Olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer patients without a germline BRCA1/BRCA2 mutation: OPINION primary analysis

Maintenance; Olaparib; Ovarian cancerManteniment; Olaparib; Càncer d'ovarisMantenimiento; Olaparib; Cáncer de ovariosObjective The phase IIIb OPINION trial (NCT03402841) investigated olaparib maintenance monotherapy in patients without a deleterious or suspected deleterious germline BRCA1/BRCA2 mutation (gBRCAm) who had platinum-sensitive relapsed ovarian cancer (PSROC) and had received ≥2 previous lines of platinum-based chemotherapy. Methods In this single-arm, open-label, international study, patients who had responded to platinum-based chemotherapy received maintenance olaparib tablets (300 mg twice daily) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS) (modified RECIST version 1.1). A key secondary endpoint was PFS by homologous recombination deficiency (HRD) and somatic BRCAm (sBRCAm) status. The primary analysis of PFS was planned for 18 months after the last patient received their first dose. Results Two hundred and seventy-nine patients were enrolled and received olaparib. At data cutoff (October 2, 2020), 210 PFS events had occurred (75.3% maturity) and median PFS was 9.2 months (95% confidence interval [CI], 7.6–10.9) in the overall population. At 12 and 18 months, 38.5% and 24.3% of patients were progression-free, respectively. In the predefined biomarker subgroups, median PFS was 16.4, 11.1, 9.7, and 7.3 months in sBRCAm, HRD-positive including sBRCAm, HRD-positive excluding sBRCAm, and HRD-negative patients, respectively. The most common treatment-emergent adverse events (TEAEs) were nausea (48.4%) and fatigue/asthenia (44.1%). TEAEs led to dose interruption, dose reduction, and treatment discontinuation in 47.0%, 22.6%, and 7.5% of patients, respectively. Conclusion Maintenance olaparib demonstrated clinical benefit in patients without a gBRCAm, and across all subgroups, compared with historical placebo controls. There were no new safety signals.This study was funded by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

The Changing Landscape of Systemic Treatment for Cervical Cancer: Rationale for Inhibition of the TGF-β and PD-L1 Pathways

Cervical cancer; Tumor microenvironmentCáncer de cuello uterino; Microambiente tumoralCàncer de coll uterí; Microambient tumoralCervical cancer is one of the most common and lethal cancers among women worldwide. Treatment options are limited in patients with persistent, recurrent, or metastatic cervical cancer, with 5 years. Persistent human papillomavirus (HPV) infection has been implicated in almost all cases of cervical cancer. HPV infection not only causes normal cervical cells to transform into cancer cells, but also creates an immunosuppressive environment for cancer cells to evade the immune system. Recent clinical trials of drugs targeting the PD-(L)1 pathway have demonstrated improvement in overall survival in patients with cervical cancer, but only 20% to 30% of patients show overall survival benefit beyond 2 years, and resistance to these treatments remains common. Therefore, novel treatment strategies targeting HPV infection–associated factors are currently being evaluated in clinical trials. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human immunoglobulin G1 monoclonal antibody that blocks PD-L1. Early clinical trials of bintrafusp alfa have shown promising results in patients with advanced cervical cancer.This work was funded by Merck (CrossRef Funder ID: 10.13039/100009945) and was previously part of an alliance between Merck and GlaxoSmithKline

Final survival analysis of topotecan and paclitaxel for first-line treatment of advanced cervical cancer: An NRG oncology randomized study

