfold increased risk of SCC for a cumulative use of greater than or equal to 200,000 mg of hydrochlorothiazide (HCTZ).
“Assuming causality, the present results suggest that 1 in 10 SCC cases diagnosed during the study period can be attributed to HCTZ use,” wrote the study authors, who were led by Sidsel Arnspang, MD, of the department of neurology at Odense (Denmark) University Hospital, which is affiliated with the University of Southern Denmark.
The authors noted that they previously had reported a sevenfold increased risk of lip squamous cell carcinoma with hydrochlorothiazide. Furthermore, the International Agency for Research on Cancer recently classified the diuretic and antihypertensive as “possibly carcinogenic to humans.”
“As HCTZ is among the most widely used drugs in the U.S. and Western Europe, a carcinogenic effect of HCTZ would have a considerable impact on public health,” they wrote in their paper, published in the Journal of American Academy of Dermatology.
According to the study authors, the few studies that have investigated a potential link between thiazide use and nonmelanoma skin cancer (NMSC) have reported inconsistent results.
They speculated that this could be because HCTZ often is prescribed in combination with other diuretics, and there may have been difficulties with disentangling its effect from those of the other drugs.
Using data from five nationwide data sources, the research team compared HCTZ use among people diagnosed with SCC or BCC of the skin to use among a matched control group without such cancers. People were excluded from the analysis if they had SCC of the lip because they had been evaluated in the research team’s previous study.
High use of HCTZ was defined as filled prescriptions totaling greater than or equal to 50,000 mg of HCTZ, which corresponds to greater than or equal to 2,000 defined daily doses (for example, approximately 6 years of cumulative use).
Overall, the study population involved 71,533 BCC and 8,629 SCC cases that were matched to 1,430,883 and 172,462 population controls, respectively.
Baseline characteristics of the cases and controls were similar, except BCC cases were slightly more educated than controls. Results showed that high use of hydrochlorothiazide was associated with odds ratios of 1.29 (95% confidence interval, 1.23-1.35) for BCC and 3.98 (95% CI, 3.68-4.31) for SCC.
A clear dose-response relationship was observed with HCTZ use for both BCC and SCC, with the highest ORs observed in the upper exposure category (greater than or equal to 200,000 mg): The OR for BCC in this category was 1.54 (95% CI, 1.38-1.71) and 7.38 for SCC (95% CI, 6.32-8.60).
The researchers observed no associations for BCC or SCC risk with use of other diuretics and other hypertensives, a finding that they said supported a potential causal association between HCTZ and NMSC risk.
Little variation was seen in the association between HCTZ use and BCC or SCC risk in the subgroup analyses, except for notably stronger associations among younger individuals and females.
In analyses stratified according to tumor localization, the authors saw stronger associations for cancers at sun-exposed skin sites, especially the skin of the lower limbs.
“Given the considerable use of HCTZ worldwide and the morbidity associated with NMSC, a causal association between HCTZ use and NMSC risk would have significant public health implications,” Dr. Arnspang and associates concluded. “The use of HCTZ should be carefully considered as several other antihypertensive agents with similar indications and efficiency are available but without known associations with skin cancer.”
The investigators cited several limitations. For example, information on ethnicity and skin type was not available. This information would have been useful in evaluating participants’ photosensitivity as a possible mechanism for a higher skin cancer risk with the use of HCTZ.
The study was funded by a grant from the Danish Cancer Society and the Danish Council of Independent Research. Several of the authors reported receiving grants and or honoraria from pharmaceutical companies.
SOURCE: Arnspang S et al. JAAD. 2017. doi: 10.1016/j.jaad.2017.11.042.
FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
Key clinical point: The use of hydrochlorothiazide should be carefully considered because it is linked to a substantially increased risk of nonmelanoma skin cancer.
Major finding: A clear, dose-response pattern was found for both basal cell carcinoma and squamous cell carcinoma, with a more than sevenfold increased risk of SCC for a cumulative use of greater than or equal to 200,000 mg of the diuretic and antihypertensive.
Study details: The study population involved 71,533 BCC and 8,629 SCC cases that were matched to 1,430,883 and 172,462 population controls, respectively.
Disclosures: The study was funded by a grant from the Danish Cancer Society and the Danish Council of Independent Research. Several of the authors reported receiving grants and or honoraria from pharmaceutical companies.
Source: Arnspang S et al. JAAD. 2017. doi: 10.1016/j.jaad.2017.11.042
More evidence backs adjunctive intranasal esketamine for refractory depression
Esketamine – the S-enantiomer of the anesthetic ketamine – continues to look promising as an adjunctive treatment for refractory depression, phase 2 results of a four-phase multicenter trial suggested.
“We observed a significant and clinically meaningful treatment effect (vs. placebo) with 28-mg, 56-mg, and 84-mg doses of esketamine,” reported Ella J. Daly, MD, of Janssen, and her associates. The results were apparent 1 week after treatment, and they persisted over the follow-up phase, which lasted 8 weeks.
“,” Dr. Daly and her associates wrote in JAMA Psychiatry (2017 Dec 27. doi: 10.1001/jamapsychiatry.2017.3739).
In the study, patients aged 20-64 years with a diagnosis of major depressive disorder were recruited from several outpatient referral centers. All of the participants had treatment-resistant depression, defined by the study as an inadequate response despite the use of two or more antidepressants. Overall, 67 patients were randomized to receive one of the three doses of intranasal esketamine or a placebo nasal spray. In addition, participants continued to take oral antidepressants during the study period. People with a history of psychotic symptoms, use of substances such as alcohol and cannabis, or significant medical comorbidities were excluded.
Among participants in the treatment groups, the mean total score changes on the Montgomery-Åsberg Depression Rating Scale (MADRS) surpassed the MADRS score changes among those on placebo. Specifically, the mean MADRS score change for those on the 28-mg dose was –4.2 (P = 0.2), on the 56-mg dose was –6.3 (P = .001), and on the 84-mg dose was –9 (P less than .001).
The most common side effects among participants treated with esketamine were dizziness, headache, and dissociative symptoms. However, most adverse events were transient and “either mild or moderate in severity,” the investigators reported.
Dr. Daly and her associates cited several limitations, including the small sample size and the study’s exclusion criteria. Despite those limitations, Dr. Daly and her associates said, the results support further investigation of intranasal esketamine for treatment-resistant depression. They said a phase 3 study aimed at evaluating the frequency needed for dosing and duration of effect is underway.
Janssen funded the study. Dr. Daly and several of the other investigators are Janssen employees.
ghenderson@frontlinemedcom.com
SOURCE: Daly et al. JAMA Psychiatry. 2017 Dec 27. doi: 10.1001/jamapsychiatry.2017.3739
The study by Daly et al. is of interest for two key reasons, wrote Daniel S. Quintana, PhD, and his associates in an accompanying editorial (JAMA Psychiatry. 2017 Dec 27. doi: 10.1001/jamapsychiatry.2017.3738). First, of interest is the drug’s impact on depressive symptoms as measured on the Montgomery-Åsberg Depression Rating Scale. Second, the delivery mechanism is of interest, particularly in light of the increased bioavailability made possible by intranasal delivery. However, esketamine should be used with caution for psychiatric patients, he said.
“One of the three most common adverse effects was perceptual changes or dissociative symptoms, which fits with the known effect of ketamine and should be further clarified before starting routine in clinical practice,” he wrote. “Moreover, several issues related to long-term use, including the potential for addiction and adverse effects (somatic and cognitive) need to be carefully assessed in forthcoming studies.”
Dr. Quintana is affiliated with Oslo University Hospital & Institute of Clinical Medicine at the University of Oslo.
The study by Daly et al. is of interest for two key reasons, wrote Daniel S. Quintana, PhD, and his associates in an accompanying editorial (JAMA Psychiatry. 2017 Dec 27. doi: 10.1001/jamapsychiatry.2017.3738). First, of interest is the drug’s impact on depressive symptoms as measured on the Montgomery-Åsberg Depression Rating Scale. Second, the delivery mechanism is of interest, particularly in light of the increased bioavailability made possible by intranasal delivery. However, esketamine should be used with caution for psychiatric patients, he said.
“One of the three most common adverse effects was perceptual changes or dissociative symptoms, which fits with the known effect of ketamine and should be further clarified before starting routine in clinical practice,” he wrote. “Moreover, several issues related to long-term use, including the potential for addiction and adverse effects (somatic and cognitive) need to be carefully assessed in forthcoming studies.”
Dr. Quintana is affiliated with Oslo University Hospital & Institute of Clinical Medicine at the University of Oslo.
The study by Daly et al. is of interest for two key reasons, wrote Daniel S. Quintana, PhD, and his associates in an accompanying editorial (JAMA Psychiatry. 2017 Dec 27. doi: 10.1001/jamapsychiatry.2017.3738). First, of interest is the drug’s impact on depressive symptoms as measured on the Montgomery-Åsberg Depression Rating Scale. Second, the delivery mechanism is of interest, particularly in light of the increased bioavailability made possible by intranasal delivery. However, esketamine should be used with caution for psychiatric patients, he said.
“One of the three most common adverse effects was perceptual changes or dissociative symptoms, which fits with the known effect of ketamine and should be further clarified before starting routine in clinical practice,” he wrote. “Moreover, several issues related to long-term use, including the potential for addiction and adverse effects (somatic and cognitive) need to be carefully assessed in forthcoming studies.”
Dr. Quintana is affiliated with Oslo University Hospital & Institute of Clinical Medicine at the University of Oslo.
Esketamine – the S-enantiomer of the anesthetic ketamine – continues to look promising as an adjunctive treatment for refractory depression, phase 2 results of a four-phase multicenter trial suggested.
“We observed a significant and clinically meaningful treatment effect (vs. placebo) with 28-mg, 56-mg, and 84-mg doses of esketamine,” reported Ella J. Daly, MD, of Janssen, and her associates. The results were apparent 1 week after treatment, and they persisted over the follow-up phase, which lasted 8 weeks.
“,” Dr. Daly and her associates wrote in JAMA Psychiatry (2017 Dec 27. doi: 10.1001/jamapsychiatry.2017.3739).
In the study, patients aged 20-64 years with a diagnosis of major depressive disorder were recruited from several outpatient referral centers. All of the participants had treatment-resistant depression, defined by the study as an inadequate response despite the use of two or more antidepressants. Overall, 67 patients were randomized to receive one of the three doses of intranasal esketamine or a placebo nasal spray. In addition, participants continued to take oral antidepressants during the study period. People with a history of psychotic symptoms, use of substances such as alcohol and cannabis, or significant medical comorbidities were excluded.
Among participants in the treatment groups, the mean total score changes on the Montgomery-Åsberg Depression Rating Scale (MADRS) surpassed the MADRS score changes among those on placebo. Specifically, the mean MADRS score change for those on the 28-mg dose was –4.2 (P = 0.2), on the 56-mg dose was –6.3 (P = .001), and on the 84-mg dose was –9 (P less than .001).
The most common side effects among participants treated with esketamine were dizziness, headache, and dissociative symptoms. However, most adverse events were transient and “either mild or moderate in severity,” the investigators reported.
Dr. Daly and her associates cited several limitations, including the small sample size and the study’s exclusion criteria. Despite those limitations, Dr. Daly and her associates said, the results support further investigation of intranasal esketamine for treatment-resistant depression. They said a phase 3 study aimed at evaluating the frequency needed for dosing and duration of effect is underway.
Janssen funded the study. Dr. Daly and several of the other investigators are Janssen employees.
ghenderson@frontlinemedcom.com
SOURCE: Daly et al. JAMA Psychiatry. 2017 Dec 27. doi: 10.1001/jamapsychiatry.2017.3739
Esketamine – the S-enantiomer of the anesthetic ketamine – continues to look promising as an adjunctive treatment for refractory depression, phase 2 results of a four-phase multicenter trial suggested.
“We observed a significant and clinically meaningful treatment effect (vs. placebo) with 28-mg, 56-mg, and 84-mg doses of esketamine,” reported Ella J. Daly, MD, of Janssen, and her associates. The results were apparent 1 week after treatment, and they persisted over the follow-up phase, which lasted 8 weeks.
“,” Dr. Daly and her associates wrote in JAMA Psychiatry (2017 Dec 27. doi: 10.1001/jamapsychiatry.2017.3739).
In the study, patients aged 20-64 years with a diagnosis of major depressive disorder were recruited from several outpatient referral centers. All of the participants had treatment-resistant depression, defined by the study as an inadequate response despite the use of two or more antidepressants. Overall, 67 patients were randomized to receive one of the three doses of intranasal esketamine or a placebo nasal spray. In addition, participants continued to take oral antidepressants during the study period. People with a history of psychotic symptoms, use of substances such as alcohol and cannabis, or significant medical comorbidities were excluded.
Among participants in the treatment groups, the mean total score changes on the Montgomery-Åsberg Depression Rating Scale (MADRS) surpassed the MADRS score changes among those on placebo. Specifically, the mean MADRS score change for those on the 28-mg dose was –4.2 (P = 0.2), on the 56-mg dose was –6.3 (P = .001), and on the 84-mg dose was –9 (P less than .001).
The most common side effects among participants treated with esketamine were dizziness, headache, and dissociative symptoms. However, most adverse events were transient and “either mild or moderate in severity,” the investigators reported.
Dr. Daly and her associates cited several limitations, including the small sample size and the study’s exclusion criteria. Despite those limitations, Dr. Daly and her associates said, the results support further investigation of intranasal esketamine for treatment-resistant depression. They said a phase 3 study aimed at evaluating the frequency needed for dosing and duration of effect is underway.
Janssen funded the study. Dr. Daly and several of the other investigators are Janssen employees.
ghenderson@frontlinemedcom.com
SOURCE: Daly et al. JAMA Psychiatry. 2017 Dec 27. doi: 10.1001/jamapsychiatry.2017.3739
FROM JAMA PSYCHIATRY
Key clinical point: Adjunctive intranasal esketamine appears to lift treatment-resistant depression symptoms quickly, and the results last for more than 2 months “with a lower dosing frequency.”
Major finding: The MADRS mean score change for participants on the 28-mg dose was –4.2 (P = .2), –6.3 (P = .001) for those on the 56-mg dose, and –.9.0 (P greater than .001) for those on the 84-mg dose.
Study details: A phase 2 placebo-controlled study of 67 participants with treatment-resistant depression conducted in four phases at several outpatient treatment centers.
Disclosures: Janssen funded the study, and Dr. Daly and several of the other investigators are Janssen employees.
Source: Daly et al. JAMA Psychiatry. 2017 Dec. 27. doi: 10.1001/jamapsychiatry.2017.3739.
Survival improvements lag for young Hispanic patients with myeloma
ATLANTA –
Among U.S. adults diagnosed with multiple myeloma by age 40 years, 5-year and 10-year survival improved significantly (P less than .0001) for non-Hispanic blacks and whites, but not for Hispanics (5-year survival, P = .08; 10-year survival, P = .13), Abdel-Ghani Azzouqa, MD, and colleagues reported in a poster at the annual meeting of the American Society of Hematology.
Other population-based studies have uncovered racial and ethnic disparities in myeloma outcomes but had not honed in on the experience of young adult patients, who make up a growing proportion of diagnosed patients, said Dr. Azzouqa.
