Hematology Times

Crowd at 2015 ASH

Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—The BTK inhibitor ibrutinib should be considered the treatment of choice for patients with relapsed or refractory mantle cell lymphoma (MCL), according to a speaker at the 2015 ASH Annual Meeting.

Results of the phase 3 RAY trial showed that ibrutinib can prolong progression-free survival (PFS) when compared to the mTOR inhibitor temsirolimus.

There was no significant difference in overall survival (OS) between the treatment arms, but this outcome was influenced by the fact that patients were allowed to cross over from the temsirolimus arm to the ibrutinib arm after they progressed.

A majority of patients in both arms experienced adverse events (AEs), and the incidence of grade 3 or higher AEs was high—about 70% with ibrutinib and 90% with temsirolimus.

Simon Rule, MD, of Derriford Hospital in Plymouth, UK, presented these results at the meeting as abstract 469. The study has been published in The Lancet as well.

The research was sponsored by Janssen Biotech, Inc., which is jointly developing and commercializing ibrutinib with Pharmacyclics LLC, an AbbVie company.

Study design

The trial included 280 patients with relapsed or refractory MCL. They were enrolled from December 2012 to November 2013.

The patients were randomized to receive oral ibrutinib (n=139) at 560 mg or intravenous temsirolimus (n=141) at 175 mg on days 1, 8, and 15 of cycle 1 and 75 mg on days 1, 8, and 15 of all subsequent 21-day cycles until disease progression or unacceptable toxicity.

Starting July 2014, patients were allowed to cross over from the ibrutinib arm to the temsirolimus arm if they had progressive disease, as confirmed by an independent review committee. Thirty-two patients ultimately crossed over.

Patient characteristics

Baseline characteristics were similar between the treatment arms. The median age was 67 (range, 39-84) in the ibrutinib arm and 68 (range, 34-88) in the temsirolimus arm. Most patients had an ECOG performance status of 0 (48.2% and 47.5%, respectively) or 1 (51.1% in both arms).

The median number of prior therapies was 2 in both arms (range, 1-9). A majority of patients had 1 to 2 prior lines of therapy—68.3% in the ibrutinib arm and 66% in the temsirolimus arm.

The median time from the end of last therapy was 8.25 months for the ibrutinib arm and 7.03 months for the temsirolimus arm. And about 30% of patients in each arm were refractory to their last therapy—25.9% and 33.3%, respectively.

About half of patients in each arm had intermediate-risk disease (46.8% in the ibrutinib arm and 48.9% in the temsirolimus arm), followed by low-risk (31.7% and 29.8%, respectively) and high-risk disease (21.6% and 21.3%, respectively).

Most patients had stage IV disease—80.6% in the ibrutinib arm and 85.1% in the temsirolimus arm.

PFS

The study’s primary endpoint was PFS, as assessed by an independent review committee.

At a median follow-up of 20 months, the median PFS was 14.6 months for patients in the ibrutinib arm and 6.2 months for patients in the temsirolimus arm (hazard ratio=0.43, P<0.0001). At 2 years, the PFS was 41% in the ibrutinib arm and 7% in the temsirolimus arm.

Dr Rule noted that, looking at these data, people might question the validity of temsirolimus as a comparator to ibrutinib for this patient population.

“If you look at the median PFS for temsirolimus here, it’s 6.2 months,” he said. “In the registration study for Velcade—bortezomib—in the US, PFS was 6.5 months. If you look at the median PFS in the lenalidomide study that got registration, it was 4 months. So [the PFS for temsirolimus] is very representative of an oral novel agent in the context of mantle cell lymphoma.”

Dr Rule also pointed out that the improvement in PFS with ibrutinib was consistent across subgroups (ie, older age, risk score, tumor bulk, refractory disease). The only exception was patients with blastoid histology, but this was a very small group.

Secondary endpoints

The median OS was not reached in the ibrutinib arm but was 21.3 months in the temsirolimus arm.

This difference was not statistically significant, but Dr Rule noted that the trial was not powered for OS, and the analysis is confounded by the crossover. Twenty-three percent of patients in the temsirolimus arm ultimately received ibrutinib.

The overall response rate (ORR) was 71.9% in the ibrutinib arm and 40.4% in the temsirolimus arm (P<0.0001), according to the independent review committee. The complete response rates were 18.7% (n=26) and 1.4% (n=2), respectively.

The median duration of response was not reached with ibrutinib but was 7 months for temsirolimus. The median time to next treatment was not reached with ibrutinib, but it was 11.6 months in the temsirolimus arm (P<0.0001).

And the median duration of study treatment was 14.4 months in the ibrutinib arm and 3 months in the temsirolimus arm.

Timing counts

Dr Rule also presented response and PFS data according to the number of prior therapies patients received.

He noted that patients were more likely to respond to temsirolimus if they had received fewer prior therapies, but this was not the case with ibrutinib. Ibrutinib produced consistent ORRs regardless of when it was given.

In the ibrutinib arm, the ORR was 71.9% for patients who had received 1 prior line of therapy, 68.4% for those who received 2 prior therapies, and 75% for those who received 3 prior therapies. In the temsirolimus arm, the ORRs were 48%, 39.5%, and 33.3%, respectively.

Conversely, patients had a greater PFS benefit if they received ibrutinib earlier in their treatment course, but this was not true for temsirolimus.

At the median follow-up of 20 months, PFS was more than 60% for ibrutinib-treated patients who had received 1 prior line of therapy and less than 30% for ibrutinib-treated patients who received 2 or more prior lines of therapy. PFS was less than 15% for patients in the temsirolimus arm, regardless of their number of prior therapies.

“So that’s perhaps the first hint that, if we’re going to be using [ibrutinib], we should be using it earlier on,” Dr Rule said. “And I also suspect that, with further follow-up with this study, if this holds up, there will be, indeed, a survival benefit observed.”

Safety

“Despite patients on the ibrutinib arm being exposed to drug more than 4 times longer than those with temsirolimus, the frequency of most cumulative adverse events was lower in the ibrutinib arm,” Dr Rule said.

Still, he noted that most patients had some adverse events. And grade 3 or higher adverse events were reported in 67.6% of patients on ibrutinib and 87.1% of patients on temsirolimus.

Grade 3 or higher AEs included atrial fibrillation (AFib) and major bleeding. AFib occurred in 4.3% of patients in the ibrutinib arm and 1.4% in the temsirolimus arm. Major bleeding occurred in 10.1% and 6.5%, respectively.

Five of the 6 patients with AFib in the ibrutinib arm and all 3 patients who developed AFib in the temsirolimus arm had risk factors for AFib prior to treatment. None of these patients discontinued treatment due to AFib.

Dr Rule said there was no evidence to suggest that either drug increases the risk of second primary malignancies, although 3.6% of patients in the ibrutinib arm and 2.9% in the temsirolimus arm were diagnosed with second primary malignancies (mostly non-melanoma skin cancers).

The most common treatment-emergent AEs (≥20%) of any grade for the ibrutinib arm were diarrhea (28.8%), cough (22.3%), and fatigue (22.3%).

The most common treatment-emergent AEs (>20%) of any grade for the temsirolimus arm were thrombocytopenia (56.1%), anemia (43.2%), diarrhea (30.9%), fatigue (28.8%), neutropenia (25.9%), epistaxis (23.7%), cough (22.3%), peripheral edema (22.3%), nausea (21.6%), pyrexia (20.9%), and stomatitis (20.9%).

The most common hematologic AEs (≥10%) in the ibrutinib and temsirolimus arms, respectively, were thrombocytopenia (18% vs 56.1%), anemia (18% vs 43.2%), and neutropenia (15.8% vs 25.9%).

Six percent of patients in the ibrutinib arm and 26% in the temsirolimus arm discontinued treatment due to AEs.

At a median follow-up of 20 months, 42% of patients in the ibrutinib arm and 45% in the temsirolimus arm had died. The most common cause of death associated with ibrutinib was disease progression, and deaths in the temsirolimus arm were primarily attributed to AEs.

Crowd at 2015 ASH

Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—The BTK inhibitor ibrutinib should be considered the treatment of choice for patients with relapsed or refractory mantle cell lymphoma (MCL), according to a speaker at the 2015 ASH Annual Meeting.

Results of the phase 3 RAY trial showed that ibrutinib can prolong progression-free survival (PFS) when compared to the mTOR inhibitor temsirolimus.

There was no significant difference in overall survival (OS) between the treatment arms, but this outcome was influenced by the fact that patients were allowed to cross over from the temsirolimus arm to the ibrutinib arm after they progressed.

A majority of patients in both arms experienced adverse events (AEs), and the incidence of grade 3 or higher AEs was high—about 70% with ibrutinib and 90% with temsirolimus.

Simon Rule, MD, of Derriford Hospital in Plymouth, UK, presented these results at the meeting as abstract 469. The study has been published in The Lancet as well.

The research was sponsored by Janssen Biotech, Inc., which is jointly developing and commercializing ibrutinib with Pharmacyclics LLC, an AbbVie company.

Study design

The trial included 280 patients with relapsed or refractory MCL. They were enrolled from December 2012 to November 2013.

The patients were randomized to receive oral ibrutinib (n=139) at 560 mg or intravenous temsirolimus (n=141) at 175 mg on days 1, 8, and 15 of cycle 1 and 75 mg on days 1, 8, and 15 of all subsequent 21-day cycles until disease progression or unacceptable toxicity.

Starting July 2014, patients were allowed to cross over from the ibrutinib arm to the temsirolimus arm if they had progressive disease, as confirmed by an independent review committee. Thirty-two patients ultimately crossed over.

Patient characteristics

Baseline characteristics were similar between the treatment arms. The median age was 67 (range, 39-84) in the ibrutinib arm and 68 (range, 34-88) in the temsirolimus arm. Most patients had an ECOG performance status of 0 (48.2% and 47.5%, respectively) or 1 (51.1% in both arms).

The median number of prior therapies was 2 in both arms (range, 1-9). A majority of patients had 1 to 2 prior lines of therapy—68.3% in the ibrutinib arm and 66% in the temsirolimus arm.

The median time from the end of last therapy was 8.25 months for the ibrutinib arm and 7.03 months for the temsirolimus arm. And about 30% of patients in each arm were refractory to their last therapy—25.9% and 33.3%, respectively.

About half of patients in each arm had intermediate-risk disease (46.8% in the ibrutinib arm and 48.9% in the temsirolimus arm), followed by low-risk (31.7% and 29.8%, respectively) and high-risk disease (21.6% and 21.3%, respectively).

Most patients had stage IV disease—80.6% in the ibrutinib arm and 85.1% in the temsirolimus arm.

PFS

The study’s primary endpoint was PFS, as assessed by an independent review committee.

At a median follow-up of 20 months, the median PFS was 14.6 months for patients in the ibrutinib arm and 6.2 months for patients in the temsirolimus arm (hazard ratio=0.43, P<0.0001). At 2 years, the PFS was 41% in the ibrutinib arm and 7% in the temsirolimus arm.

Dr Rule noted that, looking at these data, people might question the validity of temsirolimus as a comparator to ibrutinib for this patient population.

“If you look at the median PFS for temsirolimus here, it’s 6.2 months,” he said. “In the registration study for Velcade—bortezomib—in the US, PFS was 6.5 months. If you look at the median PFS in the lenalidomide study that got registration, it was 4 months. So [the PFS for temsirolimus] is very representative of an oral novel agent in the context of mantle cell lymphoma.”

Dr Rule also pointed out that the improvement in PFS with ibrutinib was consistent across subgroups (ie, older age, risk score, tumor bulk, refractory disease). The only exception was patients with blastoid histology, but this was a very small group.

Secondary endpoints

The median OS was not reached in the ibrutinib arm but was 21.3 months in the temsirolimus arm.

This difference was not statistically significant, but Dr Rule noted that the trial was not powered for OS, and the analysis is confounded by the crossover. Twenty-three percent of patients in the temsirolimus arm ultimately received ibrutinib.

The overall response rate (ORR) was 71.9% in the ibrutinib arm and 40.4% in the temsirolimus arm (P<0.0001), according to the independent review committee. The complete response rates were 18.7% (n=26) and 1.4% (n=2), respectively.

