Mary Ann Moon

The dapivirine vaginal ring reduced the rate of new HIV-1 infection by 31% in a phase III clinical trial involving 1,959 high-risk women in sub-Saharan Africa, according to a report published in the New England Journal of Medicine.

The dapivirine-containing ring is replaced every month and was used in this study for up to 2 years. It was not associated with any safety concerns, said Annalene Nel, MD, PhD, of the International Partnership for Microbicides, Silver Spring, Md., and her associates.

The International Partnership for Microbicides is a nonprofit group that developed the ring, which can be self-inserted and removed and which provides a sustained release of the antiretroviral drug for at least 4 weeks. QPharma of Malmö, Sweden, manufactures the rings and donated the ones used in this study, but was not otherwise involved in the trial.

The study participants were sexually active women aged 18-45 years (mean age, 26) treated at seven research centers in South Africa and Uganda. Almost all of them (98%) had only one male sexual partner. For the purposes of this trial, the women were asked to attend the participating clinics every 4 weeks to have the rings replaced and to provide a plasma sample. This allowed the researchers to measure the residual amount of dapivirine in the used rings and to measure plasma levels of the drug, both of which were indicators of compliance.

A total of 1,307 women were randomly assigned to receive dapivirine rings and 652 to receive placebo rings. At the data cutoff point, 615 women (31.4%) were still in the trial and 761 (38.8%) had completed it; 583 women (29.8%) had discontinued early. All the participants at one medical center were withdrawn by the sponsor because of high rates of protocol violation at that facility and corresponding high rates of patient nonadherence with the device.

The primary efficacy endpoint – the rate of HIV-1 seroconversion during follow-up – was 4.1 per 100 person-years with the dapivirine ring, compared with 6.1 per 100 person-years with the placebo ring. This represents a 31% lower infection rate with the active treatment (hazard ratio, 0.69). A subgroup analysis that excluded participants at the protocol-violating facility showed a seroconversion rate of 3.6 per 100 person-years with the active treatment vs. 5.4 per 100 person-years with the placebo, a 30% reduction in the infection rate, the investigators said (N Engl J Med. 2016 Dec 1. doi: 10.1056/NEJMoa1602046).

The findings were consistent across other subgroup analyses, including those that categorized the participants according to their adherence levels, as measured by plasma levels and residual ring levels of dapivirine.

The cumulative incidence of adverse events was similar between the two study groups (87.4% and 85.7%, respectively), as was the incidence of grade 3 or 4 adverse events. None of the more serious adverse events were judged to be related to the devices. Mild product-related adverse events occurred in 5 women (0.4%) in the dapivirine group and 3 (0.5%) in the placebo group. There also were no significant differences between the two study groups in the incidence of laboratory abnormalities, rates of sexually transmitted and other genital infections, or pregnancy rates.

The study was funded by the International Partnership for Microbicides, which is supported by the Bill and Melinda Gates Foundation, Irish Aid, the Ministry of Foreign Affairs of Denmark, the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for Development Cooperation, the U.K. Department for International Development, the U.S. Agency for International Development, and the President’s Emergency Plan for AIDS Relief.

Dr. Nel reported having no relevant financial disclosures; one of her associates reported ties to Janssen and Johnson & Johnson.

The dapivirine vaginal ring reduced the rate of new HIV-1 infection by 31% in a phase III clinical trial involving 1,959 high-risk women in sub-Saharan Africa, according to a report published in the New England Journal of Medicine.

The dapivirine-containing ring is replaced every month and was used in this study for up to 2 years. It was not associated with any safety concerns, said Annalene Nel, MD, PhD, of the International Partnership for Microbicides, Silver Spring, Md., and her associates.

The International Partnership for Microbicides is a nonprofit group that developed the ring, which can be self-inserted and removed and which provides a sustained release of the antiretroviral drug for at least 4 weeks. QPharma of Malmö, Sweden, manufactures the rings and donated the ones used in this study, but was not otherwise involved in the trial.

The study participants were sexually active women aged 18-45 years (mean age, 26) treated at seven research centers in South Africa and Uganda. Almost all of them (98%) had only one male sexual partner. For the purposes of this trial, the women were asked to attend the participating clinics every 4 weeks to have the rings replaced and to provide a plasma sample. This allowed the researchers to measure the residual amount of dapivirine in the used rings and to measure plasma levels of the drug, both of which were indicators of compliance.

A total of 1,307 women were randomly assigned to receive dapivirine rings and 652 to receive placebo rings. At the data cutoff point, 615 women (31.4%) were still in the trial and 761 (38.8%) had completed it; 583 women (29.8%) had discontinued early. All the participants at one medical center were withdrawn by the sponsor because of high rates of protocol violation at that facility and corresponding high rates of patient nonadherence with the device.

The primary efficacy endpoint – the rate of HIV-1 seroconversion during follow-up – was 4.1 per 100 person-years with the dapivirine ring, compared with 6.1 per 100 person-years with the placebo ring. This represents a 31% lower infection rate with the active treatment (hazard ratio, 0.69). A subgroup analysis that excluded participants at the protocol-violating facility showed a seroconversion rate of 3.6 per 100 person-years with the active treatment vs. 5.4 per 100 person-years with the placebo, a 30% reduction in the infection rate, the investigators said (N Engl J Med. 2016 Dec 1. doi: 10.1056/NEJMoa1602046).

The findings were consistent across other subgroup analyses, including those that categorized the participants according to their adherence levels, as measured by plasma levels and residual ring levels of dapivirine.

The cumulative incidence of adverse events was similar between the two study groups (87.4% and 85.7%, respectively), as was the incidence of grade 3 or 4 adverse events. None of the more serious adverse events were judged to be related to the devices. Mild product-related adverse events occurred in 5 women (0.4%) in the dapivirine group and 3 (0.5%) in the placebo group. There also were no significant differences between the two study groups in the incidence of laboratory abnormalities, rates of sexually transmitted and other genital infections, or pregnancy rates.

The study was funded by the International Partnership for Microbicides, which is supported by the Bill and Melinda Gates Foundation, Irish Aid, the Ministry of Foreign Affairs of Denmark, the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for Development Cooperation, the U.K. Department for International Development, the U.S. Agency for International Development, and the President’s Emergency Plan for AIDS Relief.

Dr. Nel reported having no relevant financial disclosures; one of her associates reported ties to Janssen and Johnson & Johnson.

The dapivirine vaginal ring reduced the rate of new HIV-1 infection by 31% in a phase III clinical trial involving 1,959 high-risk women in sub-Saharan Africa, according to a report published in the New England Journal of Medicine.

The dapivirine-containing ring is replaced every month and was used in this study for up to 2 years. It was not associated with any safety concerns, said Annalene Nel, MD, PhD, of the International Partnership for Microbicides, Silver Spring, Md., and her associates.

The International Partnership for Microbicides is a nonprofit group that developed the ring, which can be self-inserted and removed and which provides a sustained release of the antiretroviral drug for at least 4 weeks. QPharma of Malmö, Sweden, manufactures the rings and donated the ones used in this study, but was not otherwise involved in the trial.

The study participants were sexually active women aged 18-45 years (mean age, 26) treated at seven research centers in South Africa and Uganda. Almost all of them (98%) had only one male sexual partner. For the purposes of this trial, the women were asked to attend the participating clinics every 4 weeks to have the rings replaced and to provide a plasma sample. This allowed the researchers to measure the residual amount of dapivirine in the used rings and to measure plasma levels of the drug, both of which were indicators of compliance.

A total of 1,307 women were randomly assigned to receive dapivirine rings and 652 to receive placebo rings. At the data cutoff point, 615 women (31.4%) were still in the trial and 761 (38.8%) had completed it; 583 women (29.8%) had discontinued early. All the participants at one medical center were withdrawn by the sponsor because of high rates of protocol violation at that facility and corresponding high rates of patient nonadherence with the device.