He and his associates analyzed Surveillance Epidemiology and End Results (SEER) data on patients diagnosed between ages 18 and 40 years with histologically confirmed multiple myeloma. The dataset spanned 1973-2014 and included 1,460 patients, of whom about 60% were male. Median age at diagnosis was 37 years; 47% of patients were non-Hispanic white, 28% were non-Hispanic black, 18% were Hispanic, 5.5% were Asian, and about 1% were of other ethnicities.
For young Hispanic patients with myeloma, 5-year survival improved from 39% before 1996, when stem cell transplants and novel therapies became available, to 56% from 2002 onward. This change was not statistically significant (P = .08), and 10-year survival rates also did not change significantly (from 21% to 33%; P = .13).
Five-year and 10-year survival did improve significantly for both genders (P = .0001) and among non-Hispanic blacks (P = .0001) and non-Hispanic whites (P = .0001).
Racial/ethnic subgroups did not differ significantly by median age at diagnosis, gender distribution, or listed cause of death, Dr. Azzouqa noted. Thus, reasons for the difference in survival for Hispanic patients remain unclear. Perhaps they reflect differences in disease biology, treatment response, or access or use of effective novel therapies, he said.
The researchers had no external funding sources. Dr. Azzouqa had no conflicts of interest. Lead author Dr. Sikander Ailawadhi disclosed ties to funding Pharmacyclics, Amgen, Novartis, and Takeda.
SOURCE: Ailawadhi S et al. ASH Abstract 2149
ATLANTA –
Among U.S. adults diagnosed with multiple myeloma by age 40 years, 5-year and 10-year survival improved significantly (P less than .0001) for non-Hispanic blacks and whites, but not for Hispanics (5-year survival, P = .08; 10-year survival, P = .13), Abdel-Ghani Azzouqa, MD, and colleagues reported in a poster at the annual meeting of the American Society of Hematology.
Other population-based studies have uncovered racial and ethnic disparities in myeloma outcomes but had not honed in on the experience of young adult patients, who make up a growing proportion of diagnosed patients, said Dr. Azzouqa.
He and his associates analyzed Surveillance Epidemiology and End Results (SEER) data on patients diagnosed between ages 18 and 40 years with histologically confirmed multiple myeloma. The dataset spanned 1973-2014 and included 1,460 patients, of whom about 60% were male. Median age at diagnosis was 37 years; 47% of patients were non-Hispanic white, 28% were non-Hispanic black, 18% were Hispanic, 5.5% were Asian, and about 1% were of other ethnicities.
For young Hispanic patients with myeloma, 5-year survival improved from 39% before 1996, when stem cell transplants and novel therapies became available, to 56% from 2002 onward. This change was not statistically significant (P = .08), and 10-year survival rates also did not change significantly (from 21% to 33%; P = .13).
Five-year and 10-year survival did improve significantly for both genders (P = .0001) and among non-Hispanic blacks (P = .0001) and non-Hispanic whites (P = .0001).
Racial/ethnic subgroups did not differ significantly by median age at diagnosis, gender distribution, or listed cause of death, Dr. Azzouqa noted. Thus, reasons for the difference in survival for Hispanic patients remain unclear. Perhaps they reflect differences in disease biology, treatment response, or access or use of effective novel therapies, he said.
The researchers had no external funding sources. Dr. Azzouqa had no conflicts of interest. Lead author Dr. Sikander Ailawadhi disclosed ties to funding Pharmacyclics, Amgen, Novartis, and Takeda.
SOURCE: Ailawadhi S et al. ASH Abstract 2149
ATLANTA –
Among U.S. adults diagnosed with multiple myeloma by age 40 years, 5-year and 10-year survival improved significantly (P less than .0001) for non-Hispanic blacks and whites, but not for Hispanics (5-year survival, P = .08; 10-year survival, P = .13), Abdel-Ghani Azzouqa, MD, and colleagues reported in a poster at the annual meeting of the American Society of Hematology.
Other population-based studies have uncovered racial and ethnic disparities in myeloma outcomes but had not honed in on the experience of young adult patients, who make up a growing proportion of diagnosed patients, said Dr. Azzouqa.
He and his associates analyzed Surveillance Epidemiology and End Results (SEER) data on patients diagnosed between ages 18 and 40 years with histologically confirmed multiple myeloma. The dataset spanned 1973-2014 and included 1,460 patients, of whom about 60% were male. Median age at diagnosis was 37 years; 47% of patients were non-Hispanic white, 28% were non-Hispanic black, 18% were Hispanic, 5.5% were Asian, and about 1% were of other ethnicities.
For young Hispanic patients with myeloma, 5-year survival improved from 39% before 1996, when stem cell transplants and novel therapies became available, to 56% from 2002 onward. This change was not statistically significant (P = .08), and 10-year survival rates also did not change significantly (from 21% to 33%; P = .13).
Five-year and 10-year survival did improve significantly for both genders (P = .0001) and among non-Hispanic blacks (P = .0001) and non-Hispanic whites (P = .0001).
Racial/ethnic subgroups did not differ significantly by median age at diagnosis, gender distribution, or listed cause of death, Dr. Azzouqa noted. Thus, reasons for the difference in survival for Hispanic patients remain unclear. Perhaps they reflect differences in disease biology, treatment response, or access or use of effective novel therapies, he said.
The researchers had no external funding sources. Dr. Azzouqa had no conflicts of interest. Lead author Dr. Sikander Ailawadhi disclosed ties to funding Pharmacyclics, Amgen, Novartis, and Takeda.
SOURCE: Ailawadhi S et al. ASH Abstract 2149
REPORTING FROM ASH 2017
Key clinical point: Recent improvements in multiple myeloma survival have left young Hispanics behind.
Major finding: Five-year and 10-year survival have improved significantly among young blacks and non-Hispanic whites with multiple myeloma (P less than .0001 for all comparisons) but not Hispanics (5-year survival P = .08; 10-year survival P = .13).
Data source: Surveillance Epidemiology and End Results (SEER) data for 1,460 adults up to 40 years old when diagnosed with multiple myeloma.
Disclosures: The researchers had no external funding sources. Dr. Azzouqa had no conflicts of interest. Lead author Dr. Sikander Ailawadhi disclosed funding from Pharmacyclics, Amgen, Novartis, and Takeda.
Source: Ailawadhi S et al. ASH Abstract 2149.
FDA expands approval of nivolumab for melanoma treatment
The Food and Drug Administration has approved nivolumab for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or in patients with metastatic disease who have undergone complete resection.
Nivolumab was previously approved for the treatment of patients with unresectable or metastatic melanoma, the FDA said in a press statement.
Approval was based on results from the CHECKMATE-238 trial, where 906 patients with completely resected stage IIIB/C or stage IV melanoma received either nivolumab or ipilimumab for up to 1 year. Recurrence-free survival was superior in patients who received nivolumab, with 34% of patients in the nivolumab group experiencing recurrence/death, compared to 45.5% in the ipilimumab group.
The recommended dose and schedule of nivolumab in adjuvant melanoma is 240 mg administered as an IV infusion over 60 minutes every 2 weeks until disease recurrence or unacceptable toxicity, for a maximum of 1 year, according to the FDA.
Nivolumab is marketed as Opdivo by Bristol-Myers Squibb Company.
Find the full press release on the FDA website.
The Food and Drug Administration has approved nivolumab for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or in patients with metastatic disease who have undergone complete resection.
Nivolumab was previously approved for the treatment of patients with unresectable or metastatic melanoma, the FDA said in a press statement.
Approval was based on results from the CHECKMATE-238 trial, where 906 patients with completely resected stage IIIB/C or stage IV melanoma received either nivolumab or ipilimumab for up to 1 year. Recurrence-free survival was superior in patients who received nivolumab, with 34% of patients in the nivolumab group experiencing recurrence/death, compared to 45.5% in the ipilimumab group.
The recommended dose and schedule of nivolumab in adjuvant melanoma is 240 mg administered as an IV infusion over 60 minutes every 2 weeks until disease recurrence or unacceptable toxicity, for a maximum of 1 year, according to the FDA.
Nivolumab is marketed as Opdivo by Bristol-Myers Squibb Company.
Find the full press release on the FDA website.
The Food and Drug Administration has approved nivolumab for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or in patients with metastatic disease who have undergone complete resection.
Nivolumab was previously approved for the treatment of patients with unresectable or metastatic melanoma, the FDA said in a press statement.
Approval was based on results from the CHECKMATE-238 trial, where 906 patients with completely resected stage IIIB/C or stage IV melanoma received either nivolumab or ipilimumab for up to 1 year. Recurrence-free survival was superior in patients who received nivolumab, with 34% of patients in the nivolumab group experiencing recurrence/death, compared to 45.5% in the ipilimumab group.
The recommended dose and schedule of nivolumab in adjuvant melanoma is 240 mg administered as an IV infusion over 60 minutes every 2 weeks until disease recurrence or unacceptable toxicity, for a maximum of 1 year, according to the FDA.
Nivolumab is marketed as Opdivo by Bristol-Myers Squibb Company.
Find the full press release on the FDA website.
Venetoclax/rituximab boosts PFS in relapsed/refractory CLL
ATLANTA – In patients with relapsed/refractory chronic lymphocytic leukemia (CLL), a combination of venetoclax (Venclexta) and rituximab was superior to bendamustine (Treanda) and rituximab for prolonging progression-free survival (PFS), with effects consistent across subgroups, regardless of mutational status, and a clinically meaningful improvement in overall survival.
An interim analysis from the phase 3 MURANO trial showed that after a median follow-up of 23.8 months, the median PFS for patients randomized to venetoclax/rituximab had not been reached, compared with 17 months for patients assigned to bendamustine/rituximab, reported John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne.
Relapsed/refractory CLL often has a suboptimal response to conventional chemotherapy because of adverse biological features that can accumulate in cells, he said.
The combination of bendamustine and rituximab has been associated with about 60% overall responses rates, a median PFS of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, he noted.
The rationale for pairing venetoclax with rituximab in this population comes from evidence showing efficacy of the monoclonal antibody, an oral B-cell lymphoma–2 (BCL-2) inhibitor, as monotherapy in patients with relapsed/refractory CLL, including those with poor prognostic features such as the 17p deletion (del17p).
Dr. Seymour and his colleagues recently published results from a phase 1b trial of venetoclax/rituximab in patients with relapsed/refractory CLL. The combination was associated with a 51% complete response rate, and a 28% rate of negative marrow minimal residual disease (MRD) (Lancet Oncol. 2017 Feb;18[2]:230-40)
In the MURANO study (NCT02005471), the investigators evaluated whether time-limited therapy with venetoclax/rituximab could improve PFS over bendamustine/rituximab.
Patients 18 and older with CLL who had been treated with one to three prior lines of therapy, including at least one chemotherapy-containing regimen, were enrolled. Prior treatment with bendamustine was allowed only if patients had had a duration of response of at least 24 months.
After stratification by del17p status, responsiveness to prior therapy, and geographic region, 389 patients were randomly assigned to receive rituximab 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 through 6, plus either bendamustine 70 mg/m2 on days 1 and 2 of each of six cycles, or venetoclax 400 mg orally once daily until disease progression, cessation for toxicity, or up to a maximum of 2 years starting from day 1 of cycle 1.
As noted,
The respective 1- and 2-year PFS rates with venetoclax were 91.2% and 82.8%, compared with 74.1% and 37.4% with bendamustine.
The venetoclax/rituximab combination was also significantly superior across all subgroups, regardless of the number of prior therapies, refractory vs. relapsed after most recent prior therapy, del17p status, TP53 mutational status, or baseline immunoglobulin heavy chain variable (IGHV) mutated or unmutated status
Response rates assessed by both investigators and independent reviewers were also better with venetoclax. The investigator-assessed overall response rate (ORR) was 93.3%, compared with 67.7% for bendamustine/rituximab, including 26.8% complete responses (CR), compared with 8.2%. Independent reviewers decreed an ORR of 92.3% for venentoclax, vs. 72.3% for bendamustine, including respective CR rates of 8.2% and 3.6%.
The investigators also found that the percentage of MRD negativity was higher with venetoclax/rituximab, with 62% of patients in this group being MRD negative at 9 months. This rate remained fairly constant at 12-, 15- and 18-month follow-ups (60%, 57%, and 60%, respectively).
In contrast, 13% of patients treated with bendamustine were MRD negative at 9 months, and the rates gradually declined over time to 10%, 9%, and 5%.
Investigators also saw a clinically meaningful improvement in overall survival with the venetoclax/rituximab duo, although survival data are still not mature in this ongoing trial. The median OS had not been reached in either group at the time of data cutoff.
Respective 1- and 2-year OS rates with venetoclax were 95.9% and 91.9%, and with bendamustine were 91.1% and 86.6%.
At the time of this interim analysis, the hazard ratio favoring venetoclax/rituximab was 0.48 (P = .0186).
Drug discontinuation was more frequent with venetoclax/rituximab (25% vs, 17%), with disease progression and adverse events without progression being the most frequent reasons for stopping in each arm.
Serious adverse events occurred in 46% of patients on venetoclax/rituximab and 43% on bendamustine/rituximab. A higher percentage of patients on venetoclax/rituximab had grade 3 or 4 adverse events (82% vs, 70%). Ten patients (5%) in the venetoclax/rituximab arm died, and 11 patients (6%) on bendamustine/rituximab died.
Events with a greater than 2% difference included more frequent neutropenia, tumor lysis syndrome, hyperglycemia and hypogammaglobulinema with venetoclax/rituximab, and more frequent anemia, thrombocytopenia, febrile neutropenia, pneumonia, infusion-related reactions, and hypotension with bendamustine/rituximab.
In the question-and-response portion following Dr. Seymour’s presentation, an audience member commented that the continuation of venetoclax/rituximab beyond the initial treatment cycles amounted to a maintenance strategy, and that patients in the experimental arm were in treatment longer, which likely influenced the results.
“You’re absolutely correct that the treatment duration differed, although, of course, the capacity to deliver more than six cycles of bendamustine/rituximab would have been problematic,” Dr. Seymour replied.
“There are some data that antibody treatment may prolong progression-free survival. However, when this study was designed in 2013 that data was certainly not available, and I believe currently even maintenance antibodies are not an accepted standard of treatment,” he added.
The MURANO trial was funded by AbbVie and Genentech. Dr. Seymour disclosed honoraria, speakers bureau, research funding, and advisory activities with AbbVie and other companies.
SOURCE: Seymour J et al. ASH 2017 LBA-2.
ATLANTA – In patients with relapsed/refractory chronic lymphocytic leukemia (CLL), a combination of venetoclax (Venclexta) and rituximab was superior to bendamustine (Treanda) and rituximab for prolonging progression-free survival (PFS), with effects consistent across subgroups, regardless of mutational status, and a clinically meaningful improvement in overall survival.
An interim analysis from the phase 3 MURANO trial showed that after a median follow-up of 23.8 months, the median PFS for patients randomized to venetoclax/rituximab had not been reached, compared with 17 months for patients assigned to bendamustine/rituximab, reported John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne.
Relapsed/refractory CLL often has a suboptimal response to conventional chemotherapy because of adverse biological features that can accumulate in cells, he said.
The combination of bendamustine and rituximab has been associated with about 60% overall responses rates, a median PFS of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, he noted.
