Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199

Purpose Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Patients and Methods Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. Results The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. Conclusion In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter

Glecaprevir/Pibrentasvir Treatment in Liver or Kidney Transplant Patients With Hepatitis C Virus Infection

Well-tolerated, ribavirin-free, pangenotypic hepatitis C virus (HCV) treatments for transplant recipients remain a high priority. Once-daily glecaprevir/pibrentasvir demonstrates high rates of sustained virologic response at 12 weeks posttreatment (SVR12) across all major HCV genotypes (GTs). This trial evaluated the safety and efficacy of glecaprevir/pibrentasvir for patients with chronic HCV GT1-6 infection who had received a liver or kidney transplant. MAGELLAN-2 was a phase 3, open-label trial conducted in patients who were ≥3 months posttransplant. Patients without cirrhosis who were HCV treatment-naive (GT1-6) or treatment-experienced (GT1, 2, 4-6; with interferon-based therapy with or without sofosbuvir, or sofosbuvir plus ribavirin) received glecaprevir/pibrentasvir (300/120 mg) once daily for 12 weeks. The primary endpoint compared the percentage of patients receiving glecaprevir/pibrentasvir with SVR12 to a historic SVR12 rate based on the standard of care. Safety of glecaprevir/pibrentasvir was assessed. In total, 80 liver transplant and 20 kidney transplant patients participated in the trial. Most patients had no or minimal fibrosis (80% had fibrosis scores F0-F1) and were infected with HCV GT1 (57%) or GT3 (24%). The overall SVR12 was 98% (n/N = 98/100; 95% confidence interval, 95.3%-100%), which exceeded the prespecified historic standard-of-care SVR12 threshold of 94%. One patient experienced virologic failure. One patient discontinued because of an adverse event considered to be unrelated to treatment; this patient achieved SVR12. Adverse events were mostly mild in severity, and laboratory abnormalities were infrequent. CONCLUSION: Once-daily glecaprevir/pibrentasvir for 12 weeks is a well-tolerated and efficacious, ribavirin-free treatment for patients with chronic HCV GT1-6 infection who have received a liver or kidney transplant. (ClinicalTrials.gov NCT02692703.) (Hepatology 2018; 00:000-000)

Model Organisms Reveal Insight into Human Neurodegenerative Disease: Ataxin-2 Intermediate-Length Polyglutamine Expansions Are a Risk Factor for ALS

Model organisms include yeast Saccromyces cerevisae and fly Drosophila melanogaster. These systems have powerful genetic approaches, as well as highly conserved pathways, both for normal function and disease. Here, we review and highlight how we applied these systems to provide mechanistic insight into the toxicity of TDP-43. TDP-43 accumulates in pathological aggregates in ALS and about half of FTD. Yeast and fly studies revealed an interaction with the counterparts of human Ataxin-2, a gene whose polyglutamine repeat expansion is associated with spinocerebellar ataxia type 2. This finding raised the hypothesis that repeat expansions in ataxin-2 may associate with diseases characterized by TDP-43 pathology such as ALS. DNA analysis of patients revealed that intermediate-length polyglutamine expansions in ataxin-2 are a risk factor for ALS, such that repeat lengths are greater than normal, but lower than that associated with spinocerebellar ataxia type 2 (SCA2), and are more frequent in ALS patients than in matched controls. Moreover, repeat expansions associated with ALS are interrupted CAA-CAG sequences as opposed to the pure CAG repeat expansions typically associated with SCA2. These studies provide an example of how model systems, when extended to human cells and human patient tissue, can reveal new mechanistic insight into disease

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Maternal-Fetal Pharmacokinetics and Dynamics of a Single Intrapartum Dose of Maraviroc in Rhesus Macaques▿

