Purpose: Small-cell lung cancer (SCLC) is a rapidly-progressive and highly fatal disease, and new treatments are needed. Increased expression of ß-III tubulin (TUBB3) correlates with decreased response to paclitaxel in multiple cancers. We have discovered that TUBB3 is highly expressed in SCLC pathology samples. CK2 is a serine/threonine kinase with over 300 substrates and is overexpressed in many cancers. CK2 interacts with the microtubule apparatus and may be related to TUBB3-mediated drug resistance in cancer cells. Our hypothesis is that simultaneous targeting of microtubules and CK2 will be an effective strategy in decreasing SCLC proliferation.

Methods: Cell proliferation experiments were conducted as follows. SCLC cell lines H69 and H209 were maintained in appropriate media at 5% CO2 and 37°C. A 96-well microtiter plate was seeded with 100 μL of cell suspension at 1 x 104 cells/well. After 20 hours or 68 hours of incubation with Ixabepilone (LC Laboratories), 10 μL of Cell Counting Kit-8 (Dojindo) reagent was added to each well, followed by incubation for 4 hours for total incubations of 24 hours or 72 hours. Absorbance was read at 450 nm. All experiments were performed in triplicate. Cells were lysed in lysis buffer and cleared by centrifugation at 4°C. Proteins were resolved on 10% or 12% SDS PAGE gels, transferred onto PVDF membranes, and blocked with 5% nonfat dry milk in TBS-T followed by incubation with primary antibody diluted in TBS-T (mouse TUBB3 [MMS-435P, Covance] at a dilution of 1:2,000 or rabbit CK2α [A300-197A, Bethyl Laboratories]) plus Anti-CK2α’ (A300-199A, Bethyl Laboratories) at a dilution of 1:3,000. Blots were washed and incubated with horseradish peroxidase-conjugated secondary antibody diluted in TBS-T (Anti-mouse [Santa Cruz Biotech] at 1:25,000 and Anti-rabbit at 1:1,000). Antibody complexes were visualized, using an enhanced chemiluminescent Western blot detection system (Thermo Fisher Scientific).

Results: Previously, we demonstrated that TUBB3 is highly expressed in about 85% of SCLC cases. In the current study, multiple SCLC cell lines were evaluated for TUBB3 and CK2 expression via immunoblotting. In all cell lines, bands corresponding to the molecular weights of TUBB3 and CK2 were observed at multiple protein lysate concentrations. Ixabepilone is a microtubule-stabilizing analogue of epothilone B that is thought to preferentially bind the TUBB3 isotype. Incubation of ixabepilone with H69 and H209 SCLC cell lines at 25 mM resulted in 8.6% and 5.3% inhibition, respectively, after 24 hours and 14.0% and 20.6% inhibition, respectively, after 72 hours. Incubation of ixabepilone with H69 and H209 SCLC cell lines at 100 mM resulted in 29.2% and 7.0% inhibition, respectively, after 24 hours and 47.5% and 32.2% inhibition, respectively, after 72 hours.

Conclusions: TUBB3 and CK2 were expressed in SCLC cell lines. Ixabepilone has modest activity against SCLC cell lines and will be further evaluated to obtain IC50 values. We will further evaluate the effect of CK2 inhibition in the presence and absence of ixabepilone and paclitaxel. The work described here may contribute to new therapeutic strategies for SCLC.

Purpose: Small-cell lung cancer (SCLC) is a rapidly-progressive and highly fatal disease, and new treatments are needed. Increased expression of ß-III tubulin (TUBB3) correlates with decreased response to paclitaxel in multiple cancers. We have discovered that TUBB3 is highly expressed in SCLC pathology samples. CK2 is a serine/threonine kinase with over 300 substrates and is overexpressed in many cancers. CK2 interacts with the microtubule apparatus and may be related to TUBB3-mediated drug resistance in cancer cells. Our hypothesis is that simultaneous targeting of microtubules and CK2 will be an effective strategy in decreasing SCLC proliferation.

Methods: Cell proliferation experiments were conducted as follows. SCLC cell lines H69 and H209 were maintained in appropriate media at 5% CO2 and 37°C. A 96-well microtiter plate was seeded with 100 μL of cell suspension at 1 x 104 cells/well. After 20 hours or 68 hours of incubation with Ixabepilone (LC Laboratories), 10 μL of Cell Counting Kit-8 (Dojindo) reagent was added to each well, followed by incubation for 4 hours for total incubations of 24 hours or 72 hours. Absorbance was read at 450 nm. All experiments were performed in triplicate. Cells were lysed in lysis buffer and cleared by centrifugation at 4°C. Proteins were resolved on 10% or 12% SDS PAGE gels, transferred onto PVDF membranes, and blocked with 5% nonfat dry milk in TBS-T followed by incubation with primary antibody diluted in TBS-T (mouse TUBB3 [MMS-435P, Covance] at a dilution of 1:2,000 or rabbit CK2α [A300-197A, Bethyl Laboratories]) plus Anti-CK2α’ (A300-199A, Bethyl Laboratories) at a dilution of 1:3,000. Blots were washed and incubated with horseradish peroxidase-conjugated secondary antibody diluted in TBS-T (Anti-mouse [Santa Cruz Biotech] at 1:25,000 and Anti-rabbit at 1:1,000). Antibody complexes were visualized, using an enhanced chemiluminescent Western blot detection system (Thermo Fisher Scientific).

Results: Previously, we demonstrated that TUBB3 is highly expressed in about 85% of SCLC cases. In the current study, multiple SCLC cell lines were evaluated for TUBB3 and CK2 expression via immunoblotting. In all cell lines, bands corresponding to the molecular weights of TUBB3 and CK2 were observed at multiple protein lysate concentrations. Ixabepilone is a microtubule-stabilizing analogue of epothilone B that is thought to preferentially bind the TUBB3 isotype. Incubation of ixabepilone with H69 and H209 SCLC cell lines at 25 mM resulted in 8.6% and 5.3% inhibition, respectively, after 24 hours and 14.0% and 20.6% inhibition, respectively, after 72 hours. Incubation of ixabepilone with H69 and H209 SCLC cell lines at 100 mM resulted in 29.2% and 7.0% inhibition, respectively, after 24 hours and 47.5% and 32.2% inhibition, respectively, after 72 hours.

Conclusions: TUBB3 and CK2 were expressed in SCLC cell lines. Ixabepilone has modest activity against SCLC cell lines and will be further evaluated to obtain IC50 values. We will further evaluate the effect of CK2 inhibition in the presence and absence of ixabepilone and paclitaxel. The work described here may contribute to new therapeutic strategies for SCLC.

Purpose: Small-cell lung cancer (SCLC) is a rapidly-progressive and highly fatal disease, and new treatments are needed. Increased expression of ß-III tubulin (TUBB3) correlates with decreased response to paclitaxel in multiple cancers. We have discovered that TUBB3 is highly expressed in SCLC pathology samples. CK2 is a serine/threonine kinase with over 300 substrates and is overexpressed in many cancers. CK2 interacts with the microtubule apparatus and may be related to TUBB3-mediated drug resistance in cancer cells. Our hypothesis is that simultaneous targeting of microtubules and CK2 will be an effective strategy in decreasing SCLC proliferation.

Methods: Cell proliferation experiments were conducted as follows. SCLC cell lines H69 and H209 were maintained in appropriate media at 5% CO2 and 37°C. A 96-well microtiter plate was seeded with 100 μL of cell suspension at 1 x 104 cells/well. After 20 hours or 68 hours of incubation with Ixabepilone (LC Laboratories), 10 μL of Cell Counting Kit-8 (Dojindo) reagent was added to each well, followed by incubation for 4 hours for total incubations of 24 hours or 72 hours. Absorbance was read at 450 nm. All experiments were performed in triplicate. Cells were lysed in lysis buffer and cleared by centrifugation at 4°C. Proteins were resolved on 10% or 12% SDS PAGE gels, transferred onto PVDF membranes, and blocked with 5% nonfat dry milk in TBS-T followed by incubation with primary antibody diluted in TBS-T (mouse TUBB3 [MMS-435P, Covance] at a dilution of 1:2,000 or rabbit CK2α [A300-197A, Bethyl Laboratories]) plus Anti-CK2α’ (A300-199A, Bethyl Laboratories) at a dilution of 1:3,000. Blots were washed and incubated with horseradish peroxidase-conjugated secondary antibody diluted in TBS-T (Anti-mouse [Santa Cruz Biotech] at 1:25,000 and Anti-rabbit at 1:1,000). Antibody complexes were visualized, using an enhanced chemiluminescent Western blot detection system (Thermo Fisher Scientific).