The rationale for pairing venetoclax with rituximab in this population comes from evidence showing efficacy of the monoclonal antibody, an oral B-cell lymphoma–2 (BCL-2) inhibitor, as monotherapy in patients with relapsed/refractory CLL, including those with poor prognostic features such as the 17p deletion (del17p).
Dr. Seymour and his colleagues recently published results from a phase 1b trial of venetoclax/rituximab in patients with relapsed/refractory CLL. The combination was associated with a 51% complete response rate, and a 28% rate of negative marrow minimal residual disease (MRD) (Lancet Oncol. 2017 Feb;18[2]:230-40)
In the MURANO study (NCT02005471), the investigators evaluated whether time-limited therapy with venetoclax/rituximab could improve PFS over bendamustine/rituximab.
Patients 18 and older with CLL who had been treated with one to three prior lines of therapy, including at least one chemotherapy-containing regimen, were enrolled. Prior treatment with bendamustine was allowed only if patients had had a duration of response of at least 24 months.
After stratification by del17p status, responsiveness to prior therapy, and geographic region, 389 patients were randomly assigned to receive rituximab 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 through 6, plus either bendamustine 70 mg/m2 on days 1 and 2 of each of six cycles, or venetoclax 400 mg orally once daily until disease progression, cessation for toxicity, or up to a maximum of 2 years starting from day 1 of cycle 1.
As noted,
The respective 1- and 2-year PFS rates with venetoclax were 91.2% and 82.8%, compared with 74.1% and 37.4% with bendamustine.
The venetoclax/rituximab combination was also significantly superior across all subgroups, regardless of the number of prior therapies, refractory vs. relapsed after most recent prior therapy, del17p status, TP53 mutational status, or baseline immunoglobulin heavy chain variable (IGHV) mutated or unmutated status
Response rates assessed by both investigators and independent reviewers were also better with venetoclax. The investigator-assessed overall response rate (ORR) was 93.3%, compared with 67.7% for bendamustine/rituximab, including 26.8% complete responses (CR), compared with 8.2%. Independent reviewers decreed an ORR of 92.3% for venentoclax, vs. 72.3% for bendamustine, including respective CR rates of 8.2% and 3.6%.
The investigators also found that the percentage of MRD negativity was higher with venetoclax/rituximab, with 62% of patients in this group being MRD negative at 9 months. This rate remained fairly constant at 12-, 15- and 18-month follow-ups (60%, 57%, and 60%, respectively).
In contrast, 13% of patients treated with bendamustine were MRD negative at 9 months, and the rates gradually declined over time to 10%, 9%, and 5%.
Investigators also saw a clinically meaningful improvement in overall survival with the venetoclax/rituximab duo, although survival data are still not mature in this ongoing trial. The median OS had not been reached in either group at the time of data cutoff.
Respective 1- and 2-year OS rates with venetoclax were 95.9% and 91.9%, and with bendamustine were 91.1% and 86.6%.
At the time of this interim analysis, the hazard ratio favoring venetoclax/rituximab was 0.48 (P = .0186).
Drug discontinuation was more frequent with venetoclax/rituximab (25% vs, 17%), with disease progression and adverse events without progression being the most frequent reasons for stopping in each arm.
Serious adverse events occurred in 46% of patients on venetoclax/rituximab and 43% on bendamustine/rituximab. A higher percentage of patients on venetoclax/rituximab had grade 3 or 4 adverse events (82% vs, 70%). Ten patients (5%) in the venetoclax/rituximab arm died, and 11 patients (6%) on bendamustine/rituximab died.
Events with a greater than 2% difference included more frequent neutropenia, tumor lysis syndrome, hyperglycemia and hypogammaglobulinema with venetoclax/rituximab, and more frequent anemia, thrombocytopenia, febrile neutropenia, pneumonia, infusion-related reactions, and hypotension with bendamustine/rituximab.
In the question-and-response portion following Dr. Seymour’s presentation, an audience member commented that the continuation of venetoclax/rituximab beyond the initial treatment cycles amounted to a maintenance strategy, and that patients in the experimental arm were in treatment longer, which likely influenced the results.
“You’re absolutely correct that the treatment duration differed, although, of course, the capacity to deliver more than six cycles of bendamustine/rituximab would have been problematic,” Dr. Seymour replied.
“There are some data that antibody treatment may prolong progression-free survival. However, when this study was designed in 2013 that data was certainly not available, and I believe currently even maintenance antibodies are not an accepted standard of treatment,” he added.
The MURANO trial was funded by AbbVie and Genentech. Dr. Seymour disclosed honoraria, speakers bureau, research funding, and advisory activities with AbbVie and other companies.
SOURCE: Seymour J et al. ASH 2017 LBA-2.
ATLANTA – In patients with relapsed/refractory chronic lymphocytic leukemia (CLL), a combination of venetoclax (Venclexta) and rituximab was superior to bendamustine (Treanda) and rituximab for prolonging progression-free survival (PFS), with effects consistent across subgroups, regardless of mutational status, and a clinically meaningful improvement in overall survival.
An interim analysis from the phase 3 MURANO trial showed that after a median follow-up of 23.8 months, the median PFS for patients randomized to venetoclax/rituximab had not been reached, compared with 17 months for patients assigned to bendamustine/rituximab, reported John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne.
Relapsed/refractory CLL often has a suboptimal response to conventional chemotherapy because of adverse biological features that can accumulate in cells, he said.
The combination of bendamustine and rituximab has been associated with about 60% overall responses rates, a median PFS of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, he noted.
The rationale for pairing venetoclax with rituximab in this population comes from evidence showing efficacy of the monoclonal antibody, an oral B-cell lymphoma–2 (BCL-2) inhibitor, as monotherapy in patients with relapsed/refractory CLL, including those with poor prognostic features such as the 17p deletion (del17p).
Dr. Seymour and his colleagues recently published results from a phase 1b trial of venetoclax/rituximab in patients with relapsed/refractory CLL. The combination was associated with a 51% complete response rate, and a 28% rate of negative marrow minimal residual disease (MRD) (Lancet Oncol. 2017 Feb;18[2]:230-40)
In the MURANO study (NCT02005471), the investigators evaluated whether time-limited therapy with venetoclax/rituximab could improve PFS over bendamustine/rituximab.
Patients 18 and older with CLL who had been treated with one to three prior lines of therapy, including at least one chemotherapy-containing regimen, were enrolled. Prior treatment with bendamustine was allowed only if patients had had a duration of response of at least 24 months.
After stratification by del17p status, responsiveness to prior therapy, and geographic region, 389 patients were randomly assigned to receive rituximab 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 through 6, plus either bendamustine 70 mg/m2 on days 1 and 2 of each of six cycles, or venetoclax 400 mg orally once daily until disease progression, cessation for toxicity, or up to a maximum of 2 years starting from day 1 of cycle 1.
As noted,
The respective 1- and 2-year PFS rates with venetoclax were 91.2% and 82.8%, compared with 74.1% and 37.4% with bendamustine.
The venetoclax/rituximab combination was also significantly superior across all subgroups, regardless of the number of prior therapies, refractory vs. relapsed after most recent prior therapy, del17p status, TP53 mutational status, or baseline immunoglobulin heavy chain variable (IGHV) mutated or unmutated status
Response rates assessed by both investigators and independent reviewers were also better with venetoclax. The investigator-assessed overall response rate (ORR) was 93.3%, compared with 67.7% for bendamustine/rituximab, including 26.8% complete responses (CR), compared with 8.2%. Independent reviewers decreed an ORR of 92.3% for venentoclax, vs. 72.3% for bendamustine, including respective CR rates of 8.2% and 3.6%.
The investigators also found that the percentage of MRD negativity was higher with venetoclax/rituximab, with 62% of patients in this group being MRD negative at 9 months. This rate remained fairly constant at 12-, 15- and 18-month follow-ups (60%, 57%, and 60%, respectively).
In contrast, 13% of patients treated with bendamustine were MRD negative at 9 months, and the rates gradually declined over time to 10%, 9%, and 5%.
Investigators also saw a clinically meaningful improvement in overall survival with the venetoclax/rituximab duo, although survival data are still not mature in this ongoing trial. The median OS had not been reached in either group at the time of data cutoff.
Respective 1- and 2-year OS rates with venetoclax were 95.9% and 91.9%, and with bendamustine were 91.1% and 86.6%.
At the time of this interim analysis, the hazard ratio favoring venetoclax/rituximab was 0.48 (P = .0186).
Drug discontinuation was more frequent with venetoclax/rituximab (25% vs, 17%), with disease progression and adverse events without progression being the most frequent reasons for stopping in each arm.
Serious adverse events occurred in 46% of patients on venetoclax/rituximab and 43% on bendamustine/rituximab. A higher percentage of patients on venetoclax/rituximab had grade 3 or 4 adverse events (82% vs, 70%). Ten patients (5%) in the venetoclax/rituximab arm died, and 11 patients (6%) on bendamustine/rituximab died.
Events with a greater than 2% difference included more frequent neutropenia, tumor lysis syndrome, hyperglycemia and hypogammaglobulinema with venetoclax/rituximab, and more frequent anemia, thrombocytopenia, febrile neutropenia, pneumonia, infusion-related reactions, and hypotension with bendamustine/rituximab.
In the question-and-response portion following Dr. Seymour’s presentation, an audience member commented that the continuation of venetoclax/rituximab beyond the initial treatment cycles amounted to a maintenance strategy, and that patients in the experimental arm were in treatment longer, which likely influenced the results.
“You’re absolutely correct that the treatment duration differed, although, of course, the capacity to deliver more than six cycles of bendamustine/rituximab would have been problematic,” Dr. Seymour replied.
“There are some data that antibody treatment may prolong progression-free survival. However, when this study was designed in 2013 that data was certainly not available, and I believe currently even maintenance antibodies are not an accepted standard of treatment,” he added.
The MURANO trial was funded by AbbVie and Genentech. Dr. Seymour disclosed honoraria, speakers bureau, research funding, and advisory activities with AbbVie and other companies.
SOURCE: Seymour J et al. ASH 2017 LBA-2.
REPORTING FROM ASH 2017
Key clinical point: Compared with bendamustine/rituximab, venetoclax/rituximab was associated with significantly superior progression-free survival of relapsed/refractory chronic lymphocytic leukemia.
Major finding: The hazard ratio for PFS with venetoclax/rituximab was 0.17 (P less than .001).
Data source: A randomized phase 3, open-label trial in 389 patients with relapsed/refractory CLL.
Disclosures: The MURANO trial was funded by AbbVie and Genetech. Dr. Seymour disclosed honoraria, speakers bureau, research funding, and advisory activities with AbbVie and other companies.
Source: Seymour J et al. ASH 2017 LBA-2.
Lapatinib plus trastuzumab improves outcomes in HER2+ breast cancer
SAN ANTONIO – Dual HER2 targeting with lapatinib added to 16 weeks of trastuzumab significantly improved event-free survival (EFS), compared with trastuzumab alone, among women with HER2-positive breast cancer.
EFS was significantly longer in the combination arm versus single-blockade therapy (hazard ratio, 0.35; 95% confidence interval, 0.15-0.84; P = .013).
“Overall survival was also increased, but the number of events was very small,” said study author Ian E. Krop, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study results at the San Antonio Breast Cancer Symposium.
As expected, and consistent with other studies, the pathologic complete response (pCR) rate with dual blockade was associated with favorable long-term outcomes, and the effect was most pronounced in HR- and HER2 enriched cancers.
However, Dr. Krop cautioned that these results need to be seen in the context of two larger trials that failed to find a benefit for dual-blockade HER2 therapy in either the adjuvant or neoadjuvant setting.
Previous research has shown that trastuzumab and lapatinib are synergistic, potently inhibiting HER2 signaling in preclinical trials. The combination of both agents is also active in both untreated and heavily pretreated HER2+ advanced breast cancer. The addition of lapatinib to trastuzumab plus chemotherapy has also been associated with a pCR rate that was statistically significant in many studies.
But despite this “wealth of evidence,” the largest of these studies, the phase 3 ALTTO study, failed to show a benefit for dual HER2 blockade. The same was true for the neoadjuvant Neo ALTTO study. Both studies failed to show an improvement in EFS or overall survival.
The current trial, CALGB 40601, a randomized phase 3 trial, assessed the effect of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel on rates of pCR, and the researchers also looked at tumor and microenvironment molecular features. Dr. Krop noted that they had previously found that rates of pCR were numerically but not significantly increased with combination-blockade therapy; they had also found that the tumor molecular subtype and evidence of immune activation were independent factors affecting rates of pCR.
Dr. Krop presented results from a secondary analysis in which they evaluated the effects of treatment arm and gene expression–defined subgroups on EFS.
A total of 305 patients with stage II and III HER2+ breast cancer were randomized to receive 16 weeks of either paclitaxel plus trastuzumab alone or that combination with lapatinib as well before undergoing surgery. Evaluable information regarding EFS and RNA-sequencing gene expression was available for 265 patients.
“Despite the lack of significant benefits in other studies, we did demonstrate an improvement in EFS,” said Dr. Krop, noting that it was more pronounced in the subset of HR- patients (HR, 0.12; P = .0160).
EFS was also significantly longer among those who achieved pCR than those who didn’t (HR, 0.34; P = .0032).
In an exploratory analysis, Dr. Krop and his colleagues assessed whether there was a difference in rates of pCR by subtype, and they found that luminal A and luminal B did not have much of an effect on rates of pCR. However, patients with HER2-enriched disease who had a pCR had significantly better EFS than those who did not (HR, 0.14; 95% CI, 0.04-0.44; P less than .0001).
Conversely, patients with HER2-enriched disease who did not achieve pCR had a substantial risk of recurrence.
When looking at EFS by intrinsic subtype, the addition of lapatinib had the most effect on luminal A cancers. “This shows that there was some discordance between analyses by pCR and by long-term endpoint,” Dr. Krop said.
Finally, among gene expression signatures, only immune activation measured by an immunoglobulin G signature was associated with an improvement in EFS (HR, 0.70; 95% CI, 0.50-0.98; P = .04).
“These data are hypothesis generating and require validation,” Dr. Krop concluded. He added that a combined analysis of this trial, along with the Neo ALTTO and others, is planned.
SOURCE: Krop IE et al. SABCS 2017 Abstract GS3-02.
SAN ANTONIO – Dual HER2 targeting with lapatinib added to 16 weeks of trastuzumab significantly improved event-free survival (EFS), compared with trastuzumab alone, among women with HER2-positive breast cancer.
EFS was significantly longer in the combination arm versus single-blockade therapy (hazard ratio, 0.35; 95% confidence interval, 0.15-0.84; P = .013).
“Overall survival was also increased, but the number of events was very small,” said study author Ian E. Krop, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study results at the San Antonio Breast Cancer Symposium.
As expected, and consistent with other studies, the pathologic complete response (pCR) rate with dual blockade was associated with favorable long-term outcomes, and the effect was most pronounced in HR- and HER2 enriched cancers.
However, Dr. Krop cautioned that these results need to be seen in the context of two larger trials that failed to find a benefit for dual-blockade HER2 therapy in either the adjuvant or neoadjuvant setting.
Previous research has shown that trastuzumab and lapatinib are synergistic, potently inhibiting HER2 signaling in preclinical trials. The combination of both agents is also active in both untreated and heavily pretreated HER2+ advanced breast cancer. The addition of lapatinib to trastuzumab plus chemotherapy has also been associated with a pCR rate that was statistically significant in many studies.