The median duration of response was not reached with ibrutinib but was 7 months for temsirolimus. The median time to next treatment was not reached with ibrutinib, but it was 11.6 months in the temsirolimus arm (P<0.0001).

And the median duration of study treatment was 14.4 months in the ibrutinib arm and 3 months in the temsirolimus arm.

Timing counts

Dr Rule also presented response and PFS data according to the number of prior therapies patients received.

He noted that patients were more likely to respond to temsirolimus if they had received fewer prior therapies, but this was not the case with ibrutinib. Ibrutinib produced consistent ORRs regardless of when it was given.

In the ibrutinib arm, the ORR was 71.9% for patients who had received 1 prior line of therapy, 68.4% for those who received 2 prior therapies, and 75% for those who received 3 prior therapies. In the temsirolimus arm, the ORRs were 48%, 39.5%, and 33.3%, respectively.

Conversely, patients had a greater PFS benefit if they received ibrutinib earlier in their treatment course, but this was not true for temsirolimus.

At the median follow-up of 20 months, PFS was more than 60% for ibrutinib-treated patients who had received 1 prior line of therapy and less than 30% for ibrutinib-treated patients who received 2 or more prior lines of therapy. PFS was less than 15% for patients in the temsirolimus arm, regardless of their number of prior therapies.

“So that’s perhaps the first hint that, if we’re going to be using [ibrutinib], we should be using it earlier on,” Dr Rule said. “And I also suspect that, with further follow-up with this study, if this holds up, there will be, indeed, a survival benefit observed.”

Safety

“Despite patients on the ibrutinib arm being exposed to drug more than 4 times longer than those with temsirolimus, the frequency of most cumulative adverse events was lower in the ibrutinib arm,” Dr Rule said.

Still, he noted that most patients had some adverse events. And grade 3 or higher adverse events were reported in 67.6% of patients on ibrutinib and 87.1% of patients on temsirolimus.

Grade 3 or higher AEs included atrial fibrillation (AFib) and major bleeding. AFib occurred in 4.3% of patients in the ibrutinib arm and 1.4% in the temsirolimus arm. Major bleeding occurred in 10.1% and 6.5%, respectively.

Five of the 6 patients with AFib in the ibrutinib arm and all 3 patients who developed AFib in the temsirolimus arm had risk factors for AFib prior to treatment. None of these patients discontinued treatment due to AFib.

Dr Rule said there was no evidence to suggest that either drug increases the risk of second primary malignancies, although 3.6% of patients in the ibrutinib arm and 2.9% in the temsirolimus arm were diagnosed with second primary malignancies (mostly non-melanoma skin cancers).

The most common treatment-emergent AEs (≥20%) of any grade for the ibrutinib arm were diarrhea (28.8%), cough (22.3%), and fatigue (22.3%).

The most common treatment-emergent AEs (>20%) of any grade for the temsirolimus arm were thrombocytopenia (56.1%), anemia (43.2%), diarrhea (30.9%), fatigue (28.8%), neutropenia (25.9%), epistaxis (23.7%), cough (22.3%), peripheral edema (22.3%), nausea (21.6%), pyrexia (20.9%), and stomatitis (20.9%).

The most common hematologic AEs (≥10%) in the ibrutinib and temsirolimus arms, respectively, were thrombocytopenia (18% vs 56.1%), anemia (18% vs 43.2%), and neutropenia (15.8% vs 25.9%).

Six percent of patients in the ibrutinib arm and 26% in the temsirolimus arm discontinued treatment due to AEs.

At a median follow-up of 20 months, 42% of patients in the ibrutinib arm and 45% in the temsirolimus arm had died. The most common cause of death associated with ibrutinib was disease progression, and deaths in the temsirolimus arm were primarily attributed to AEs.

Crowd at 2015 ASH

Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—The BTK inhibitor ibrutinib should be considered the treatment of choice for patients with relapsed or refractory mantle cell lymphoma (MCL), according to a speaker at the 2015 ASH Annual Meeting.

Results of the phase 3 RAY trial showed that ibrutinib can prolong progression-free survival (PFS) when compared to the mTOR inhibitor temsirolimus.

There was no significant difference in overall survival (OS) between the treatment arms, but this outcome was influenced by the fact that patients were allowed to cross over from the temsirolimus arm to the ibrutinib arm after they progressed.

A majority of patients in both arms experienced adverse events (AEs), and the incidence of grade 3 or higher AEs was high—about 70% with ibrutinib and 90% with temsirolimus.

Simon Rule, MD, of Derriford Hospital in Plymouth, UK, presented these results at the meeting as abstract 469. The study has been published in The Lancet as well.

The research was sponsored by Janssen Biotech, Inc., which is jointly developing and commercializing ibrutinib with Pharmacyclics LLC, an AbbVie company.

Study design

The trial included 280 patients with relapsed or refractory MCL. They were enrolled from December 2012 to November 2013.

The patients were randomized to receive oral ibrutinib (n=139) at 560 mg or intravenous temsirolimus (n=141) at 175 mg on days 1, 8, and 15 of cycle 1 and 75 mg on days 1, 8, and 15 of all subsequent 21-day cycles until disease progression or unacceptable toxicity.

Starting July 2014, patients were allowed to cross over from the ibrutinib arm to the temsirolimus arm if they had progressive disease, as confirmed by an independent review committee. Thirty-two patients ultimately crossed over.

Patient characteristics

Baseline characteristics were similar between the treatment arms. The median age was 67 (range, 39-84) in the ibrutinib arm and 68 (range, 34-88) in the temsirolimus arm. Most patients had an ECOG performance status of 0 (48.2% and 47.5%, respectively) or 1 (51.1% in both arms).

The median number of prior therapies was 2 in both arms (range, 1-9). A majority of patients had 1 to 2 prior lines of therapy—68.3% in the ibrutinib arm and 66% in the temsirolimus arm.

The median time from the end of last therapy was 8.25 months for the ibrutinib arm and 7.03 months for the temsirolimus arm. And about 30% of patients in each arm were refractory to their last therapy—25.9% and 33.3%, respectively.

About half of patients in each arm had intermediate-risk disease (46.8% in the ibrutinib arm and 48.9% in the temsirolimus arm), followed by low-risk (31.7% and 29.8%, respectively) and high-risk disease (21.6% and 21.3%, respectively).

Most patients had stage IV disease—80.6% in the ibrutinib arm and 85.1% in the temsirolimus arm.

PFS

The study’s primary endpoint was PFS, as assessed by an independent review committee.

At a median follow-up of 20 months, the median PFS was 14.6 months for patients in the ibrutinib arm and 6.2 months for patients in the temsirolimus arm (hazard ratio=0.43, P<0.0001). At 2 years, the PFS was 41% in the ibrutinib arm and 7% in the temsirolimus arm.

Dr Rule noted that, looking at these data, people might question the validity of temsirolimus as a comparator to ibrutinib for this patient population.

“If you look at the median PFS for temsirolimus here, it’s 6.2 months,” he said. “In the registration study for Velcade—bortezomib—in the US, PFS was 6.5 months. If you look at the median PFS in the lenalidomide study that got registration, it was 4 months. So [the PFS for temsirolimus] is very representative of an oral novel agent in the context of mantle cell lymphoma.”

Dr Rule also pointed out that the improvement in PFS with ibrutinib was consistent across subgroups (ie, older age, risk score, tumor bulk, refractory disease). The only exception was patients with blastoid histology, but this was a very small group.

Secondary endpoints

The median OS was not reached in the ibrutinib arm but was 21.3 months in the temsirolimus arm.

This difference was not statistically significant, but Dr Rule noted that the trial was not powered for OS, and the analysis is confounded by the crossover. Twenty-three percent of patients in the temsirolimus arm ultimately received ibrutinib.

The overall response rate (ORR) was 71.9% in the ibrutinib arm and 40.4% in the temsirolimus arm (P<0.0001), according to the independent review committee. The complete response rates were 18.7% (n=26) and 1.4% (n=2), respectively.

The median duration of response was not reached with ibrutinib but was 7 months for temsirolimus. The median time to next treatment was not reached with ibrutinib, but it was 11.6 months in the temsirolimus arm (P<0.0001).

And the median duration of study treatment was 14.4 months in the ibrutinib arm and 3 months in the temsirolimus arm.

Timing counts

Dr Rule also presented response and PFS data according to the number of prior therapies patients received.

He noted that patients were more likely to respond to temsirolimus if they had received fewer prior therapies, but this was not the case with ibrutinib. Ibrutinib produced consistent ORRs regardless of when it was given.

In the ibrutinib arm, the ORR was 71.9% for patients who had received 1 prior line of therapy, 68.4% for those who received 2 prior therapies, and 75% for those who received 3 prior therapies. In the temsirolimus arm, the ORRs were 48%, 39.5%, and 33.3%, respectively.

Conversely, patients had a greater PFS benefit if they received ibrutinib earlier in their treatment course, but this was not true for temsirolimus.

At the median follow-up of 20 months, PFS was more than 60% for ibrutinib-treated patients who had received 1 prior line of therapy and less than 30% for ibrutinib-treated patients who received 2 or more prior lines of therapy. PFS was less than 15% for patients in the temsirolimus arm, regardless of their number of prior therapies.

“So that’s perhaps the first hint that, if we’re going to be using [ibrutinib], we should be using it earlier on,” Dr Rule said. “And I also suspect that, with further follow-up with this study, if this holds up, there will be, indeed, a survival benefit observed.”

Safety

“Despite patients on the ibrutinib arm being exposed to drug more than 4 times longer than those with temsirolimus, the frequency of most cumulative adverse events was lower in the ibrutinib arm,” Dr Rule said.

Still, he noted that most patients had some adverse events. And grade 3 or higher adverse events were reported in 67.6% of patients on ibrutinib and 87.1% of patients on temsirolimus.

Grade 3 or higher AEs included atrial fibrillation (AFib) and major bleeding. AFib occurred in 4.3% of patients in the ibrutinib arm and 1.4% in the temsirolimus arm. Major bleeding occurred in 10.1% and 6.5%, respectively.

Five of the 6 patients with AFib in the ibrutinib arm and all 3 patients who developed AFib in the temsirolimus arm had risk factors for AFib prior to treatment. None of these patients discontinued treatment due to AFib.

Dr Rule said there was no evidence to suggest that either drug increases the risk of second primary malignancies, although 3.6% of patients in the ibrutinib arm and 2.9% in the temsirolimus arm were diagnosed with second primary malignancies (mostly non-melanoma skin cancers).

The most common treatment-emergent AEs (≥20%) of any grade for the ibrutinib arm were diarrhea (28.8%), cough (22.3%), and fatigue (22.3%).

The most common treatment-emergent AEs (>20%) of any grade for the temsirolimus arm were thrombocytopenia (56.1%), anemia (43.2%), diarrhea (30.9%), fatigue (28.8%), neutropenia (25.9%), epistaxis (23.7%), cough (22.3%), peripheral edema (22.3%), nausea (21.6%), pyrexia (20.9%), and stomatitis (20.9%).

The most common hematologic AEs (≥10%) in the ibrutinib and temsirolimus arms, respectively, were thrombocytopenia (18% vs 56.1%), anemia (18% vs 43.2%), and neutropenia (15.8% vs 25.9%).

Six percent of patients in the ibrutinib arm and 26% in the temsirolimus arm discontinued treatment due to AEs.

At a median follow-up of 20 months, 42% of patients in the ibrutinib arm and 45% in the temsirolimus arm had died. The most common cause of death associated with ibrutinib was disease progression, and deaths in the temsirolimus arm were primarily attributed to AEs.

Wendy Landier, PhD, CRNP

Photo courtesy of ASH

ORLANDO, FL—A study comparing subjective versus objective reporting of treatment compliance in patients with acute lymphoblastic leukemia (ALL) has shown that about a fourth of patients over-report how compliant they are with taking 6-mercaptopurine (6MP) as part of their maintenance therapy.

An earlier analysis of the Children’s Oncology Group (COG) AALL03N1 compliance study showed that adherence rates of less than 95% were associated with a 3.7-fold increased risk of relapse.

And about 40% of patients were non-adherent. Yet patients indicate they are taking their medication when questioned.