The primary efficacy endpoint – the rate of HIV-1 seroconversion during follow-up – was 4.1 per 100 person-years with the dapivirine ring, compared with 6.1 per 100 person-years with the placebo ring. This represents a 31% lower infection rate with the active treatment (hazard ratio, 0.69). A subgroup analysis that excluded participants at the protocol-violating facility showed a seroconversion rate of 3.6 per 100 person-years with the active treatment vs. 5.4 per 100 person-years with the placebo, a 30% reduction in the infection rate, the investigators said (N Engl J Med. 2016 Dec 1. doi: 10.1056/NEJMoa1602046).

The findings were consistent across other subgroup analyses, including those that categorized the participants according to their adherence levels, as measured by plasma levels and residual ring levels of dapivirine.

The cumulative incidence of adverse events was similar between the two study groups (87.4% and 85.7%, respectively), as was the incidence of grade 3 or 4 adverse events. None of the more serious adverse events were judged to be related to the devices. Mild product-related adverse events occurred in 5 women (0.4%) in the dapivirine group and 3 (0.5%) in the placebo group. There also were no significant differences between the two study groups in the incidence of laboratory abnormalities, rates of sexually transmitted and other genital infections, or pregnancy rates.

The study was funded by the International Partnership for Microbicides, which is supported by the Bill and Melinda Gates Foundation, Irish Aid, the Ministry of Foreign Affairs of Denmark, the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for Development Cooperation, the U.K. Department for International Development, the U.S. Agency for International Development, and the President’s Emergency Plan for AIDS Relief.

Dr. Nel reported having no relevant financial disclosures; one of her associates reported ties to Janssen and Johnson & Johnson.

An experimental biological agent, GP2015, demonstrated equivalent efficacy and comparable safety to etanercept for moderate to severe plaque psoriasis in a manufacturer-sponsored study, according to a report published online in the British Journal of Dermatology.

These findings should contribute to the confirmation of GP2015 as an etanercept (Enbrel) biosimilar for this patient population. Proposed biosimilars such as GP2015 are follow-on versions of authorized biological products, and regulatory authorities require that they demonstrate similarity with a large body of physiochemical and clinical data before they can be confirmed as biosimilars, said Christopher Griffiths, MD, of the Dermatology Centre, Salford Royal Hospital, University of Manchester (England), and his associates.

To contribute such data, Dr. Griffiths and his associates studied the efficacy and safety of GP2015 compared with etanercept, a tumor necrosis factor blocker, in the 2-year EGALITY trial. They assessed 531 adults at 74 medical centers in 11 European countries and South Africa, all of whom had active but stable chronic plaque psoriasis affecting 10% or more of their body surface area and Psoriasis Area and Severity Index (PASI) scores of 10 or more.

The study participants were randomly assigned in approximately equal numbers in a double-blind fashion to self administer GP2015 or etanercept subcutaneously, twice weekly for 12 weeks. Those who achieved at least a 50% improvement in PASI score were then randomized to continue the same treatment once weekly or to undergo a series of three treatment “switches” between GP2015 and etanercept at 6-week intervals until week 30. During an extension phase of the study, participants could then continue to receive the same treatment they had ended on, until week 52.

The primary efficacy endpoint – the percentage of patients who showed at least a 75% improvement from baseline in PASI score (PASI 75) at 12 weeks – was 73.4% with GP2015 and 75.7% with etanercept, which demonstrated therapeutic equivalence. A secondary efficacy end point – mean change in PASI score from baseline to week 12 – also was similar between the two study drugs. In all treatment groups, both PASI mean scores and change in PASI scores over time were comparable between the two study groups, regardless of switching between the two agents. In addition, in all groups, PASI 75 and PASI 90 scores increased gradually over time until week 30, and then remained stable through week 52, the investigators said (Br J Dermatol. 2016. doi: 10.1111/bjd.15152).

The proportion of patients with at least one treatment-emergent adverse event was similar in the GP2015 and etanercept groups who did not switch agents (59.8% and 57.3%, respectively), and was also similar among those who did switch agents between GP2015 (61%) and etanercept (59.4%).

The rates of serious adverse events and of adverse events that led to withdrawal from the study were similar across all treatment groups. Immunogenicity of GP2015 was similar to etanercept.

However, the rate of “adverse events of special interest” – those referred to in special warnings and precautions on the etanercept label – was markedly higher for continued GP2015 than for continued etanercept (11.0% vs. 4.7%) and for switched GP2015 than for switched etanercept (11.0% vs. 5.2%). One patient who took etanercept throughout the trial developed malignant melanoma.

The results of the study “confirm biosimilarity that was established with all previous analytical comparisons to the reference product in that equivalent efficacy was demonstrated as well as similar safety and immunogenicity of GP2015” with etanercept, “in a highly sensitive, generally immune-competent population,” the authors concluded.

The study was funded by Hexal AG, a Sandoz company, which was involved in the study design, data collection and analysis, and manuscript preparation. Dr. Griffiths reported ties to AbbVie, BMS. Galderma, Janssen, Leo-Pharma, Lilly, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz, and UCB Pharma, and his associates reported ties to numerous industry sources.

An experimental biological agent, GP2015, demonstrated equivalent efficacy and comparable safety to etanercept for moderate to severe plaque psoriasis in a manufacturer-sponsored study, according to a report published online in the British Journal of Dermatology.

These findings should contribute to the confirmation of GP2015 as an etanercept (Enbrel) biosimilar for this patient population. Proposed biosimilars such as GP2015 are follow-on versions of authorized biological products, and regulatory authorities require that they demonstrate similarity with a large body of physiochemical and clinical data before they can be confirmed as biosimilars, said Christopher Griffiths, MD, of the Dermatology Centre, Salford Royal Hospital, University of Manchester (England), and his associates.

To contribute such data, Dr. Griffiths and his associates studied the efficacy and safety of GP2015 compared with etanercept, a tumor necrosis factor blocker, in the 2-year EGALITY trial. They assessed 531 adults at 74 medical centers in 11 European countries and South Africa, all of whom had active but stable chronic plaque psoriasis affecting 10% or more of their body surface area and Psoriasis Area and Severity Index (PASI) scores of 10 or more.

The study participants were randomly assigned in approximately equal numbers in a double-blind fashion to self administer GP2015 or etanercept subcutaneously, twice weekly for 12 weeks. Those who achieved at least a 50% improvement in PASI score were then randomized to continue the same treatment once weekly or to undergo a series of three treatment “switches” between GP2015 and etanercept at 6-week intervals until week 30. During an extension phase of the study, participants could then continue to receive the same treatment they had ended on, until week 52.

The primary efficacy endpoint – the percentage of patients who showed at least a 75% improvement from baseline in PASI score (PASI 75) at 12 weeks – was 73.4% with GP2015 and 75.7% with etanercept, which demonstrated therapeutic equivalence. A secondary efficacy end point – mean change in PASI score from baseline to week 12 – also was similar between the two study drugs. In all treatment groups, both PASI mean scores and change in PASI scores over time were comparable between the two study groups, regardless of switching between the two agents. In addition, in all groups, PASI 75 and PASI 90 scores increased gradually over time until week 30, and then remained stable through week 52, the investigators said (Br J Dermatol. 2016. doi: 10.1111/bjd.15152).

The proportion of patients with at least one treatment-emergent adverse event was similar in the GP2015 and etanercept groups who did not switch agents (59.8% and 57.3%, respectively), and was also similar among those who did switch agents between GP2015 (61%) and etanercept (59.4%).

The rates of serious adverse events and of adverse events that led to withdrawal from the study were similar across all treatment groups. Immunogenicity of GP2015 was similar to etanercept.

However, the rate of “adverse events of special interest” – those referred to in special warnings and precautions on the etanercept label – was markedly higher for continued GP2015 than for continued etanercept (11.0% vs. 4.7%) and for switched GP2015 than for switched etanercept (11.0% vs. 5.2%). One patient who took etanercept throughout the trial developed malignant melanoma.

The results of the study “confirm biosimilarity that was established with all previous analytical comparisons to the reference product in that equivalent efficacy was demonstrated as well as similar safety and immunogenicity of GP2015” with etanercept, “in a highly sensitive, generally immune-competent population,” the authors concluded.

The study was funded by Hexal AG, a Sandoz company, which was involved in the study design, data collection and analysis, and manuscript preparation. Dr. Griffiths reported ties to AbbVie, BMS. Galderma, Janssen, Leo-Pharma, Lilly, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz, and UCB Pharma, and his associates reported ties to numerous industry sources.