Results: Previously, we demonstrated that TUBB3 is highly expressed in about 85% of SCLC cases. In the current study, multiple SCLC cell lines were evaluated for TUBB3 and CK2 expression via immunoblotting. In all cell lines, bands corresponding to the molecular weights of TUBB3 and CK2 were observed at multiple protein lysate concentrations. Ixabepilone is a microtubule-stabilizing analogue of epothilone B that is thought to preferentially bind the TUBB3 isotype. Incubation of ixabepilone with H69 and H209 SCLC cell lines at 25 mM resulted in 8.6% and 5.3% inhibition, respectively, after 24 hours and 14.0% and 20.6% inhibition, respectively, after 72 hours. Incubation of ixabepilone with H69 and H209 SCLC cell lines at 100 mM resulted in 29.2% and 7.0% inhibition, respectively, after 24 hours and 47.5% and 32.2% inhibition, respectively, after 72 hours.

Conclusions: TUBB3 and CK2 were expressed in SCLC cell lines. Ixabepilone has modest activity against SCLC cell lines and will be further evaluated to obtain IC50 values. We will further evaluate the effect of CK2 inhibition in the presence and absence of ixabepilone and paclitaxel. The work described here may contribute to new therapeutic strategies for SCLC.

Purpose: Recent studies have suggested that incorporation of palliative care concomitantly with therapy for metastatic cancer may be beneficial. The American Society of Clinical Oncology has published a provisional clinical opinion recommending incorporation of palliative care alongside chemotherapy in patients with metastatic cancer or a high symptom burden from cancer. In this project, we evaluate the feasibility of incorporation of palliative care in patients with head and neck (H&N) cancer treated with concurrent chemotherapy and radiation.

Methods: The primary goal of this quality improvement project is to assess the feasibility of participation in a palliative care program for patients with H&N cancer undergoing treatment. Patients are recommended for palliative care consultation if they have squamous cell carcinoma of the head and neck and are treated with concurrent chemotherapy and radiation (definitive or adjuvant therapy). Patients are offered palliative care consultation in their first week of treatment. They are approached in person to discuss goals and potential benefits of concomitant palliative care and chemotherapy/radiation. All patients are provided with informational material to review. If interested in palliative care, the participant is asked to fill out 5 non-mandatory questionnaires. These include the FACT-H&N, FACIT-Sp-12, PHQ-9, EAT-10, and HADS. Patients are seen by the palliative care service at 6, 12, 26, and 52 weeks after starting chemotherapy/radiation, and patients are asked to fill out the questionnaires at those time points as well. In addition, data on several potential quality elements (weight, use of enteral nutrition, laboratory values, site of disease, p16ink4a status, etc) are collected for comparison with a retrospective cohort.

Results: Retrospective data from the charts of 51 patients have been abstracted and analyzed for comparison with the prospective quality improvement cohort. The median age was 63 (range 48 to 87). Forty-four patients were either stage IVa or IVb. The location of primary tumors included the oropharynx (59%), oral cavity (11.8%), hypopharynx (9.8%), larynx (9.8%), and the nasopharnyx (7.8%). Forty-four of the 51 patients had a percutaneous endoscopic gastrostomy tube (for potential enteral nutrition) placed either prophylactically (before or within the first week of treatment, 19 patients) or reactively (after the first week of treatment, 25 patients). In the prospective cohort, 14 patients have thus far been offered palliative care consultation. Six patients agreed to palliative care consultation and 8 declined. The median age was 62, and all patients were male. Data collection and analysis are ongoing.

Conclusions: The results of this project may be able to guide incorporation of routine palliative care with the treatment of patients with (H&N) cancer. Barriers to enrolling in palliative care concomitantly with chemotherapy and radiation should be considered to aid incorporation of early palliative care for patients with H&N cancer.

Purpose: Recent studies have suggested that incorporation of palliative care concomitantly with therapy for metastatic cancer may be beneficial. The American Society of Clinical Oncology has published a provisional clinical opinion recommending incorporation of palliative care alongside chemotherapy in patients with metastatic cancer or a high symptom burden from cancer. In this project, we evaluate the feasibility of incorporation of palliative care in patients with head and neck (H&N) cancer treated with concurrent chemotherapy and radiation.

Methods: The primary goal of this quality improvement project is to assess the feasibility of participation in a palliative care program for patients with H&N cancer undergoing treatment. Patients are recommended for palliative care consultation if they have squamous cell carcinoma of the head and neck and are treated with concurrent chemotherapy and radiation (definitive or adjuvant therapy). Patients are offered palliative care consultation in their first week of treatment. They are approached in person to discuss goals and potential benefits of concomitant palliative care and chemotherapy/radiation. All patients are provided with informational material to review. If interested in palliative care, the participant is asked to fill out 5 non-mandatory questionnaires. These include the FACT-H&N, FACIT-Sp-12, PHQ-9, EAT-10, and HADS. Patients are seen by the palliative care service at 6, 12, 26, and 52 weeks after starting chemotherapy/radiation, and patients are asked to fill out the questionnaires at those time points as well. In addition, data on several potential quality elements (weight, use of enteral nutrition, laboratory values, site of disease, p16ink4a status, etc) are collected for comparison with a retrospective cohort.

Results: Retrospective data from the charts of 51 patients have been abstracted and analyzed for comparison with the prospective quality improvement cohort. The median age was 63 (range 48 to 87). Forty-four patients were either stage IVa or IVb. The location of primary tumors included the oropharynx (59%), oral cavity (11.8%), hypopharynx (9.8%), larynx (9.8%), and the nasopharnyx (7.8%). Forty-four of the 51 patients had a percutaneous endoscopic gastrostomy tube (for potential enteral nutrition) placed either prophylactically (before or within the first week of treatment, 19 patients) or reactively (after the first week of treatment, 25 patients). In the prospective cohort, 14 patients have thus far been offered palliative care consultation. Six patients agreed to palliative care consultation and 8 declined. The median age was 62, and all patients were male. Data collection and analysis are ongoing.

Conclusions: The results of this project may be able to guide incorporation of routine palliative care with the treatment of patients with (H&N) cancer. Barriers to enrolling in palliative care concomitantly with chemotherapy and radiation should be considered to aid incorporation of early palliative care for patients with H&N cancer.

Purpose: Recent studies have suggested that incorporation of palliative care concomitantly with therapy for metastatic cancer may be beneficial. The American Society of Clinical Oncology has published a provisional clinical opinion recommending incorporation of palliative care alongside chemotherapy in patients with metastatic cancer or a high symptom burden from cancer. In this project, we evaluate the feasibility of incorporation of palliative care in patients with head and neck (H&N) cancer treated with concurrent chemotherapy and radiation.

Methods: The primary goal of this quality improvement project is to assess the feasibility of participation in a palliative care program for patients with H&N cancer undergoing treatment. Patients are recommended for palliative care consultation if they have squamous cell carcinoma of the head and neck and are treated with concurrent chemotherapy and radiation (definitive or adjuvant therapy). Patients are offered palliative care consultation in their first week of treatment. They are approached in person to discuss goals and potential benefits of concomitant palliative care and chemotherapy/radiation. All patients are provided with informational material to review. If interested in palliative care, the participant is asked to fill out 5 non-mandatory questionnaires. These include the FACT-H&N, FACIT-Sp-12, PHQ-9, EAT-10, and HADS. Patients are seen by the palliative care service at 6, 12, 26, and 52 weeks after starting chemotherapy/radiation, and patients are asked to fill out the questionnaires at those time points as well. In addition, data on several potential quality elements (weight, use of enteral nutrition, laboratory values, site of disease, p16ink4a status, etc) are collected for comparison with a retrospective cohort.