“We ask our patients if they are taking their meds,” said Wendy Landier, PhD, “and they tell us they are.”

“Even in this cohort who were being closely monitored and knew that they were being closely monitored electronically and were asked to self-report, we found over-reporting.”

Dr Landier, of the University of Alabama at Birmingham, reported these findings comparing self-reported adherence with electronic monitoring of 6MP intake at the 2015 ASH Annual Meeting (abstract 82).

The investigators collected data over 6 months from 416 ALL patients who were 21 years at diagnosis or younger and were receiving 6MP as part of their maintenance therapy.

Investigators measured subjective self-reporting by a patient questionnaire, which included patient demographic information in addition to the number of days the patient took 6MP over the past month.

For the objective medication event-monitoring system (MEMS), patients received a 6MP bottle that was fitted with a TrackCap^TM. The cap had a microprocessor chip that recorded the date and time of each bottle opening.

Investigators downloaded the data at the end of the study. They then compared the MEMS with the self-reported data.

The investigators classified perfect reporters as those whose self-report corresponded to their MEMS.

They classified over-reporters as those whose self-report was greater than their MEMS data for 5 days or more and 50% of the months.

The rest they classified as others.

Patients were a median age of 6.0 years, and 277 (66.6%) were male. Parents completed the survey for patients younger than 12.

Two hundred forty-two patients (60.9%) had fathers whose education was less than some college, 159 (38.4%) had NCI high-risk disease, and 168 (40.4%) were non-adherent to 6MP as determined by earlier analysis of the COG AALL03N1 study.

Thirty-six percent were non-Hispanic white, 37% were Hispanic, 14% Asian, and 13% African American.

The investigators monitored the patients’ 6MP intake for a total of 1344 patient-months at 87 COG sites.

And the correlation between subjective and objective reporting was moderate, Dr Landier said, with the correlation ranging from 0.36 to 0.58.

Twelve percent of the patients were perfect reporters, with no difference between the reporting methods.

Twenty-four percent over-reported their intake, 1% under-reported their intake, and 64% were other.

The investigators analyzed variables associated with over-reporting and found that age 12 years or older (P=0.02), being Hispanic (P=0.02), Asian (P=0.02), or African American (P<0.001), paternal education less than college (P=0.02), and being classified as 6MP non-adherent (P<0.001) were all significant.

“Over-reporting of 6MP ingestion is common,” Dr Landier said, with 88% of patients or parents over-reporting the number of days 6MP was taken.

“What we’ve learned from this study is that we cannot rely on patients’ self-report in the clinic,” she said. “What we found is that only 12% of our patients are perfect, so to speak, and that the others mainly over-estimate, and I don’t believe intentionally.”

“[W]e need to have a better way of identifying which patients are at risk for over-reporting their intake, whether they’re aware of it or not,” she added.

Wendy Landier, PhD, CRNP

Photo courtesy of ASH

ORLANDO, FL—A study comparing subjective versus objective reporting of treatment compliance in patients with acute lymphoblastic leukemia (ALL) has shown that about a fourth of patients over-report how compliant they are with taking 6-mercaptopurine (6MP) as part of their maintenance therapy.

An earlier analysis of the Children’s Oncology Group (COG) AALL03N1 compliance study showed that adherence rates of less than 95% were associated with a 3.7-fold increased risk of relapse.

And about 40% of patients were non-adherent. Yet patients indicate they are taking their medication when questioned.

“We ask our patients if they are taking their meds,” said Wendy Landier, PhD, “and they tell us they are.”

“Even in this cohort who were being closely monitored and knew that they were being closely monitored electronically and were asked to self-report, we found over-reporting.”

Dr Landier, of the University of Alabama at Birmingham, reported these findings comparing self-reported adherence with electronic monitoring of 6MP intake at the 2015 ASH Annual Meeting (abstract 82).

The investigators collected data over 6 months from 416 ALL patients who were 21 years at diagnosis or younger and were receiving 6MP as part of their maintenance therapy.

Investigators measured subjective self-reporting by a patient questionnaire, which included patient demographic information in addition to the number of days the patient took 6MP over the past month.

For the objective medication event-monitoring system (MEMS), patients received a 6MP bottle that was fitted with a TrackCap^TM. The cap had a microprocessor chip that recorded the date and time of each bottle opening.

Investigators downloaded the data at the end of the study. They then compared the MEMS with the self-reported data.

The investigators classified perfect reporters as those whose self-report corresponded to their MEMS.

They classified over-reporters as those whose self-report was greater than their MEMS data for 5 days or more and 50% of the months.

The rest they classified as others.

Patients were a median age of 6.0 years, and 277 (66.6%) were male. Parents completed the survey for patients younger than 12.

Two hundred forty-two patients (60.9%) had fathers whose education was less than some college, 159 (38.4%) had NCI high-risk disease, and 168 (40.4%) were non-adherent to 6MP as determined by earlier analysis of the COG AALL03N1 study.

Thirty-six percent were non-Hispanic white, 37% were Hispanic, 14% Asian, and 13% African American.

The investigators monitored the patients’ 6MP intake for a total of 1344 patient-months at 87 COG sites.

And the correlation between subjective and objective reporting was moderate, Dr Landier said, with the correlation ranging from 0.36 to 0.58.

Twelve percent of the patients were perfect reporters, with no difference between the reporting methods.

Twenty-four percent over-reported their intake, 1% under-reported their intake, and 64% were other.

The investigators analyzed variables associated with over-reporting and found that age 12 years or older (P=0.02), being Hispanic (P=0.02), Asian (P=0.02), or African American (P<0.001), paternal education less than college (P=0.02), and being classified as 6MP non-adherent (P<0.001) were all significant.

“Over-reporting of 6MP ingestion is common,” Dr Landier said, with 88% of patients or parents over-reporting the number of days 6MP was taken.

“What we’ve learned from this study is that we cannot rely on patients’ self-report in the clinic,” she said. “What we found is that only 12% of our patients are perfect, so to speak, and that the others mainly over-estimate, and I don’t believe intentionally.”

“[W]e need to have a better way of identifying which patients are at risk for over-reporting their intake, whether they’re aware of it or not,” she added.

Wendy Landier, PhD, CRNP

Photo courtesy of ASH

ORLANDO, FL—A study comparing subjective versus objective reporting of treatment compliance in patients with acute lymphoblastic leukemia (ALL) has shown that about a fourth of patients over-report how compliant they are with taking 6-mercaptopurine (6MP) as part of their maintenance therapy.

An earlier analysis of the Children’s Oncology Group (COG) AALL03N1 compliance study showed that adherence rates of less than 95% were associated with a 3.7-fold increased risk of relapse.

And about 40% of patients were non-adherent. Yet patients indicate they are taking their medication when questioned.

“We ask our patients if they are taking their meds,” said Wendy Landier, PhD, “and they tell us they are.”

“Even in this cohort who were being closely monitored and knew that they were being closely monitored electronically and were asked to self-report, we found over-reporting.”

Dr Landier, of the University of Alabama at Birmingham, reported these findings comparing self-reported adherence with electronic monitoring of 6MP intake at the 2015 ASH Annual Meeting (abstract 82).

The investigators collected data over 6 months from 416 ALL patients who were 21 years at diagnosis or younger and were receiving 6MP as part of their maintenance therapy.

Investigators measured subjective self-reporting by a patient questionnaire, which included patient demographic information in addition to the number of days the patient took 6MP over the past month.

For the objective medication event-monitoring system (MEMS), patients received a 6MP bottle that was fitted with a TrackCap^TM. The cap had a microprocessor chip that recorded the date and time of each bottle opening.

Investigators downloaded the data at the end of the study. They then compared the MEMS with the self-reported data.

The investigators classified perfect reporters as those whose self-report corresponded to their MEMS.

They classified over-reporters as those whose self-report was greater than their MEMS data for 5 days or more and 50% of the months.

The rest they classified as others.

Patients were a median age of 6.0 years, and 277 (66.6%) were male. Parents completed the survey for patients younger than 12.

Two hundred forty-two patients (60.9%) had fathers whose education was less than some college, 159 (38.4%) had NCI high-risk disease, and 168 (40.4%) were non-adherent to 6MP as determined by earlier analysis of the COG AALL03N1 study.

Thirty-six percent were non-Hispanic white, 37% were Hispanic, 14% Asian, and 13% African American.

The investigators monitored the patients’ 6MP intake for a total of 1344 patient-months at 87 COG sites.

And the correlation between subjective and objective reporting was moderate, Dr Landier said, with the correlation ranging from 0.36 to 0.58.

Twelve percent of the patients were perfect reporters, with no difference between the reporting methods.

Twenty-four percent over-reported their intake, 1% under-reported their intake, and 64% were other.

The investigators analyzed variables associated with over-reporting and found that age 12 years or older (P=0.02), being Hispanic (P=0.02), Asian (P=0.02), or African American (P<0.001), paternal education less than college (P=0.02), and being classified as 6MP non-adherent (P<0.001) were all significant.

“Over-reporting of 6MP ingestion is common,” Dr Landier said, with 88% of patients or parents over-reporting the number of days 6MP was taken.

“What we’ve learned from this study is that we cannot rely on patients’ self-report in the clinic,” she said. “What we found is that only 12% of our patients are perfect, so to speak, and that the others mainly over-estimate, and I don’t believe intentionally.”

“[W]e need to have a better way of identifying which patients are at risk for over-reporting their intake, whether they’re aware of it or not,” she added.

Sheet of hydrogel bonded to

a matrix of polymer islands

(red) that can encapsulate

electronic components

Photo by Melanie Gonick/MIT

Engineers say they have designed “smart wound dressing,” a sticky, stretchy, gel-like material that can incorporate temperature sensors, LED lights, and other electronics, as well as tiny, drug-delivering reservoirs and channels.

The dressing releases medicine in response to changes in skin temperature and can be designed to light up if, say, medicine is running low.

When the dressing is applied to a highly flexible area, such as the elbow or knee, it stretches with the body, keeping the embedded electronics functional and intact.

The key to the design is a hydrogel matrix designed by Xuanhe Zhao, PhD, of the Massachusetts Institute of Technology in Cambridge.

The hydrogel, which was describe in Nature Materials last month, is a rubbery material, mostly composed of water, designed to bond strongly to surfaces such as gold, titanium, aluminum, silicon, glass, and ceramic.

In a paper published in Advanced Materials, Dr Zhao and his colleagues described embedding various electronics within the hydrogel, such as conductive wires, semiconductor chips, LED lights, and temperature sensors.

Dr Zhao said electronics coated in hydrogel may be used not just on the surface of the skin but also inside the body; for example, as implanted, biocompatible glucose sensors, or even soft, compliant neural probes.

“Electronics are usually hard and dry, but the human body is soft and wet,” Dr Zhao said. “These two systems have drastically different properties. If you want to put electronics in close contact with the human body for applications such as healthcare monitoring and drug delivery, it is highly desirable to make the electronic devices soft and stretchable to fit the environment of the human body. That’s the motivation for stretchable hydrogel electronics.”

A strong and stretchy bond

Typical synthetic hydrogels are brittle, barely stretchable, and adhere weakly to other surfaces.

“They’re often used as degradable biomaterials at the current stage,” Dr Zhao said. “If you want to make an electronic device out of hydrogels, you need to think of long-term stability of the hydrogels and interfaces.”

To get around these challenges, his team came up with a design strategy for robust hydrogels, mixing water with a small amount of selected biopolymers to create soft, stretchy materials with a stiffness of 10 to 100 kilopascals—about the range of human soft tissues. The researchers also devised a method to strongly bond the hydrogel to various nonporous surfaces.

In the new study, the researchers applied their techniques to demonstrate several uses for the hydrogel, including encapsulating a titanium wire to form a transparent, stretchable conductor. In experiments, they stretched the encapsulated wire multiple times and found it maintained constant electrical conductivity.

Dr Zhao also created an array of LED lights embedded in a sheet of hydrogel. When attached to different regions of the body, the array continued working, even when stretched across highly deformable areas such as the knee and elbow.

A versatile matrix

Finally, the group embedded various electronic components within a sheet of hydrogel to create a “smart wound dressing,” comprising regularly spaced temperature sensors and tiny drug reservoirs.