An experimental biological agent, GP2015, demonstrated equivalent efficacy and comparable safety to etanercept for moderate to severe plaque psoriasis in a manufacturer-sponsored study, according to a report published online in the British Journal of Dermatology.

These findings should contribute to the confirmation of GP2015 as an etanercept (Enbrel) biosimilar for this patient population. Proposed biosimilars such as GP2015 are follow-on versions of authorized biological products, and regulatory authorities require that they demonstrate similarity with a large body of physiochemical and clinical data before they can be confirmed as biosimilars, said Christopher Griffiths, MD, of the Dermatology Centre, Salford Royal Hospital, University of Manchester (England), and his associates.

To contribute such data, Dr. Griffiths and his associates studied the efficacy and safety of GP2015 compared with etanercept, a tumor necrosis factor blocker, in the 2-year EGALITY trial. They assessed 531 adults at 74 medical centers in 11 European countries and South Africa, all of whom had active but stable chronic plaque psoriasis affecting 10% or more of their body surface area and Psoriasis Area and Severity Index (PASI) scores of 10 or more.

The study participants were randomly assigned in approximately equal numbers in a double-blind fashion to self administer GP2015 or etanercept subcutaneously, twice weekly for 12 weeks. Those who achieved at least a 50% improvement in PASI score were then randomized to continue the same treatment once weekly or to undergo a series of three treatment “switches” between GP2015 and etanercept at 6-week intervals until week 30. During an extension phase of the study, participants could then continue to receive the same treatment they had ended on, until week 52.

The primary efficacy endpoint – the percentage of patients who showed at least a 75% improvement from baseline in PASI score (PASI 75) at 12 weeks – was 73.4% with GP2015 and 75.7% with etanercept, which demonstrated therapeutic equivalence. A secondary efficacy end point – mean change in PASI score from baseline to week 12 – also was similar between the two study drugs. In all treatment groups, both PASI mean scores and change in PASI scores over time were comparable between the two study groups, regardless of switching between the two agents. In addition, in all groups, PASI 75 and PASI 90 scores increased gradually over time until week 30, and then remained stable through week 52, the investigators said (Br J Dermatol. 2016. doi: 10.1111/bjd.15152).

The proportion of patients with at least one treatment-emergent adverse event was similar in the GP2015 and etanercept groups who did not switch agents (59.8% and 57.3%, respectively), and was also similar among those who did switch agents between GP2015 (61%) and etanercept (59.4%).

The rates of serious adverse events and of adverse events that led to withdrawal from the study were similar across all treatment groups. Immunogenicity of GP2015 was similar to etanercept.

However, the rate of “adverse events of special interest” – those referred to in special warnings and precautions on the etanercept label – was markedly higher for continued GP2015 than for continued etanercept (11.0% vs. 4.7%) and for switched GP2015 than for switched etanercept (11.0% vs. 5.2%). One patient who took etanercept throughout the trial developed malignant melanoma.

The results of the study “confirm biosimilarity that was established with all previous analytical comparisons to the reference product in that equivalent efficacy was demonstrated as well as similar safety and immunogenicity of GP2015” with etanercept, “in a highly sensitive, generally immune-competent population,” the authors concluded.

The study was funded by Hexal AG, a Sandoz company, which was involved in the study design, data collection and analysis, and manuscript preparation. Dr. Griffiths reported ties to AbbVie, BMS. Galderma, Janssen, Leo-Pharma, Lilly, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz, and UCB Pharma, and his associates reported ties to numerous industry sources.

The failure of type 2 alveolar epithelial cells (AEC2s), which are critical to the repair and regeneration of lung tissue, appears to be a major cause of pulmonary fibrosis, according to a report published online in Nature Medicine.

Researchers performed a series of in vitro and murine studies to better understand the molecular mechanisms underlying pulmonary fibrosis, which is believed to result from repeated microinjuries to the alveolar epithelium that in turn promote excessive, sustained fibroblast activation with matrix-producing myofibroblasts. They found that expression of both hyaluronan (HA) and Toll-like receptor 4 (TLR4) on AEC2s is deficient in a mouse model of pulmonary fibrosis and in samples of lung tissue from patients with the disease, but not in samples from healthy control subjects or from patients with chronic obstructive pulmonary disease (COPD).

“The main finding here is that the endogenous matrix glycosaminoglycan HA and the innate immune receptor TLR4 are required for optimal AEC2 renewal and for limiting fibrosis after lung injury,” said Carol Liang, MD, of the department of medicine and the Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, and her associates.

“These findings are the first published evidence that pulmonary fibrosis is primarily a disease of AEC2 stem cell failure,” Dr. Liang said, in a written statement.

The investigators began by showing that AEC2s engineered to stop expressing hyaluronan or TLR4 (by deleting the genes that encode for that expression) showed impaired self-renewal in vitro, compared with normal AEC2s. In a mouse model, the engineered AEC2s also caused impairment in the healing of deliberately induced lung injury.

In addition, the researchers developed a mouse model of pulmonary fibrosis and showed that treatment with exogenous interleukin 6 “enhanced AEC2 renewal and partially reversed the fibrotic phenotype” in vivo.

“To determine whether our observations in the mouse model of [deficient] AEC2s have relevance to human disease, we isolated AEC2s from lung explants of human subjects who had undergone lung transplantation because of [idiopathic pulmonary fibrosis],” the researchers said. These samples showed marked depletion in the number of AEC2s, compared with samples taken from healthy control subjects and from patients with COPD.

In addition, the few remaining AEC2s in the samples affected by pulmonary fibrosis were deficient in the expression of HA, compared with those in the samples from control subjects. This suggests that loss of cell-surface HA is unique to severe pulmonary fibrosis, the researchers said (Nature Med. 2016. doi: 10.1038/nm.4192).

Since pulmonary fibrosis is characterized by patchy areas of parenchymal fibrosis alternating with relatively normal lung tissue, the investigators then compared AEC2s taken from these two distinct types of tissue in the patient group. They found that AEC2 cells from affected areas of the lung showed much more markedly reduced expression of HA than those from healthy areas of the lung. Flow cytometry testing further demonstrated that the number of AEC2s also was greatly reduced in affected lung tissue but relatively higher in more normal lung tissue. However, even the “healthy” lung tissue from affected patients had lower numbers of AEC2s and impaired cell renewal when compared with tissue from unaffected control subjects, the researchers noted.

“In future studies, we will explore how the loss of hyaluronan promotes fibrosis and how it might be restored to cell surfaces. These endeavors could lead to new therapeutic approaches” for this progressive, fatal disease for which there is no effective treatment at present, Dr. Liang said, in the written statement.

The researchers reported having no relevant financial disclosures.

The failure of type 2 alveolar epithelial cells (AEC2s), which are critical to the repair and regeneration of lung tissue, appears to be a major cause of pulmonary fibrosis, according to a report published online in Nature Medicine.

Researchers performed a series of in vitro and murine studies to better understand the molecular mechanisms underlying pulmonary fibrosis, which is believed to result from repeated microinjuries to the alveolar epithelium that in turn promote excessive, sustained fibroblast activation with matrix-producing myofibroblasts. They found that expression of both hyaluronan (HA) and Toll-like receptor 4 (TLR4) on AEC2s is deficient in a mouse model of pulmonary fibrosis and in samples of lung tissue from patients with the disease, but not in samples from healthy control subjects or from patients with chronic obstructive pulmonary disease (COPD).

“The main finding here is that the endogenous matrix glycosaminoglycan HA and the innate immune receptor TLR4 are required for optimal AEC2 renewal and for limiting fibrosis after lung injury,” said Carol Liang, MD, of the department of medicine and the Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, and her associates.

“These findings are the first published evidence that pulmonary fibrosis is primarily a disease of AEC2 stem cell failure,” Dr. Liang said, in a written statement.

The investigators began by showing that AEC2s engineered to stop expressing hyaluronan or TLR4 (by deleting the genes that encode for that expression) showed impaired self-renewal in vitro, compared with normal AEC2s. In a mouse model, the engineered AEC2s also caused impairment in the healing of deliberately induced lung injury.