Single-dose nevirapine (NVP) is effective in reducing mother-to-child transmission (MTCT) of HIV; however, the subsequent development of drug resistance is problematic. The pharmacokinetic profile of the HIV entry inhibitor maraviroc after a single intrapartum dose in rhesus macaques was studied to determine whether maraviroc could serve as an alternative to NVP in a single-dose strategy. Four pregnant macaques received an oral dose of maraviroc 2 h before delivery, and both infant and maternal plasma maraviroc concentrations and CCR5 receptor occupancy on CD4+ lymphocytes were measured over time. Maximum plasma maraviroc concentrations were found at delivery (2-h-postintrapartum dose) in both the mothers and infants, with median concentrations of 974 ng/ml (range, 86 to 2,830 ng/ml) and 22 ng/ml (range, 4 to 99 ng/ml), respectively. Maraviroc was detected in the plasma of mothers up to 48 h after dosing but only as long as 3.5 h in the infants. The median fetal-maternal area under the concentration-time curve (AUC) ratio was 0.009 (range, 0.000 to 0.015). Maraviroc receptor occupancy data showed evidence of unprotected CCR5 receptors on CD4+ cells in the mothers 24 to 48 h after dosing. Extremely low CCR5 expression on CD4+ cells of newborn macaques prevented determination of receptor occupancy in the infants. In rhesus macaques, maraviroc was poorly transferred across the placenta and was quickly cleared from the infants’ blood. The low concentrations of fetal maraviroc and short pharmacokinetic profile in infants suggest that a single maternal intrapartum dose of maraviroc would not be effective in reducing the risk of MTCT of HIV

Review of Quality Measures for Breast Cancer Care by Country Income Level

Purpose Measurement of the quality of cancer care is essential for quality improvement and is widely implemented in oncology programs in high-income countries. Growing efforts are being made to measure care quality in emerging cancer care delivery systems in low- and middle-income countries (LMICs). This will require the development of measures that are clinically important, actionable, relevant to existing resources, and feasible to routinely evaluate. As part of a project to develop resource-adapted quality measures for Rwanda and other LMICs, we conducted a systematic review of the literature to identify published quality measures for the diagnosis and treatment of breast cancer. Methods We performed a literature search in accordance with PRISMA guidelines using the following terms in PubMed: ‘breast cancer’ and ‘quality indicator,’ ‘quality measure,’ or ‘quality metric’; and the following MeSH terms: ‘breast neoplasms’ and ‘healthcare quality indicator.’ We included English-language articles published before August 2017 that described the systematic identification of process measures for breast cancer diagnosis or treatment through literature review, clinical validation, and/or expert panel determination. We directly searched the Web sites of prominent cancer care organizations to identify additional publicly available measures. Income level was classified using World Bank definitions. Results We identified 521 published quality measures, including 419 measures from 27 peer-reviewed journal articles and 102 measures from the Web sites of national and international cancer care organizations. Twenty-five peer-reviewed publications (93%) originated from high-income countries, one from an upper-middle income country (People’s Republic of China), and one from the international Breast Health Global Initiative with process measures to assess the phased implementation of breast cancer services. No resources or articles other than that from the Breast Health Global Initiative provided suggestions for adapting measures to limited resources. Conclusion A large number of quality measures for breast cancer care have been identified and published in high-income countries; however, no breast cancer care quality measures have been systematically developed and validated for use in settings where resource limitations crucially affect care delivery and measurement feasibility. We are collaborating with clinicians in LMICs and global breast cancer experts to develop and validate quality measures that will enable quality improvement initiatives in Rwanda and other emerging cancer care delivery systems. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc . No COIs from the authors

Quality of Breast Cancer Treatment at a Rural Cancer Center in Rwanda

Purpose: As breast cancer incidence and mortality rise in sub-Saharan Africa, it is critical to identify strategies for delivery of high-quality breast cancer care in settings with limited resources and few oncology specialists. We investigated the quality of treatments received by a cohort of patients with breast cancer at Butaro Cancer Center of Excellence (BCCOE), Rwanda’s first public cancer center. Patients and Methods: We reviewed medical records of all female patients diagnosed with invasive breast cancer at BCCOE between July 2012 and December 2013. We evaluated the provision of chemotherapy, endocrine therapy, surgery, and chemotherapy dose densities. We also applied modified international quality metrics and estimated overall survival using interval-censored analysis. Results: Among 150 patients, 28 presented with early-stage, 64 with locally advanced, and 53 with metastatic disease. Among potentially curable patients (ie, those with early-stage or locally advanced disease), 74% received at least four cycles of chemotherapy and 63% received surgery. Among hormone receptor–positive patients, 83% received endocrine therapy within 1 year of diagnosis. Fifty-seven percent of potentially curable patients completed surgery and chemotherapy and initiated endocrine therapy if indicated within 1 year of biopsy. Radiotherapy was not available. At the end of follow-up, 62% of potentially curable patients were alive, 24% were dead, and 14% were lost to follow-up. Conclusion: Appropriate delivery of chemotherapy and endocrine therapy for breast cancer is possible in rural sub-Saharan African even without oncologists based on site. Performing timely surgery and ensuring treatment completion were key challenges after the opening of BCCOE. Further investigation should examine persistent quality gaps and the relationship between treatment quality and survival