Results: Retrospective data from the charts of 51 patients have been abstracted and analyzed for comparison with the prospective quality improvement cohort. The median age was 63 (range 48 to 87). Forty-four patients were either stage IVa or IVb. The location of primary tumors included the oropharynx (59%), oral cavity (11.8%), hypopharynx (9.8%), larynx (9.8%), and the nasopharnyx (7.8%). Forty-four of the 51 patients had a percutaneous endoscopic gastrostomy tube (for potential enteral nutrition) placed either prophylactically (before or within the first week of treatment, 19 patients) or reactively (after the first week of treatment, 25 patients). In the prospective cohort, 14 patients have thus far been offered palliative care consultation. Six patients agreed to palliative care consultation and 8 declined. The median age was 62, and all patients were male. Data collection and analysis are ongoing.

Conclusions: The results of this project may be able to guide incorporation of routine palliative care with the treatment of patients with (H&N) cancer. Barriers to enrolling in palliative care concomitantly with chemotherapy and radiation should be considered to aid incorporation of early palliative care for patients with H&N cancer.

Purpose: For the definitive treatment of stage III NSCLC, the optimal chemotherapy regimen to use with radiation is not clearly defined. Using a large cohort of patients treated across VHAs, we compare the outcome of patents treated with cisplatin and etoposide (EP) vs those treated with carboplatin and paclitaxel (CP).

Methods: Using the VA Central Cancer Registry, patients with stage III non-small cell lung cancer (NSCLC) diagnosed between 2001 and 2010 were identified. For analysis, patients were included if concurrent chemoradiotherapy was initiated within 4 months of diagnosis and excluded if treated with surgery or sequential chemoradiotherapy (ie, chemotherapy was not started within 7 days of the start of radiotherapy).

Results: Out of 17,010 patients identified, 1,856 patients were eligible for analysis of which 28% (n = 565) received EP. In multivariable analysis, the use of EP was not associated with any survival advantage (HR 0.88; 95% CI 0.79-0.99; P = .0254). In a propensity score analysis that matched 382 patients treated with EP with the same number of patients treated with CP, there was no survival advantage for EP (HR 0.96; 95% CI 0.83-1.11; P = .5572). Subsequently, a multivariate model weighted on the inverse propensity for being treated with EP was fitted and similarly showed no survival advantage for EP (HR 0.95; 95% CI, 0.84-1.08; P = .4525). Finally, an instrumental variable analysis was used to compare matched patients between 8 VHAs that were “EP-encouraged” (ie, > 50% received EP, mean 71.1%) with 11 VHAs that were “EP-discouraged” (ie, < 10% received EP, mean 2.8%). This analysis found no survival advantage for EP (HR 1.06; 95% CI, 0.90-1.26; P = .4766). When adverse events were compared with CP, patients treated with EP had increased hospitalization (2.4 vs 1.7, P < .01), outpatient visits (17.6 vs 12.6, P <.01), infectious complications (47.6% vs 39.6%, P < .0001), acute renal failure (30.3 vs 21.3%, P <.0001), and mucositis/esophagitis (18.7 vs 14.5%, P = 0.0251).

Conclusions: After accounting for various prognostic variables, matched cohorts, and regional differences, there were no differences in survival between patients treated with EP and CP; however, EP was associated with increased morbidity.

Purpose: For the definitive treatment of stage III NSCLC, the optimal chemotherapy regimen to use with radiation is not clearly defined. Using a large cohort of patients treated across VHAs, we compare the outcome of patents treated with cisplatin and etoposide (EP) vs those treated with carboplatin and paclitaxel (CP).

Methods: Using the VA Central Cancer Registry, patients with stage III non-small cell lung cancer (NSCLC) diagnosed between 2001 and 2010 were identified. For analysis, patients were included if concurrent chemoradiotherapy was initiated within 4 months of diagnosis and excluded if treated with surgery or sequential chemoradiotherapy (ie, chemotherapy was not started within 7 days of the start of radiotherapy).

Results: Out of 17,010 patients identified, 1,856 patients were eligible for analysis of which 28% (n = 565) received EP. In multivariable analysis, the use of EP was not associated with any survival advantage (HR 0.88; 95% CI 0.79-0.99; P = .0254). In a propensity score analysis that matched 382 patients treated with EP with the same number of patients treated with CP, there was no survival advantage for EP (HR 0.96; 95% CI 0.83-1.11; P = .5572). Subsequently, a multivariate model weighted on the inverse propensity for being treated with EP was fitted and similarly showed no survival advantage for EP (HR 0.95; 95% CI, 0.84-1.08; P = .4525). Finally, an instrumental variable analysis was used to compare matched patients between 8 VHAs that were “EP-encouraged” (ie, > 50% received EP, mean 71.1%) with 11 VHAs that were “EP-discouraged” (ie, < 10% received EP, mean 2.8%). This analysis found no survival advantage for EP (HR 1.06; 95% CI, 0.90-1.26; P = .4766). When adverse events were compared with CP, patients treated with EP had increased hospitalization (2.4 vs 1.7, P < .01), outpatient visits (17.6 vs 12.6, P <.01), infectious complications (47.6% vs 39.6%, P < .0001), acute renal failure (30.3 vs 21.3%, P <.0001), and mucositis/esophagitis (18.7 vs 14.5%, P = 0.0251).

Conclusions: After accounting for various prognostic variables, matched cohorts, and regional differences, there were no differences in survival between patients treated with EP and CP; however, EP was associated with increased morbidity.

Purpose: For the definitive treatment of stage III NSCLC, the optimal chemotherapy regimen to use with radiation is not clearly defined. Using a large cohort of patients treated across VHAs, we compare the outcome of patents treated with cisplatin and etoposide (EP) vs those treated with carboplatin and paclitaxel (CP).

Methods: Using the VA Central Cancer Registry, patients with stage III non-small cell lung cancer (NSCLC) diagnosed between 2001 and 2010 were identified. For analysis, patients were included if concurrent chemoradiotherapy was initiated within 4 months of diagnosis and excluded if treated with surgery or sequential chemoradiotherapy (ie, chemotherapy was not started within 7 days of the start of radiotherapy).

Results: Out of 17,010 patients identified, 1,856 patients were eligible for analysis of which 28% (n = 565) received EP. In multivariable analysis, the use of EP was not associated with any survival advantage (HR 0.88; 95% CI 0.79-0.99; P = .0254). In a propensity score analysis that matched 382 patients treated with EP with the same number of patients treated with CP, there was no survival advantage for EP (HR 0.96; 95% CI 0.83-1.11; P = .5572). Subsequently, a multivariate model weighted on the inverse propensity for being treated with EP was fitted and similarly showed no survival advantage for EP (HR 0.95; 95% CI, 0.84-1.08; P = .4525). Finally, an instrumental variable analysis was used to compare matched patients between 8 VHAs that were “EP-encouraged” (ie, > 50% received EP, mean 71.1%) with 11 VHAs that were “EP-discouraged” (ie, < 10% received EP, mean 2.8%). This analysis found no survival advantage for EP (HR 1.06; 95% CI, 0.90-1.26; P = .4766). When adverse events were compared with CP, patients treated with EP had increased hospitalization (2.4 vs 1.7, P < .01), outpatient visits (17.6 vs 12.6, P <.01), infectious complications (47.6% vs 39.6%, P < .0001), acute renal failure (30.3 vs 21.3%, P <.0001), and mucositis/esophagitis (18.7 vs 14.5%, P = 0.0251).

Conclusions: After accounting for various prognostic variables, matched cohorts, and regional differences, there were no differences in survival between patients treated with EP and CP; however, EP was associated with increased morbidity.