The researchers also created pathways for drugs to flow through the hydrogel, by either inserting patterned tubes or drilling tiny holes through the matrix. They placed the dressing over various regions of the body and found that, even when highly stretched, the dressing continued to monitor skin temperature and release drugs according to the sensor readings.

An immediate application of the technology may be as a stretchable, on-demand treatment for burns or other skin conditions, said Hyunwoo Yuk, a graduate student at MIT.

“It’s a very versatile matrix,” Yuk said. “The unique capability here is, when a sensor senses something different, like an abnormal increase in temperature, the device can, on demand, release drugs to that specific location and select a specific drug from one of the reservoirs, which can diffuse in the hydrogel matrix for sustained release over time.”

Delving deeper, Dr Zhao envisions hydrogel to be an ideal, biocompatible vehicle for delivering electronics inside the body. He is currently exploring hydrogel’s potential as a carrier for glucose sensors as well as neural probes.

Sheet of hydrogel bonded to

a matrix of polymer islands

(red) that can encapsulate

electronic components

Photo by Melanie Gonick/MIT

Engineers say they have designed “smart wound dressing,” a sticky, stretchy, gel-like material that can incorporate temperature sensors, LED lights, and other electronics, as well as tiny, drug-delivering reservoirs and channels.

The dressing releases medicine in response to changes in skin temperature and can be designed to light up if, say, medicine is running low.

When the dressing is applied to a highly flexible area, such as the elbow or knee, it stretches with the body, keeping the embedded electronics functional and intact.

The key to the design is a hydrogel matrix designed by Xuanhe Zhao, PhD, of the Massachusetts Institute of Technology in Cambridge.

The hydrogel, which was describe in Nature Materials last month, is a rubbery material, mostly composed of water, designed to bond strongly to surfaces such as gold, titanium, aluminum, silicon, glass, and ceramic.

In a paper published in Advanced Materials, Dr Zhao and his colleagues described embedding various electronics within the hydrogel, such as conductive wires, semiconductor chips, LED lights, and temperature sensors.

Dr Zhao said electronics coated in hydrogel may be used not just on the surface of the skin but also inside the body; for example, as implanted, biocompatible glucose sensors, or even soft, compliant neural probes.

“Electronics are usually hard and dry, but the human body is soft and wet,” Dr Zhao said. “These two systems have drastically different properties. If you want to put electronics in close contact with the human body for applications such as healthcare monitoring and drug delivery, it is highly desirable to make the electronic devices soft and stretchable to fit the environment of the human body. That’s the motivation for stretchable hydrogel electronics.”

A strong and stretchy bond

Typical synthetic hydrogels are brittle, barely stretchable, and adhere weakly to other surfaces.

“They’re often used as degradable biomaterials at the current stage,” Dr Zhao said. “If you want to make an electronic device out of hydrogels, you need to think of long-term stability of the hydrogels and interfaces.”

To get around these challenges, his team came up with a design strategy for robust hydrogels, mixing water with a small amount of selected biopolymers to create soft, stretchy materials with a stiffness of 10 to 100 kilopascals—about the range of human soft tissues. The researchers also devised a method to strongly bond the hydrogel to various nonporous surfaces.

In the new study, the researchers applied their techniques to demonstrate several uses for the hydrogel, including encapsulating a titanium wire to form a transparent, stretchable conductor. In experiments, they stretched the encapsulated wire multiple times and found it maintained constant electrical conductivity.

Dr Zhao also created an array of LED lights embedded in a sheet of hydrogel. When attached to different regions of the body, the array continued working, even when stretched across highly deformable areas such as the knee and elbow.

A versatile matrix

Finally, the group embedded various electronic components within a sheet of hydrogel to create a “smart wound dressing,” comprising regularly spaced temperature sensors and tiny drug reservoirs.

The researchers also created pathways for drugs to flow through the hydrogel, by either inserting patterned tubes or drilling tiny holes through the matrix. They placed the dressing over various regions of the body and found that, even when highly stretched, the dressing continued to monitor skin temperature and release drugs according to the sensor readings.

An immediate application of the technology may be as a stretchable, on-demand treatment for burns or other skin conditions, said Hyunwoo Yuk, a graduate student at MIT.

“It’s a very versatile matrix,” Yuk said. “The unique capability here is, when a sensor senses something different, like an abnormal increase in temperature, the device can, on demand, release drugs to that specific location and select a specific drug from one of the reservoirs, which can diffuse in the hydrogel matrix for sustained release over time.”

Delving deeper, Dr Zhao envisions hydrogel to be an ideal, biocompatible vehicle for delivering electronics inside the body. He is currently exploring hydrogel’s potential as a carrier for glucose sensors as well as neural probes.

Sheet of hydrogel bonded to

a matrix of polymer islands

(red) that can encapsulate

electronic components

Photo by Melanie Gonick/MIT

Engineers say they have designed “smart wound dressing,” a sticky, stretchy, gel-like material that can incorporate temperature sensors, LED lights, and other electronics, as well as tiny, drug-delivering reservoirs and channels.

The dressing releases medicine in response to changes in skin temperature and can be designed to light up if, say, medicine is running low.

When the dressing is applied to a highly flexible area, such as the elbow or knee, it stretches with the body, keeping the embedded electronics functional and intact.

The key to the design is a hydrogel matrix designed by Xuanhe Zhao, PhD, of the Massachusetts Institute of Technology in Cambridge.

The hydrogel, which was describe in Nature Materials last month, is a rubbery material, mostly composed of water, designed to bond strongly to surfaces such as gold, titanium, aluminum, silicon, glass, and ceramic.

In a paper published in Advanced Materials, Dr Zhao and his colleagues described embedding various electronics within the hydrogel, such as conductive wires, semiconductor chips, LED lights, and temperature sensors.

Dr Zhao said electronics coated in hydrogel may be used not just on the surface of the skin but also inside the body; for example, as implanted, biocompatible glucose sensors, or even soft, compliant neural probes.

“Electronics are usually hard and dry, but the human body is soft and wet,” Dr Zhao said. “These two systems have drastically different properties. If you want to put electronics in close contact with the human body for applications such as healthcare monitoring and drug delivery, it is highly desirable to make the electronic devices soft and stretchable to fit the environment of the human body. That’s the motivation for stretchable hydrogel electronics.”

A strong and stretchy bond

Typical synthetic hydrogels are brittle, barely stretchable, and adhere weakly to other surfaces.

“They’re often used as degradable biomaterials at the current stage,” Dr Zhao said. “If you want to make an electronic device out of hydrogels, you need to think of long-term stability of the hydrogels and interfaces.”

To get around these challenges, his team came up with a design strategy for robust hydrogels, mixing water with a small amount of selected biopolymers to create soft, stretchy materials with a stiffness of 10 to 100 kilopascals—about the range of human soft tissues. The researchers also devised a method to strongly bond the hydrogel to various nonporous surfaces.

In the new study, the researchers applied their techniques to demonstrate several uses for the hydrogel, including encapsulating a titanium wire to form a transparent, stretchable conductor. In experiments, they stretched the encapsulated wire multiple times and found it maintained constant electrical conductivity.

Dr Zhao also created an array of LED lights embedded in a sheet of hydrogel. When attached to different regions of the body, the array continued working, even when stretched across highly deformable areas such as the knee and elbow.

A versatile matrix

Finally, the group embedded various electronic components within a sheet of hydrogel to create a “smart wound dressing,” comprising regularly spaced temperature sensors and tiny drug reservoirs.

The researchers also created pathways for drugs to flow through the hydrogel, by either inserting patterned tubes or drilling tiny holes through the matrix. They placed the dressing over various regions of the body and found that, even when highly stretched, the dressing continued to monitor skin temperature and release drugs according to the sensor readings.

An immediate application of the technology may be as a stretchable, on-demand treatment for burns or other skin conditions, said Hyunwoo Yuk, a graduate student at MIT.

“It’s a very versatile matrix,” Yuk said. “The unique capability here is, when a sensor senses something different, like an abnormal increase in temperature, the device can, on demand, release drugs to that specific location and select a specific drug from one of the reservoirs, which can diffuse in the hydrogel matrix for sustained release over time.”

Delving deeper, Dr Zhao envisions hydrogel to be an ideal, biocompatible vehicle for delivering electronics inside the body. He is currently exploring hydrogel’s potential as a carrier for glucose sensors as well as neural probes.

Chemotherapy drugs

Photo by Bill Branson

The price of cancer drugs varies widely between European countries, Australia, and New Zealand, according to a study published in The Lancet Oncology.

The study indicates that, overall, the UK and Mediterranean countries such as Greece, Spain, and Portugal pay the lowest average unit manufacturer prices for a group of 31 originator cancer drugs (new drugs under patent).

And Sweden, Switzerland, and Germany pay the highest prices.

The greatest differences in price were noted for gemcitabine, which costs €209 per vial in New Zealand and €43 in Australia, and zoledronic acid, which costs €330 per vial in New Zealand but €128 in Greece.*

“Public payers in Germany are paying 223% more in terms of official prices for interferon alfa 2b for melanoma and leukemia treatment than those in Greece,” noted study author Sabine Vogler, PhD, of the WHO Collaborating Centre for Pharmaceutical Pricing and Reimbursement Policies in Vienna, Austria.

“For gefitinib to treat non-small-lung cancer, the price in Germany is 172% higher than in New Zealand.”

To uncover these price differences, Dr Vogler and her colleagues reviewed official drug price data from the Pharma Price Information (PPI) service of the Austrian Public Health Institute for 16 European countries**, and from the pharmaceutical schedules in Australia and New Zealand.

The researchers compared what manufacturers charged for a unit (ie, price per tablet or vial) of 31 originator cancer drugs in June 2013.

None of these drugs had a unit price lower than €10. Four drugs (13%) had an average unit manufacturer price between €250 and €500, and 2 drugs (6%) had an average unit price between €500 and €1000.

Seven drugs (23%) had an average unit price higher than €1000. For example, plerixafor cost over €5000 per injection.

The price differences between the highest- and lowest-priced countries ranged from 28% to 50% for a third of the drugs sampled, between 50% and 100% for half of the drugs, and between 100% and 200% for 3 drugs (10%).

The researchers noted that information on real drug prices is scarce. The cancer drug prices they surveyed did not include confidential discounts such as those agreed upon in managed-entry arrangements that are increasingly used in countries such as Australia, Italy, the UK, and the Netherlands.

“Some high-income countries have managed to barter the manufacturers down to lower prices, but these agreements, including the agreed prices, are confidential,” Dr Vogler explained.

“Although these agreements ensure patient access to new drugs, other countries risk overpaying when setting drug prices through the common practice of external price referencing, or international price comparison, because they can only use the official undiscounted prices as a benchmark. There needs to be far more transparency.”

“We hope that our findings will provide concrete evidence for policymakers to take action to address high prices and ensure more transparency in cancer drug pricing so that costs and access to new drugs does not depend on where a patient lives.”

*Gemcitabine and zoledronic acid have generic versions in several countries, and originator prices were decreased in some countries following patent expiry but not in others.

**Austria, Belgium, Denmark, Germany, Greece, Finland, France, Italy, Ireland, the Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, and the UK.

Chemotherapy drugs

Photo by Bill Branson

The price of cancer drugs varies widely between European countries, Australia, and New Zealand, according to a study published in The Lancet Oncology.

The study indicates that, overall, the UK and Mediterranean countries such as Greece, Spain, and Portugal pay the lowest average unit manufacturer prices for a group of 31 originator cancer drugs (new drugs under patent).

And Sweden, Switzerland, and Germany pay the highest prices.

The greatest differences in price were noted for gemcitabine, which costs €209 per vial in New Zealand and €43 in Australia, and zoledronic acid, which costs €330 per vial in New Zealand but €128 in Greece.*

“Public payers in Germany are paying 223% more in terms of official prices for interferon alfa 2b for melanoma and leukemia treatment than those in Greece,” noted study author Sabine Vogler, PhD, of the WHO Collaborating Centre for Pharmaceutical Pricing and Reimbursement Policies in Vienna, Austria.

“For gefitinib to treat non-small-lung cancer, the price in Germany is 172% higher than in New Zealand.”