But despite this “wealth of evidence,” the largest of these studies, the phase 3 ALTTO study, failed to show a benefit for dual HER2 blockade. The same was true for the neoadjuvant Neo ALTTO study. Both studies failed to show an improvement in EFS or overall survival.
The current trial, CALGB 40601, a randomized phase 3 trial, assessed the effect of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel on rates of pCR, and the researchers also looked at tumor and microenvironment molecular features. Dr. Krop noted that they had previously found that rates of pCR were numerically but not significantly increased with combination-blockade therapy; they had also found that the tumor molecular subtype and evidence of immune activation were independent factors affecting rates of pCR.
Dr. Krop presented results from a secondary analysis in which they evaluated the effects of treatment arm and gene expression–defined subgroups on EFS.
A total of 305 patients with stage II and III HER2+ breast cancer were randomized to receive 16 weeks of either paclitaxel plus trastuzumab alone or that combination with lapatinib as well before undergoing surgery. Evaluable information regarding EFS and RNA-sequencing gene expression was available for 265 patients.
“Despite the lack of significant benefits in other studies, we did demonstrate an improvement in EFS,” said Dr. Krop, noting that it was more pronounced in the subset of HR- patients (HR, 0.12; P = .0160).
EFS was also significantly longer among those who achieved pCR than those who didn’t (HR, 0.34; P = .0032).
In an exploratory analysis, Dr. Krop and his colleagues assessed whether there was a difference in rates of pCR by subtype, and they found that luminal A and luminal B did not have much of an effect on rates of pCR. However, patients with HER2-enriched disease who had a pCR had significantly better EFS than those who did not (HR, 0.14; 95% CI, 0.04-0.44; P less than .0001).
Conversely, patients with HER2-enriched disease who did not achieve pCR had a substantial risk of recurrence.
When looking at EFS by intrinsic subtype, the addition of lapatinib had the most effect on luminal A cancers. “This shows that there was some discordance between analyses by pCR and by long-term endpoint,” Dr. Krop said.
Finally, among gene expression signatures, only immune activation measured by an immunoglobulin G signature was associated with an improvement in EFS (HR, 0.70; 95% CI, 0.50-0.98; P = .04).
“These data are hypothesis generating and require validation,” Dr. Krop concluded. He added that a combined analysis of this trial, along with the Neo ALTTO and others, is planned.
SOURCE: Krop IE et al. SABCS 2017 Abstract GS3-02.
SAN ANTONIO – Dual HER2 targeting with lapatinib added to 16 weeks of trastuzumab significantly improved event-free survival (EFS), compared with trastuzumab alone, among women with HER2-positive breast cancer.
EFS was significantly longer in the combination arm versus single-blockade therapy (hazard ratio, 0.35; 95% confidence interval, 0.15-0.84; P = .013).
“Overall survival was also increased, but the number of events was very small,” said study author Ian E. Krop, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study results at the San Antonio Breast Cancer Symposium.
As expected, and consistent with other studies, the pathologic complete response (pCR) rate with dual blockade was associated with favorable long-term outcomes, and the effect was most pronounced in HR- and HER2 enriched cancers.
However, Dr. Krop cautioned that these results need to be seen in the context of two larger trials that failed to find a benefit for dual-blockade HER2 therapy in either the adjuvant or neoadjuvant setting.
Previous research has shown that trastuzumab and lapatinib are synergistic, potently inhibiting HER2 signaling in preclinical trials. The combination of both agents is also active in both untreated and heavily pretreated HER2+ advanced breast cancer. The addition of lapatinib to trastuzumab plus chemotherapy has also been associated with a pCR rate that was statistically significant in many studies.
But despite this “wealth of evidence,” the largest of these studies, the phase 3 ALTTO study, failed to show a benefit for dual HER2 blockade. The same was true for the neoadjuvant Neo ALTTO study. Both studies failed to show an improvement in EFS or overall survival.
The current trial, CALGB 40601, a randomized phase 3 trial, assessed the effect of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel on rates of pCR, and the researchers also looked at tumor and microenvironment molecular features. Dr. Krop noted that they had previously found that rates of pCR were numerically but not significantly increased with combination-blockade therapy; they had also found that the tumor molecular subtype and evidence of immune activation were independent factors affecting rates of pCR.
Dr. Krop presented results from a secondary analysis in which they evaluated the effects of treatment arm and gene expression–defined subgroups on EFS.
A total of 305 patients with stage II and III HER2+ breast cancer were randomized to receive 16 weeks of either paclitaxel plus trastuzumab alone or that combination with lapatinib as well before undergoing surgery. Evaluable information regarding EFS and RNA-sequencing gene expression was available for 265 patients.
“Despite the lack of significant benefits in other studies, we did demonstrate an improvement in EFS,” said Dr. Krop, noting that it was more pronounced in the subset of HR- patients (HR, 0.12; P = .0160).
EFS was also significantly longer among those who achieved pCR than those who didn’t (HR, 0.34; P = .0032).
In an exploratory analysis, Dr. Krop and his colleagues assessed whether there was a difference in rates of pCR by subtype, and they found that luminal A and luminal B did not have much of an effect on rates of pCR. However, patients with HER2-enriched disease who had a pCR had significantly better EFS than those who did not (HR, 0.14; 95% CI, 0.04-0.44; P less than .0001).
Conversely, patients with HER2-enriched disease who did not achieve pCR had a substantial risk of recurrence.
When looking at EFS by intrinsic subtype, the addition of lapatinib had the most effect on luminal A cancers. “This shows that there was some discordance between analyses by pCR and by long-term endpoint,” Dr. Krop said.
Finally, among gene expression signatures, only immune activation measured by an immunoglobulin G signature was associated with an improvement in EFS (HR, 0.70; 95% CI, 0.50-0.98; P = .04).
“These data are hypothesis generating and require validation,” Dr. Krop concluded. He added that a combined analysis of this trial, along with the Neo ALTTO and others, is planned.
SOURCE: Krop IE et al. SABCS 2017 Abstract GS3-02.
REPORTING FROM SABCS 2017
Key clinical point: In contrast to previous trials,
Major finding: Event-free survival was significantly longer in the dual HER2 blockade arm versus trastuzumab alone (HR, 0.35; 95% CI, 0.15-0.84; P = .013).
Data source: Phase 3 randomized trial that included 305 women with HER2+ breast cancer.
Disclosures: The study was sponsored by the Alliance for Clinical Trials in Oncology. Dr. Krop reports relationships with Genentech/Roche and MacroGenics.
Source: Krop IE et al. SABCS 2017 Abstract GS3-02.
FDA updates nilotinib product label outlining criteria for discontinuation
for patients who meet certain criteria. Nilotinib, a kinase inhibitor that blocks the BCR-ABL protein that promotes abnormal cell growth, was originally approved in 2007 and was indicated for use in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). In accordance with the new label update, patients who have early phase CML, have been using nilotinib for 3 years or more, and whose leukemia has responded to treatment according to a test that has received FDA marketing authorization, may be eligible to discontinue use of nilotinib.
The information that led to the FDA approved label update was based on two single-arm trials of patients with chronic phase Ph+ CML. The trial measured the length of time patients were able to discontinue use of nilotinib without leukemia returning, and who had entered treatment-free remission (TFR). In the first trial, among 190 newly diagnosed CML patients who discontinued taking nilotinib after using the drug for 3 or more years, 51.6% were still in TFR after about 1 year (48 weeks) and 48.9% were still in TFR after nearly 2 years (96 weeks). Similar results were seen in the second trial, among 126 patients, with 57.9% in TFR after about a year (48 weeks) and 53.2% in TFR after approximately 2 years (96 weeks).
An important element of these trials was regular monitoring of specific RNA information that specifies the level of BCR-ABL protein in the blood using a diagnostic test that has received FDA marketing authorization. Monitoring with a test that accurately detects the reductions of RNA information in the blood with accuracy and precision is critical in discontinuing the use of nilotinib. This monitoring will allow physicians to detect the first signs of relapse.
“Patients diagnosed with CML generally face a lifetime of treatment to keep their leukemia from growing or recurring,” said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval shows that some patients may be able to stop treatment with Tasigna altogether if they are showing a strong response to therapy. While we welcome this progress in patient care, it’s important to note that any discontinuation of treatment still means patients must be regularly monitored for disease recurrence,” Dr. Pazdur said in the FDA statement.
Common side effects after discontinuing use of nilotinib include body aches and pain in the bones and extremities. Severe side effects of taking nilotinib can include myelosuppression, blockages in the heart and arteries, and inflammation of the pancreas. Severe liver damage can also occur.
Severe side effects typically associated with nilotinib administration occurred less frequently in patients who discontinued the drug. However, the long-term outcomes of patients discontinuing versus continuing treatment are unknown at this time, the FDA noted.
for patients who meet certain criteria. Nilotinib, a kinase inhibitor that blocks the BCR-ABL protein that promotes abnormal cell growth, was originally approved in 2007 and was indicated for use in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). In accordance with the new label update, patients who have early phase CML, have been using nilotinib for 3 years or more, and whose leukemia has responded to treatment according to a test that has received FDA marketing authorization, may be eligible to discontinue use of nilotinib.
The information that led to the FDA approved label update was based on two single-arm trials of patients with chronic phase Ph+ CML. The trial measured the length of time patients were able to discontinue use of nilotinib without leukemia returning, and who had entered treatment-free remission (TFR). In the first trial, among 190 newly diagnosed CML patients who discontinued taking nilotinib after using the drug for 3 or more years, 51.6% were still in TFR after about 1 year (48 weeks) and 48.9% were still in TFR after nearly 2 years (96 weeks). Similar results were seen in the second trial, among 126 patients, with 57.9% in TFR after about a year (48 weeks) and 53.2% in TFR after approximately 2 years (96 weeks).
An important element of these trials was regular monitoring of specific RNA information that specifies the level of BCR-ABL protein in the blood using a diagnostic test that has received FDA marketing authorization. Monitoring with a test that accurately detects the reductions of RNA information in the blood with accuracy and precision is critical in discontinuing the use of nilotinib. This monitoring will allow physicians to detect the first signs of relapse.
“Patients diagnosed with CML generally face a lifetime of treatment to keep their leukemia from growing or recurring,” said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval shows that some patients may be able to stop treatment with Tasigna altogether if they are showing a strong response to therapy. While we welcome this progress in patient care, it’s important to note that any discontinuation of treatment still means patients must be regularly monitored for disease recurrence,” Dr. Pazdur said in the FDA statement.
Common side effects after discontinuing use of nilotinib include body aches and pain in the bones and extremities. Severe side effects of taking nilotinib can include myelosuppression, blockages in the heart and arteries, and inflammation of the pancreas. Severe liver damage can also occur.
Severe side effects typically associated with nilotinib administration occurred less frequently in patients who discontinued the drug. However, the long-term outcomes of patients discontinuing versus continuing treatment are unknown at this time, the FDA noted.
for patients who meet certain criteria. Nilotinib, a kinase inhibitor that blocks the BCR-ABL protein that promotes abnormal cell growth, was originally approved in 2007 and was indicated for use in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). In accordance with the new label update, patients who have early phase CML, have been using nilotinib for 3 years or more, and whose leukemia has responded to treatment according to a test that has received FDA marketing authorization, may be eligible to discontinue use of nilotinib.
The information that led to the FDA approved label update was based on two single-arm trials of patients with chronic phase Ph+ CML. The trial measured the length of time patients were able to discontinue use of nilotinib without leukemia returning, and who had entered treatment-free remission (TFR). In the first trial, among 190 newly diagnosed CML patients who discontinued taking nilotinib after using the drug for 3 or more years, 51.6% were still in TFR after about 1 year (48 weeks) and 48.9% were still in TFR after nearly 2 years (96 weeks). Similar results were seen in the second trial, among 126 patients, with 57.9% in TFR after about a year (48 weeks) and 53.2% in TFR after approximately 2 years (96 weeks).
An important element of these trials was regular monitoring of specific RNA information that specifies the level of BCR-ABL protein in the blood using a diagnostic test that has received FDA marketing authorization. Monitoring with a test that accurately detects the reductions of RNA information in the blood with accuracy and precision is critical in discontinuing the use of nilotinib. This monitoring will allow physicians to detect the first signs of relapse.
“Patients diagnosed with CML generally face a lifetime of treatment to keep their leukemia from growing or recurring,” said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval shows that some patients may be able to stop treatment with Tasigna altogether if they are showing a strong response to therapy. While we welcome this progress in patient care, it’s important to note that any discontinuation of treatment still means patients must be regularly monitored for disease recurrence,” Dr. Pazdur said in the FDA statement.
Common side effects after discontinuing use of nilotinib include body aches and pain in the bones and extremities. Severe side effects of taking nilotinib can include myelosuppression, blockages in the heart and arteries, and inflammation of the pancreas. Severe liver damage can also occur.
Severe side effects typically associated with nilotinib administration occurred less frequently in patients who discontinued the drug. However, the long-term outcomes of patients discontinuing versus continuing treatment are unknown at this time, the FDA noted.
FDA approves raltegravir for newborns at risk for HIV-1 infection
The Food and Drug Administration has approved the use of raltegravir (Isentress), in combination with other antiretrovirals, for HIV-1 exposed newborns who weigh at least 2 kg and are at high risk for acquiring HIV-1 infection from their mothers, according to a press release from Merck, the manufacturer of Isentress.
“With this FDA approval, Isentress becomes the only integrase inhibitor approved in the U.S. for the treatment of HIV-1, in combination with other antiretroviral agents, for neonates weighing at least 2 kg,” Eliav Barr, MD, senior vice president, global clinical development, infectious diseases and vaccines, Merck Research Laboratories, said in a statement.
The study, IMPAACT P1110, was composed of two cohorts receiving different doses of raltegravir at different time intervals. The first cohort, of 16 newborns, received two single doses of raltegravir: the first within 48 hours of birth and the second between 7 and 10 days of age. The second cohort of 26 newborns received daily doses based on weight for 6 weeks. After observation for 24 weeks, all infants were HIV-1 negative.
Raltegravir does not cure HIV-1 infection or AIDS and severe side effects have been reported, including hypersensitivity reaction and toxic epidermal necrolysis, according to the Merck release.
Raltegravir should not be used in newborns and infants weighing under 2 kg. If raltegravir has been administered to the mother 2-24 hours before delivery, the first dose for the newborn should be given between 24 and 48 hours after birth.
The Food and Drug Administration has approved the use of raltegravir (Isentress), in combination with other antiretrovirals, for HIV-1 exposed newborns who weigh at least 2 kg and are at high risk for acquiring HIV-1 infection from their mothers, according to a press release from Merck, the manufacturer of Isentress.
“With this FDA approval, Isentress becomes the only integrase inhibitor approved in the U.S. for the treatment of HIV-1, in combination with other antiretroviral agents, for neonates weighing at least 2 kg,” Eliav Barr, MD, senior vice president, global clinical development, infectious diseases and vaccines, Merck Research Laboratories, said in a statement.
The study, IMPAACT P1110, was composed of two cohorts receiving different doses of raltegravir at different time intervals. The first cohort, of 16 newborns, received two single doses of raltegravir: the first within 48 hours of birth and the second between 7 and 10 days of age. The second cohort of 26 newborns received daily doses based on weight for 6 weeks. After observation for 24 weeks, all infants were HIV-1 negative.