Purpose: Extrapulmonary small cell carcinoma (ESCC) has been a difficult disease to manage since it was first described > 80 years ago. Definitive treatment recommendations are lacking, and the treatment strategies commonly utilized are extrapolated from our experience with pulmonary small cell carcinoma. A better understanding of this entity will improve our collective management. By pooling our collective knowledge, we will hopefully be able to draw some meaningful conclusions about this disease.

Methods: The University of Kansas tumor registry was reviewed from 1990-2013. Forty-two potential cases of ESCC were identified and the charts reviewed. Of these, 35 cases met the inclusion and exclusion criteria for review. Information gathered included age, gender, smoking status, weight loss, metastatic disease related data, stage, ECOG performance status (PS), treatment received, and survival data.

Results: Patients were evaluated with a variety of primary locations of disease including gastrointestinal (GI) tract, genitourinary (GU) tract, pelvic organs, head and neck, and unknown primary. Several sites of metastatic disease were noted, with 57% and 43% of patients meeting criteria for limited disease and extensive disease, respectively. Chemotherapy, surgery, and radiation were used in several different regimens, with small-cell lung cancer-type regimens incorporating a platinum and etoposide being the most common. Kaplan-Meier survival estimates were used to identify possible prognostic variables including stage, primary site, number of treatment modalities received, use of chemotherapy in limited stage disease, and ECOG PS.

Conclusions: In our review of 35 patients, GI (29%) and GU (31%) tract tumors were the most common primary sites of disease with a male to female predominance and 57% of patients presenting with limited disease. The majority of patients treated with chemotherapy received a platinum/etoposide doublet (74%), and almost half received radiation (43%). Statistically significant prognostic factors included stage, ECOG PS, site of primary disease, use of chemotherapy, and number of treatment modalities used. Additional clinical trials are needed to better understand this rare disorder to further our knowledge of the optimum management approach.

Purpose: Extrapulmonary small cell carcinoma (ESCC) has been a difficult disease to manage since it was first described > 80 years ago. Definitive treatment recommendations are lacking, and the treatment strategies commonly utilized are extrapolated from our experience with pulmonary small cell carcinoma. A better understanding of this entity will improve our collective management. By pooling our collective knowledge, we will hopefully be able to draw some meaningful conclusions about this disease.

Methods: The University of Kansas tumor registry was reviewed from 1990-2013. Forty-two potential cases of ESCC were identified and the charts reviewed. Of these, 35 cases met the inclusion and exclusion criteria for review. Information gathered included age, gender, smoking status, weight loss, metastatic disease related data, stage, ECOG performance status (PS), treatment received, and survival data.

Results: Patients were evaluated with a variety of primary locations of disease including gastrointestinal (GI) tract, genitourinary (GU) tract, pelvic organs, head and neck, and unknown primary. Several sites of metastatic disease were noted, with 57% and 43% of patients meeting criteria for limited disease and extensive disease, respectively. Chemotherapy, surgery, and radiation were used in several different regimens, with small-cell lung cancer-type regimens incorporating a platinum and etoposide being the most common. Kaplan-Meier survival estimates were used to identify possible prognostic variables including stage, primary site, number of treatment modalities received, use of chemotherapy in limited stage disease, and ECOG PS.

Conclusions: In our review of 35 patients, GI (29%) and GU (31%) tract tumors were the most common primary sites of disease with a male to female predominance and 57% of patients presenting with limited disease. The majority of patients treated with chemotherapy received a platinum/etoposide doublet (74%), and almost half received radiation (43%). Statistically significant prognostic factors included stage, ECOG PS, site of primary disease, use of chemotherapy, and number of treatment modalities used. Additional clinical trials are needed to better understand this rare disorder to further our knowledge of the optimum management approach.

Purpose: Extrapulmonary small cell carcinoma (ESCC) has been a difficult disease to manage since it was first described > 80 years ago. Definitive treatment recommendations are lacking, and the treatment strategies commonly utilized are extrapolated from our experience with pulmonary small cell carcinoma. A better understanding of this entity will improve our collective management. By pooling our collective knowledge, we will hopefully be able to draw some meaningful conclusions about this disease.

Methods: The University of Kansas tumor registry was reviewed from 1990-2013. Forty-two potential cases of ESCC were identified and the charts reviewed. Of these, 35 cases met the inclusion and exclusion criteria for review. Information gathered included age, gender, smoking status, weight loss, metastatic disease related data, stage, ECOG performance status (PS), treatment received, and survival data.

Results: Patients were evaluated with a variety of primary locations of disease including gastrointestinal (GI) tract, genitourinary (GU) tract, pelvic organs, head and neck, and unknown primary. Several sites of metastatic disease were noted, with 57% and 43% of patients meeting criteria for limited disease and extensive disease, respectively. Chemotherapy, surgery, and radiation were used in several different regimens, with small-cell lung cancer-type regimens incorporating a platinum and etoposide being the most common. Kaplan-Meier survival estimates were used to identify possible prognostic variables including stage, primary site, number of treatment modalities received, use of chemotherapy in limited stage disease, and ECOG PS.

Conclusions: In our review of 35 patients, GI (29%) and GU (31%) tract tumors were the most common primary sites of disease with a male to female predominance and 57% of patients presenting with limited disease. The majority of patients treated with chemotherapy received a platinum/etoposide doublet (74%), and almost half received radiation (43%). Statistically significant prognostic factors included stage, ECOG PS, site of primary disease, use of chemotherapy, and number of treatment modalities used. Additional clinical trials are needed to better understand this rare disorder to further our knowledge of the optimum management approach.

Purpose: Women with breast cancer (BC) are increasingly diagnosed and treated within the VHA. Breast cancer requires specialized care in tertiary settings such as VAMCs, typically located in urban settings, placing BC patients in rural areas at a disadvantage. Assigning rural-urban status is complicated by the presence of multiple classification plans. In this report, we compare rural-urban status of BC patients in the VHA and its association with distance to nearest VAMC, using 2 plans: USDA Economic Research Service (ERS) Rural Urban Continuum (RUC) and University of Washington’s Rural Urban Commuting Areas 2.0 (RUCA).

Methods: Between 2000 and 2012, 3,622 women were diagnosed with and/or treated for BC within the VHA and recorded in the VA Central Cancer Registry (VA CCR). The patient’s zip code of residence at the time of diagnosis and rural-urban status according to USDA ERS RUC were obtained from the VA CCR. Rural urban commuting status was aggregated into 3 categories: metropolitan, large nonmetropolitan, and rural. Using zip code of residence, rural-urban status of all but 63 women was determined using the University of Washington’s (RUCA) plan and aggregated into 3 categories: urban (metropolitan), large rural or micropolitan, and small rural/isolated small rural. The VHA is organized into 21 regional administrative service networks, or VISNs. The geographic distribution of BC in VHA was determined using the RUC and RUCA scheme, then reported by VISN Census Bureau geographic region: Northeast, Midwest, South, and West. The two plans were compared, using Cohen’s Kappa statistic. The distance between zip code of residence and the nearest within-VISN VAMC was obtained from the VA Planning Systems Support Group database. The association between rural-urban status according to RUC and RUCA and the distance to the nearest VAMC was determined using analysis of variance (ANOVA).

Results: Rural-urban status according to RUC and RUCA were strongly associated (Cohen’s Kappa 0.74, P < .001). About 80% of women with BC in VHA resided in metropolitan areas; the remaining women were split evenly between large nonmetropolitan/micropolitan and rural/small, isolated rural. The Midwest had the highest percentages of both large rural (14%) and small/isolated rural patients (17%), whereas patients in the Northeast had the smallest percentages of large rural (8%) and small/isolated rural patients (7%). Patients living in the Northeast had the shortest travel distances to the nearest within-VISN VAMC, whereas patients in the West had the longest distances. In the Northeast, the average distance to nearest VAMC increased from 11 miles for patients living in metropolitan areas, to 44 miles in small/isolated rural areas. In the West, patients living in metropolitan areas were on average, 37 miles from nearest VAMC. This increased to 124 miles for patients in small/isolated rural areas in the West. Both classifications were significantly associated with increased distance to nearest VAMC (P < .001). On multivariate analysis, rural residence remained significantly associated with increased distance to nearest VAMC (P = .01) even after adjusting for RUCA.