To uncover these price differences, Dr Vogler and her colleagues reviewed official drug price data from the Pharma Price Information (PPI) service of the Austrian Public Health Institute for 16 European countries**, and from the pharmaceutical schedules in Australia and New Zealand.

The researchers compared what manufacturers charged for a unit (ie, price per tablet or vial) of 31 originator cancer drugs in June 2013.

None of these drugs had a unit price lower than €10. Four drugs (13%) had an average unit manufacturer price between €250 and €500, and 2 drugs (6%) had an average unit price between €500 and €1000.

Seven drugs (23%) had an average unit price higher than €1000. For example, plerixafor cost over €5000 per injection.

The price differences between the highest- and lowest-priced countries ranged from 28% to 50% for a third of the drugs sampled, between 50% and 100% for half of the drugs, and between 100% and 200% for 3 drugs (10%).

The researchers noted that information on real drug prices is scarce. The cancer drug prices they surveyed did not include confidential discounts such as those agreed upon in managed-entry arrangements that are increasingly used in countries such as Australia, Italy, the UK, and the Netherlands.

“Some high-income countries have managed to barter the manufacturers down to lower prices, but these agreements, including the agreed prices, are confidential,” Dr Vogler explained.

“Although these agreements ensure patient access to new drugs, other countries risk overpaying when setting drug prices through the common practice of external price referencing, or international price comparison, because they can only use the official undiscounted prices as a benchmark. There needs to be far more transparency.”

“We hope that our findings will provide concrete evidence for policymakers to take action to address high prices and ensure more transparency in cancer drug pricing so that costs and access to new drugs does not depend on where a patient lives.”

*Gemcitabine and zoledronic acid have generic versions in several countries, and originator prices were decreased in some countries following patent expiry but not in others.

**Austria, Belgium, Denmark, Germany, Greece, Finland, France, Italy, Ireland, the Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, and the UK.

Chemotherapy drugs

Photo by Bill Branson

The price of cancer drugs varies widely between European countries, Australia, and New Zealand, according to a study published in The Lancet Oncology.

The study indicates that, overall, the UK and Mediterranean countries such as Greece, Spain, and Portugal pay the lowest average unit manufacturer prices for a group of 31 originator cancer drugs (new drugs under patent).

And Sweden, Switzerland, and Germany pay the highest prices.

The greatest differences in price were noted for gemcitabine, which costs €209 per vial in New Zealand and €43 in Australia, and zoledronic acid, which costs €330 per vial in New Zealand but €128 in Greece.*

“Public payers in Germany are paying 223% more in terms of official prices for interferon alfa 2b for melanoma and leukemia treatment than those in Greece,” noted study author Sabine Vogler, PhD, of the WHO Collaborating Centre for Pharmaceutical Pricing and Reimbursement Policies in Vienna, Austria.

“For gefitinib to treat non-small-lung cancer, the price in Germany is 172% higher than in New Zealand.”

To uncover these price differences, Dr Vogler and her colleagues reviewed official drug price data from the Pharma Price Information (PPI) service of the Austrian Public Health Institute for 16 European countries**, and from the pharmaceutical schedules in Australia and New Zealand.

The researchers compared what manufacturers charged for a unit (ie, price per tablet or vial) of 31 originator cancer drugs in June 2013.

None of these drugs had a unit price lower than €10. Four drugs (13%) had an average unit manufacturer price between €250 and €500, and 2 drugs (6%) had an average unit price between €500 and €1000.

Seven drugs (23%) had an average unit price higher than €1000. For example, plerixafor cost over €5000 per injection.

The price differences between the highest- and lowest-priced countries ranged from 28% to 50% for a third of the drugs sampled, between 50% and 100% for half of the drugs, and between 100% and 200% for 3 drugs (10%).

The researchers noted that information on real drug prices is scarce. The cancer drug prices they surveyed did not include confidential discounts such as those agreed upon in managed-entry arrangements that are increasingly used in countries such as Australia, Italy, the UK, and the Netherlands.

“Some high-income countries have managed to barter the manufacturers down to lower prices, but these agreements, including the agreed prices, are confidential,” Dr Vogler explained.

“Although these agreements ensure patient access to new drugs, other countries risk overpaying when setting drug prices through the common practice of external price referencing, or international price comparison, because they can only use the official undiscounted prices as a benchmark. There needs to be far more transparency.”

“We hope that our findings will provide concrete evidence for policymakers to take action to address high prices and ensure more transparency in cancer drug pricing so that costs and access to new drugs does not depend on where a patient lives.”

*Gemcitabine and zoledronic acid have generic versions in several countries, and originator prices were decreased in some countries following patent expiry but not in others.

**Austria, Belgium, Denmark, Germany, Greece, Finland, France, Italy, Ireland, the Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, and the UK.

Reef stonefish

Photo by Richard Ling

Research involving the stonefish—an animal that protects itself using razor-sharp, venom-filled spines—has provided unexpected insight into the human immune response that causes hematopoietic stem cell transplants (HSCTs) to fail.

The insight is now being used to develop immunosuppressants that could potentially improve the success rate of HSCTs.

Researchers explained this surprising connection in PNAS.

Their study indicated that the lethal component of stonefish venom, a protein called stonustoxin, is an ancient relative of the human immune protein perforin.

The body unleashes perforin to destroy virally infected and cancerous cells. Unwanted or excessive perforin activity is responsible for a range of medical problems, including the rejection of HSCTs.

Perforin proteins attach themselves to a cell and assemble to form giant pores on the cell surface. Each pore contains around 20 perforin proteins that stick together in a symmetrical fashion. The pores are big enough to allow toxins to enter the cell, killing it from within.

How these pores form is a mystery, but the current study has revealed a key part of the pore-assembly mechanism.

To make this discovery, the researchers used synchrotron radiation to visualize the atomic structure of stonustoxin. They found the toxin contains 2 perforin-like proteins stuck together.

Seeing how these 2 proteins interact has helped the researchers on their way to understanding how the full assembly of 20 perforin molecules forms a complete pore.

The team is also using their new insight to develop perforin inhibitors.

“Already, the structure of stonustoxin is starting to inform our drug development program, and we now understand the very first stages of perforin pore formation,” said James Whisstock, PhD, of Monash University in Melbourne, Victoria, Australia.

“This type of mechanistic information is extremely useful in developing new strategies to inhibit perforin itself.”

Reef stonefish

Photo by Richard Ling

Research involving the stonefish—an animal that protects itself using razor-sharp, venom-filled spines—has provided unexpected insight into the human immune response that causes hematopoietic stem cell transplants (HSCTs) to fail.

The insight is now being used to develop immunosuppressants that could potentially improve the success rate of HSCTs.

Researchers explained this surprising connection in PNAS.

Their study indicated that the lethal component of stonefish venom, a protein called stonustoxin, is an ancient relative of the human immune protein perforin.

The body unleashes perforin to destroy virally infected and cancerous cells. Unwanted or excessive perforin activity is responsible for a range of medical problems, including the rejection of HSCTs.

Perforin proteins attach themselves to a cell and assemble to form giant pores on the cell surface. Each pore contains around 20 perforin proteins that stick together in a symmetrical fashion. The pores are big enough to allow toxins to enter the cell, killing it from within.

How these pores form is a mystery, but the current study has revealed a key part of the pore-assembly mechanism.

To make this discovery, the researchers used synchrotron radiation to visualize the atomic structure of stonustoxin. They found the toxin contains 2 perforin-like proteins stuck together.

Seeing how these 2 proteins interact has helped the researchers on their way to understanding how the full assembly of 20 perforin molecules forms a complete pore.

The team is also using their new insight to develop perforin inhibitors.

“Already, the structure of stonustoxin is starting to inform our drug development program, and we now understand the very first stages of perforin pore formation,” said James Whisstock, PhD, of Monash University in Melbourne, Victoria, Australia.

“This type of mechanistic information is extremely useful in developing new strategies to inhibit perforin itself.”

Reef stonefish

Photo by Richard Ling

Research involving the stonefish—an animal that protects itself using razor-sharp, venom-filled spines—has provided unexpected insight into the human immune response that causes hematopoietic stem cell transplants (HSCTs) to fail.

The insight is now being used to develop immunosuppressants that could potentially improve the success rate of HSCTs.

Researchers explained this surprising connection in PNAS.

Their study indicated that the lethal component of stonefish venom, a protein called stonustoxin, is an ancient relative of the human immune protein perforin.

The body unleashes perforin to destroy virally infected and cancerous cells. Unwanted or excessive perforin activity is responsible for a range of medical problems, including the rejection of HSCTs.

Perforin proteins attach themselves to a cell and assemble to form giant pores on the cell surface. Each pore contains around 20 perforin proteins that stick together in a symmetrical fashion. The pores are big enough to allow toxins to enter the cell, killing it from within.

How these pores form is a mystery, but the current study has revealed a key part of the pore-assembly mechanism.

To make this discovery, the researchers used synchrotron radiation to visualize the atomic structure of stonustoxin. They found the toxin contains 2 perforin-like proteins stuck together.

Seeing how these 2 proteins interact has helped the researchers on their way to understanding how the full assembly of 20 perforin molecules forms a complete pore.

The team is also using their new insight to develop perforin inhibitors.

“Already, the structure of stonustoxin is starting to inform our drug development program, and we now understand the very first stages of perforin pore formation,” said James Whisstock, PhD, of Monash University in Melbourne, Victoria, Australia.

“This type of mechanistic information is extremely useful in developing new strategies to inhibit perforin itself.”

Prescription drugs

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has approved the use of imatinib mesylate, a generic version of Novartis’s Gleevec being developed by a subsidiary of Sun Pharmaceuticals Limited.

Under the terms of a settlement agreement with Novartis, the Sun Pharma subsidiary is allowed to launch its generic imatinib in the US on February 1, 2016.

The drug will be available in 100 mg and 400 mg tablets.

The Sun Pharma subsidiary was the first company to file an abbreviated new drug application for generic imatinib with a para IV certification and is therefore eligible for 180 days of marketing exclusivity in the US.

Sun Pharma’s imatinib mesylate is approved for the following indications:

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with (Ph+ CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
•  Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1- PDGFRα fusion kinase negative or unknown
• Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

The drug is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Prescription drugs

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has approved the use of imatinib mesylate, a generic version of Novartis’s Gleevec being developed by a subsidiary of Sun Pharmaceuticals Limited.

Under the terms of a settlement agreement with Novartis, the Sun Pharma subsidiary is allowed to launch its generic imatinib in the US on February 1, 2016.

The drug will be available in 100 mg and 400 mg tablets.

The Sun Pharma subsidiary was the first company to file an abbreviated new drug application for generic imatinib with a para IV certification and is therefore eligible for 180 days of marketing exclusivity in the US.

Sun Pharma’s imatinib mesylate is approved for the following indications:

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with (Ph+ CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
•  Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1- PDGFRα fusion kinase negative or unknown
• Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

The drug is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Prescription drugs

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has approved the use of imatinib mesylate, a generic version of Novartis’s Gleevec being developed by a subsidiary of Sun Pharmaceuticals Limited.

Under the terms of a settlement agreement with Novartis, the Sun Pharma subsidiary is allowed to launch its generic imatinib in the US on February 1, 2016.

The drug will be available in 100 mg and 400 mg tablets.

The Sun Pharma subsidiary was the first company to file an abbreviated new drug application for generic imatinib with a para IV certification and is therefore eligible for 180 days of marketing exclusivity in the US.

Sun Pharma’s imatinib mesylate is approved for the following indications:

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with (Ph+ CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
•  Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1- PDGFRα fusion kinase negative or unknown
• Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

The drug is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

CML cells

Image by Difu Wu

Researchers say they have identified a mechanism governing malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs).

And their discovery has revealed a potential new therapeutic approach for chronic myeloid leukemia (CML).

Experiments in mice showed that a targeted monoclonal antibody could impair LSCs’ ability to regenerate and made them easier to eradicate with a tyrosine kinase inhibitor.

Catriona Jamieson, MD, PhD, of the University of California, San Diego, and her colleagues described this research in PNAS.

The researchers found that downregulation of Muscleblind-like 3 (MBNL3) RNA binding proteins resulted in re-expression of a human embryonic stem cell-specific alternative splicing gene regulatory network—a mechanism that controls embryonic stem cell pluripotency and fate. One effect of this was reprogramming of progenitor cells into LSCs in blast crisis CML.