In addition, the researchers developed a mouse model of pulmonary fibrosis and showed that treatment with exogenous interleukin 6 “enhanced AEC2 renewal and partially reversed the fibrotic phenotype” in vivo.

“To determine whether our observations in the mouse model of [deficient] AEC2s have relevance to human disease, we isolated AEC2s from lung explants of human subjects who had undergone lung transplantation because of [idiopathic pulmonary fibrosis],” the researchers said. These samples showed marked depletion in the number of AEC2s, compared with samples taken from healthy control subjects and from patients with COPD.

In addition, the few remaining AEC2s in the samples affected by pulmonary fibrosis were deficient in the expression of HA, compared with those in the samples from control subjects. This suggests that loss of cell-surface HA is unique to severe pulmonary fibrosis, the researchers said (Nature Med. 2016. doi: 10.1038/nm.4192).

Since pulmonary fibrosis is characterized by patchy areas of parenchymal fibrosis alternating with relatively normal lung tissue, the investigators then compared AEC2s taken from these two distinct types of tissue in the patient group. They found that AEC2 cells from affected areas of the lung showed much more markedly reduced expression of HA than those from healthy areas of the lung. Flow cytometry testing further demonstrated that the number of AEC2s also was greatly reduced in affected lung tissue but relatively higher in more normal lung tissue. However, even the “healthy” lung tissue from affected patients had lower numbers of AEC2s and impaired cell renewal when compared with tissue from unaffected control subjects, the researchers noted.

“In future studies, we will explore how the loss of hyaluronan promotes fibrosis and how it might be restored to cell surfaces. These endeavors could lead to new therapeutic approaches” for this progressive, fatal disease for which there is no effective treatment at present, Dr. Liang said, in the written statement.

The researchers reported having no relevant financial disclosures.

The failure of type 2 alveolar epithelial cells (AEC2s), which are critical to the repair and regeneration of lung tissue, appears to be a major cause of pulmonary fibrosis, according to a report published online in Nature Medicine.

Researchers performed a series of in vitro and murine studies to better understand the molecular mechanisms underlying pulmonary fibrosis, which is believed to result from repeated microinjuries to the alveolar epithelium that in turn promote excessive, sustained fibroblast activation with matrix-producing myofibroblasts. They found that expression of both hyaluronan (HA) and Toll-like receptor 4 (TLR4) on AEC2s is deficient in a mouse model of pulmonary fibrosis and in samples of lung tissue from patients with the disease, but not in samples from healthy control subjects or from patients with chronic obstructive pulmonary disease (COPD).

“The main finding here is that the endogenous matrix glycosaminoglycan HA and the innate immune receptor TLR4 are required for optimal AEC2 renewal and for limiting fibrosis after lung injury,” said Carol Liang, MD, of the department of medicine and the Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, and her associates.

“These findings are the first published evidence that pulmonary fibrosis is primarily a disease of AEC2 stem cell failure,” Dr. Liang said, in a written statement.

The investigators began by showing that AEC2s engineered to stop expressing hyaluronan or TLR4 (by deleting the genes that encode for that expression) showed impaired self-renewal in vitro, compared with normal AEC2s. In a mouse model, the engineered AEC2s also caused impairment in the healing of deliberately induced lung injury.

In addition, the researchers developed a mouse model of pulmonary fibrosis and showed that treatment with exogenous interleukin 6 “enhanced AEC2 renewal and partially reversed the fibrotic phenotype” in vivo.

“To determine whether our observations in the mouse model of [deficient] AEC2s have relevance to human disease, we isolated AEC2s from lung explants of human subjects who had undergone lung transplantation because of [idiopathic pulmonary fibrosis],” the researchers said. These samples showed marked depletion in the number of AEC2s, compared with samples taken from healthy control subjects and from patients with COPD.

In addition, the few remaining AEC2s in the samples affected by pulmonary fibrosis were deficient in the expression of HA, compared with those in the samples from control subjects. This suggests that loss of cell-surface HA is unique to severe pulmonary fibrosis, the researchers said (Nature Med. 2016. doi: 10.1038/nm.4192).

Since pulmonary fibrosis is characterized by patchy areas of parenchymal fibrosis alternating with relatively normal lung tissue, the investigators then compared AEC2s taken from these two distinct types of tissue in the patient group. They found that AEC2 cells from affected areas of the lung showed much more markedly reduced expression of HA than those from healthy areas of the lung. Flow cytometry testing further demonstrated that the number of AEC2s also was greatly reduced in affected lung tissue but relatively higher in more normal lung tissue. However, even the “healthy” lung tissue from affected patients had lower numbers of AEC2s and impaired cell renewal when compared with tissue from unaffected control subjects, the researchers noted.

“In future studies, we will explore how the loss of hyaluronan promotes fibrosis and how it might be restored to cell surfaces. These endeavors could lead to new therapeutic approaches” for this progressive, fatal disease for which there is no effective treatment at present, Dr. Liang said, in the written statement.

The researchers reported having no relevant financial disclosures.

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.

Adding the CDK inhibitor palbociclib to standard endocrine therapy (letrozole) extended progression-free survival in a manufacturer-sponsored phase III trial of advanced ER-positive, HER2-negative breast cancer, investigators reported in the New England Journal of Medicine.

Compared with placebo, palbociclib significantly improved progression-free survival regardless of patient age, patient performance status, site of metastasis, prior use of chemotherapy, prior use of endocrine therapy, length of the disease-free interval before progression, or the cancer’s histologic subtype. “The median progression-free survival of 24.8 months in [our study] is longer than that seen in other phase III studies involving women with advanced breast cancer. Whether this progression-free survival will result in longer overall survival is uncertain until further follow-up is completed,” wrote Richard S. Finn, MD, of the University of California, Los Angeles, and his associates.

2014 AACR/Todd Buchanan

Adding the CDK inhibitor palbociclib to standard endocrine therapy (letrozole) extended progression-free survival in a manufacturer-sponsored phase III trial of advanced ER-positive, HER2-negative breast cancer, investigators reported in the New England Journal of Medicine.

Compared with placebo, palbociclib significantly improved progression-free survival regardless of patient age, patient performance status, site of metastasis, prior use of chemotherapy, prior use of endocrine therapy, length of the disease-free interval before progression, or the cancer’s histologic subtype. “The median progression-free survival of 24.8 months in [our study] is longer than that seen in other phase III studies involving women with advanced breast cancer. Whether this progression-free survival will result in longer overall survival is uncertain until further follow-up is completed,” wrote Richard S. Finn, MD, of the University of California, Los Angeles, and his associates.

2014 AACR/Todd Buchanan

Adding the CDK inhibitor palbociclib to standard endocrine therapy (letrozole) extended progression-free survival in a manufacturer-sponsored phase III trial of advanced ER-positive, HER2-negative breast cancer, investigators reported in the New England Journal of Medicine.

Compared with placebo, palbociclib significantly improved progression-free survival regardless of patient age, patient performance status, site of metastasis, prior use of chemotherapy, prior use of endocrine therapy, length of the disease-free interval before progression, or the cancer’s histologic subtype. “The median progression-free survival of 24.8 months in [our study] is longer than that seen in other phase III studies involving women with advanced breast cancer. Whether this progression-free survival will result in longer overall survival is uncertain until further follow-up is completed,” wrote Richard S. Finn, MD, of the University of California, Los Angeles, and his associates.

2014 AACR/Todd Buchanan

NEW ORLEANS – An interatrial septal shunt device continued to provide “sustained and meaningful clinical benefit” at 1-year follow-up for 64 patients who had heart failure with preserved ejection fraction (HFpEF), David M. Kaye, MD, PhD, reported at the American Heart Association scientific sessions.

The device is implanted via cardiac catheterization and is intended to reduce elevated left atrial pressure, particularly that associated with exertion, by allowing a small amount but not excessive left-to-right shunting. Patients showed improvements in 6-minute walk distance, New York Heart Association class, and HF-related quality of life scores at 6 months, and those effects persisted at the most recent (12-month) follow-up, he said in a presentation that was simultaneously published online in Circulation (2016 Nov 16).