Conclusions: Women with BC living in rural areas must travel longer distances to their VHA facility to receive specialized cancer care. Various plans define rural-urban status, using different methodologies. The rural-urban status of women with BC in VHA was similar using either RUC or RUCA. Rural residence defined by RUC was significantly associated with longer distances to VAMC even after adjusting for RUCA. This suggests that the 2 methodologies are not identical but are highly related when being compared with distance from tertiary care. The choice of rural classification methodology should be considered carefully when researching rural status and cancer outcomes.

Purpose: Women with breast cancer (BC) are increasingly diagnosed and treated within the VHA. Breast cancer requires specialized care in tertiary settings such as VAMCs, typically located in urban settings, placing BC patients in rural areas at a disadvantage. Assigning rural-urban status is complicated by the presence of multiple classification plans. In this report, we compare rural-urban status of BC patients in the VHA and its association with distance to nearest VAMC, using 2 plans: USDA Economic Research Service (ERS) Rural Urban Continuum (RUC) and University of Washington’s Rural Urban Commuting Areas 2.0 (RUCA).

Methods: Between 2000 and 2012, 3,622 women were diagnosed with and/or treated for BC within the VHA and recorded in the VA Central Cancer Registry (VA CCR). The patient’s zip code of residence at the time of diagnosis and rural-urban status according to USDA ERS RUC were obtained from the VA CCR. Rural urban commuting status was aggregated into 3 categories: metropolitan, large nonmetropolitan, and rural. Using zip code of residence, rural-urban status of all but 63 women was determined using the University of Washington’s (RUCA) plan and aggregated into 3 categories: urban (metropolitan), large rural or micropolitan, and small rural/isolated small rural. The VHA is organized into 21 regional administrative service networks, or VISNs. The geographic distribution of BC in VHA was determined using the RUC and RUCA scheme, then reported by VISN Census Bureau geographic region: Northeast, Midwest, South, and West. The two plans were compared, using Cohen’s Kappa statistic. The distance between zip code of residence and the nearest within-VISN VAMC was obtained from the VA Planning Systems Support Group database. The association between rural-urban status according to RUC and RUCA and the distance to the nearest VAMC was determined using analysis of variance (ANOVA).

Results: Rural-urban status according to RUC and RUCA were strongly associated (Cohen’s Kappa 0.74, P < .001). About 80% of women with BC in VHA resided in metropolitan areas; the remaining women were split evenly between large nonmetropolitan/micropolitan and rural/small, isolated rural. The Midwest had the highest percentages of both large rural (14%) and small/isolated rural patients (17%), whereas patients in the Northeast had the smallest percentages of large rural (8%) and small/isolated rural patients (7%). Patients living in the Northeast had the shortest travel distances to the nearest within-VISN VAMC, whereas patients in the West had the longest distances. In the Northeast, the average distance to nearest VAMC increased from 11 miles for patients living in metropolitan areas, to 44 miles in small/isolated rural areas. In the West, patients living in metropolitan areas were on average, 37 miles from nearest VAMC. This increased to 124 miles for patients in small/isolated rural areas in the West. Both classifications were significantly associated with increased distance to nearest VAMC (P < .001). On multivariate analysis, rural residence remained significantly associated with increased distance to nearest VAMC (P = .01) even after adjusting for RUCA.

Conclusions: Women with BC living in rural areas must travel longer distances to their VHA facility to receive specialized cancer care. Various plans define rural-urban status, using different methodologies. The rural-urban status of women with BC in VHA was similar using either RUC or RUCA. Rural residence defined by RUC was significantly associated with longer distances to VAMC even after adjusting for RUCA. This suggests that the 2 methodologies are not identical but are highly related when being compared with distance from tertiary care. The choice of rural classification methodology should be considered carefully when researching rural status and cancer outcomes.

Purpose: Women with breast cancer (BC) are increasingly diagnosed and treated within the VHA. Breast cancer requires specialized care in tertiary settings such as VAMCs, typically located in urban settings, placing BC patients in rural areas at a disadvantage. Assigning rural-urban status is complicated by the presence of multiple classification plans. In this report, we compare rural-urban status of BC patients in the VHA and its association with distance to nearest VAMC, using 2 plans: USDA Economic Research Service (ERS) Rural Urban Continuum (RUC) and University of Washington’s Rural Urban Commuting Areas 2.0 (RUCA).

Methods: Between 2000 and 2012, 3,622 women were diagnosed with and/or treated for BC within the VHA and recorded in the VA Central Cancer Registry (VA CCR). The patient’s zip code of residence at the time of diagnosis and rural-urban status according to USDA ERS RUC were obtained from the VA CCR. Rural urban commuting status was aggregated into 3 categories: metropolitan, large nonmetropolitan, and rural. Using zip code of residence, rural-urban status of all but 63 women was determined using the University of Washington’s (RUCA) plan and aggregated into 3 categories: urban (metropolitan), large rural or micropolitan, and small rural/isolated small rural. The VHA is organized into 21 regional administrative service networks, or VISNs. The geographic distribution of BC in VHA was determined using the RUC and RUCA scheme, then reported by VISN Census Bureau geographic region: Northeast, Midwest, South, and West. The two plans were compared, using Cohen’s Kappa statistic. The distance between zip code of residence and the nearest within-VISN VAMC was obtained from the VA Planning Systems Support Group database. The association between rural-urban status according to RUC and RUCA and the distance to the nearest VAMC was determined using analysis of variance (ANOVA).

Results: Rural-urban status according to RUC and RUCA were strongly associated (Cohen’s Kappa 0.74, P < .001). About 80% of women with BC in VHA resided in metropolitan areas; the remaining women were split evenly between large nonmetropolitan/micropolitan and rural/small, isolated rural. The Midwest had the highest percentages of both large rural (14%) and small/isolated rural patients (17%), whereas patients in the Northeast had the smallest percentages of large rural (8%) and small/isolated rural patients (7%). Patients living in the Northeast had the shortest travel distances to the nearest within-VISN VAMC, whereas patients in the West had the longest distances. In the Northeast, the average distance to nearest VAMC increased from 11 miles for patients living in metropolitan areas, to 44 miles in small/isolated rural areas. In the West, patients living in metropolitan areas were on average, 37 miles from nearest VAMC. This increased to 124 miles for patients in small/isolated rural areas in the West. Both classifications were significantly associated with increased distance to nearest VAMC (P < .001). On multivariate analysis, rural residence remained significantly associated with increased distance to nearest VAMC (P = .01) even after adjusting for RUCA.

Conclusions: Women with BC living in rural areas must travel longer distances to their VHA facility to receive specialized cancer care. Various plans define rural-urban status, using different methodologies. The rural-urban status of women with BC in VHA was similar using either RUC or RUCA. Rural residence defined by RUC was significantly associated with longer distances to VAMC even after adjusting for RUCA. This suggests that the 2 methodologies are not identical but are highly related when being compared with distance from tertiary care. The choice of rural classification methodology should be considered carefully when researching rural status and cancer outcomes.

Purpose: The incidence of the second primary cancer after treatment with radioactive iodine (RAI) is a concern for patients and clinicians. Our objective was to examine the changes that have occurred over a 20-year period in a single institution, by comparing the lifetime observed incidence of the second primary cancer vs those patients with the incidence after the treatment with RAI.

Method: We reviewed all thyroid cancer cases (n = 51) between 1991 and 2010 in the VA New Jersey cancer registry. Patients were distributed into 4 groups consisting of 5-year intervals. These groups were based on accession year and then segregated again into groups that received radioactive iodine and groups that did not. Then, we reviewed the incidence of multiple primaries during the life of the patient and the incidence of a second primary after the diagnoses of thyroid cancer. The incidence of second primary malignancy and age distribution of these groups over the study period was also compared.