“This is the first description of cancer stem cell generation through decreased expression of a transcriptional repressor of an embryonic pattern of alternative splicing that enhances stem cell self-renewal and survival,” Dr Jamieson said.

“Rather than acquiring multiple DNA mutations, as was previously thought, cancer stem cells in chronic myeloid leukemia switch to embryonic RNA splicing, which enhances their capacity to self-renew or clone themselves.”

“If we can detect and turn off embryonic splicing, we may be able to prevent cancer stem cells from propagating themselves. Also, if we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase inhibitors, we may be able to circumvent cancer relapse—a leading cause of cancer-related mortality.”

The researchers tested this theory in mice. They found that treatment with a humanized pan-CD44 monoclonal antibody and a targeted tyrosine kinase antagonist disrupted the development of LSCs in their protected microenvironment.

This forced the cells to enter the bloodstream, where dasatinib could effectively target them.

CML cells

Image by Difu Wu

Researchers say they have identified a mechanism governing malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs).

And their discovery has revealed a potential new therapeutic approach for chronic myeloid leukemia (CML).

Experiments in mice showed that a targeted monoclonal antibody could impair LSCs’ ability to regenerate and made them easier to eradicate with a tyrosine kinase inhibitor.

Catriona Jamieson, MD, PhD, of the University of California, San Diego, and her colleagues described this research in PNAS.

The researchers found that downregulation of Muscleblind-like 3 (MBNL3) RNA binding proteins resulted in re-expression of a human embryonic stem cell-specific alternative splicing gene regulatory network—a mechanism that controls embryonic stem cell pluripotency and fate. One effect of this was reprogramming of progenitor cells into LSCs in blast crisis CML.

“This is the first description of cancer stem cell generation through decreased expression of a transcriptional repressor of an embryonic pattern of alternative splicing that enhances stem cell self-renewal and survival,” Dr Jamieson said.

“Rather than acquiring multiple DNA mutations, as was previously thought, cancer stem cells in chronic myeloid leukemia switch to embryonic RNA splicing, which enhances their capacity to self-renew or clone themselves.”

“If we can detect and turn off embryonic splicing, we may be able to prevent cancer stem cells from propagating themselves. Also, if we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase inhibitors, we may be able to circumvent cancer relapse—a leading cause of cancer-related mortality.”

The researchers tested this theory in mice. They found that treatment with a humanized pan-CD44 monoclonal antibody and a targeted tyrosine kinase antagonist disrupted the development of LSCs in their protected microenvironment.

This forced the cells to enter the bloodstream, where dasatinib could effectively target them.

CML cells

Image by Difu Wu

Researchers say they have identified a mechanism governing malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs).

And their discovery has revealed a potential new therapeutic approach for chronic myeloid leukemia (CML).

Experiments in mice showed that a targeted monoclonal antibody could impair LSCs’ ability to regenerate and made them easier to eradicate with a tyrosine kinase inhibitor.

Catriona Jamieson, MD, PhD, of the University of California, San Diego, and her colleagues described this research in PNAS.

The researchers found that downregulation of Muscleblind-like 3 (MBNL3) RNA binding proteins resulted in re-expression of a human embryonic stem cell-specific alternative splicing gene regulatory network—a mechanism that controls embryonic stem cell pluripotency and fate. One effect of this was reprogramming of progenitor cells into LSCs in blast crisis CML.

“This is the first description of cancer stem cell generation through decreased expression of a transcriptional repressor of an embryonic pattern of alternative splicing that enhances stem cell self-renewal and survival,” Dr Jamieson said.

“Rather than acquiring multiple DNA mutations, as was previously thought, cancer stem cells in chronic myeloid leukemia switch to embryonic RNA splicing, which enhances their capacity to self-renew or clone themselves.”

“If we can detect and turn off embryonic splicing, we may be able to prevent cancer stem cells from propagating themselves. Also, if we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase inhibitors, we may be able to circumvent cancer relapse—a leading cause of cancer-related mortality.”

The researchers tested this theory in mice. They found that treatment with a humanized pan-CD44 monoclonal antibody and a targeted tyrosine kinase antagonist disrupted the development of LSCs in their protected microenvironment.

This forced the cells to enter the bloodstream, where dasatinib could effectively target them.

Dormant MM cells adjacent

to the tibia of a mouse

Image courtesy of the Garvan

Institute of Medical Research

Cancer cells that lie dormant in the bone can be “woken up” by changes in their surroundings, according to researchers.

The group used microscopy techniques to study multiple myeloma (MM) cells that lay “sleeping” in mouse bones.

The experiment revealed that dormant cells can be reactivated when bone tissue is broken down around them, suggesting new possibilities for

treating metastatic cancers in bone.

“Once a cancer spreads to bone, it becomes notoriously difficult to treat,” said study author Peter Croucher, PhD, of the Garvan Institute of Medical Research in Sydney, New South Wales, Australia.

“So it’s important to establish exactly what wakes those cells in bone. Is it some signal within the cells themselves, or is it a change in their environment?”

The researchers set out to discover which scenario is correct and reported their findings in Nature Communications.

Using a technique called intravital 2-photon microscopy, the team tracked the fate of dormant MM cells in the tibia of living mice.

They introduced MM cells into the mice and watched as a small number of the cells lodged in the tibia and “went to sleep.” These cells could be detected because they contained a fluorescent dye that was quickly lost from dividing cells.

“Because we were looking at a long bone like a tibia, we could watch the same sleeping cancer cells, in the same bone, in the same mouse, over a long period of time, and this is something that hasn’t been done before,” said Tri Giang Phan, PhD, of the Garvan Institute of Medical Research.

Dr Croucher said that studying the same set of cells over a period of months revealed vital clues about what caused them to reactivate.

“Because we’ve done it this way, we can show that there are a great many dormant cells, yet only some of them get woken up, and those that do wake, wake at different times,” he noted.

“We even saw some cells that woke then went back to sleep again. The fact that these myeloma cells behave so differently, despite coming from the same cancer cell line, gave us our first clue that it is a signal from outside the cells that is controlling when they wake.”

Explaining the phenomenon

The researchers’ next challenge was to determine the precise nature of the “wake-up call” from bone.

“[W]e’ve shown that bone’s dynamic process of building up and breaking down can send signals to cancer cells to stay sleeping or to wake,” said Michelle McDonald, PhD, of the Garvan Institute of Medical Research.

“We were able to show that myeloma cells are usually kept asleep by close association with a layer of osteoblast-like cells, called bone-lining cells, in the endosteum. The bone-lining cells are essentially inactive, so we can think of them as providing a quiet environment in which myeloma cells sleep undisturbed.”

“Crucially, we can wake those myeloma cells by activating osteoclasts, which break down bone tissue. We think the osteoclasts are physically changing the local environment of the cancer cells and waking them up in the process, as if they were literally throwing them out of bed.”

“We know that bone remodeling is going on in all of us. So a myeloma cell could be woken in an essentially random fashion, by having its local environment remodeled by osteoclasts. Essentially, a cancer cell could be woken by being in the wrong place at the wrong time.”

Implications for treatment

So what do these findings mean for treating secondary cancers in bone?

“Now we can see that the cancer cells are woken by changes in the surrounding bone, we can think in a whole new way about treating bone metastasis,” Dr Croucher said. “And there are 2 treatment approaches in particular that have promise.”

“The first is that we could inhibit the breakdown of bone by osteoclasts so as to keep cancer cells in long-term hibernation. In fact, there are already drugs that can do this, such as bisphosphonates, and there’s already evidence that these drugs do improve survival in breast cancer patients.”

“The other, more radical, option is to do the opposite—to wake the sleeping cells by activating osteoclasts and driving the breakdown of bone. Most cancer treatments target active, dividing cells. So waking the sleeping cells should make them susceptible to those therapies and, ultimately, could eradicate any residual disease.”

Dormant MM cells adjacent

to the tibia of a mouse

Image courtesy of the Garvan

Institute of Medical Research

Cancer cells that lie dormant in the bone can be “woken up” by changes in their surroundings, according to researchers.

The group used microscopy techniques to study multiple myeloma (MM) cells that lay “sleeping” in mouse bones.

The experiment revealed that dormant cells can be reactivated when bone tissue is broken down around them, suggesting new possibilities for

treating metastatic cancers in bone.

“Once a cancer spreads to bone, it becomes notoriously difficult to treat,” said study author Peter Croucher, PhD, of the Garvan Institute of Medical Research in Sydney, New South Wales, Australia.

“So it’s important to establish exactly what wakes those cells in bone. Is it some signal within the cells themselves, or is it a change in their environment?”

The researchers set out to discover which scenario is correct and reported their findings in Nature Communications.

Using a technique called intravital 2-photon microscopy, the team tracked the fate of dormant MM cells in the tibia of living mice.

They introduced MM cells into the mice and watched as a small number of the cells lodged in the tibia and “went to sleep.” These cells could be detected because they contained a fluorescent dye that was quickly lost from dividing cells.

“Because we were looking at a long bone like a tibia, we could watch the same sleeping cancer cells, in the same bone, in the same mouse, over a long period of time, and this is something that hasn’t been done before,” said Tri Giang Phan, PhD, of the Garvan Institute of Medical Research.

Dr Croucher said that studying the same set of cells over a period of months revealed vital clues about what caused them to reactivate.

“Because we’ve done it this way, we can show that there are a great many dormant cells, yet only some of them get woken up, and those that do wake, wake at different times,” he noted.

“We even saw some cells that woke then went back to sleep again. The fact that these myeloma cells behave so differently, despite coming from the same cancer cell line, gave us our first clue that it is a signal from outside the cells that is controlling when they wake.”

Explaining the phenomenon

The researchers’ next challenge was to determine the precise nature of the “wake-up call” from bone.

“[W]e’ve shown that bone’s dynamic process of building up and breaking down can send signals to cancer cells to stay sleeping or to wake,” said Michelle McDonald, PhD, of the Garvan Institute of Medical Research.

“We were able to show that myeloma cells are usually kept asleep by close association with a layer of osteoblast-like cells, called bone-lining cells, in the endosteum. The bone-lining cells are essentially inactive, so we can think of them as providing a quiet environment in which myeloma cells sleep undisturbed.”

“Crucially, we can wake those myeloma cells by activating osteoclasts, which break down bone tissue. We think the osteoclasts are physically changing the local environment of the cancer cells and waking them up in the process, as if they were literally throwing them out of bed.”

“We know that bone remodeling is going on in all of us. So a myeloma cell could be woken in an essentially random fashion, by having its local environment remodeled by osteoclasts. Essentially, a cancer cell could be woken by being in the wrong place at the wrong time.”

Implications for treatment

So what do these findings mean for treating secondary cancers in bone?

“Now we can see that the cancer cells are woken by changes in the surrounding bone, we can think in a whole new way about treating bone metastasis,” Dr Croucher said. “And there are 2 treatment approaches in particular that have promise.”

“The first is that we could inhibit the breakdown of bone by osteoclasts so as to keep cancer cells in long-term hibernation. In fact, there are already drugs that can do this, such as bisphosphonates, and there’s already evidence that these drugs do improve survival in breast cancer patients.”

“The other, more radical, option is to do the opposite—to wake the sleeping cells by activating osteoclasts and driving the breakdown of bone. Most cancer treatments target active, dividing cells. So waking the sleeping cells should make them susceptible to those therapies and, ultimately, could eradicate any residual disease.”

Dormant MM cells adjacent

to the tibia of a mouse

Image courtesy of the Garvan

Institute of Medical Research

Cancer cells that lie dormant in the bone can be “woken up” by changes in their surroundings, according to researchers.

The group used microscopy techniques to study multiple myeloma (MM) cells that lay “sleeping” in mouse bones.

The experiment revealed that dormant cells can be reactivated when bone tissue is broken down around them, suggesting new possibilities for

treating metastatic cancers in bone.

“Once a cancer spreads to bone, it becomes notoriously difficult to treat,” said study author Peter Croucher, PhD, of the Garvan Institute of Medical Research in Sydney, New South Wales, Australia.

“So it’s important to establish exactly what wakes those cells in bone. Is it some signal within the cells themselves, or is it a change in their environment?”