American Heart Association

American Heart Association

NEW ORLEANS – An interatrial septal shunt device continued to provide “sustained and meaningful clinical benefit” at 1-year follow-up for 64 patients who had heart failure with preserved ejection fraction (HFpEF), David M. Kaye, MD, PhD, reported at the American Heart Association scientific sessions.

The device is implanted via cardiac catheterization and is intended to reduce elevated left atrial pressure, particularly that associated with exertion, by allowing a small amount but not excessive left-to-right shunting. Patients showed improvements in 6-minute walk distance, New York Heart Association class, and HF-related quality of life scores at 6 months, and those effects persisted at the most recent (12-month) follow-up, he said in a presentation that was simultaneously published online in Circulation (2016 Nov 16).

American Heart Association

American Heart Association

NEW ORLEANS – An interatrial septal shunt device continued to provide “sustained and meaningful clinical benefit” at 1-year follow-up for 64 patients who had heart failure with preserved ejection fraction (HFpEF), David M. Kaye, MD, PhD, reported at the American Heart Association scientific sessions.

The device is implanted via cardiac catheterization and is intended to reduce elevated left atrial pressure, particularly that associated with exertion, by allowing a small amount but not excessive left-to-right shunting. Patients showed improvements in 6-minute walk distance, New York Heart Association class, and HF-related quality of life scores at 6 months, and those effects persisted at the most recent (12-month) follow-up, he said in a presentation that was simultaneously published online in Circulation (2016 Nov 16).

American Heart Association

American Heart Association

CSL112, a plasma-derived apolipoprotein A-1 (apoA-1) that enhances cholesterol efflux capacity, was found safe for use after acute MI in a manufacturer-sponsored phase IIb trial, Michael Gibson, MD, reported at the American Heart Association scientific sessions.

Cholesterol efflux capacity is a measure of HDL cholesterol’s ability to remove excess cholesterol from atherosclerotic plaque for transport to the liver. Drugs that improve this capacity rather than simply raising HDL cholesterol are expected to reduce plaque burden and stabilize vulnerable plaque immediately following acute MI, when cholesterol efflux is significantly impaired. But they have not been tested in this patient population until now, said Dr. Gibson of Beth Israel Deaconess Medical Center and Harvard, both in Boston.

An earlier prototype formulation of CSL112 was discontinued because of concerns about transient elevations in liver enzymes and the potential for renal toxicity due to the agent’s high sucrose content. Dr. Gibson and his associates in the AEGIS-1 trial (ApoA-1 Event Reducing in Ischemic Syndromes 1) now report their findings for the current formulation of CSL112, which contains lower phosphatidylcholine and lower sucrose levels, in 1,258 patients who had MI during the preceding week and who had normal or only mildly impaired renal function. These results were reported at the meeting and simultaneously published online in Circulation (2016, Nov 15. doi: 10.1161/CIRCULATION AHA.116.025687).

The study participants were enrolled in 16 countries during an 11-month period. They were randomly assigned to receive low-dose (2 g) CSL112 (419 patients), high-dose (6 g) CSL112 (421 patients), or a matching placebo (418 patients) via IV infusion every week for 4 consecutive weeks. The median duration of follow-up at the time of this report was 7.5 months.

The two primary safety end points – the rate of hepatic impairment and the rate of renal impairment during treatment – were not significantly different across the three study groups. Hepatic impairment developed in 1.0% of the low-dose group, 0.5% of the high-dose group, and 0.0% of the placebo group. Renal impairment developed in 0.0% of the low-dose group, 0.7% of the high-dose group, and 0.2% of the placebo group.

Similarly, rates of major adverse cardiovascular events were comparable across the three study groups, as were rates of any grade of bleeding, rates of serious and life-threatening adverse events, and rates of adverse events leading to drug discontinuation.

This study focused on safety and tolerability and was not designed or powered to assess efficacy. Nevertheless, CSL112 caused a substantial and dose-dependent increase in both apoA-1 and cholesterol efflux capacity. The low-dose drug raised total cholesterol efflux capacity by 1.87-fold, and the high-dose drug raised it 2.45-fold.

As the first study to establish the safety and feasibility of adding CSL112 to standard care for acute MI, this trial demonstrates that an adequately powered, multicenter, phase III trial is warranted, Dr. Gibson said.

The current formulation of CSL112 didn’t provoke hepatic toxicity, and even though it was given shortly after contrast studies in MI patients, it also didn’t provoke renal toxicity. “This demonstrates the feasibility of administering CSL112 to patients with MI who have normal renal function or mild renal impairment shortly after angiography. A study in MI patients who have moderate renal impairment is now under way,” he noted.
 

This study was sponsored by CSL Behring, maker of CSL112. Dr. Gibson and his associates reported financial ties to Behring and numerous other industry sources.

CSL112, a plasma-derived apolipoprotein A-1 (apoA-1) that enhances cholesterol efflux capacity, was found safe for use after acute MI in a manufacturer-sponsored phase IIb trial, Michael Gibson, MD, reported at the American Heart Association scientific sessions.

Cholesterol efflux capacity is a measure of HDL cholesterol’s ability to remove excess cholesterol from atherosclerotic plaque for transport to the liver. Drugs that improve this capacity rather than simply raising HDL cholesterol are expected to reduce plaque burden and stabilize vulnerable plaque immediately following acute MI, when cholesterol efflux is significantly impaired. But they have not been tested in this patient population until now, said Dr. Gibson of Beth Israel Deaconess Medical Center and Harvard, both in Boston.

An earlier prototype formulation of CSL112 was discontinued because of concerns about transient elevations in liver enzymes and the potential for renal toxicity due to the agent’s high sucrose content. Dr. Gibson and his associates in the AEGIS-1 trial (ApoA-1 Event Reducing in Ischemic Syndromes 1) now report their findings for the current formulation of CSL112, which contains lower phosphatidylcholine and lower sucrose levels, in 1,258 patients who had MI during the preceding week and who had normal or only mildly impaired renal function. These results were reported at the meeting and simultaneously published online in Circulation (2016, Nov 15. doi: 10.1161/CIRCULATION AHA.116.025687).

The study participants were enrolled in 16 countries during an 11-month period. They were randomly assigned to receive low-dose (2 g) CSL112 (419 patients), high-dose (6 g) CSL112 (421 patients), or a matching placebo (418 patients) via IV infusion every week for 4 consecutive weeks. The median duration of follow-up at the time of this report was 7.5 months.

The two primary safety end points – the rate of hepatic impairment and the rate of renal impairment during treatment – were not significantly different across the three study groups. Hepatic impairment developed in 1.0% of the low-dose group, 0.5% of the high-dose group, and 0.0% of the placebo group. Renal impairment developed in 0.0% of the low-dose group, 0.7% of the high-dose group, and 0.2% of the placebo group.

Similarly, rates of major adverse cardiovascular events were comparable across the three study groups, as were rates of any grade of bleeding, rates of serious and life-threatening adverse events, and rates of adverse events leading to drug discontinuation.

This study focused on safety and tolerability and was not designed or powered to assess efficacy. Nevertheless, CSL112 caused a substantial and dose-dependent increase in both apoA-1 and cholesterol efflux capacity. The low-dose drug raised total cholesterol efflux capacity by 1.87-fold, and the high-dose drug raised it 2.45-fold.

As the first study to establish the safety and feasibility of adding CSL112 to standard care for acute MI, this trial demonstrates that an adequately powered, multicenter, phase III trial is warranted, Dr. Gibson said.

The current formulation of CSL112 didn’t provoke hepatic toxicity, and even though it was given shortly after contrast studies in MI patients, it also didn’t provoke renal toxicity. “This demonstrates the feasibility of administering CSL112 to patients with MI who have normal renal function or mild renal impairment shortly after angiography. A study in MI patients who have moderate renal impairment is now under way,” he noted.
 

This study was sponsored by CSL Behring, maker of CSL112. Dr. Gibson and his associates reported financial ties to Behring and numerous other industry sources.