Results: An increase in the number of cases diagnosed over the last 20 years was noted. There were a total of 12 cases in the first 10 years compared with 39 cases in the last 10 years. During this period, the total number of all cancer cases accessioned by the registry per year remained stable and constant. However, the increases were significant in the last 5 years; comprising more than half of all cases diagnosed in this 20-year period. There was an observed difference in the average age at diagnosis with the mean age for the first 10 years being 56 years in comparison to the past 10 years, which was 61 years. Also, patients who received radioactive iodine were consistently younger than the group who did not receive RAI. The lifetime incidence of multiple primaries was about 50% in the entire group. The incidence remains similar in each period examined and in all the groups. However, there is an observed difference in the incidence of second primary in the RAI group after treatment compared with those who did not received RAI.

Conclusions: There was an increase in the incidence of thyroid cancer diagnosed over the 20-year period, and the overall incidence of multiple primaries during this time span remained consistent. However, the observed incidence of the second primary after the diagnoses of thyroid cancer was higher in the group who received RAI treatment.

Purpose: The incidence of the second primary cancer after treatment with radioactive iodine (RAI) is a concern for patients and clinicians. Our objective was to examine the changes that have occurred over a 20-year period in a single institution, by comparing the lifetime observed incidence of the second primary cancer vs those patients with the incidence after the treatment with RAI.

Method: We reviewed all thyroid cancer cases (n = 51) between 1991 and 2010 in the VA New Jersey cancer registry. Patients were distributed into 4 groups consisting of 5-year intervals. These groups were based on accession year and then segregated again into groups that received radioactive iodine and groups that did not. Then, we reviewed the incidence of multiple primaries during the life of the patient and the incidence of a second primary after the diagnoses of thyroid cancer. The incidence of second primary malignancy and age distribution of these groups over the study period was also compared.

Results: An increase in the number of cases diagnosed over the last 20 years was noted. There were a total of 12 cases in the first 10 years compared with 39 cases in the last 10 years. During this period, the total number of all cancer cases accessioned by the registry per year remained stable and constant. However, the increases were significant in the last 5 years; comprising more than half of all cases diagnosed in this 20-year period. There was an observed difference in the average age at diagnosis with the mean age for the first 10 years being 56 years in comparison to the past 10 years, which was 61 years. Also, patients who received radioactive iodine were consistently younger than the group who did not receive RAI. The lifetime incidence of multiple primaries was about 50% in the entire group. The incidence remains similar in each period examined and in all the groups. However, there is an observed difference in the incidence of second primary in the RAI group after treatment compared with those who did not received RAI.

Conclusions: There was an increase in the incidence of thyroid cancer diagnosed over the 20-year period, and the overall incidence of multiple primaries during this time span remained consistent. However, the observed incidence of the second primary after the diagnoses of thyroid cancer was higher in the group who received RAI treatment.

Purpose: The incidence of the second primary cancer after treatment with radioactive iodine (RAI) is a concern for patients and clinicians. Our objective was to examine the changes that have occurred over a 20-year period in a single institution, by comparing the lifetime observed incidence of the second primary cancer vs those patients with the incidence after the treatment with RAI.

Method: We reviewed all thyroid cancer cases (n = 51) between 1991 and 2010 in the VA New Jersey cancer registry. Patients were distributed into 4 groups consisting of 5-year intervals. These groups were based on accession year and then segregated again into groups that received radioactive iodine and groups that did not. Then, we reviewed the incidence of multiple primaries during the life of the patient and the incidence of a second primary after the diagnoses of thyroid cancer. The incidence of second primary malignancy and age distribution of these groups over the study period was also compared.

Results: An increase in the number of cases diagnosed over the last 20 years was noted. There were a total of 12 cases in the first 10 years compared with 39 cases in the last 10 years. During this period, the total number of all cancer cases accessioned by the registry per year remained stable and constant. However, the increases were significant in the last 5 years; comprising more than half of all cases diagnosed in this 20-year period. There was an observed difference in the average age at diagnosis with the mean age for the first 10 years being 56 years in comparison to the past 10 years, which was 61 years. Also, patients who received radioactive iodine were consistently younger than the group who did not receive RAI. The lifetime incidence of multiple primaries was about 50% in the entire group. The incidence remains similar in each period examined and in all the groups. However, there is an observed difference in the incidence of second primary in the RAI group after treatment compared with those who did not received RAI.

Conclusions: There was an increase in the incidence of thyroid cancer diagnosed over the 20-year period, and the overall incidence of multiple primaries during this time span remained consistent. However, the observed incidence of the second primary after the diagnoses of thyroid cancer was higher in the group who received RAI treatment.

Recently, Federal Practitioner talked with Sanjai Sharma, MD, about how signaling pathways in chronic lymphocytic leukemia (CLL) is critical to the development of therapeutic agents to treat this disease. Ibrutinib and idelalisib are therapeutic agents that block signaling pathways and, therefore, inhibit the growth of CLL cells.

For more information about CLL, read "Signaling Pathways and Novel Inhibitors in Chronic Lymphocytic Leukemia," in our August 2014 issue.

Dr. Sharma is a physician at the West Los Angeles VA Medical Center and associate professor in the Department of Medicine, Hematology/Oncology at UCLA, both in California.

Recently, Federal Practitioner talked with Sanjai Sharma, MD, about how signaling pathways in chronic lymphocytic leukemia (CLL) is critical to the development of therapeutic agents to treat this disease. Ibrutinib and idelalisib are therapeutic agents that block signaling pathways and, therefore, inhibit the growth of CLL cells.

For more information about CLL, read "Signaling Pathways and Novel Inhibitors in Chronic Lymphocytic Leukemia," in our August 2014 issue.

Dr. Sharma is a physician at the West Los Angeles VA Medical Center and associate professor in the Department of Medicine, Hematology/Oncology at UCLA, both in California.

Recently, Federal Practitioner talked with Sanjai Sharma, MD, about how signaling pathways in chronic lymphocytic leukemia (CLL) is critical to the development of therapeutic agents to treat this disease. Ibrutinib and idelalisib are therapeutic agents that block signaling pathways and, therefore, inhibit the growth of CLL cells.

For more information about CLL, read "Signaling Pathways and Novel Inhibitors in Chronic Lymphocytic Leukemia," in our August 2014 issue.

Dr. Sharma is a physician at the West Los Angeles VA Medical Center and associate professor in the Department of Medicine, Hematology/Oncology at UCLA, both in California.

Lab mouse

A new study helps explain why some chronic myeloid leukemia (CML) patients develop resistance to imatinib despite the absence of BCR-ABL mutations.

Researchers discovered that a signaling pathway associated with cell division and growth acts as an alternative survival signal underlying imatinib resistance.

But blocking this pathway with an inhibitor known as trametinib can prevent resistance to imatinib and increase survival in mice.

The researchers recounted these discoveries in Science Translational Medicine.

Michael R. Green, MD, PhD, of the University of Massachusetts Medical School in Worcester, and his colleagues began this research with a large-scale RNA interference screen. This revealed a set of genes that promote imatinib sensitivity.

The team then set out to identify the regulatory pathways through which these genes promote imatinib sensitivity. They found that knocking down the genes in BCR-ABL+ cells results in sustained RAF/MEK/ERK signaling after treatment with imatinib.

Further investigation revealed it is PRKCH, which encodes the protein kinase C family member PKCη, that increases RAF/MEK/ERK signaling through phosphorylation and activation of CRAF.

Dr Green and his colleagues also found that PRKCH is upregulated in CML cell lines and patient samples that exhibit BCR-ABL-independent imatinib resistance. Experiments in mice revealed that PRKCH modulates the proliferation of BCR-ABL+ cells, CML progression, and imatinib sensitivity.

Furthermore, imatinib-resistant murine and human CML stem cells contained high levels of PRKCH. And experiments confirmed that high PRKCH expression contributed to the imatinib resistance observed in these cells.

Fortunately, the researchers discovered that combining imatinib with the MEK inhibitor trametinib can overcome BCR-ABL-independent imatinib resistance in CML cells. The combination also prolonged survival in mouse models of imatinib-resistant CML.