Càncer de coll uterí; Platí; TopotecanCáncer de cuello uterino; Platino; TopotecanCervical cancer; Platinum; TopotecanObjective To determine whether a non‑platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma. Methods Gynecologic Oncology Group protocol 240 is a phase 3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m2 plus topotecan 0.75 mg/m2 days 1–3 (n = 223) vs cisplatin 50 mg/m2 plus paclitaxel 135 or 175 mg/m2 (n = 229), in 452 patients with recurrent/metastatic cervical cancer. Each chemotherapy doublet was also studied with and without bevacizumab (15 mg/kg). Cycles were repeated every 21 days until progression, unacceptable toxicity, or complete response. The primary endpoints were OS and the frequency and severity of adverse effects. We report the final analysis of OS. Results At the protocol-specified final analysis, median OS was 16.3 (cisplatin-paclitaxel backbone) and 13.8 months (topotecan-paclitaxel backbone) (HR 1.12; 95% CI, 0.91–1.38; p = 0.28). Median OS for cisplatin-paclitaxel and topotecan-paclitaxel was 15 vs 12 months, respectively (HR 1.10; 95% CI,0.82–1.48; p = 0.52), and for cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab was 17.5 vs 16.2 months, respectively (HR 1.16; 95% CI, 0.86–1.56; p = 0.34). Among the 75% of patients in the study population previously exposed to platinum, median OS was 14.6 (cisplatin-paclitaxel backbone) vs 12.9 months (topotecan-paclitaxel backbone), respectively (HR 1.09; 95% CI, 0.86–1.38;p = 0.48). Post-progression survival was 7.9 (cisplatin-paclitaxel backbone) vs 8.1 months (topotecan-paclitaxel backbone) (HR 0.95; 95% CI, 0.75–1.19). Grade 4 hematologic toxicity was similar between chemotherapy backbones. Conclusions Topotecan plus paclitaxel does not confer a survival benefit to women with recurrent/metastatic cervical cancer, even among platinum-exposed patients. Topotecan-paclitaxel should not be routinely recommended in this population.This study was supported by the following National Cancer Institute and Genentech grants: NRG Oncology (1U10CA180822), NRG Operations (U10CA180868) and NCORP grant UG1CA189867

Witnessing and re-enacting in Cambodia: reflection on shifting testimonies

Thirty years after the collapse of the Khmer Rouge regime (1975-1979) how do Cambodians cope with the traumatic legacy of Pol Pot's reign of terror? What forms does witnessing take on in post-socialist and transitional Cambodia as senior Khmer Rouge leaders await prosecution at the Cambodian Tribunal? The paper examines aspects of witnessing in today's Cambodia, expressing each in its own way the idea of the 'shifting' of witnessing: the transformation of testimonies due to time passing and contrasted systems of justice through a comparison of testimonies in the trial of the 'Pol Pot/Ieng Sary clique' (1979) and the current Cambodian Tribunal; the complex forms of witnessing emerging from participatory projects developed with Western authors in 'We want (u) to know' (documentary movie made by an international film crew with the inhabitants of the village of Thnol Lok in 2009) and 'Breaking the silence' (theatre play realised by the Dutch dramaturge Annemarie Prins that premiered in Phnom Penh in 2009 and toured Cambodia in the following years); the relationship between documentary and legal forms of witnessing through the example of Vann Nath, a survivor of S-21/Tuol Sleng, the prison where the Khmer Rouge tortured and killed thousands of their fellow countrymen. The paper analyses the difficulty Western organisers of participatory projects experienced in applying the hybrid model of transitional justice to sociocultural contexts of witnessing. Nevertheless it points out their contribution to processes of 'recognition beyond recognition' in which cultural differences in coming to terms with historical trauma are expressed and recorded

Retracing Micro-Epidemics of Chagas Disease Using Epicenter Regression

Vector-borne transmission of Chagas disease has become an urban problem in the city of Arequipa, Peru, yet the debilitating symptoms that can occur in the chronic stage of the disease are rarely seen in hospitals in the city. The lack of obvious clinical disease in Arequipa has led to speculation that the local strain of the etiologic agent, Trypanosoma cruzi, has low chronic pathogenicity. The long asymptomatic period of Chagas disease leads us to an alternative hypothesis for the absence of clinical cases in Arequipa: transmission in the city may be so recent that most infected individuals have yet to progress to late stage disease. Here we describe a new method, epicenter regression, that allows us to infer the spatial and temporal history of disease transmission from a snapshot of a population's infection status. We show that in a community of Arequipa, transmission of T. cruzi by the insect vector Triatoma infestans occurred as a series of focal micro-epidemics, the oldest of which began only around 20 years ago. These micro-epidemics infected nearly 5% of the community before transmission of the parasite was disrupted through insecticide application in 2004. Most extant human infections in our study community arose over a brief period of time immediately prior to vector control. According to our findings, the symptoms of chronic Chagas disease are expected to be absent, even if the strain is pathogenic in the chronic phase of disease, given the long asymptomatic period of the disease and short history of intense transmission. Traducción al español disponible en Alternative Language Text S1/A Spanish translation of this article is available in Alternative Language Text S