CSL112, a plasma-derived apolipoprotein A-1 (apoA-1) that enhances cholesterol efflux capacity, was found safe for use after acute MI in a manufacturer-sponsored phase IIb trial, Michael Gibson, MD, reported at the American Heart Association scientific sessions.

Cholesterol efflux capacity is a measure of HDL cholesterol’s ability to remove excess cholesterol from atherosclerotic plaque for transport to the liver. Drugs that improve this capacity rather than simply raising HDL cholesterol are expected to reduce plaque burden and stabilize vulnerable plaque immediately following acute MI, when cholesterol efflux is significantly impaired. But they have not been tested in this patient population until now, said Dr. Gibson of Beth Israel Deaconess Medical Center and Harvard, both in Boston.

An earlier prototype formulation of CSL112 was discontinued because of concerns about transient elevations in liver enzymes and the potential for renal toxicity due to the agent’s high sucrose content. Dr. Gibson and his associates in the AEGIS-1 trial (ApoA-1 Event Reducing in Ischemic Syndromes 1) now report their findings for the current formulation of CSL112, which contains lower phosphatidylcholine and lower sucrose levels, in 1,258 patients who had MI during the preceding week and who had normal or only mildly impaired renal function. These results were reported at the meeting and simultaneously published online in Circulation (2016, Nov 15. doi: 10.1161/CIRCULATION AHA.116.025687).

The study participants were enrolled in 16 countries during an 11-month period. They were randomly assigned to receive low-dose (2 g) CSL112 (419 patients), high-dose (6 g) CSL112 (421 patients), or a matching placebo (418 patients) via IV infusion every week for 4 consecutive weeks. The median duration of follow-up at the time of this report was 7.5 months.

The two primary safety end points – the rate of hepatic impairment and the rate of renal impairment during treatment – were not significantly different across the three study groups. Hepatic impairment developed in 1.0% of the low-dose group, 0.5% of the high-dose group, and 0.0% of the placebo group. Renal impairment developed in 0.0% of the low-dose group, 0.7% of the high-dose group, and 0.2% of the placebo group.

Similarly, rates of major adverse cardiovascular events were comparable across the three study groups, as were rates of any grade of bleeding, rates of serious and life-threatening adverse events, and rates of adverse events leading to drug discontinuation.

This study focused on safety and tolerability and was not designed or powered to assess efficacy. Nevertheless, CSL112 caused a substantial and dose-dependent increase in both apoA-1 and cholesterol efflux capacity. The low-dose drug raised total cholesterol efflux capacity by 1.87-fold, and the high-dose drug raised it 2.45-fold.

As the first study to establish the safety and feasibility of adding CSL112 to standard care for acute MI, this trial demonstrates that an adequately powered, multicenter, phase III trial is warranted, Dr. Gibson said.

The current formulation of CSL112 didn’t provoke hepatic toxicity, and even though it was given shortly after contrast studies in MI patients, it also didn’t provoke renal toxicity. “This demonstrates the feasibility of administering CSL112 to patients with MI who have normal renal function or mild renal impairment shortly after angiography. A study in MI patients who have moderate renal impairment is now under way,” he noted.
 

This study was sponsored by CSL Behring, maker of CSL112. Dr. Gibson and his associates reported financial ties to Behring and numerous other industry sources.

In patients taking nivolumab for advanced melanoma, most immunologic adverse effects are mild to moderate in intensity and resolve when existing management guidelines are followed, investigators report.

Nivolumab, a programmed death-1 (PD-1) checkpoint inhibitor antibody, is effective in several tumor types, including melanoma, but its safety profile has not been well characterized to date. Researchers pooled data from two phase I exploratory and two phase III comparative clinical trials of advanced melanoma to better examine safety outcomes, in what they described as “the largest and most comprehensive analysis to date of ... anti-PD-1 monotherapy.”

The study included 576 patients (median age, 61 years) taking nivolumab. Slightly more than half had received ipilimumab, another immune checkpoint inhibitor, previously. Twelve percent had brain metastases. The median duration of nivolumab therapy was 3.7 months, reflecting a median of nine doses of the agent per patient. Median follow-up was 7.2 months (range, 0.3-62.5 months), said Jeffrey S. Weber, MD, PhD, of Dana-Farber Cancer Institute, Boston, and his associates.

The overall rate of adverse events likely to have an immunologic etiology was 49%, and most of these were mild to moderate; severe immunologic adverse effects occurred in less than 4% of patients. Prior ipilimumab therapy did not influence the number or severity of adverse reactions to nivolumab. Most immunologic adverse effects involved the skin and GI tract, and most of them, including the few severe effects, resolved when treated according to safety management guidelines.

The types of immunologic adverse events in this study were similar to those previously reported for this class of drug. However, pneumonitis developed less frequently (less than 2% of patients) in this study population than has been reported previously and also was less severe. Rare and unusual immunologic adverse events remain a possibility with PD-1 checkpoint inhibitor antibodies. In particular, five of these study participants developed grade 3 neurologic toxicities. Further information on such effects and on optimal management is needed, the investigators wrote (J Clin Oncol. 2016 Nov 14. doi: 10.1200/JCO.66.1389).

Immune modulators – chiefly systemic, topical, or inhaled corticosteroids – were frequently used to treat immunologic adverse effects. “Although there is a theoretic concern that [this] might interfere with an anticancer immune response, the results of our analysis suggest that immune modulators do not negatively affect the rate or quality of antitumor responses [to] nivolumab therapy,” Dr. Weber and his associates said.

In patients taking nivolumab for advanced melanoma, most immunologic adverse effects are mild to moderate in intensity and resolve when existing management guidelines are followed, investigators report.

Nivolumab, a programmed death-1 (PD-1) checkpoint inhibitor antibody, is effective in several tumor types, including melanoma, but its safety profile has not been well characterized to date. Researchers pooled data from two phase I exploratory and two phase III comparative clinical trials of advanced melanoma to better examine safety outcomes, in what they described as “the largest and most comprehensive analysis to date of ... anti-PD-1 monotherapy.”

The study included 576 patients (median age, 61 years) taking nivolumab. Slightly more than half had received ipilimumab, another immune checkpoint inhibitor, previously. Twelve percent had brain metastases. The median duration of nivolumab therapy was 3.7 months, reflecting a median of nine doses of the agent per patient. Median follow-up was 7.2 months (range, 0.3-62.5 months), said Jeffrey S. Weber, MD, PhD, of Dana-Farber Cancer Institute, Boston, and his associates.

The overall rate of adverse events likely to have an immunologic etiology was 49%, and most of these were mild to moderate; severe immunologic adverse effects occurred in less than 4% of patients. Prior ipilimumab therapy did not influence the number or severity of adverse reactions to nivolumab. Most immunologic adverse effects involved the skin and GI tract, and most of them, including the few severe effects, resolved when treated according to safety management guidelines.

The types of immunologic adverse events in this study were similar to those previously reported for this class of drug. However, pneumonitis developed less frequently (less than 2% of patients) in this study population than has been reported previously and also was less severe. Rare and unusual immunologic adverse events remain a possibility with PD-1 checkpoint inhibitor antibodies. In particular, five of these study participants developed grade 3 neurologic toxicities. Further information on such effects and on optimal management is needed, the investigators wrote (J Clin Oncol. 2016 Nov 14. doi: 10.1200/JCO.66.1389).

Immune modulators – chiefly systemic, topical, or inhaled corticosteroids – were frequently used to treat immunologic adverse effects. “Although there is a theoretic concern that [this] might interfere with an anticancer immune response, the results of our analysis suggest that immune modulators do not negatively affect the rate or quality of antitumor responses [to] nivolumab therapy,” Dr. Weber and his associates said.

In patients taking nivolumab for advanced melanoma, most immunologic adverse effects are mild to moderate in intensity and resolve when existing management guidelines are followed, investigators report.

Nivolumab, a programmed death-1 (PD-1) checkpoint inhibitor antibody, is effective in several tumor types, including melanoma, but its safety profile has not been well characterized to date. Researchers pooled data from two phase I exploratory and two phase III comparative clinical trials of advanced melanoma to better examine safety outcomes, in what they described as “the largest and most comprehensive analysis to date of ... anti-PD-1 monotherapy.”