The researchers set out to discover which scenario is correct and reported their findings in Nature Communications.

Using a technique called intravital 2-photon microscopy, the team tracked the fate of dormant MM cells in the tibia of living mice.

They introduced MM cells into the mice and watched as a small number of the cells lodged in the tibia and “went to sleep.” These cells could be detected because they contained a fluorescent dye that was quickly lost from dividing cells.

“Because we were looking at a long bone like a tibia, we could watch the same sleeping cancer cells, in the same bone, in the same mouse, over a long period of time, and this is something that hasn’t been done before,” said Tri Giang Phan, PhD, of the Garvan Institute of Medical Research.

Dr Croucher said that studying the same set of cells over a period of months revealed vital clues about what caused them to reactivate.

“Because we’ve done it this way, we can show that there are a great many dormant cells, yet only some of them get woken up, and those that do wake, wake at different times,” he noted.

“We even saw some cells that woke then went back to sleep again. The fact that these myeloma cells behave so differently, despite coming from the same cancer cell line, gave us our first clue that it is a signal from outside the cells that is controlling when they wake.”

Explaining the phenomenon

The researchers’ next challenge was to determine the precise nature of the “wake-up call” from bone.

“[W]e’ve shown that bone’s dynamic process of building up and breaking down can send signals to cancer cells to stay sleeping or to wake,” said Michelle McDonald, PhD, of the Garvan Institute of Medical Research.

“We were able to show that myeloma cells are usually kept asleep by close association with a layer of osteoblast-like cells, called bone-lining cells, in the endosteum. The bone-lining cells are essentially inactive, so we can think of them as providing a quiet environment in which myeloma cells sleep undisturbed.”

“Crucially, we can wake those myeloma cells by activating osteoclasts, which break down bone tissue. We think the osteoclasts are physically changing the local environment of the cancer cells and waking them up in the process, as if they were literally throwing them out of bed.”

“We know that bone remodeling is going on in all of us. So a myeloma cell could be woken in an essentially random fashion, by having its local environment remodeled by osteoclasts. Essentially, a cancer cell could be woken by being in the wrong place at the wrong time.”

Implications for treatment

So what do these findings mean for treating secondary cancers in bone?

“Now we can see that the cancer cells are woken by changes in the surrounding bone, we can think in a whole new way about treating bone metastasis,” Dr Croucher said. “And there are 2 treatment approaches in particular that have promise.”

“The first is that we could inhibit the breakdown of bone by osteoclasts so as to keep cancer cells in long-term hibernation. In fact, there are already drugs that can do this, such as bisphosphonates, and there’s already evidence that these drugs do improve survival in breast cancer patients.”

“The other, more radical, option is to do the opposite—to wake the sleeping cells by activating osteoclasts and driving the breakdown of bone. Most cancer treatments target active, dividing cells. So waking the sleeping cells should make them susceptible to those therapies and, ultimately, could eradicate any residual disease.”

Vials and a syringe

Results observed in healthy subjects suggest ACE910, a factor VIIIa-mimetic bispecific antibody, may be safe and effective for patients with severe hemophilia A.

The data indicate that a weekly injection of ACE910 may prevent excessive bleeding, whereas existing hemophilia treatments require 2 to 3 injections per week.

Furthermore, ACE910 may be less likely to prompt factor VIII inhibitors, and the drug may be effective in patients who already have inhibitors.

Researchers reported the results of this phase 1 trial in Blood.

The team enrolled healthy male volunteers (ages 20 to 44), 40 of whom were Japanese and 24 of whom were Caucasian.

In part A of the study, the Japanese volunteers were randomized to receive 1 of 5 doses of ACE910 (ranging from 0.001 to 1 mg/kg) or placebo subcutaneously. There were 6 subjects per ACE910 dose group and 10 subjects who received placebo.

In part B, the Caucasian volunteers were randomized to receive 1 of 3 doses (ranging from 0.1 to 1 mg/kg) or placebo subcutaneously. There were 6 subjects in each group.

The volunteers were monitored based on their dose group, ranging from 4 weeks of observation for 0.001 mg/kg to 24 weeks for 1 mg/kg.

In all 48, subjects received ACE910. The researchers said that doses up to 1 mg/kg appeared to be safe. There were 15 adverse events (AEs) in 13 (27.1%) subjects receiving ACE910, compared to 6 AEs in 4 (25%) subjects receiving placebo.

There was 1 moderate AE (nasopharyngitis in 1 Caucasian subject receiving ACE910 at 0.1 mg/kg), but all other events were mild. There were no serious AEs or AEs that led to study withdrawal. The incidence of AEs did not differ according to dose or ethnicity.

The researchers did not observe any cases of hypercoagulability, hypersensitivity, serum cytokine concentration abnormality, or injection site reaction.

ACE910 absorbed into the plasma at a steady rate similar for both Japanese and Caucasian volunteers and remained in the blood with a half-life of 4 to 5 weeks, suggesting the drug’s therapeutic effects could be sustained with once-weekly subcutaneous dosing of ACE910.

Two subjects (1 Japanese and 1 Caucasian) were positive for anti-ACE910 antibodies. One subject was positive for antibodies before and after receiving ACE910, and the other was only positive after.

“These data are very encouraging for patients with severe hemophilia A, irrespective of the presence of factor VIII inhibitors, as ACE910 has the potential to offer the opportunity to live more normal lives without constantly planning around the next injection,” said study author Midori Shima, MD, PhD, of Nara Medical University in Kashihara, Japan.

“The first clinical investigation of this drug in hemophilia A patients with or without factor VIII inhibitors has already been implemented, and phase 3 studies are being planned to start in the near future.”

Interim results of a phase 1 study of ACE910 in hemophilia A patients (with and without inhibitors) were presented at ISTH 2015. And ACE910 was recently granted breakthrough designation from the US Food and Drug Administration.

Vials and a syringe

Results observed in healthy subjects suggest ACE910, a factor VIIIa-mimetic bispecific antibody, may be safe and effective for patients with severe hemophilia A.

The data indicate that a weekly injection of ACE910 may prevent excessive bleeding, whereas existing hemophilia treatments require 2 to 3 injections per week.

Furthermore, ACE910 may be less likely to prompt factor VIII inhibitors, and the drug may be effective in patients who already have inhibitors.

Researchers reported the results of this phase 1 trial in Blood.

The team enrolled healthy male volunteers (ages 20 to 44), 40 of whom were Japanese and 24 of whom were Caucasian.

In part A of the study, the Japanese volunteers were randomized to receive 1 of 5 doses of ACE910 (ranging from 0.001 to 1 mg/kg) or placebo subcutaneously. There were 6 subjects per ACE910 dose group and 10 subjects who received placebo.

In part B, the Caucasian volunteers were randomized to receive 1 of 3 doses (ranging from 0.1 to 1 mg/kg) or placebo subcutaneously. There were 6 subjects in each group.

The volunteers were monitored based on their dose group, ranging from 4 weeks of observation for 0.001 mg/kg to 24 weeks for 1 mg/kg.

In all 48, subjects received ACE910. The researchers said that doses up to 1 mg/kg appeared to be safe. There were 15 adverse events (AEs) in 13 (27.1%) subjects receiving ACE910, compared to 6 AEs in 4 (25%) subjects receiving placebo.

There was 1 moderate AE (nasopharyngitis in 1 Caucasian subject receiving ACE910 at 0.1 mg/kg), but all other events were mild. There were no serious AEs or AEs that led to study withdrawal. The incidence of AEs did not differ according to dose or ethnicity.

The researchers did not observe any cases of hypercoagulability, hypersensitivity, serum cytokine concentration abnormality, or injection site reaction.

ACE910 absorbed into the plasma at a steady rate similar for both Japanese and Caucasian volunteers and remained in the blood with a half-life of 4 to 5 weeks, suggesting the drug’s therapeutic effects could be sustained with once-weekly subcutaneous dosing of ACE910.

Two subjects (1 Japanese and 1 Caucasian) were positive for anti-ACE910 antibodies. One subject was positive for antibodies before and after receiving ACE910, and the other was only positive after.

“These data are very encouraging for patients with severe hemophilia A, irrespective of the presence of factor VIII inhibitors, as ACE910 has the potential to offer the opportunity to live more normal lives without constantly planning around the next injection,” said study author Midori Shima, MD, PhD, of Nara Medical University in Kashihara, Japan.

“The first clinical investigation of this drug in hemophilia A patients with or without factor VIII inhibitors has already been implemented, and phase 3 studies are being planned to start in the near future.”

Interim results of a phase 1 study of ACE910 in hemophilia A patients (with and without inhibitors) were presented at ISTH 2015. And ACE910 was recently granted breakthrough designation from the US Food and Drug Administration.

Vials and a syringe

Results observed in healthy subjects suggest ACE910, a factor VIIIa-mimetic bispecific antibody, may be safe and effective for patients with severe hemophilia A.

The data indicate that a weekly injection of ACE910 may prevent excessive bleeding, whereas existing hemophilia treatments require 2 to 3 injections per week.

Furthermore, ACE910 may be less likely to prompt factor VIII inhibitors, and the drug may be effective in patients who already have inhibitors.

Researchers reported the results of this phase 1 trial in Blood.

The team enrolled healthy male volunteers (ages 20 to 44), 40 of whom were Japanese and 24 of whom were Caucasian.

In part A of the study, the Japanese volunteers were randomized to receive 1 of 5 doses of ACE910 (ranging from 0.001 to 1 mg/kg) or placebo subcutaneously. There were 6 subjects per ACE910 dose group and 10 subjects who received placebo.

In part B, the Caucasian volunteers were randomized to receive 1 of 3 doses (ranging from 0.1 to 1 mg/kg) or placebo subcutaneously. There were 6 subjects in each group.

The volunteers were monitored based on their dose group, ranging from 4 weeks of observation for 0.001 mg/kg to 24 weeks for 1 mg/kg.

In all 48, subjects received ACE910. The researchers said that doses up to 1 mg/kg appeared to be safe. There were 15 adverse events (AEs) in 13 (27.1%) subjects receiving ACE910, compared to 6 AEs in 4 (25%) subjects receiving placebo.

There was 1 moderate AE (nasopharyngitis in 1 Caucasian subject receiving ACE910 at 0.1 mg/kg), but all other events were mild. There were no serious AEs or AEs that led to study withdrawal. The incidence of AEs did not differ according to dose or ethnicity.

The researchers did not observe any cases of hypercoagulability, hypersensitivity, serum cytokine concentration abnormality, or injection site reaction.

ACE910 absorbed into the plasma at a steady rate similar for both Japanese and Caucasian volunteers and remained in the blood with a half-life of 4 to 5 weeks, suggesting the drug’s therapeutic effects could be sustained with once-weekly subcutaneous dosing of ACE910.

Two subjects (1 Japanese and 1 Caucasian) were positive for anti-ACE910 antibodies. One subject was positive for antibodies before and after receiving ACE910, and the other was only positive after.

“These data are very encouraging for patients with severe hemophilia A, irrespective of the presence of factor VIII inhibitors, as ACE910 has the potential to offer the opportunity to live more normal lives without constantly planning around the next injection,” said study author Midori Shima, MD, PhD, of Nara Medical University in Kashihara, Japan.

“The first clinical investigation of this drug in hemophilia A patients with or without factor VIII inhibitors has already been implemented, and phase 3 studies are being planned to start in the near future.”

Interim results of a phase 1 study of ACE910 in hemophilia A patients (with and without inhibitors) were presented at ISTH 2015. And ACE910 was recently granted breakthrough designation from the US Food and Drug Administration.

Thrombus

Image by Andre E.X. Brown

A group of biophysicists have developed a mathematical model of arterial thrombus formation.

The team described the process of platelet aggregation as being similar to the video game Tetris and derived equations that allowed them to reproduce the wave process of platelet aggregate formation in a blood vessel.

Mikhail Panteleev, PhD, of Moscow State University in Russia, and his colleagues described this work in PLOS ONE.

Looking at thrombus formation in the same way as the tiles stack up in Tetris is a key aspect of the team’s model. In the game, the tiles either drop down onto a flat surface or become attached to parts sticking out from the rest of the block.