Dr Green and his colleagues said these results reveal a mechanism of BCR-ABL-independent imatinib resistance that can be targeted with therapy. And, as treatment with trametinib and imatinib kills CML stem cells but spares normal hematopoietic stem cells, it may be a feasible treatment option for CML patients.

Lab mouse

A new study helps explain why some chronic myeloid leukemia (CML) patients develop resistance to imatinib despite the absence of BCR-ABL mutations.

Researchers discovered that a signaling pathway associated with cell division and growth acts as an alternative survival signal underlying imatinib resistance.

But blocking this pathway with an inhibitor known as trametinib can prevent resistance to imatinib and increase survival in mice.

The researchers recounted these discoveries in Science Translational Medicine.

Michael R. Green, MD, PhD, of the University of Massachusetts Medical School in Worcester, and his colleagues began this research with a large-scale RNA interference screen. This revealed a set of genes that promote imatinib sensitivity.

The team then set out to identify the regulatory pathways through which these genes promote imatinib sensitivity. They found that knocking down the genes in BCR-ABL+ cells results in sustained RAF/MEK/ERK signaling after treatment with imatinib.

Further investigation revealed it is PRKCH, which encodes the protein kinase C family member PKCη, that increases RAF/MEK/ERK signaling through phosphorylation and activation of CRAF.

Dr Green and his colleagues also found that PRKCH is upregulated in CML cell lines and patient samples that exhibit BCR-ABL-independent imatinib resistance. Experiments in mice revealed that PRKCH modulates the proliferation of BCR-ABL+ cells, CML progression, and imatinib sensitivity.

Furthermore, imatinib-resistant murine and human CML stem cells contained high levels of PRKCH. And experiments confirmed that high PRKCH expression contributed to the imatinib resistance observed in these cells.

Fortunately, the researchers discovered that combining imatinib with the MEK inhibitor trametinib can overcome BCR-ABL-independent imatinib resistance in CML cells. The combination also prolonged survival in mouse models of imatinib-resistant CML.

Dr Green and his colleagues said these results reveal a mechanism of BCR-ABL-independent imatinib resistance that can be targeted with therapy. And, as treatment with trametinib and imatinib kills CML stem cells but spares normal hematopoietic stem cells, it may be a feasible treatment option for CML patients.

Lab mouse

A new study helps explain why some chronic myeloid leukemia (CML) patients develop resistance to imatinib despite the absence of BCR-ABL mutations.

Researchers discovered that a signaling pathway associated with cell division and growth acts as an alternative survival signal underlying imatinib resistance.

But blocking this pathway with an inhibitor known as trametinib can prevent resistance to imatinib and increase survival in mice.

The researchers recounted these discoveries in Science Translational Medicine.

Michael R. Green, MD, PhD, of the University of Massachusetts Medical School in Worcester, and his colleagues began this research with a large-scale RNA interference screen. This revealed a set of genes that promote imatinib sensitivity.

The team then set out to identify the regulatory pathways through which these genes promote imatinib sensitivity. They found that knocking down the genes in BCR-ABL+ cells results in sustained RAF/MEK/ERK signaling after treatment with imatinib.

Further investigation revealed it is PRKCH, which encodes the protein kinase C family member PKCη, that increases RAF/MEK/ERK signaling through phosphorylation and activation of CRAF.

Dr Green and his colleagues also found that PRKCH is upregulated in CML cell lines and patient samples that exhibit BCR-ABL-independent imatinib resistance. Experiments in mice revealed that PRKCH modulates the proliferation of BCR-ABL+ cells, CML progression, and imatinib sensitivity.

Furthermore, imatinib-resistant murine and human CML stem cells contained high levels of PRKCH. And experiments confirmed that high PRKCH expression contributed to the imatinib resistance observed in these cells.

Fortunately, the researchers discovered that combining imatinib with the MEK inhibitor trametinib can overcome BCR-ABL-independent imatinib resistance in CML cells. The combination also prolonged survival in mouse models of imatinib-resistant CML.

Dr Green and his colleagues said these results reveal a mechanism of BCR-ABL-independent imatinib resistance that can be targeted with therapy. And, as treatment with trametinib and imatinib kills CML stem cells but spares normal hematopoietic stem cells, it may be a feasible treatment option for CML patients.

Anne Moore, PhD, displays

patches on her hand

Credit: Tómas Tyner

Delivering malaria vaccines via a skin patch can streamline the vaccination process, according to preclinical research published in Scientific Reports.

The patch has arrays of tiny silicon microneedles that painlessly create temporary pores in the outermost layer of the skin, permitting the vaccine to flow into the skin.

Researchers used the patch to vaccinate mice with a live adenovirus engineered to deliver a protein from the malaria parasite Plasmodium yoelii.

The team found the patch could overcome one of the main problems with this type of vaccine—namely, although it induces high levels of immunity to malaria, it can also induce a strong immune response to the adenovirus itself.

This anti-adenovirus immunity prevents its repeated use as a vaccine, as the immune system recognizes the adenovirus and prevents it from delivering the malaria protein. So another vaccine type or adenovirus strain needs to be used in the booster immunization.

“What’s exciting from this work is that administration of this vaccine with the microneedle patch did not induce this strong anti-adenovirus immunity, even though very potent immunity to the malaria antigen is generated,” said study author Anne Moore, PhD, of University College Cork in Ireland.

This suggests the patch can facilitate the repeated use of the same adenovirus vaccine, thereby potentially reducing manufacturing costs of multiple vaccines.

In their experiments with mice, Dr Moore and her colleagues demonstrated that using the microneedle patch in the primary immunization does indeed permit repeated use of the same adenovirus vaccine. And this immunization method induced potent and highly protective immune responses against malaria.

Specifically, the researchers delivered a vaccine known as HAdV5-PyMSP1₄₂ to mice. They found the patch induced equivalent or enhanced antibody responses but decreased anti-vector responses when compared to intradermal delivery of the vaccine.

The addition of a heterologous vaccine known as MVA-PyMSP1₄₂ also produced greater antibody responses in mice primed with HAdV5-PyMSP1₄₂ via the patch, compared to those vaccinated intradermally.

The researchers observed the highest protection against blood-stage malaria when mice were vaccinated first with the patch and then intradermally.

In an attempt to commercialize this research, Dr Moore is heading to Silicon Valley next week to meet with venture capitalists and technology companies.

Anne Moore, PhD, displays

patches on her hand

Credit: Tómas Tyner

Delivering malaria vaccines via a skin patch can streamline the vaccination process, according to preclinical research published in Scientific Reports.

The patch has arrays of tiny silicon microneedles that painlessly create temporary pores in the outermost layer of the skin, permitting the vaccine to flow into the skin.

Researchers used the patch to vaccinate mice with a live adenovirus engineered to deliver a protein from the malaria parasite Plasmodium yoelii.

The team found the patch could overcome one of the main problems with this type of vaccine—namely, although it induces high levels of immunity to malaria, it can also induce a strong immune response to the adenovirus itself.

This anti-adenovirus immunity prevents its repeated use as a vaccine, as the immune system recognizes the adenovirus and prevents it from delivering the malaria protein. So another vaccine type or adenovirus strain needs to be used in the booster immunization.

“What’s exciting from this work is that administration of this vaccine with the microneedle patch did not induce this strong anti-adenovirus immunity, even though very potent immunity to the malaria antigen is generated,” said study author Anne Moore, PhD, of University College Cork in Ireland.

This suggests the patch can facilitate the repeated use of the same adenovirus vaccine, thereby potentially reducing manufacturing costs of multiple vaccines.

In their experiments with mice, Dr Moore and her colleagues demonstrated that using the microneedle patch in the primary immunization does indeed permit repeated use of the same adenovirus vaccine. And this immunization method induced potent and highly protective immune responses against malaria.

Specifically, the researchers delivered a vaccine known as HAdV5-PyMSP1₄₂ to mice. They found the patch induced equivalent or enhanced antibody responses but decreased anti-vector responses when compared to intradermal delivery of the vaccine.

The addition of a heterologous vaccine known as MVA-PyMSP1₄₂ also produced greater antibody responses in mice primed with HAdV5-PyMSP1₄₂ via the patch, compared to those vaccinated intradermally.