The study included 576 patients (median age, 61 years) taking nivolumab. Slightly more than half had received ipilimumab, another immune checkpoint inhibitor, previously. Twelve percent had brain metastases. The median duration of nivolumab therapy was 3.7 months, reflecting a median of nine doses of the agent per patient. Median follow-up was 7.2 months (range, 0.3-62.5 months), said Jeffrey S. Weber, MD, PhD, of Dana-Farber Cancer Institute, Boston, and his associates.

The overall rate of adverse events likely to have an immunologic etiology was 49%, and most of these were mild to moderate; severe immunologic adverse effects occurred in less than 4% of patients. Prior ipilimumab therapy did not influence the number or severity of adverse reactions to nivolumab. Most immunologic adverse effects involved the skin and GI tract, and most of them, including the few severe effects, resolved when treated according to safety management guidelines.

The types of immunologic adverse events in this study were similar to those previously reported for this class of drug. However, pneumonitis developed less frequently (less than 2% of patients) in this study population than has been reported previously and also was less severe. Rare and unusual immunologic adverse events remain a possibility with PD-1 checkpoint inhibitor antibodies. In particular, five of these study participants developed grade 3 neurologic toxicities. Further information on such effects and on optimal management is needed, the investigators wrote (J Clin Oncol. 2016 Nov 14. doi: 10.1200/JCO.66.1389).

Immune modulators – chiefly systemic, topical, or inhaled corticosteroids – were frequently used to treat immunologic adverse effects. “Although there is a theoretic concern that [this] might interfere with an anticancer immune response, the results of our analysis suggest that immune modulators do not negatively affect the rate or quality of antitumor responses [to] nivolumab therapy,” Dr. Weber and his associates said.

Cabozantinib showed significant improvements in progression-free survival and objective response rate over standard-of-care sunitinib in a phase II clinical trial of adults with metastatic renal cell carcinoma, according to a report published in the Journal of Clinical Oncology.

As a first-line therapy for patients with poor- to intermediate-risk renal cell carcinoma (RCC), cabozantinib improved progression-free survival by approximately 3 months, corresponding to a 34% reduction in the rate of disease progression or death. This is the first study in this patient population in which another agent demonstrated “notable and clinically meaningful” superiority over sunitinib, which has been an established standard of care for more than 10 years, wrote Toni K. Choueiri, MD, director of the Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, and his associates.

In the open-label study, participants were randomly assigned to receive daily oral cabozantinib (79 patients) or daily oral sunitinib (78 patients) in 6-week cycles until disease progressed, intolerance developed, or patients withdrew from treatment. A total of 36% had bone metastases at baseline, an indicator of poor prognosis.

The primary endpoint – median duration of progression-free survival or time to death from any cause – was 8.2 months with cabozantinib and 5.6 months with sunitinib (adjusted hazard ratio, 0.66). Analyses of patient subgroups defined by disease severity consistently favored cabozantinib. Reductions in target lesion size, as measured by CT or MRI, were observed in 87% of the cabozantinib group, compared with 44% of the sunitinib group, the investigators reported (J Clin Oncol. 2016 Nov 14. doi: 10.1200/JCO.2016.70.7398).

Preliminary data showed that overall survival was 30.3 months with cabozantinib and 21.8 months with sunitinib. This represents a 20% decrease in mortality with cabozantinib.

The median number of treatment cycles was greater in the cabozantinib group (five cycles) than in the sunitinib group (two cycles), and corresponded to median treatment durations of 6.9 months and 2.8 months, respectively. Rates of treatment discontinuation due to adverse events were similar between the two study groups, as were the rates of adverse events of any grade, adverse events of grade 3 or 4, and adverse events of grade 5.

These findings indicate that cabozantinib may represent a new treatment option for previously untreated poor- or intermediate-risk metastatic RCC, Dr. Choueiri and his associates wrote.

The study was supported by the National Institutes of Health and Exelixis, which provided the cabozantinib. Dr. Choueiri and many of his associates reported ties to numerous industry sources.

Cabozantinib showed significant improvements in progression-free survival and objective response rate over standard-of-care sunitinib in a phase II clinical trial of adults with metastatic renal cell carcinoma, according to a report published in the Journal of Clinical Oncology.

As a first-line therapy for patients with poor- to intermediate-risk renal cell carcinoma (RCC), cabozantinib improved progression-free survival by approximately 3 months, corresponding to a 34% reduction in the rate of disease progression or death. This is the first study in this patient population in which another agent demonstrated “notable and clinically meaningful” superiority over sunitinib, which has been an established standard of care for more than 10 years, wrote Toni K. Choueiri, MD, director of the Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, and his associates.

In the open-label study, participants were randomly assigned to receive daily oral cabozantinib (79 patients) or daily oral sunitinib (78 patients) in 6-week cycles until disease progressed, intolerance developed, or patients withdrew from treatment. A total of 36% had bone metastases at baseline, an indicator of poor prognosis.

The primary endpoint – median duration of progression-free survival or time to death from any cause – was 8.2 months with cabozantinib and 5.6 months with sunitinib (adjusted hazard ratio, 0.66). Analyses of patient subgroups defined by disease severity consistently favored cabozantinib. Reductions in target lesion size, as measured by CT or MRI, were observed in 87% of the cabozantinib group, compared with 44% of the sunitinib group, the investigators reported (J Clin Oncol. 2016 Nov 14. doi: 10.1200/JCO.2016.70.7398).

Preliminary data showed that overall survival was 30.3 months with cabozantinib and 21.8 months with sunitinib. This represents a 20% decrease in mortality with cabozantinib.

The median number of treatment cycles was greater in the cabozantinib group (five cycles) than in the sunitinib group (two cycles), and corresponded to median treatment durations of 6.9 months and 2.8 months, respectively. Rates of treatment discontinuation due to adverse events were similar between the two study groups, as were the rates of adverse events of any grade, adverse events of grade 3 or 4, and adverse events of grade 5.

These findings indicate that cabozantinib may represent a new treatment option for previously untreated poor- or intermediate-risk metastatic RCC, Dr. Choueiri and his associates wrote.

The study was supported by the National Institutes of Health and Exelixis, which provided the cabozantinib. Dr. Choueiri and many of his associates reported ties to numerous industry sources.

Cabozantinib showed significant improvements in progression-free survival and objective response rate over standard-of-care sunitinib in a phase II clinical trial of adults with metastatic renal cell carcinoma, according to a report published in the Journal of Clinical Oncology.

As a first-line therapy for patients with poor- to intermediate-risk renal cell carcinoma (RCC), cabozantinib improved progression-free survival by approximately 3 months, corresponding to a 34% reduction in the rate of disease progression or death. This is the first study in this patient population in which another agent demonstrated “notable and clinically meaningful” superiority over sunitinib, which has been an established standard of care for more than 10 years, wrote Toni K. Choueiri, MD, director of the Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, and his associates.

In the open-label study, participants were randomly assigned to receive daily oral cabozantinib (79 patients) or daily oral sunitinib (78 patients) in 6-week cycles until disease progressed, intolerance developed, or patients withdrew from treatment. A total of 36% had bone metastases at baseline, an indicator of poor prognosis.

The primary endpoint – median duration of progression-free survival or time to death from any cause – was 8.2 months with cabozantinib and 5.6 months with sunitinib (adjusted hazard ratio, 0.66). Analyses of patient subgroups defined by disease severity consistently favored cabozantinib. Reductions in target lesion size, as measured by CT or MRI, were observed in 87% of the cabozantinib group, compared with 44% of the sunitinib group, the investigators reported (J Clin Oncol. 2016 Nov 14. doi: 10.1200/JCO.2016.70.7398).

Preliminary data showed that overall survival was 30.3 months with cabozantinib and 21.8 months with sunitinib. This represents a 20% decrease in mortality with cabozantinib.

The median number of treatment cycles was greater in the cabozantinib group (five cycles) than in the sunitinib group (two cycles), and corresponded to median treatment durations of 6.9 months and 2.8 months, respectively. Rates of treatment discontinuation due to adverse events were similar between the two study groups, as were the rates of adverse events of any grade, adverse events of grade 3 or 4, and adverse events of grade 5.