The researchers said there are only 2 differences between thrombus formation and the game.

Unlike in Tetris, when a layer of a thrombus is complete, it does not disappear. So, as time passes, a thrombus is capable of obstructing the space it is in.

And Tetris includes tiles of several different shapes. But, in a thrombus, the “falling tiles” are always the same—thrombocytes.

Having described the mathematical process of how vacant areas on the surface of a growing thrombus are filled, the researchers were able to build first a 1-dimensional model (as in Tetris) and then a 2-dimensional model (where thrombocytes are deposited in a dimensional plane).

At one point, the researchers began to consider certain thrombocytes as being dimensionless and the thrombus itself as being continuous. In other words, they went from a discrete model to a continuous model.

In a discrete model, the system under study consists of individual particles, and the behavior of each particle can be tracked individually. In a continuous model, the system under study consists of solid objects that can freely change their size or any other characteristic.

The sequential solution of the equations enabled the researchers to reproduce the dynamics of thrombus growth and study clot behavior under various conditions—in the case of damage to the vascular wall, for example.

Active media and autowaves

The researchers said the process of thrombus formation is like an autowave. And the blood, which carries platelets and proteins for coagulation, is an active medium.

The term “active medium” plays a key role in non-linear dynamics—the science of mathematical modeling of a range of systems, from mixtures of interacting chemicals and lasers to forest fires and even social networks.

One way to describe an active medium is to use the example of a forest fire. Every dry tree is not simply a passive object but a potential source of thermal energy. If there is a fire near a dry tree, it too will start to burn and provide more heat, which can then ignite other trees. The ability of elements in the system to release energy is a key feature of an active medium.

In active media, a local event (lightning striking a tree, for example) can initiate a transition process in a system from one state to another (in this case, a dry tree becomes a burning tree).

This process spreads like a wave in space, and the specific physical nature of the system is not so important. The same equation can be used to describe entirely different cases.

The term “autowave” means the wave propagation process is not passive, as in the case of seismic waves traveling from an earthquake’s epicenter, but active. At each point, the wave receives more energy.

In the case of thrombus formation, these terms apply to thrombocytes flowing in plasma. The thrombocytes can go from a free-flowing state to a deposited state.

Under normal circumstances, thrombocytes flow freely in the bloodstream, but if the vascular wall becomes damaged, they start to adhere to one another and to the vascular wall.

The blood also contains proteins required for thrombus formation. Even if there are no thrombocytes, reactions with these proteins are able to help form a clot to block a damaged vessel, and these reactions also occur in the form of autowaves.

Normally, thrombi prevent blood loss in the human body when a blood vessel has become damaged. Sometimes, however, thrombus formation occurs not as a result of an injury with damage to a blood vessel, but as a result of a reaction to a pathological process.

This type of thrombus formation can block a vessel completely and cut off the blood supply to tissues and organs. This, in turn, can lead to myocardial infarction, stroke, or gangrene of the extremities.

The researchers say their new model correctly describes arterial thrombus formation. These particular thrombi consist mainly of thrombocytes, and blood proteins play a relatively small role in the process.

“We have always had difficulty working with arterial blood clots in particular, in terms of developing and implementing computer models, because the subject involves a very difficult combination of mechanics (cell attachments), hydrodynamics with variable geometry, and biochemistry,” Dr Panteleev said.

“In our paper in PLOS ONE, we tried to use the most primitive description of a thrombus as a continuous medium, rather than discrete particles. This approximation is rough in many respects, and it limits the scope of the research, but it is able to give us some common patterns.”

“On the one hand, we plan to continue to apply it to specific tasks, as far as is possible, and on the other hand, we are developing more sophisticated and advanced models with 3-dimensional blood cells, the full mechanics of their interaction, and the proper biochemistry.”

Thrombus

Image by Andre E.X. Brown

A group of biophysicists have developed a mathematical model of arterial thrombus formation.

The team described the process of platelet aggregation as being similar to the video game Tetris and derived equations that allowed them to reproduce the wave process of platelet aggregate formation in a blood vessel.

Mikhail Panteleev, PhD, of Moscow State University in Russia, and his colleagues described this work in PLOS ONE.

Looking at thrombus formation in the same way as the tiles stack up in Tetris is a key aspect of the team’s model. In the game, the tiles either drop down onto a flat surface or become attached to parts sticking out from the rest of the block.

The researchers said there are only 2 differences between thrombus formation and the game.

Unlike in Tetris, when a layer of a thrombus is complete, it does not disappear. So, as time passes, a thrombus is capable of obstructing the space it is in.

And Tetris includes tiles of several different shapes. But, in a thrombus, the “falling tiles” are always the same—thrombocytes.

Having described the mathematical process of how vacant areas on the surface of a growing thrombus are filled, the researchers were able to build first a 1-dimensional model (as in Tetris) and then a 2-dimensional model (where thrombocytes are deposited in a dimensional plane).

At one point, the researchers began to consider certain thrombocytes as being dimensionless and the thrombus itself as being continuous. In other words, they went from a discrete model to a continuous model.

In a discrete model, the system under study consists of individual particles, and the behavior of each particle can be tracked individually. In a continuous model, the system under study consists of solid objects that can freely change their size or any other characteristic.

The sequential solution of the equations enabled the researchers to reproduce the dynamics of thrombus growth and study clot behavior under various conditions—in the case of damage to the vascular wall, for example.

Active media and autowaves

The researchers said the process of thrombus formation is like an autowave. And the blood, which carries platelets and proteins for coagulation, is an active medium.

The term “active medium” plays a key role in non-linear dynamics—the science of mathematical modeling of a range of systems, from mixtures of interacting chemicals and lasers to forest fires and even social networks.

One way to describe an active medium is to use the example of a forest fire. Every dry tree is not simply a passive object but a potential source of thermal energy. If there is a fire near a dry tree, it too will start to burn and provide more heat, which can then ignite other trees. The ability of elements in the system to release energy is a key feature of an active medium.

In active media, a local event (lightning striking a tree, for example) can initiate a transition process in a system from one state to another (in this case, a dry tree becomes a burning tree).

This process spreads like a wave in space, and the specific physical nature of the system is not so important. The same equation can be used to describe entirely different cases.

The term “autowave” means the wave propagation process is not passive, as in the case of seismic waves traveling from an earthquake’s epicenter, but active. At each point, the wave receives more energy.

In the case of thrombus formation, these terms apply to thrombocytes flowing in plasma. The thrombocytes can go from a free-flowing state to a deposited state.

Under normal circumstances, thrombocytes flow freely in the bloodstream, but if the vascular wall becomes damaged, they start to adhere to one another and to the vascular wall.

The blood also contains proteins required for thrombus formation. Even if there are no thrombocytes, reactions with these proteins are able to help form a clot to block a damaged vessel, and these reactions also occur in the form of autowaves.

Normally, thrombi prevent blood loss in the human body when a blood vessel has become damaged. Sometimes, however, thrombus formation occurs not as a result of an injury with damage to a blood vessel, but as a result of a reaction to a pathological process.

This type of thrombus formation can block a vessel completely and cut off the blood supply to tissues and organs. This, in turn, can lead to myocardial infarction, stroke, or gangrene of the extremities.

The researchers say their new model correctly describes arterial thrombus formation. These particular thrombi consist mainly of thrombocytes, and blood proteins play a relatively small role in the process.

“We have always had difficulty working with arterial blood clots in particular, in terms of developing and implementing computer models, because the subject involves a very difficult combination of mechanics (cell attachments), hydrodynamics with variable geometry, and biochemistry,” Dr Panteleev said.

“In our paper in PLOS ONE, we tried to use the most primitive description of a thrombus as a continuous medium, rather than discrete particles. This approximation is rough in many respects, and it limits the scope of the research, but it is able to give us some common patterns.”

“On the one hand, we plan to continue to apply it to specific tasks, as far as is possible, and on the other hand, we are developing more sophisticated and advanced models with 3-dimensional blood cells, the full mechanics of their interaction, and the proper biochemistry.”

Thrombus

Image by Andre E.X. Brown

A group of biophysicists have developed a mathematical model of arterial thrombus formation.

The team described the process of platelet aggregation as being similar to the video game Tetris and derived equations that allowed them to reproduce the wave process of platelet aggregate formation in a blood vessel.

Mikhail Panteleev, PhD, of Moscow State University in Russia, and his colleagues described this work in PLOS ONE.

Looking at thrombus formation in the same way as the tiles stack up in Tetris is a key aspect of the team’s model. In the game, the tiles either drop down onto a flat surface or become attached to parts sticking out from the rest of the block.

The researchers said there are only 2 differences between thrombus formation and the game.

Unlike in Tetris, when a layer of a thrombus is complete, it does not disappear. So, as time passes, a thrombus is capable of obstructing the space it is in.

And Tetris includes tiles of several different shapes. But, in a thrombus, the “falling tiles” are always the same—thrombocytes.

Having described the mathematical process of how vacant areas on the surface of a growing thrombus are filled, the researchers were able to build first a 1-dimensional model (as in Tetris) and then a 2-dimensional model (where thrombocytes are deposited in a dimensional plane).

At one point, the researchers began to consider certain thrombocytes as being dimensionless and the thrombus itself as being continuous. In other words, they went from a discrete model to a continuous model.

In a discrete model, the system under study consists of individual particles, and the behavior of each particle can be tracked individually. In a continuous model, the system under study consists of solid objects that can freely change their size or any other characteristic.

The sequential solution of the equations enabled the researchers to reproduce the dynamics of thrombus growth and study clot behavior under various conditions—in the case of damage to the vascular wall, for example.

Active media and autowaves

The researchers said the process of thrombus formation is like an autowave. And the blood, which carries platelets and proteins for coagulation, is an active medium.

The term “active medium” plays a key role in non-linear dynamics—the science of mathematical modeling of a range of systems, from mixtures of interacting chemicals and lasers to forest fires and even social networks.

One way to describe an active medium is to use the example of a forest fire. Every dry tree is not simply a passive object but a potential source of thermal energy. If there is a fire near a dry tree, it too will start to burn and provide more heat, which can then ignite other trees. The ability of elements in the system to release energy is a key feature of an active medium.

In active media, a local event (lightning striking a tree, for example) can initiate a transition process in a system from one state to another (in this case, a dry tree becomes a burning tree).

This process spreads like a wave in space, and the specific physical nature of the system is not so important. The same equation can be used to describe entirely different cases.

The term “autowave” means the wave propagation process is not passive, as in the case of seismic waves traveling from an earthquake’s epicenter, but active. At each point, the wave receives more energy.

In the case of thrombus formation, these terms apply to thrombocytes flowing in plasma. The thrombocytes can go from a free-flowing state to a deposited state.

Under normal circumstances, thrombocytes flow freely in the bloodstream, but if the vascular wall becomes damaged, they start to adhere to one another and to the vascular wall.

The blood also contains proteins required for thrombus formation. Even if there are no thrombocytes, reactions with these proteins are able to help form a clot to block a damaged vessel, and these reactions also occur in the form of autowaves.

Normally, thrombi prevent blood loss in the human body when a blood vessel has become damaged. Sometimes, however, thrombus formation occurs not as a result of an injury with damage to a blood vessel, but as a result of a reaction to a pathological process.

This type of thrombus formation can block a vessel completely and cut off the blood supply to tissues and organs. This, in turn, can lead to myocardial infarction, stroke, or gangrene of the extremities.

The researchers say their new model correctly describes arterial thrombus formation. These particular thrombi consist mainly of thrombocytes, and blood proteins play a relatively small role in the process.

“We have always had difficulty working with arterial blood clots in particular, in terms of developing and implementing computer models, because the subject involves a very difficult combination of mechanics (cell attachments), hydrodynamics with variable geometry, and biochemistry,” Dr Panteleev said.

“In our paper in PLOS ONE, we tried to use the most primitive description of a thrombus as a continuous medium, rather than discrete particles. This approximation is rough in many respects, and it limits the scope of the research, but it is able to give us some common patterns.”

“On the one hand, we plan to continue to apply it to specific tasks, as far as is possible, and on the other hand, we are developing more sophisticated and advanced models with 3-dimensional blood cells, the full mechanics of their interaction, and the proper biochemistry.”