Raltegravir does not cure HIV-1 infection or AIDS and severe side effects have been reported, including hypersensitivity reaction and toxic epidermal necrolysis, according to the Merck release.
Raltegravir should not be used in newborns and infants weighing under 2 kg. If raltegravir has been administered to the mother 2-24 hours before delivery, the first dose for the newborn should be given between 24 and 48 hours after birth.
The Food and Drug Administration has approved the use of raltegravir (Isentress), in combination with other antiretrovirals, for HIV-1 exposed newborns who weigh at least 2 kg and are at high risk for acquiring HIV-1 infection from their mothers, according to a press release from Merck, the manufacturer of Isentress.
“With this FDA approval, Isentress becomes the only integrase inhibitor approved in the U.S. for the treatment of HIV-1, in combination with other antiretroviral agents, for neonates weighing at least 2 kg,” Eliav Barr, MD, senior vice president, global clinical development, infectious diseases and vaccines, Merck Research Laboratories, said in a statement.
The study, IMPAACT P1110, was composed of two cohorts receiving different doses of raltegravir at different time intervals. The first cohort, of 16 newborns, received two single doses of raltegravir: the first within 48 hours of birth and the second between 7 and 10 days of age. The second cohort of 26 newborns received daily doses based on weight for 6 weeks. After observation for 24 weeks, all infants were HIV-1 negative.
Raltegravir does not cure HIV-1 infection or AIDS and severe side effects have been reported, including hypersensitivity reaction and toxic epidermal necrolysis, according to the Merck release.
Raltegravir should not be used in newborns and infants weighing under 2 kg. If raltegravir has been administered to the mother 2-24 hours before delivery, the first dose for the newborn should be given between 24 and 48 hours after birth.
Management of Isolated Greater Tuberosity Fractures: A Systematic Review
Take-Home Points
- Fractures of the greater tuberosity are often mismanaged.
- Comprehension of greater tuberosity fractures involves classification into nonoperative and operative treatment, displacement >5mm or <5 mm, and open vs arthroscopic surgery.
- Nearly a third of patients may suffer concomitant anterior glenohumeral instability.
- Stiffness is the most common postoperative complication.
- Surgery is associated with high patient satisfaction and low rates of complications and reoperations.
Although proximal humerus fractures are common in the elderly, isolated fractures of the greater tuberosity occur less often. Management depends on several factors, including fracture pattern and displacement.1,2 Nondisplaced fractures are often successfully managed with sling immobilization and early range of motion.3,4 Although surgical intervention improves outcomes in displaced greater tuberosity fractures, the ideal surgical treatment is less clear.5
Displaced greater tuberosity fractures may require surgery for prevention of subacromial impingement and range-of-motion deficits.2 Superior fracture displacement results in decreased shoulder abduction, and posterior displacement can limit external rotation.6 Although the greater tuberosity can displace in any direction, posterosuperior displacement has the worst outcomes.1 The exact surgery-warranting displacement amount ranges from 3 mm to 10 mm but is yet to be clearly elucidated.5,6 Less displacement is tolerated by young overhead athletes, and more displacement by older less active patients.5,7,8 Surgical options for isolated greater tuberosity fractures include fragment excision, open reduction and internal fixation (ORIF), closed reduction with percutaneous fixation, and arthroscopically assisted reduction with internal fixation.3,9,10
We conducted a study to determine the management patterns for isolated greater tuberosity fractures. We hypothesized that greater tuberosity fractures displaced <5 mm may be managed nonoperatively and that greater tuberosity fractures displaced >5 mm require surgical fixation.
Methods
Search Strategy
We performed this systematic review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist11 and registered it (CRD42014010691) with the PROSPERO international prospective register of systematic reviews. Literature searches using the PubMed/Medline database and the Cochrane Central Register of Clinical Trials were completed in August 2014. There were no date or year restrictions. Key words were used to capture all English- language studies with level I to IV evidence (Oxford Centre for Evidence-Based Medicine) and reported clinical or radiographic outcomes. Initial exclusion criteria were cadaveric, biomechanical, histologic, and kinematic results. An electronic search algorithm with key words and a series of NOT phrases was designed to match our exclusion criteria:
((((((((((((((((((((((((((((((((((((((((((((((((((greater[Title/Abstract]) AND tuberosity [Title/Abstract] OR tubercle [Title/Abstract]) AND fracture[Title/Abstract]) AND proximal[Title/Abstract] AND (English[lang]))) NOT intramedullary[Title] AND (English[lang]))) NOT nonunion[Title] AND (English[lang]))) NOT malunion[Title] AND (English[lang]))) NOT biomechanical[Title/Abstract] AND (English[lang]))) NOT cadaveric[Title/Abstract] AND (English[lang]))) NOT cadaver[Title/Abstract] AND (English[lang]))) NOT ((basic[Title/Abstract]) AND science[Title/Abstract] AND (English[lang])) AND (English[lang]))) NOT revision[Title] AND (English[lang]))) NOT pediatric[Title] AND (English[lang]))) NOT physeal[Title] AND (English[lang]))) NOT children[Title] AND (English[lang]))) NOT instability[Title] AND (English[lang]))) NOT imaging[Title])) NOT salter[Title])) NOT physis[Title])) NOT shaft[Title])) NOT distal[Title])) NOT clavicle[Title])) NOT scapula[Title])) NOT ((diaphysis[Title]) AND diaphyseal[Title]))) NOT infection[Title])) NOT laboratory[Title/Abstract])) NOT metastatic[Title/Abstract])) NOT (((((((malignancy[Title/Abstract]) OR malignant[Title/Abstract]) OR tumor[Title/Abstract]) OR oncologic[Title/Abstract]) OR cyst[Title/Abstract]) OR aneurysmal[Title/Abstract]) OR unicameral[Title/Abstract]).
Study Selection
Data Extraction
We extracted data from the 13 studies that met the eligibility criteria. Details of study design, sample size, and patient demographics, including age, sex, and hand dominance, were recorded, as were mechanism of injury and concomitant anterior shoulder instability. To capture the most patients, we noted radiographic fracture displacement categorically rather than continuously; patients were divided into 2 displacement groups (<5 mm, >5 mm). Most studies did not define degree of comminution or specific direction of displacement per fracture, so these variables were not included in the data analysis. Nonoperative management and operative management were studied. We abstracted surgical factors, such as approach, method, fixation type (screws or sutures), and technique (suture anchors or transosseous tunnels). Clinical outcomes included physical examination findings, functional assessment results (patient satisfaction; Constant and University of California Los Angeles [UCLA] shoulder scores), and the number of revisions. Radiologic outcomes, retrieved from radiographs or computed tomography scans, focused on loss of reduction (as determined by the respective authors), malunion, nonunion, and heterotopic ossification. Each study’s methodologic quality and bias were evaluated with the 15-item Modified Coleman Methodology Score (MCMS), which was described by Cowan and colleagues.23 The MCMS has been used to assess randomized and nonrandomized patient trials.24,25 Its scaled potential score ranges from 0 to 100 (85-100, excellent; 70-84, good; 55-69, fair; <55, poor).
Statistical Analysis
We report our data as weighted means (SDs). A mean was calculated for each study that reported a respective data point, and each mean was then weighed according to its study sample size. This calculation was performed by multiplying a study’s individual mean by the number of patients enrolled in that study and dividing the sum of these weighted data points by the number of eligible patients in all relevant studies. The result was that the nonweighted means from studies with smaller sample sizes did not carry as much weight as the nonweighted means from larger studies. We compared 3 paired groups: treatment type (nonoperative vs operative), fracture displacement amount (<5 mm vs >5 mm), and surgery type (open vs arthroscopic). Regarding all patient, surgery, and outcomes data, unpaired Student t tests were used for continuous variables and 2-tailed Fisher exact tests for categorical variables with α = 0.05 (SPSS Version 18; IBM).
Results
Postoperative physical examination findings were underreported so that surgical groups could be compared. Of all the surgical studies, 4 reported postoperative forward elevation (mean, 160°; SD, 9.8°) and external rotation (mean, 46.4°; SD 26.3°).14,15,18,22 No malunions and only 1 nonunion were reported in all 13 studies. No deaths or other serious medical complications were reported. Patients with anterior instability more often underwent surgery than were treated nonoperatively (39.2% vs 12.0%; P < .01) and more often had fractures displaced >5 mm than <5 mm (44.3% vs 14.5%; P < .01).
Fisher exact tests were used to perform isolated comparisons of screws and sutures as well as suture anchors and transosseous tunnels. Patients with screw fixation were significantly (P = .051) less likely to require reoperation (0/56; 0%) than patients with suture fixation (8/100; 8.0%). Screw fixation also led to significantly less stiffness (0% vs 12.0%; P < .01) but trended toward a higher rate of superficial infection (3.6% vs 0%; P = .13). There was no statistical difference in nerve injury rates between screws and sutures (1.8% vs 3.0%; P = 1.0). There were no significant differences in reoperations, stiffness, superficial infections, or nerve injuries between suture anchor and transosseous tunnel constructs.
For all 13 studies, mean (SD) MCMS was 41.1 (8.6).
Discussion
Five percent of all fractures involve the proximal humerus, and 20% of proximal humerus fractures are isolated greater tuberosity fractures.26,27 In his classic 1970 article, Neer6 formulated the 4-part proximal humerus fracture classification and defined greater tuberosity fracture “parts” using the same criteria as for other fracture “parts.” Neer6 recommended nonoperative management for isolated greater tuberosity fractures displaced <1 cm but did not present evidence corroborating his recommendation. More recent cutoffs for nonoperative management include 5 mm (general population) and 3 mm (athletes).7,17
In the present systematic review of greater tuberosity fractures, 3 separate comparisons were made: treatment type (nonoperative vs operative), fracture displacement amount (<5 mm vs >5 mm), and surgery type (open vs arthroscopic).
Treatment Type. Only 4 studies reported data on nonoperative treatment outcomes.5,12,16,17 Of these 4 studies, 2 found successful outcomes for fractures displaced <5 mm.12,17 Platzer and colleagues17 found good or excellent results in 97% of 135 shoulders after 4 years. Good results were defined with shoulder scores of ≥80 (Constant), <8 (Vienna), and >28 (UCLA), and excellent results were defined with maximum scores on 2 of the 3 systems. Platzer and colleagues17 also found nonsignificantly worse shoulder scores with superior displacement of 3 mm to 5 mm and recommended surgery for overhead athletes in this group. Rath and colleagues12 described a successful 3-phase rehabilitation protocol of sling immobilization for 3 weeks, pendulum exercises for 3 weeks, and active exercises thereafter. By an average of 31 months, patient satisfaction scores improved to 9.5 from 4.2 (10-point scale), though the authors cautioned that pain and decreased motion lasted 8 months on average. Conservative treatment was far less successful in the 2 studies of fractures displaced >5 mm.5,16 Keene and colleagues16 reported unsatisfactory results in all 4 patients with fractures displaced >1.5 cm. In a study separate from their 2005 analysis,17 Platzer and colleagues5 in 2008 evaluated displaced fractures and found function and patient satisfaction were inferior after nonoperative treatment than after surgery. The studies by Keene and colleagues16 and Platzer and colleagues5 support the finding of an overall lower patient satisfaction rate in nonoperative patients.
Fracture Displacement Amount. Only 2 arthroscopic studies and no open studies addressed surgery for fractures displaced <5 mm. Fewer than 16% of these fractures were managed operatively, and <1% required reoperation. By contrast, almost all fractures displaced >5 mm were managed operatively, and 3.6% required reoperation. Radiographic loss of reduction was more common in fractures displaced <5 mm, primarily because they were managed without fixation. Radiographic loss of reduction was reported in only 9 operatively treated patients, none of whom was symptomatic enough to require another surgery.5 Reoperations were most commonly performed for stiffness, which itself was significantly more common in fractures displaced >5 mm. Bhatia and colleagues14 reported the highest reoperation rate (14.3%; 3/21), but they studied more complex, comminuted fractures of the greater tuberosity. Two of their 3 reoperations were biceps tenodeses for inflamed, stiff tenosynovitis, and the third patient had a foreign body giant cell reaction to suture material. Fewer than 1% of patients with operatively managed displaced fractures required revision ORIF, and <2% developed a superficial infection or postoperative nerve palsy.19,22 For displaced greater tuberosity fractures, surgery is highly successful overall, complication rates are very low, and 90% of patients report being satisfied.
Surgery Type. Patients were divided into 2 groups. In the nonarthroscopic group, open and percutaneous approaches were used. All studies that described a percutaneous approach used screw fixation5,21; in addition, 32 patients were treated with screws through an open approach.2,5 The other open and arthroscopic studies used suture fixation. Interestingly, no studies reported on clinical outcomes of fragment excision. There were no statistically significant differences in rates of reoperation, stiffness, infection, or neurologic injury between the arthroscopic and nonarthroscopic groups. Patient satisfaction scores were slightly higher in the nonarthroscopic group (91.0% vs 87.8%), but the difference was not statistically significant.
With surgical techniques isolated, there were no significant differences between suture anchors and transosseous tunnel constructs, but screws performed significantly better than suture techniques. Compared with suture fixation, screw fixation led to significantly fewer cases of stiffness and reoperation, which suggests surgeons need to give screws more consideration in the operative management of these fractures. However, the number of patients treated with screws was smaller than the number treated with suture fixation; it is possible the differences between these cohorts would be eliminated if there were more patients in the screw cohort. In addition, screw fixation was universally performed with an open or percutaneous approach and trended toward a higher infection rate. As screw and suture techniques have low rates of complications and reoperations, we recommend leaving fixation choice to the surgeon.
Anterior shoulder instability has been associated with greater tuberosity fractures.1,8,19 The supraspinatus, infraspinatus, and teres minor muscles all insert into the greater tuberosity and resist anterior translation of the proximal humerus. Loss of this dynamic muscle stabilization is amplified by tuberosity fracture displacement: Anterior shoulder instability was significantly more common in fractures displaced >5 mm (44.3%) vs <5 mm (14.5%). In turn, glenohumeral instability was more common in patients treated with surgery, specifically open surgery, because displaced fractures may not be as easily accessed with arthroscopic techniques. No studies reported concomitant labral repair or capsular plication techniques.
This systematic review was limited by the studies analyzed. All but 1 study5 had level IV evidence. Mean (SD) MCMS was 41.8 (8.6). Any MCMS score <54 indicates a poor methodology level, but this scoring system is designed for randomized controlled trials,23 and there were none in this study. Physical examination findings, such as range of motion, were underreported. In addition, radiographic parameters were not consistently described but rather were determined by the respective authors’ subjective interpretations of malunion, nonunion, and loss of reduction. Publication bias is present in that we excluded non- English language studies and medical conference abstracts and may have omitted potentially eligible studies not discoverable with our search methodology. Performance bias is a factor in any systematic review with multiple surgeons and wide variation in surgical technique.
Conclusion
Greater tuberosity fractures displaced <5 mm may be safely managed nonoperatively, as there are no reports of nonoperatively managed fractures that subsequently required surgery. Nonoperative treatment was initially associated with low patient satisfaction, but only because displaced fractures were conservatively managed in early studies.5,16 Fractures displaced >5 mm respond well to operative fixation with screws, suture anchors, or transosseous suture tunnels. Stiffness is the most common postoperative complication (<6%), followed by heterotopic ossification, transient neurapraxias, and superficial infection. There are no discernible differences in outcome between open and arthroscopic techniques, but screw fixation may lead to significantly fewer cases of stiffness and reoperation in comparison with suture constructs.