Retracing Micro-Epidemics of Chagas Disease Using Epicenter Regression

Vector-borne transmission of Chagas disease has become an urban problem in the city of Arequipa, Peru, yet the debilitating symptoms that can occur in the chronic stage of the disease are rarely seen in hospitals in the city. The lack of obvious clinical disease in Arequipa has led to speculation that the local strain of the etiologic agent, Trypanosoma cruzi, has low chronic pathogenicity. The long asymptomatic period of Chagas disease leads us to an alternative hypothesis for the absence of clinical cases in Arequipa: transmission in the city may be so recent that most infected individuals have yet to progress to late stage disease. Here we describe a new method, epicenter regression, that allows us to infer the spatial and temporal history of disease transmission from a snapshot of a population\u27s infection status. We show that in a community of Arequipa, transmission of T. cruzi by the insect vector Triatoma infestans occurred as a series of focal micro-epidemics, the oldest of which began only around 20 years ago. These micro-epidemics infected nearly 5% of the community before transmission of the parasite was disrupted through insecticide application in 2004. Most extant human infections in our study community arose over a brief period of time immediately prior to vector control. According to our findings, the symptoms of chronic Chagas disease are expected to be absent, even if the strain is pathogenic in the chronic phase of disease, given the long asymptomatic period of the disease and short history of intense transmission

Quality of life of asthmatic children and adolescents: relation to maternal coping

OBJECTIVE: To evaluate the quality of life of asthmatic children and adolescents, its relation with sociodemographic and clinical variables, and maternal coping strategies. METHODS: Cross-sectional study in which children and adolescents with asthma answered a quality of life questionnaire, and their mothers did the same with a coping scale. RESULTS: Out of the 42 children and adolescents investigated, 74% were classified as having mild/severe persistent asthma; 19%, mild persistent asthma; and 7%, intermittent asthma. A total of 69% of the participants showed impaired quality of life with mean scores ranging between 4.7 and 3.5, with greater harm in the domain of symptoms (score=3.6). There was a significant association between maternal schooling and the general index of quality of life, whereas maternal coping strategies were not associated with the severity of asthma. A large number of strategies used by mothers to cope with their children's crises were related to the management of stressors or to religious practices, and the latter presented negative correlation with the children's quality of life general index, showing that mothers whose children had worse quality of life used more religious coping. CONCLUSIONS: Asthmatic children, particularly those with moderate/severe persistent asthma, showed significant alterations as to quality of life. The high percentage of mothers using religious strategies, particularly in face of more severe clinical conditions, seem to indicate that they feel powerless to act, thus requiring concrete and useful orientation to low income families.OBJETIVO: Avaliar a qualidade de vida de crianças e adolescentes asmáticos, sua relação com variáveis sociodemográficas e clínicas e estratégias de enfrentamento materno. MÉTODOS: Estudo transversal no qual crianças e adolescentes com asma responderam a um questionário de qualidade de vida, e suas mães a uma escala de enfrentamento. RESULTADOS: Foram estudadas 42 crianças e adolescentes com idades entre 7 e 15 anos, sendo 74% classificados como tendo um quadro de asma persistente moderada/grave, 19% como persistente leve e 7% asma intermitente; 69% dos entrevistados apresentaram prejuízo na qualidade de vida, com escores médios variando de 4,7 a 3,5 e maior prejuízo no domínio sintomas (escore=3,6). Houve associação significativa entre escolaridade materna e índice geral de qualidade de vida, mas não entre gravidade da asma e tipo de enfrentamento materno. Grande parte das estratégias utilizadas pelas mães para enfrentar as crises do filho estava direcionada ao manejo de estressores ou práticas religiosas, estas com correlação negativa com o índice geral de qualidade de vida da criança, sinalizando que mães cujos filhos tinham pior qualidade de vida usavam mais enfrentamentos religiosos. CONCLUSÕES: Crianças asmáticas, especialmente com asma persistente moderada/grave, apresentaram alterações significativas em sua qualidade de vida. A alta porcentagem de uso de estratégias religiosas por parte das mães, especialmente frente a quadros mais graves, parece indicar que elas se sentem impotentes para atuar, necessitando de orientações concretas e factíveis para uma população de baixa renda.OBJETIVO: Evaluar la calidad de vida de niños y adolescentes asmáticos, su relación con variables sociodemográficas, clínicas y estratégicas de enfrentamiento materno. MÉTODOS: Estudio transversal en el que niños y adolescentes con asma contestaron un cuestionario de calidad de vida (PAQLQ-A) y sus madres a una escala de enfrentamiento (EMEP). RESULTADOS: Se estudiaron 42 niños y adolescentes con edad de 7-15 años y, entre ellos, el 74% fueron clasificados como teniendo un cuadro de asma persistente moderada/grave, el 19% como persistente y el 7% asma intermitente; el 69% de los entrevistados presentaron perjuicio en la calidad de vida, con escores medianos variando de 4,7 a 3,5 y mayor perjuicio en el dominio de síntomas (escore=3,6). Hubo asociación significativa entre escolaridad materna e índice general de calidad de vida, pero no hubo asociación entre gravedad del asma y tipo de enfrentamiento materno. Gran parte de las estrategias utilizadas por las madres para enfrentar las crisis de los hijos estaba dirigida al manejo de estresores o prácticas religiosas. Estas últimas con correlación negativa con el índice general de calidad de vida del niño, señalizando que madres cuyos hijos tenían peor calidad de vida usaban más enfrentamientos religiosos. CONCLUSIONES: Niños asmáticos, especialmente con asma persistente moderada/grave, presentaron alteraciones significativas en su calidad de vida. El alto porcentaje de uso de estrategias religiosas por parte de las madres, especialmente frente a cuadros más graves, parece indicar que ellas se sienten impotentes para actuar, necesitando de orientaciones concretas y factibles para una población de bajos ingresos.14515