These findings indicate that cabozantinib may represent a new treatment option for previously untreated poor- or intermediate-risk metastatic RCC, Dr. Choueiri and his associates wrote.

The study was supported by the National Institutes of Health and Exelixis, which provided the cabozantinib. Dr. Choueiri and many of his associates reported ties to numerous industry sources.

Instruments used for robotic surgery are “virtually impossible” to clean completely, according to a report published in Infection Control & Hospital Epidemiology.

“A new standard for the cleaning of complex surgical instruments needs to be established, especially for those used in robotic surgery,” wrote Yuhei Saito of the surgical center at the University of Tokyo Hospital and associates.

They assessed the residual contamination of both robotic and regular surgical instruments at their medical center because “hospital staff in central sterile supply departments are troubled by the reprocessing of robotic instruments because they cannot be disassembled for cleaning like other endoscopic instruments. Their complex structure impairs brushing the inner surface of narrow lumens, resulting in failure to [completely] remove contaminants,” the researchers wrote.

In the first phase of the study, the researchers examined 41 instruments immediately after they were used in robotic surgery (7 radical prostatectomies and 2 anterior resections of the rectum) and 27 regular instruments immediately after they were used for open surgery (gastrectomy and colectomy). The robotic instruments were contaminated with 72.3 × 10³ mcg of protein each, compared with 5.5 × 10³ mcg of protein on the regular instruments, the investigators reported (Infect Control Hosp Epidemiol. 2016 Oct 31. doi: 10.1017/ice.2016.249).

In the second phase of the study, the researchers examined another 24 robotic instruments and 40 regular instruments after they were used in surgery and then cleaned according to the manufacturers’ instructions three successive times. For the robotic instruments, this involved manually brushing the outer surface while moving the instrument “wrists” through their full range of motion, followed by 15 minutes of ultrasonication with enzymatic detergent, flushing the lumen with a water gun through flush ports, and rinsing the entire instrument. For regular instruments, cleaning involved washer-disinfectors and included 5 minutes of ultrasonication, 10 minutes of spraying with an alkaline detergent, and 10 minutes of disinfection via heating.

The level of contamination declined with each successive cleaning but still remained comparatively high for the robotic instruments. The amount of protein contaminants released in the three cleanings was 650, 550, and 530 mcg per robotic instrument, compared with 16, 17, and 17 mcg per ordinary instrument.

The efficacy of cleaning was 97.6% for robotic instruments and 99.1% for regular instruments, the researchers reported.

This study was not designed to assess whether residual contamination is associated with adverse events such as infection in subsequent patients, and there are few data available on this topic.

“We have to recognize that there might be a considerable volume of insufficient cleaning or occult surgical site infections,” the investigators wrote.

New instrument washers equipped with a specific cleaning function for narrow lumens are becoming available, they noted, and “further study should be conducted using these washers with improved cleaning efficacy.”

The study was supported by the Japan Society for the Promotion of Science. The investigators reported having no relevant financial disclosures.

Instruments used for robotic surgery are “virtually impossible” to clean completely, according to a report published in Infection Control & Hospital Epidemiology.

“A new standard for the cleaning of complex surgical instruments needs to be established, especially for those used in robotic surgery,” wrote Yuhei Saito of the surgical center at the University of Tokyo Hospital and associates.

They assessed the residual contamination of both robotic and regular surgical instruments at their medical center because “hospital staff in central sterile supply departments are troubled by the reprocessing of robotic instruments because they cannot be disassembled for cleaning like other endoscopic instruments. Their complex structure impairs brushing the inner surface of narrow lumens, resulting in failure to [completely] remove contaminants,” the researchers wrote.

In the first phase of the study, the researchers examined 41 instruments immediately after they were used in robotic surgery (7 radical prostatectomies and 2 anterior resections of the rectum) and 27 regular instruments immediately after they were used for open surgery (gastrectomy and colectomy). The robotic instruments were contaminated with 72.3 × 10³ mcg of protein each, compared with 5.5 × 10³ mcg of protein on the regular instruments, the investigators reported (Infect Control Hosp Epidemiol. 2016 Oct 31. doi: 10.1017/ice.2016.249).

In the second phase of the study, the researchers examined another 24 robotic instruments and 40 regular instruments after they were used in surgery and then cleaned according to the manufacturers’ instructions three successive times. For the robotic instruments, this involved manually brushing the outer surface while moving the instrument “wrists” through their full range of motion, followed by 15 minutes of ultrasonication with enzymatic detergent, flushing the lumen with a water gun through flush ports, and rinsing the entire instrument. For regular instruments, cleaning involved washer-disinfectors and included 5 minutes of ultrasonication, 10 minutes of spraying with an alkaline detergent, and 10 minutes of disinfection via heating.

The level of contamination declined with each successive cleaning but still remained comparatively high for the robotic instruments. The amount of protein contaminants released in the three cleanings was 650, 550, and 530 mcg per robotic instrument, compared with 16, 17, and 17 mcg per ordinary instrument.

The efficacy of cleaning was 97.6% for robotic instruments and 99.1% for regular instruments, the researchers reported.

This study was not designed to assess whether residual contamination is associated with adverse events such as infection in subsequent patients, and there are few data available on this topic.

“We have to recognize that there might be a considerable volume of insufficient cleaning or occult surgical site infections,” the investigators wrote.

New instrument washers equipped with a specific cleaning function for narrow lumens are becoming available, they noted, and “further study should be conducted using these washers with improved cleaning efficacy.”

The study was supported by the Japan Society for the Promotion of Science. The investigators reported having no relevant financial disclosures.

Instruments used for robotic surgery are “virtually impossible” to clean completely, according to a report published in Infection Control & Hospital Epidemiology.

“A new standard for the cleaning of complex surgical instruments needs to be established, especially for those used in robotic surgery,” wrote Yuhei Saito of the surgical center at the University of Tokyo Hospital and associates.

They assessed the residual contamination of both robotic and regular surgical instruments at their medical center because “hospital staff in central sterile supply departments are troubled by the reprocessing of robotic instruments because they cannot be disassembled for cleaning like other endoscopic instruments. Their complex structure impairs brushing the inner surface of narrow lumens, resulting in failure to [completely] remove contaminants,” the researchers wrote.

In the first phase of the study, the researchers examined 41 instruments immediately after they were used in robotic surgery (7 radical prostatectomies and 2 anterior resections of the rectum) and 27 regular instruments immediately after they were used for open surgery (gastrectomy and colectomy). The robotic instruments were contaminated with 72.3 × 10³ mcg of protein each, compared with 5.5 × 10³ mcg of protein on the regular instruments, the investigators reported (Infect Control Hosp Epidemiol. 2016 Oct 31. doi: 10.1017/ice.2016.249).

In the second phase of the study, the researchers examined another 24 robotic instruments and 40 regular instruments after they were used in surgery and then cleaned according to the manufacturers’ instructions three successive times. For the robotic instruments, this involved manually brushing the outer surface while moving the instrument “wrists” through their full range of motion, followed by 15 minutes of ultrasonication with enzymatic detergent, flushing the lumen with a water gun through flush ports, and rinsing the entire instrument. For regular instruments, cleaning involved washer-disinfectors and included 5 minutes of ultrasonication, 10 minutes of spraying with an alkaline detergent, and 10 minutes of disinfection via heating.

The level of contamination declined with each successive cleaning but still remained comparatively high for the robotic instruments. The amount of protein contaminants released in the three cleanings was 650, 550, and 530 mcg per robotic instrument, compared with 16, 17, and 17 mcg per ordinary instrument.

The efficacy of cleaning was 97.6% for robotic instruments and 99.1% for regular instruments, the researchers reported.

This study was not designed to assess whether residual contamination is associated with adverse events such as infection in subsequent patients, and there are few data available on this topic.

“We have to recognize that there might be a considerable volume of insufficient cleaning or occult surgical site infections,” the investigators wrote.

New instrument washers equipped with a specific cleaning function for narrow lumens are becoming available, they noted, and “further study should be conducted using these washers with improved cleaning efficacy.”

The study was supported by the Japan Society for the Promotion of Science. The investigators reported having no relevant financial disclosures.