1. Verdano MA, Aliani D, Pellegrini A, Baudi P, Pedrazzi G, Ceccarelli F. Isolated fractures of the greater tuberosity in proximal humerus: does the direction of displacement influence functional outcome? An analysis of displacement in greater tuberosity fractures. Acta Biomed. 2013;84(3):219-228.
2. Yin B, Moen TC, Thompson SA, Bigliani LU, Ahmad CS, Levine WN. Operative treatment of isolated greater tuberosity fractures: retrospective review of clinical and functional outcomes. Orthopedics. 2012;35(6):e807-e814.
3. Green A, Izzi J. Isolated fractures of the greater tuberosity of the proximal humerus. J Shoulder Elbow Surg. 2003;12(6):641-649.
4. Norouzi M, Naderi MN, Komasi MH, Sharifzadeh SR, Shahrezaei M, Eajazi A. Clinical results of using the proximal humeral internal locking system plate for internal fixation of displaced proximal humeral fractures. Am J Orthop. 2012;41(5):E64-E68.
5. Platzer P, Thalhammer G, Oberleitner G, et al. Displaced fractures of the greater tuberosity: a comparison of operative and nonoperative treatment. J Trauma. 2008;65(4):843-848.
6. Neer CS. Displaced proximal humeral fractures. I. Classification and evaluation. J Bone Joint Surg Am. 1970;52(6):1077-1089.
7. Park TS, Choi IY, Kim YH, Park MR, Shon JH, Kim SI. A new suggestion for the treatment of minimally displaced fractures of the greater tuberosity of the proximal humerus. Bull Hosp Jt Dis. 1997;56(3):171-176.
8. McLaughlin HL. Dislocation of the shoulder with tuberosity fracture. Surg Clin North Am. 1963;43:1615-1620.
9. DeBottis D, Anavian J, Green A. Surgical management of isolated greater tuberosity fractures of the proximal humerus. Orthop Clin North Am. 2014;45(2):207-218.
10. Monga P, Verma R, Sharma VK. Closed reduction and external fixation for displaced proximal humeral fractures. J Orthop Surg (Hong Kong). 2009;17(2):142-145.
11. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. J Clin Epidemiol. 2009;62(10):1006-1012.
12. Rath E, Alkrinawi N, Levy O, Debbi R, Amar E, Atoun E. Minimally displaced fractures of the greater tuberosity: outcome of non-operative treatment. J Shoulder Elbow Surg. 2013;22(10):e8-e11.
13. Dimakopoulos P, Panagopoulos A, Kasimatis G. Transosseous suture fixation of proximal humeral fractures. J Bone Joint Surg Am. 2007;89(8):1700-1709.
14. Bhatia DN, van Rooyen KS, Toit du DF, de Beer JF. Surgical treatment of comminuted, displaced fractures of the greater tuberosity of the proximal humerus: a new technique of double-row suture-anchor fixation and long-term results. Injury. 2006;37(10):946-952.
15. Flatow EL, Cuomo F, Maday MG, Miller SR, McIlveen SJ, Bigliani LU. Open reduction and internal fixation of two-part displaced fractures of the greater tuberosity of the proximal part of the humerus. J Bone Joint Surg Am. 1991;73(8):1213-1218.
16. Keene JS, Huizenga RE, Engber WD, Rogers SC. Proximal humeral fractures: a correlation of residual deformity with long-term function. Orthopedics. 1983;6(2):173-178.
17. Platzer P, Kutscha-Lissberg F, Lehr S, Vecsei V, Gaebler C. The influence of displacement on shoulder function in patients with minimally displaced fractures of the greater tuberosity. Injury. 2005;36(10):1185-1189.
18. Park SE, Ji JH, Shafi M, Jung JJ, Gil HJ, Lee HH. Arthroscopic management of occult greater tuberosity fracture of the shoulder. Eur J Orthop Surg Traumatol. 2014;24(4):475-482.
19. Dimakopoulos P, Panagopoulos A, Kasimatis G, Syggelos SA, Lambiris E. Anterior traumatic shoulder dislocation associated with displaced greater tuberosity fracture: the necessity of operative treatment. J Orthop Trauma. 2007;21(2):104-112.
20. Kim SH, Ha KI. Arthroscopic treatment of symptomatic shoulders with minimally displaced greater tuberosity fracture. Arthroscopy. 2000;16(7):695-700.
21. Chen CY, Chao EK, Tu YK, Ueng SW, Shih CH. Closed management and percutaneous fixation of unstable proximal humerus fractures. J Trauma. 1998;45(6):1039-1045.
22. Ji JH, Shafi M, Song IS, Kim YY, McFarland EG, Moon CY. Arthroscopic fixation technique for comminuted, displaced greater tuberosity fracture. Arthroscopy. 2010;26(5):600-609.
23. Cowan J, Lozano-Calderón S, Ring D. Quality of prospective controlled randomized trials. Analysis of trials of treatment for lateral epicondylitis as an example. J Bone Joint Surg Am. 2007;89(8):1693-1699.
24. Harris JD, Siston RA, Pan X, Flanigan DC. Autologous chondrocyte implantation: a systematic review. J Bone Joint Surg Am. 2010;92(12):2220-2233.
25. Harris JD, Siston RA, Brophy RH, Lattermann C, Carey JL, Flanigan DC. Failures, re-operations, and complications after autologous chondrocyte implantation—a systematic review. Osteoarthritis Cartilage. 2011;19(7):779-791.
26. Chun JM, Groh GI, Rockwood CA. Two-part fractures of the proximal humerus. J Shoulder Elbow Surg. 1994;3(5):273-287.
27. Gruson KI, Ruchelsman DE, Tejwani NC. Isolated tuberosity fractures of the proximal humeral: current concepts. Injury. 2008;39(3):284-298.
Take-Home Points
- Fractures of the greater tuberosity are often mismanaged.
- Comprehension of greater tuberosity fractures involves classification into nonoperative and operative treatment, displacement >5mm or <5 mm, and open vs arthroscopic surgery.
- Nearly a third of patients may suffer concomitant anterior glenohumeral instability.
- Stiffness is the most common postoperative complication.
- Surgery is associated with high patient satisfaction and low rates of complications and reoperations.
Although proximal humerus fractures are common in the elderly, isolated fractures of the greater tuberosity occur less often. Management depends on several factors, including fracture pattern and displacement.1,2 Nondisplaced fractures are often successfully managed with sling immobilization and early range of motion.3,4 Although surgical intervention improves outcomes in displaced greater tuberosity fractures, the ideal surgical treatment is less clear.5
Displaced greater tuberosity fractures may require surgery for prevention of subacromial impingement and range-of-motion deficits.2 Superior fracture displacement results in decreased shoulder abduction, and posterior displacement can limit external rotation.6 Although the greater tuberosity can displace in any direction, posterosuperior displacement has the worst outcomes.1 The exact surgery-warranting displacement amount ranges from 3 mm to 10 mm but is yet to be clearly elucidated.5,6 Less displacement is tolerated by young overhead athletes, and more displacement by older less active patients.5,7,8 Surgical options for isolated greater tuberosity fractures include fragment excision, open reduction and internal fixation (ORIF), closed reduction with percutaneous fixation, and arthroscopically assisted reduction with internal fixation.3,9,10
We conducted a study to determine the management patterns for isolated greater tuberosity fractures. We hypothesized that greater tuberosity fractures displaced <5 mm may be managed nonoperatively and that greater tuberosity fractures displaced >5 mm require surgical fixation.
Methods
Search Strategy
We performed this systematic review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist11 and registered it (CRD42014010691) with the PROSPERO international prospective register of systematic reviews. Literature searches using the PubMed/Medline database and the Cochrane Central Register of Clinical Trials were completed in August 2014. There were no date or year restrictions. Key words were used to capture all English- language studies with level I to IV evidence (Oxford Centre for Evidence-Based Medicine) and reported clinical or radiographic outcomes. Initial exclusion criteria were cadaveric, biomechanical, histologic, and kinematic results. An electronic search algorithm with key words and a series of NOT phrases was designed to match our exclusion criteria:
((((((((((((((((((((((((((((((((((((((((((((((((((greater[Title/Abstract]) AND tuberosity [Title/Abstract] OR tubercle [Title/Abstract]) AND fracture[Title/Abstract]) AND proximal[Title/Abstract] AND (English[lang]))) NOT intramedullary[Title] AND (English[lang]))) NOT nonunion[Title] AND (English[lang]))) NOT malunion[Title] AND (English[lang]))) NOT biomechanical[Title/Abstract] AND (English[lang]))) NOT cadaveric[Title/Abstract] AND (English[lang]))) NOT cadaver[Title/Abstract] AND (English[lang]))) NOT ((basic[Title/Abstract]) AND science[Title/Abstract] AND (English[lang])) AND (English[lang]))) NOT revision[Title] AND (English[lang]))) NOT pediatric[Title] AND (English[lang]))) NOT physeal[Title] AND (English[lang]))) NOT children[Title] AND (English[lang]))) NOT instability[Title] AND (English[lang]))) NOT imaging[Title])) NOT salter[Title])) NOT physis[Title])) NOT shaft[Title])) NOT distal[Title])) NOT clavicle[Title])) NOT scapula[Title])) NOT ((diaphysis[Title]) AND diaphyseal[Title]))) NOT infection[Title])) NOT laboratory[Title/Abstract])) NOT metastatic[Title/Abstract])) NOT (((((((malignancy[Title/Abstract]) OR malignant[Title/Abstract]) OR tumor[Title/Abstract]) OR oncologic[Title/Abstract]) OR cyst[Title/Abstract]) OR aneurysmal[Title/Abstract]) OR unicameral[Title/Abstract]).
Study Selection
Data Extraction
We extracted data from the 13 studies that met the eligibility criteria. Details of study design, sample size, and patient demographics, including age, sex, and hand dominance, were recorded, as were mechanism of injury and concomitant anterior shoulder instability. To capture the most patients, we noted radiographic fracture displacement categorically rather than continuously; patients were divided into 2 displacement groups (<5 mm, >5 mm). Most studies did not define degree of comminution or specific direction of displacement per fracture, so these variables were not included in the data analysis. Nonoperative management and operative management were studied. We abstracted surgical factors, such as approach, method, fixation type (screws or sutures), and technique (suture anchors or transosseous tunnels). Clinical outcomes included physical examination findings, functional assessment results (patient satisfaction; Constant and University of California Los Angeles [UCLA] shoulder scores), and the number of revisions. Radiologic outcomes, retrieved from radiographs or computed tomography scans, focused on loss of reduction (as determined by the respective authors), malunion, nonunion, and heterotopic ossification. Each study’s methodologic quality and bias were evaluated with the 15-item Modified Coleman Methodology Score (MCMS), which was described by Cowan and colleagues.23 The MCMS has been used to assess randomized and nonrandomized patient trials.24,25 Its scaled potential score ranges from 0 to 100 (85-100, excellent; 70-84, good; 55-69, fair; <55, poor).
Statistical Analysis
We report our data as weighted means (SDs). A mean was calculated for each study that reported a respective data point, and each mean was then weighed according to its study sample size. This calculation was performed by multiplying a study’s individual mean by the number of patients enrolled in that study and dividing the sum of these weighted data points by the number of eligible patients in all relevant studies. The result was that the nonweighted means from studies with smaller sample sizes did not carry as much weight as the nonweighted means from larger studies. We compared 3 paired groups: treatment type (nonoperative vs operative), fracture displacement amount (<5 mm vs >5 mm), and surgery type (open vs arthroscopic). Regarding all patient, surgery, and outcomes data, unpaired Student t tests were used for continuous variables and 2-tailed Fisher exact tests for categorical variables with α = 0.05 (SPSS Version 18; IBM).
Results
Postoperative physical examination findings were underreported so that surgical groups could be compared. Of all the surgical studies, 4 reported postoperative forward elevation (mean, 160°; SD, 9.8°) and external rotation (mean, 46.4°; SD 26.3°).14,15,18,22 No malunions and only 1 nonunion were reported in all 13 studies. No deaths or other serious medical complications were reported. Patients with anterior instability more often underwent surgery than were treated nonoperatively (39.2% vs 12.0%; P < .01) and more often had fractures displaced >5 mm than <5 mm (44.3% vs 14.5%; P < .01).
Fisher exact tests were used to perform isolated comparisons of screws and sutures as well as suture anchors and transosseous tunnels. Patients with screw fixation were significantly (P = .051) less likely to require reoperation (0/56; 0%) than patients with suture fixation (8/100; 8.0%). Screw fixation also led to significantly less stiffness (0% vs 12.0%; P < .01) but trended toward a higher rate of superficial infection (3.6% vs 0%; P = .13). There was no statistical difference in nerve injury rates between screws and sutures (1.8% vs 3.0%; P = 1.0). There were no significant differences in reoperations, stiffness, superficial infections, or nerve injuries between suture anchor and transosseous tunnel constructs.
For all 13 studies, mean (SD) MCMS was 41.1 (8.6).
Discussion
Five percent of all fractures involve the proximal humerus, and 20% of proximal humerus fractures are isolated greater tuberosity fractures.26,27 In his classic 1970 article, Neer6 formulated the 4-part proximal humerus fracture classification and defined greater tuberosity fracture “parts” using the same criteria as for other fracture “parts.” Neer6 recommended nonoperative management for isolated greater tuberosity fractures displaced <1 cm but did not present evidence corroborating his recommendation. More recent cutoffs for nonoperative management include 5 mm (general population) and 3 mm (athletes).7,17
In the present systematic review of greater tuberosity fractures, 3 separate comparisons were made: treatment type (nonoperative vs operative), fracture displacement amount (<5 mm vs >5 mm), and surgery type (open vs arthroscopic).
Treatment Type. Only 4 studies reported data on nonoperative treatment outcomes.5,12,16,17 Of these 4 studies, 2 found successful outcomes for fractures displaced <5 mm.12,17 Platzer and colleagues17 found good or excellent results in 97% of 135 shoulders after 4 years. Good results were defined with shoulder scores of ≥80 (Constant), <8 (Vienna), and >28 (UCLA), and excellent results were defined with maximum scores on 2 of the 3 systems. Platzer and colleagues17 also found nonsignificantly worse shoulder scores with superior displacement of 3 mm to 5 mm and recommended surgery for overhead athletes in this group. Rath and colleagues12 described a successful 3-phase rehabilitation protocol of sling immobilization for 3 weeks, pendulum exercises for 3 weeks, and active exercises thereafter. By an average of 31 months, patient satisfaction scores improved to 9.5 from 4.2 (10-point scale), though the authors cautioned that pain and decreased motion lasted 8 months on average. Conservative treatment was far less successful in the 2 studies of fractures displaced >5 mm.5,16 Keene and colleagues16 reported unsatisfactory results in all 4 patients with fractures displaced >1.5 cm. In a study separate from their 2005 analysis,17 Platzer and colleagues5 in 2008 evaluated displaced fractures and found function and patient satisfaction were inferior after nonoperative treatment than after surgery. The studies by Keene and colleagues16 and Platzer and colleagues5 support the finding of an overall lower patient satisfaction rate in nonoperative patients.