Predicting Survival after Allogeneic Hematopoietic Cell Transplantation in Myelofibrosis : Performance of the Myelofibrosis Transplant Scoring System (MTSS) and Development of a New Prognostic Model

Accurate prognostic tools are crucial to assess the risk/benefit ratio of allogeneic hematopoietic cell transplantation (allo-HCT) in patients with myelofibrosis (MF). We aimed to evaluate the performance of the Myelofibrosis Transplant Scoring System (MTSS) and identify risk factors for survival in a multicenter series of 197 patients with MF undergoing allo-HCT. After a median follow-up of 3.1 years, 47% of patients had died, and the estimated 5-year survival rate was 51%. Projected 5-year risk of nonrelapse mortality and relapse incidence was 30% and 20%, respectively. Factors independently associated with increased mortality were a hematopoietic cell transplantation-specific comorbidity index (HCT-CI) ≥3 and receiving a graft from an HLA-mismatched unrelated donor or cord blood, whereas post-transplant cyclophosphamide (PT-Cy) was associated with improved survival. Donor type was the only parameter included in the MTSS model with independent prognostic value for survival. According to the MTSS, 3-year survival was 62%, 66%, 37%, and 17% for low-, intermediate-, high-, and very high-risk groups, respectively. By pooling together the low- and intermediate-risk groups, as well as the high- and very high-risk groups, we pinpointed 2 categories: standard risk and high risk (25% of the series). Three-year survival was 62% in standard-risk and 25% in high-risk categories (P <.001). We derived a risk score based on the 3 independent risk factors for survival in our series (donor type, HCT-CI, and PT-Cy). The corresponding 5-year survival for the low-, intermediate-, and high-risk categories was 79%, 55%, and 32%, respectively (P <.001). In conclusion, the MTSS model failed to clearly delineate 4 prognostic groups in our series but may still be useful to identify a subset of patients with poor outcome. We provide a simple prognostic scoring system for risk/benefit considerations before transplantation in patients with MF

A Non Membrane-Targeted Human Soluble CD59 Attenuates Choroidal Neovascularization in a Model of Age Related Macular Degeneration

Age related macular degeneration (AMD) is the most common cause of blindness amongst the elderly. Approximately 10% of AMD patients suffer from an advanced form of AMD characterized by choroidal neovascularization (CNV). Recent evidence implicates a significant role for complement in the pathogenesis of AMD. Activation of complement terminates in the incorporation of the membrane attack complex (MAC) in biological membranes and subsequent cell lysis. Elevated levels of MAC have been documented on choroidal blood vessels and retinal pigment epithelium (RPE) of AMD patients. CD59 is a naturally occurring membrane bound inhibitor of MAC formation. Previously we have shown that membrane bound human CD59 delivered to the RPE cells of mice via an adenovirus vector can protect those cells from human complement mediated lysis ex vivo. However, application of those observations to choroidal blood vessels are limited because protection from MAC- mediated lysis was restricted only to the cells originally transduced by the vector. Here we demonstrate that subretinal delivery of an adenovirus vector expressing a transgene for a soluble non-membrane binding form of human CD59 can attenuate the formation of laser-induced choroidal neovascularization and murine MAC formation in mice even when the region of vector delivery is distal to the site of laser induced CNV. Furthermore, this same recombinant transgene delivered to the intravitreal space of mice by an adeno-associated virus vector (AAV) can also attenuate laser-induced CNV. To our knowledge, this is the first demonstration of a non-membrane targeting CD59 having biological potency in any animal model of disease in vivo. We propose that the above approaches warrant further exploration as potential approaches for alleviating complement mediated damage to ocular tissues in AMD