The researchers observed the highest protection against blood-stage malaria when mice were vaccinated first with the patch and then intradermally.

In an attempt to commercialize this research, Dr Moore is heading to Silicon Valley next week to meet with venture capitalists and technology companies.

Anne Moore, PhD, displays

patches on her hand

Credit: Tómas Tyner

Delivering malaria vaccines via a skin patch can streamline the vaccination process, according to preclinical research published in Scientific Reports.

The patch has arrays of tiny silicon microneedles that painlessly create temporary pores in the outermost layer of the skin, permitting the vaccine to flow into the skin.

Researchers used the patch to vaccinate mice with a live adenovirus engineered to deliver a protein from the malaria parasite Plasmodium yoelii.

The team found the patch could overcome one of the main problems with this type of vaccine—namely, although it induces high levels of immunity to malaria, it can also induce a strong immune response to the adenovirus itself.

This anti-adenovirus immunity prevents its repeated use as a vaccine, as the immune system recognizes the adenovirus and prevents it from delivering the malaria protein. So another vaccine type or adenovirus strain needs to be used in the booster immunization.

“What’s exciting from this work is that administration of this vaccine with the microneedle patch did not induce this strong anti-adenovirus immunity, even though very potent immunity to the malaria antigen is generated,” said study author Anne Moore, PhD, of University College Cork in Ireland.

This suggests the patch can facilitate the repeated use of the same adenovirus vaccine, thereby potentially reducing manufacturing costs of multiple vaccines.

In their experiments with mice, Dr Moore and her colleagues demonstrated that using the microneedle patch in the primary immunization does indeed permit repeated use of the same adenovirus vaccine. And this immunization method induced potent and highly protective immune responses against malaria.

Specifically, the researchers delivered a vaccine known as HAdV5-PyMSP1₄₂ to mice. They found the patch induced equivalent or enhanced antibody responses but decreased anti-vector responses when compared to intradermal delivery of the vaccine.

The addition of a heterologous vaccine known as MVA-PyMSP1₄₂ also produced greater antibody responses in mice primed with HAdV5-PyMSP1₄₂ via the patch, compared to those vaccinated intradermally.

The researchers observed the highest protection against blood-stage malaria when mice were vaccinated first with the patch and then intradermally.

In an attempt to commercialize this research, Dr Moore is heading to Silicon Valley next week to meet with venture capitalists and technology companies.

Medical/science journals

Credit: CDC/James Gathany

A review of errata reports from medical publications revealed that nearly a quarter of the errors may have changed the way study data were interpreted.

And about half of the errors were not corrected in the original text, or the errata report did not specify whether a correction was made.

This suggests authors and journals must be more vigilant and consistent in identifying and reporting errors, said Paul Hauptman, MD, of Saint Louis University in Missouri.

He and his colleagues conducted this research and reported the results in The American Journal of Medicine.

The researchers reviewed 20 prominent English language journals in the fields of general medicine and cardiology. And they identified 577 error reports over an 18-month period.

More than 24% of these reports included an error the team rated as major. Major errors were associated with material changes in the interpretation of data in text, figures, or tables, or with significant alterations in the article’s conclusions.

One of the examples of a major error report in the study comes from a paper about depression. In the original article, the incidence of new depression cases was misquoted by a factor of 10. The article initially reported 15.8% of women with new depression, rather than the real figure of 1.58%, which was later corrected.

“As the volume of research publications continues to rise, the scientific community needs to examine how it manages its mistakes,” said Eric Armbrecht, PhD, of the Saint Louis University Center for Outcomes Research.

“Transparency, consistency, and clarity are essential. Our study found that these are not common among some of the top medical journals.”

In fact, the researchers found that 51% of the errors they identified were not corrected in the original text, or the errata report did not specify whether a correction was made.

The team noted that this study did not provide any definitive explanations for why such errors appear in publications, although one possibility is that most authors don’t read and edit the final version of their manuscripts prior to publication.

“It’s noteworthy that although final approval of an article may fall to the first or corresponding author, the criteria put forth by [the International Committee of Medical Journal Editors] specifies that each author must provide final approval of the version to be published,” Dr Hauptman said.

He added that, at this point, it’s not possible to measure how frequently a journal reader incorporates errata into clinical care or the extent to which patient outcomes may be affected.

Medical/science journals

Credit: CDC/James Gathany

A review of errata reports from medical publications revealed that nearly a quarter of the errors may have changed the way study data were interpreted.

And about half of the errors were not corrected in the original text, or the errata report did not specify whether a correction was made.

This suggests authors and journals must be more vigilant and consistent in identifying and reporting errors, said Paul Hauptman, MD, of Saint Louis University in Missouri.

He and his colleagues conducted this research and reported the results in The American Journal of Medicine.

The researchers reviewed 20 prominent English language journals in the fields of general medicine and cardiology. And they identified 577 error reports over an 18-month period.

More than 24% of these reports included an error the team rated as major. Major errors were associated with material changes in the interpretation of data in text, figures, or tables, or with significant alterations in the article’s conclusions.

One of the examples of a major error report in the study comes from a paper about depression. In the original article, the incidence of new depression cases was misquoted by a factor of 10. The article initially reported 15.8% of women with new depression, rather than the real figure of 1.58%, which was later corrected.

“As the volume of research publications continues to rise, the scientific community needs to examine how it manages its mistakes,” said Eric Armbrecht, PhD, of the Saint Louis University Center for Outcomes Research.

“Transparency, consistency, and clarity are essential. Our study found that these are not common among some of the top medical journals.”

In fact, the researchers found that 51% of the errors they identified were not corrected in the original text, or the errata report did not specify whether a correction was made.

The team noted that this study did not provide any definitive explanations for why such errors appear in publications, although one possibility is that most authors don’t read and edit the final version of their manuscripts prior to publication.

“It’s noteworthy that although final approval of an article may fall to the first or corresponding author, the criteria put forth by [the International Committee of Medical Journal Editors] specifies that each author must provide final approval of the version to be published,” Dr Hauptman said.

He added that, at this point, it’s not possible to measure how frequently a journal reader incorporates errata into clinical care or the extent to which patient outcomes may be affected.

Medical/science journals

Credit: CDC/James Gathany

A review of errata reports from medical publications revealed that nearly a quarter of the errors may have changed the way study data were interpreted.

And about half of the errors were not corrected in the original text, or the errata report did not specify whether a correction was made.

This suggests authors and journals must be more vigilant and consistent in identifying and reporting errors, said Paul Hauptman, MD, of Saint Louis University in Missouri.

He and his colleagues conducted this research and reported the results in The American Journal of Medicine.

The researchers reviewed 20 prominent English language journals in the fields of general medicine and cardiology. And they identified 577 error reports over an 18-month period.

More than 24% of these reports included an error the team rated as major. Major errors were associated with material changes in the interpretation of data in text, figures, or tables, or with significant alterations in the article’s conclusions.

One of the examples of a major error report in the study comes from a paper about depression. In the original article, the incidence of new depression cases was misquoted by a factor of 10. The article initially reported 15.8% of women with new depression, rather than the real figure of 1.58%, which was later corrected.

“As the volume of research publications continues to rise, the scientific community needs to examine how it manages its mistakes,” said Eric Armbrecht, PhD, of the Saint Louis University Center for Outcomes Research.

“Transparency, consistency, and clarity are essential. Our study found that these are not common among some of the top medical journals.”

In fact, the researchers found that 51% of the errors they identified were not corrected in the original text, or the errata report did not specify whether a correction was made.

The team noted that this study did not provide any definitive explanations for why such errors appear in publications, although one possibility is that most authors don’t read and edit the final version of their manuscripts prior to publication.

“It’s noteworthy that although final approval of an article may fall to the first or corresponding author, the criteria put forth by [the International Committee of Medical Journal Editors] specifies that each author must provide final approval of the version to be published,” Dr Hauptman said.

He added that, at this point, it’s not possible to measure how frequently a journal reader incorporates errata into clinical care or the extent to which patient outcomes may be affected.