Fracture Displacement Amount. Only 2 arthroscopic studies and no open studies addressed surgery for fractures displaced <5 mm. Fewer than 16% of these fractures were managed operatively, and <1% required reoperation. By contrast, almost all fractures displaced >5 mm were managed operatively, and 3.6% required reoperation. Radiographic loss of reduction was more common in fractures displaced <5 mm, primarily because they were managed without fixation. Radiographic loss of reduction was reported in only 9 operatively treated patients, none of whom was symptomatic enough to require another surgery.5 Reoperations were most commonly performed for stiffness, which itself was significantly more common in fractures displaced >5 mm. Bhatia and colleagues14 reported the highest reoperation rate (14.3%; 3/21), but they studied more complex, comminuted fractures of the greater tuberosity. Two of their 3 reoperations were biceps tenodeses for inflamed, stiff tenosynovitis, and the third patient had a foreign body giant cell reaction to suture material. Fewer than 1% of patients with operatively managed displaced fractures required revision ORIF, and <2% developed a superficial infection or postoperative nerve palsy.19,22 For displaced greater tuberosity fractures, surgery is highly successful overall, complication rates are very low, and 90% of patients report being satisfied.
Surgery Type. Patients were divided into 2 groups. In the nonarthroscopic group, open and percutaneous approaches were used. All studies that described a percutaneous approach used screw fixation5,21; in addition, 32 patients were treated with screws through an open approach.2,5 The other open and arthroscopic studies used suture fixation. Interestingly, no studies reported on clinical outcomes of fragment excision. There were no statistically significant differences in rates of reoperation, stiffness, infection, or neurologic injury between the arthroscopic and nonarthroscopic groups. Patient satisfaction scores were slightly higher in the nonarthroscopic group (91.0% vs 87.8%), but the difference was not statistically significant.
With surgical techniques isolated, there were no significant differences between suture anchors and transosseous tunnel constructs, but screws performed significantly better than suture techniques. Compared with suture fixation, screw fixation led to significantly fewer cases of stiffness and reoperation, which suggests surgeons need to give screws more consideration in the operative management of these fractures. However, the number of patients treated with screws was smaller than the number treated with suture fixation; it is possible the differences between these cohorts would be eliminated if there were more patients in the screw cohort. In addition, screw fixation was universally performed with an open or percutaneous approach and trended toward a higher infection rate. As screw and suture techniques have low rates of complications and reoperations, we recommend leaving fixation choice to the surgeon.
Anterior shoulder instability has been associated with greater tuberosity fractures.1,8,19 The supraspinatus, infraspinatus, and teres minor muscles all insert into the greater tuberosity and resist anterior translation of the proximal humerus. Loss of this dynamic muscle stabilization is amplified by tuberosity fracture displacement: Anterior shoulder instability was significantly more common in fractures displaced >5 mm (44.3%) vs <5 mm (14.5%). In turn, glenohumeral instability was more common in patients treated with surgery, specifically open surgery, because displaced fractures may not be as easily accessed with arthroscopic techniques. No studies reported concomitant labral repair or capsular plication techniques.
This systematic review was limited by the studies analyzed. All but 1 study5 had level IV evidence. Mean (SD) MCMS was 41.8 (8.6). Any MCMS score <54 indicates a poor methodology level, but this scoring system is designed for randomized controlled trials,23 and there were none in this study. Physical examination findings, such as range of motion, were underreported. In addition, radiographic parameters were not consistently described but rather were determined by the respective authors’ subjective interpretations of malunion, nonunion, and loss of reduction. Publication bias is present in that we excluded non- English language studies and medical conference abstracts and may have omitted potentially eligible studies not discoverable with our search methodology. Performance bias is a factor in any systematic review with multiple surgeons and wide variation in surgical technique.
Conclusion
Greater tuberosity fractures displaced <5 mm may be safely managed nonoperatively, as there are no reports of nonoperatively managed fractures that subsequently required surgery. Nonoperative treatment was initially associated with low patient satisfaction, but only because displaced fractures were conservatively managed in early studies.5,16 Fractures displaced >5 mm respond well to operative fixation with screws, suture anchors, or transosseous suture tunnels. Stiffness is the most common postoperative complication (<6%), followed by heterotopic ossification, transient neurapraxias, and superficial infection. There are no discernible differences in outcome between open and arthroscopic techniques, but screw fixation may lead to significantly fewer cases of stiffness and reoperation in comparison with suture constructs.
Take-Home Points
- Fractures of the greater tuberosity are often mismanaged.
- Comprehension of greater tuberosity fractures involves classification into nonoperative and operative treatment, displacement >5mm or <5 mm, and open vs arthroscopic surgery.
- Nearly a third of patients may suffer concomitant anterior glenohumeral instability.
- Stiffness is the most common postoperative complication.
- Surgery is associated with high patient satisfaction and low rates of complications and reoperations.
Although proximal humerus fractures are common in the elderly, isolated fractures of the greater tuberosity occur less often. Management depends on several factors, including fracture pattern and displacement.1,2 Nondisplaced fractures are often successfully managed with sling immobilization and early range of motion.3,4 Although surgical intervention improves outcomes in displaced greater tuberosity fractures, the ideal surgical treatment is less clear.5
Displaced greater tuberosity fractures may require surgery for prevention of subacromial impingement and range-of-motion deficits.2 Superior fracture displacement results in decreased shoulder abduction, and posterior displacement can limit external rotation.6 Although the greater tuberosity can displace in any direction, posterosuperior displacement has the worst outcomes.1 The exact surgery-warranting displacement amount ranges from 3 mm to 10 mm but is yet to be clearly elucidated.5,6 Less displacement is tolerated by young overhead athletes, and more displacement by older less active patients.5,7,8 Surgical options for isolated greater tuberosity fractures include fragment excision, open reduction and internal fixation (ORIF), closed reduction with percutaneous fixation, and arthroscopically assisted reduction with internal fixation.3,9,10
We conducted a study to determine the management patterns for isolated greater tuberosity fractures. We hypothesized that greater tuberosity fractures displaced <5 mm may be managed nonoperatively and that greater tuberosity fractures displaced >5 mm require surgical fixation.
Methods
Search Strategy
We performed this systematic review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist11 and registered it (CRD42014010691) with the PROSPERO international prospective register of systematic reviews. Literature searches using the PubMed/Medline database and the Cochrane Central Register of Clinical Trials were completed in August 2014. There were no date or year restrictions. Key words were used to capture all English- language studies with level I to IV evidence (Oxford Centre for Evidence-Based Medicine) and reported clinical or radiographic outcomes. Initial exclusion criteria were cadaveric, biomechanical, histologic, and kinematic results. An electronic search algorithm with key words and a series of NOT phrases was designed to match our exclusion criteria:
((((((((((((((((((((((((((((((((((((((((((((((((((greater[Title/Abstract]) AND tuberosity [Title/Abstract] OR tubercle [Title/Abstract]) AND fracture[Title/Abstract]) AND proximal[Title/Abstract] AND (English[lang]))) NOT intramedullary[Title] AND (English[lang]))) NOT nonunion[Title] AND (English[lang]))) NOT malunion[Title] AND (English[lang]))) NOT biomechanical[Title/Abstract] AND (English[lang]))) NOT cadaveric[Title/Abstract] AND (English[lang]))) NOT cadaver[Title/Abstract] AND (English[lang]))) NOT ((basic[Title/Abstract]) AND science[Title/Abstract] AND (English[lang])) AND (English[lang]))) NOT revision[Title] AND (English[lang]))) NOT pediatric[Title] AND (English[lang]))) NOT physeal[Title] AND (English[lang]))) NOT children[Title] AND (English[lang]))) NOT instability[Title] AND (English[lang]))) NOT imaging[Title])) NOT salter[Title])) NOT physis[Title])) NOT shaft[Title])) NOT distal[Title])) NOT clavicle[Title])) NOT scapula[Title])) NOT ((diaphysis[Title]) AND diaphyseal[Title]))) NOT infection[Title])) NOT laboratory[Title/Abstract])) NOT metastatic[Title/Abstract])) NOT (((((((malignancy[Title/Abstract]) OR malignant[Title/Abstract]) OR tumor[Title/Abstract]) OR oncologic[Title/Abstract]) OR cyst[Title/Abstract]) OR aneurysmal[Title/Abstract]) OR unicameral[Title/Abstract]).
Study Selection
Data Extraction
We extracted data from the 13 studies that met the eligibility criteria. Details of study design, sample size, and patient demographics, including age, sex, and hand dominance, were recorded, as were mechanism of injury and concomitant anterior shoulder instability. To capture the most patients, we noted radiographic fracture displacement categorically rather than continuously; patients were divided into 2 displacement groups (<5 mm, >5 mm). Most studies did not define degree of comminution or specific direction of displacement per fracture, so these variables were not included in the data analysis. Nonoperative management and operative management were studied. We abstracted surgical factors, such as approach, method, fixation type (screws or sutures), and technique (suture anchors or transosseous tunnels). Clinical outcomes included physical examination findings, functional assessment results (patient satisfaction; Constant and University of California Los Angeles [UCLA] shoulder scores), and the number of revisions. Radiologic outcomes, retrieved from radiographs or computed tomography scans, focused on loss of reduction (as determined by the respective authors), malunion, nonunion, and heterotopic ossification. Each study’s methodologic quality and bias were evaluated with the 15-item Modified Coleman Methodology Score (MCMS), which was described by Cowan and colleagues.23 The MCMS has been used to assess randomized and nonrandomized patient trials.24,25 Its scaled potential score ranges from 0 to 100 (85-100, excellent; 70-84, good; 55-69, fair; <55, poor).
Statistical Analysis
We report our data as weighted means (SDs). A mean was calculated for each study that reported a respective data point, and each mean was then weighed according to its study sample size. This calculation was performed by multiplying a study’s individual mean by the number of patients enrolled in that study and dividing the sum of these weighted data points by the number of eligible patients in all relevant studies. The result was that the nonweighted means from studies with smaller sample sizes did not carry as much weight as the nonweighted means from larger studies. We compared 3 paired groups: treatment type (nonoperative vs operative), fracture displacement amount (<5 mm vs >5 mm), and surgery type (open vs arthroscopic). Regarding all patient, surgery, and outcomes data, unpaired Student t tests were used for continuous variables and 2-tailed Fisher exact tests for categorical variables with α = 0.05 (SPSS Version 18; IBM).
Results
Postoperative physical examination findings were underreported so that surgical groups could be compared. Of all the surgical studies, 4 reported postoperative forward elevation (mean, 160°; SD, 9.8°) and external rotation (mean, 46.4°; SD 26.3°).14,15,18,22 No malunions and only 1 nonunion were reported in all 13 studies. No deaths or other serious medical complications were reported. Patients with anterior instability more often underwent surgery than were treated nonoperatively (39.2% vs 12.0%; P < .01) and more often had fractures displaced >5 mm than <5 mm (44.3% vs 14.5%; P < .01).
Fisher exact tests were used to perform isolated comparisons of screws and sutures as well as suture anchors and transosseous tunnels. Patients with screw fixation were significantly (P = .051) less likely to require reoperation (0/56; 0%) than patients with suture fixation (8/100; 8.0%). Screw fixation also led to significantly less stiffness (0% vs 12.0%; P < .01) but trended toward a higher rate of superficial infection (3.6% vs 0%; P = .13). There was no statistical difference in nerve injury rates between screws and sutures (1.8% vs 3.0%; P = 1.0). There were no significant differences in reoperations, stiffness, superficial infections, or nerve injuries between suture anchor and transosseous tunnel constructs.
For all 13 studies, mean (SD) MCMS was 41.1 (8.6).
Discussion
Five percent of all fractures involve the proximal humerus, and 20% of proximal humerus fractures are isolated greater tuberosity fractures.26,27 In his classic 1970 article, Neer6 formulated the 4-part proximal humerus fracture classification and defined greater tuberosity fracture “parts” using the same criteria as for other fracture “parts.” Neer6 recommended nonoperative management for isolated greater tuberosity fractures displaced <1 cm but did not present evidence corroborating his recommendation. More recent cutoffs for nonoperative management include 5 mm (general population) and 3 mm (athletes).7,17
In the present systematic review of greater tuberosity fractures, 3 separate comparisons were made: treatment type (nonoperative vs operative), fracture displacement amount (<5 mm vs >5 mm), and surgery type (open vs arthroscopic).
Treatment Type. Only 4 studies reported data on nonoperative treatment outcomes.5,12,16,17 Of these 4 studies, 2 found successful outcomes for fractures displaced <5 mm.12,17 Platzer and colleagues17 found good or excellent results in 97% of 135 shoulders after 4 years. Good results were defined with shoulder scores of ≥80 (Constant), <8 (Vienna), and >28 (UCLA), and excellent results were defined with maximum scores on 2 of the 3 systems. Platzer and colleagues17 also found nonsignificantly worse shoulder scores with superior displacement of 3 mm to 5 mm and recommended surgery for overhead athletes in this group. Rath and colleagues12 described a successful 3-phase rehabilitation protocol of sling immobilization for 3 weeks, pendulum exercises for 3 weeks, and active exercises thereafter. By an average of 31 months, patient satisfaction scores improved to 9.5 from 4.2 (10-point scale), though the authors cautioned that pain and decreased motion lasted 8 months on average. Conservative treatment was far less successful in the 2 studies of fractures displaced >5 mm.5,16 Keene and colleagues16 reported unsatisfactory results in all 4 patients with fractures displaced >1.5 cm. In a study separate from their 2005 analysis,17 Platzer and colleagues5 in 2008 evaluated displaced fractures and found function and patient satisfaction were inferior after nonoperative treatment than after surgery. The studies by Keene and colleagues16 and Platzer and colleagues5 support the finding of an overall lower patient satisfaction rate in nonoperative patients.
Fracture Displacement Amount. Only 2 arthroscopic studies and no open studies addressed surgery for fractures displaced <5 mm. Fewer than 16% of these fractures were managed operatively, and <1% required reoperation. By contrast, almost all fractures displaced >5 mm were managed operatively, and 3.6% required reoperation. Radiographic loss of reduction was more common in fractures displaced <5 mm, primarily because they were managed without fixation. Radiographic loss of reduction was reported in only 9 operatively treated patients, none of whom was symptomatic enough to require another surgery.5 Reoperations were most commonly performed for stiffness, which itself was significantly more common in fractures displaced >5 mm. Bhatia and colleagues14 reported the highest reoperation rate (14.3%; 3/21), but they studied more complex, comminuted fractures of the greater tuberosity. Two of their 3 reoperations were biceps tenodeses for inflamed, stiff tenosynovitis, and the third patient had a foreign body giant cell reaction to suture material. Fewer than 1% of patients with operatively managed displaced fractures required revision ORIF, and <2% developed a superficial infection or postoperative nerve palsy.19,22 For displaced greater tuberosity fractures, surgery is highly successful overall, complication rates are very low, and 90% of patients report being satisfied.
Surgery Type. Patients were divided into 2 groups. In the nonarthroscopic group, open and percutaneous approaches were used. All studies that described a percutaneous approach used screw fixation5,21; in addition, 32 patients were treated with screws through an open approach.2,5 The other open and arthroscopic studies used suture fixation. Interestingly, no studies reported on clinical outcomes of fragment excision. There were no statistically significant differences in rates of reoperation, stiffness, infection, or neurologic injury between the arthroscopic and nonarthroscopic groups. Patient satisfaction scores were slightly higher in the nonarthroscopic group (91.0% vs 87.8%), but the difference was not statistically significant.
With surgical techniques isolated, there were no significant differences between suture anchors and transosseous tunnel constructs, but screws performed significantly better than suture techniques. Compared with suture fixation, screw fixation led to significantly fewer cases of stiffness and reoperation, which suggests surgeons need to give screws more consideration in the operative management of these fractures. However, the number of patients treated with screws was smaller than the number treated with suture fixation; it is possible the differences between these cohorts would be eliminated if there were more patients in the screw cohort. In addition, screw fixation was universally performed with an open or percutaneous approach and trended toward a higher infection rate. As screw and suture techniques have low rates of complications and reoperations, we recommend leaving fixation choice to the surgeon.
Anterior shoulder instability has been associated with greater tuberosity fractures.1,8,19 The supraspinatus, infraspinatus, and teres minor muscles all insert into the greater tuberosity and resist anterior translation of the proximal humerus. Loss of this dynamic muscle stabilization is amplified by tuberosity fracture displacement: Anterior shoulder instability was significantly more common in fractures displaced >5 mm (44.3%) vs <5 mm (14.5%). In turn, glenohumeral instability was more common in patients treated with surgery, specifically open surgery, because displaced fractures may not be as easily accessed with arthroscopic techniques. No studies reported concomitant labral repair or capsular plication techniques.
This systematic review was limited by the studies analyzed. All but 1 study5 had level IV evidence. Mean (SD) MCMS was 41.8 (8.6). Any MCMS score <54 indicates a poor methodology level, but this scoring system is designed for randomized controlled trials,23 and there were none in this study. Physical examination findings, such as range of motion, were underreported. In addition, radiographic parameters were not consistently described but rather were determined by the respective authors’ subjective interpretations of malunion, nonunion, and loss of reduction. Publication bias is present in that we excluded non- English language studies and medical conference abstracts and may have omitted potentially eligible studies not discoverable with our search methodology. Performance bias is a factor in any systematic review with multiple surgeons and wide variation in surgical technique.
Conclusion
Greater tuberosity fractures displaced <5 mm may be safely managed nonoperatively, as there are no reports of nonoperatively managed fractures that subsequently required surgery. Nonoperative treatment was initially associated with low patient satisfaction, but only because displaced fractures were conservatively managed in early studies.5,16 Fractures displaced >5 mm respond well to operative fixation with screws, suture anchors, or transosseous suture tunnels. Stiffness is the most common postoperative complication (<6%), followed by heterotopic ossification, transient neurapraxias, and superficial infection. There are no discernible differences in outcome between open and arthroscopic techniques, but screw fixation may lead to significantly fewer cases of stiffness and reoperation in comparison with suture constructs.
1. Verdano MA, Aliani D, Pellegrini A, Baudi P, Pedrazzi G, Ceccarelli F. Isolated fractures of the greater tuberosity in proximal humerus: does the direction of displacement influence functional outcome? An analysis of displacement in greater tuberosity fractures. Acta Biomed. 2013;84(3):219-228.
2. Yin B, Moen TC, Thompson SA, Bigliani LU, Ahmad CS, Levine WN. Operative treatment of isolated greater tuberosity fractures: retrospective review of clinical and functional outcomes. Orthopedics. 2012;35(6):e807-e814.
3. Green A, Izzi J. Isolated fractures of the greater tuberosity of the proximal humerus. J Shoulder Elbow Surg. 2003;12(6):641-649.
4. Norouzi M, Naderi MN, Komasi MH, Sharifzadeh SR, Shahrezaei M, Eajazi A. Clinical results of using the proximal humeral internal locking system plate for internal fixation of displaced proximal humeral fractures. Am J Orthop. 2012;41(5):E64-E68.
5. Platzer P, Thalhammer G, Oberleitner G, et al. Displaced fractures of the greater tuberosity: a comparison of operative and nonoperative treatment. J Trauma. 2008;65(4):843-848.
6. Neer CS. Displaced proximal humeral fractures. I. Classification and evaluation. J Bone Joint Surg Am. 1970;52(6):1077-1089.
7. Park TS, Choi IY, Kim YH, Park MR, Shon JH, Kim SI. A new suggestion for the treatment of minimally displaced fractures of the greater tuberosity of the proximal humerus. Bull Hosp Jt Dis. 1997;56(3):171-176.
8. McLaughlin HL. Dislocation of the shoulder with tuberosity fracture. Surg Clin North Am. 1963;43:1615-1620.
9. DeBottis D, Anavian J, Green A. Surgical management of isolated greater tuberosity fractures of the proximal humerus. Orthop Clin North Am. 2014;45(2):207-218.
10. Monga P, Verma R, Sharma VK. Closed reduction and external fixation for displaced proximal humeral fractures. J Orthop Surg (Hong Kong). 2009;17(2):142-145.
11. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. J Clin Epidemiol. 2009;62(10):1006-1012.
12. Rath E, Alkrinawi N, Levy O, Debbi R, Amar E, Atoun E. Minimally displaced fractures of the greater tuberosity: outcome of non-operative treatment. J Shoulder Elbow Surg. 2013;22(10):e8-e11.
13. Dimakopoulos P, Panagopoulos A, Kasimatis G. Transosseous suture fixation of proximal humeral fractures. J Bone Joint Surg Am. 2007;89(8):1700-1709.
14. Bhatia DN, van Rooyen KS, Toit du DF, de Beer JF. Surgical treatment of comminuted, displaced fractures of the greater tuberosity of the proximal humerus: a new technique of double-row suture-anchor fixation and long-term results. Injury. 2006;37(10):946-952.
15. Flatow EL, Cuomo F, Maday MG, Miller SR, McIlveen SJ, Bigliani LU. Open reduction and internal fixation of two-part displaced fractures of the greater tuberosity of the proximal part of the humerus. J Bone Joint Surg Am. 1991;73(8):1213-1218.
16. Keene JS, Huizenga RE, Engber WD, Rogers SC. Proximal humeral fractures: a correlation of residual deformity with long-term function. Orthopedics. 1983;6(2):173-178.
17. Platzer P, Kutscha-Lissberg F, Lehr S, Vecsei V, Gaebler C. The influence of displacement on shoulder function in patients with minimally displaced fractures of the greater tuberosity. Injury. 2005;36(10):1185-1189.
18. Park SE, Ji JH, Shafi M, Jung JJ, Gil HJ, Lee HH. Arthroscopic management of occult greater tuberosity fracture of the shoulder. Eur J Orthop Surg Traumatol. 2014;24(4):475-482.
19. Dimakopoulos P, Panagopoulos A, Kasimatis G, Syggelos SA, Lambiris E. Anterior traumatic shoulder dislocation associated with displaced greater tuberosity fracture: the necessity of operative treatment. J Orthop Trauma. 2007;21(2):104-112.
20. Kim SH, Ha KI. Arthroscopic treatment of symptomatic shoulders with minimally displaced greater tuberosity fracture. Arthroscopy. 2000;16(7):695-700.
21. Chen CY, Chao EK, Tu YK, Ueng SW, Shih CH. Closed management and percutaneous fixation of unstable proximal humerus fractures. J Trauma. 1998;45(6):1039-1045.
22. Ji JH, Shafi M, Song IS, Kim YY, McFarland EG, Moon CY. Arthroscopic fixation technique for comminuted, displaced greater tuberosity fracture. Arthroscopy. 2010;26(5):600-609.
23. Cowan J, Lozano-Calderón S, Ring D. Quality of prospective controlled randomized trials. Analysis of trials of treatment for lateral epicondylitis as an example. J Bone Joint Surg Am. 2007;89(8):1693-1699.
24. Harris JD, Siston RA, Pan X, Flanigan DC. Autologous chondrocyte implantation: a systematic review. J Bone Joint Surg Am. 2010;92(12):2220-2233.
25. Harris JD, Siston RA, Brophy RH, Lattermann C, Carey JL, Flanigan DC. Failures, re-operations, and complications after autologous chondrocyte implantation—a systematic review. Osteoarthritis Cartilage. 2011;19(7):779-791.
26. Chun JM, Groh GI, Rockwood CA. Two-part fractures of the proximal humerus. J Shoulder Elbow Surg. 1994;3(5):273-287.
27. Gruson KI, Ruchelsman DE, Tejwani NC. Isolated tuberosity fractures of the proximal humeral: current concepts. Injury. 2008;39(3):284-298.
1. Verdano MA, Aliani D, Pellegrini A, Baudi P, Pedrazzi G, Ceccarelli F. Isolated fractures of the greater tuberosity in proximal humerus: does the direction of displacement influence functional outcome? An analysis of displacement in greater tuberosity fractures. Acta Biomed. 2013;84(3):219-228.
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3. Green A, Izzi J. Isolated fractures of the greater tuberosity of the proximal humerus. J Shoulder Elbow Surg. 2003;12(6):641-649.
4. Norouzi M, Naderi MN, Komasi MH, Sharifzadeh SR, Shahrezaei M, Eajazi A. Clinical results of using the proximal humeral internal locking system plate for internal fixation of displaced proximal humeral fractures. Am J Orthop. 2012;41(5):E64-E68.
5. Platzer P, Thalhammer G, Oberleitner G, et al. Displaced fractures of the greater tuberosity: a comparison of operative and nonoperative treatment. J Trauma. 2008;65(4):843-848.
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11. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. J Clin Epidemiol. 2009;62(10):1006-1012.
12. Rath E, Alkrinawi N, Levy O, Debbi R, Amar E, Atoun E. Minimally displaced fractures of the greater tuberosity: outcome of non-operative treatment. J Shoulder Elbow Surg. 2013;22(10):e8-e11.
13. Dimakopoulos P, Panagopoulos A, Kasimatis G. Transosseous suture fixation of proximal humeral fractures. J Bone Joint Surg Am. 2007;89(8):1700-1709.
14. Bhatia DN, van Rooyen KS, Toit du DF, de Beer JF. Surgical treatment of comminuted, displaced fractures of the greater tuberosity of the proximal humerus: a new technique of double-row suture-anchor fixation and long-term results. Injury. 2006;37(10):946-952.
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20. Kim SH, Ha KI. Arthroscopic treatment of symptomatic shoulders with minimally displaced greater tuberosity fracture. Arthroscopy. 2000;16(7):695-700.
21. Chen CY, Chao EK, Tu YK, Ueng SW, Shih CH. Closed management and percutaneous fixation of unstable proximal humerus fractures. J Trauma. 1998;45(6):1039-1045.
22. Ji JH, Shafi M, Song IS, Kim YY, McFarland EG, Moon CY. Arthroscopic fixation technique for comminuted, displaced greater tuberosity fracture. Arthroscopy. 2010;26(5):600-609.
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25. Harris JD, Siston RA, Brophy RH, Lattermann C, Carey JL, Flanigan DC. Failures, re-operations, and complications after autologous chondrocyte implantation—a systematic review. Osteoarthritis Cartilage. 2011;19(7):779-791.
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How Long Can Corneas Be Saved Before Transplantation?
The belief that corneas that have been preserved for > 7 days are not viable for transplantation is not based on evidence, says Jonathan Lass, MD. In fact, he led a study that found corneas can be preserved safely for 11 days without negative impact on the success of transplantation. In the Cornea Preservation Time Study, funded by the National Eye Institute, Lass and other researchers looked at 3-year graft success rates among 1,090 participants (1,330 eyes) who underwent transplantation via Descemet’s stripping automated endothelial keratoplasty by 70 surgeons at 40 surgical sites. Most of the patients had Fuchs’ endothelial corneal dystrophy, a progressive disease.
The researchers were “unable to conclude” that the success rates were the same for corneas preserved for 8 to 14 days, versus up to 7 days (92% vs 95%). However, they found that much of the difference between the groups was accounted for by patients receiving corneas preserved for 12 to 14 days.
In a separate analysis, the researchers looked to see if differences in corneal preservation time affected endothelial cell loss after 3 years. They found that corneas preserved for up to 7 days had a 37% loss of cells versus 40% in those preserved for 8 to 14 days. A closer look at the data showed that the effect of corneal preservation time on the loss of endothelial cells was comparable from 4 to 13 days.
Dr. Lass emphasizes that while patients who received the older corneas had lower success rates, even those success rates were “impressively high” at 89%.
Donor corneas are not in short supply in the U.S. Outside the U.S., however, corneal disease is the third leading cause of blindness and corneal donor tissue is scarce.
The belief that corneas that have been preserved for > 7 days are not viable for transplantation is not based on evidence, says Jonathan Lass, MD. In fact, he led a study that found corneas can be preserved safely for 11 days without negative impact on the success of transplantation. In the Cornea Preservation Time Study, funded by the National Eye Institute, Lass and other researchers looked at 3-year graft success rates among 1,090 participants (1,330 eyes) who underwent transplantation via Descemet’s stripping automated endothelial keratoplasty by 70 surgeons at 40 surgical sites. Most of the patients had Fuchs’ endothelial corneal dystrophy, a progressive disease.
The researchers were “unable to conclude” that the success rates were the same for corneas preserved for 8 to 14 days, versus up to 7 days (92% vs 95%). However, they found that much of the difference between the groups was accounted for by patients receiving corneas preserved for 12 to 14 days.
In a separate analysis, the researchers looked to see if differences in corneal preservation time affected endothelial cell loss after 3 years. They found that corneas preserved for up to 7 days had a 37% loss of cells versus 40% in those preserved for 8 to 14 days. A closer look at the data showed that the effect of corneal preservation time on the loss of endothelial cells was comparable from 4 to 13 days.
Dr. Lass emphasizes that while patients who received the older corneas had lower success rates, even those success rates were “impressively high” at 89%.
Donor corneas are not in short supply in the U.S. Outside the U.S., however, corneal disease is the third leading cause of blindness and corneal donor tissue is scarce.
The belief that corneas that have been preserved for > 7 days are not viable for transplantation is not based on evidence, says Jonathan Lass, MD. In fact, he led a study that found corneas can be preserved safely for 11 days without negative impact on the success of transplantation. In the Cornea Preservation Time Study, funded by the National Eye Institute, Lass and other researchers looked at 3-year graft success rates among 1,090 participants (1,330 eyes) who underwent transplantation via Descemet’s stripping automated endothelial keratoplasty by 70 surgeons at 40 surgical sites. Most of the patients had Fuchs’ endothelial corneal dystrophy, a progressive disease.
The researchers were “unable to conclude” that the success rates were the same for corneas preserved for 8 to 14 days, versus up to 7 days (92% vs 95%). However, they found that much of the difference between the groups was accounted for by patients receiving corneas preserved for 12 to 14 days.
In a separate analysis, the researchers looked to see if differences in corneal preservation time affected endothelial cell loss after 3 years. They found that corneas preserved for up to 7 days had a 37% loss of cells versus 40% in those preserved for 8 to 14 days. A closer look at the data showed that the effect of corneal preservation time on the loss of endothelial cells was comparable from 4 to 13 days.
Dr. Lass emphasizes that while patients who received the older corneas had lower success rates, even those success rates were “impressively high” at 89%.
Donor corneas are not in short supply in the U.S. Outside the U.S., however, corneal disease is the third leading cause of blindness and corneal donor tissue is scarce.