Citations

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune activation and dysregulation resulting in extreme and often life‐threatening inflammation. HLH has been well recognized in pediatric populations, and most current diagnostic and therapeutic guidelines are based on pediatric HLH. Recently there has been recognition of HLH in adults, especially secondary to immune deregulation by an underlying rheumatologic, infectious, or malignant condition. This review is focused on malignancy‐associated HLH (M‐HLH), in which possible mechanisms of pathogenesis include severe inflammation, persistent antigen stimulation by the tumor cells, and loss of immune homeostasis because of chemotherapy, hematopoietic stem cell transplantation, or infection. Previously considered rare, M‐HLH may occur in up to 1% of patients with hematologic malignancies. M‐HLH is often missed or diagnosed late in most published studies, and it has been associated with a poor median survival of less than 2 months. Identification of the clinical and laboratory features specific to M‐HLH in adults may allow early detection, consultation with HLH experts, and intervention. Improved management of adult M‐HLH with optimal combinations of T‐lympholytic and immunosuppressive agents and the incorporation of novel agents based on the pediatric experience hopefully will improve outcomes in adults with M‐HLH. Cancer 2017;123:3229‐40. © 2017 American Cancer Society.

Undifferentiated uterine sarcomas (UUS) are a heterogenous group of high-grade mesenchymal tumors. Although these tumors are highly aggressive, a subset of patients may experience long-term survival. These tumors have previously been divided morphologically into uniform and pleomorphic types. A previous study demonstrated that a mitotic index cutoff of 25 mitoses/10 high-power fields (corresponding to 11.16 mitotic figures/mm2) could successfully divide tumors into 2 prognostic groups with significantly different overall survival. The goals of the current study were to (1) validate this mitotic index cutoff in an independent, multicenter cohort and (2) explore the prognostic value of the mitotic index groups in relation to other clinicopathologic variables. Cases were included from 3 independent institutions: The Norwegian Radium Hospital, The Mayo Clinic, and Skåne University Hospital. A total of 40 tumors were included after central review. All cases were negative for the YWHAE-FAM22A/B and JAZF1-JJAZ1 translocations. Survival data were available on all patients. In this study, one-third of patients with UUS survived beyond 5 years. The crude (unadjusted) Cox Proportional Hazards model revealed a number of parameters that significantly impacted overall survival, including mitotic index group, patient age, stage, and the presence of tumor necrosis. Classification into the uniform and pleomorphic types was not prognostic. Combining these parameters into an adjusted model revealed that only the mitotic index group and stage were prognostic. On the basis of these findings, it is proposed that UUS be subdivided into “mitogenic” and “not otherwise specified” types.

Abstract Germline and somatic mutations in BRCA1 and BRCA2 (BRCA) confer PARP inhibitor sensitivity. Promoter hypermethylation is an alternate mechanism of gene down-regulation, and BRCA1 promoter methylation is relatively common in sporadic ovarian cancer. The clinical significance of BRCA1 methylation is less clear than for mutations, as the Cancer Genome Atlas (TCGA) and others have failed to show improved survival in ovarian carcinomas with BRCA1 methylation. No one has previously tested whether BRCA1 methylation confers in vivo sensitivity to PARP inhibitors in patients with ovarian cancer. ARIEL2 is a phase 2 study of the PARP inhibitor rucaparib in patients with recurrent platinum sensitive high-grade ovarian, peritoneal or fallopian tube carcinoma. At enrollment, ARIEL2 required pre-treatment tumor biopsies with the goal of developing tissue predictors of PARP inhibitor sensitivity other than BRCA mutations. The number of women with known germline mutations was capped at 15 patients in order to predominantly enroll BRCA wildtype cases. As presented at ASCO 2016, in cases with no BRCA mutations, a high fraction of genomic loss of heterozygosity (LOH) significantly predicted a better progression-free survival (the primary endpoint), longer duration of response, and a higher fraction of responders compared to cases with low LOH. We assessed BRCA1 and RAD51C promoter hypermethylation using methylation-sensitive polymerase chain reaction in paired archival and pre-treatment biopsies from patients on ARIEL2. Of 165 cases for which methylation analyses were completed, 21 (12.7%) were methylated at the BRCA1 promoter and four (2.4%) at the RAD51C promoter. Methylation of BRCA1 and RAD51C was mutually exclusive with mutation in BRCA or other homologous recombination genes. All four cases with RAD51C methylation and 15/19 (78.9%) with BRCA1 methylation were associated with high LOH. In 90 paired samples archival and pre-treatment tissues, RAD51C methylation was 100% concordant and BRCA1 methylation was highly concordant (p<0·001). For 13 cases with BRCA1 methylation in the archival specimen, 4 (30·8%) were unmethylated in the paired pretreatment tumor, but for 77 unmethylated archival specimens, gain of methylation in the pretreatment biopsy was observed just once. Confirmed RECIST responses were seen in 52.4% (11/21) BRCA1 methylated and 75.0% (3/4) RAD51C methylated cases. In conclusion, BRCA1 and RAD51C methylation in ovarian carcinomas correlates with a high response rate to PARP inhibitors. If methylation was to be used as a predictor of PARP inhibitor sensitivity, it would need to be assessed in a pre-treatment (not archival) specimen. The loss of BRCA1 methylation in recurrent ovarian carcinoma, which was common even in these platinum sensitive cases, could explain why BRCA1 methylation is associated with similar survival to methylated cases, despite initial improved therapeutic sensitivity. Citation Format: Elizabeth Swisher, Maria Harrell, Kevin K. Lin, Clare Scott, Sandra Goble, Amit Oza, Robert L. Coleman, Gottfried Konecny, Anna V. Tinker, David M. O'Malley, Rebecca Kristeleit, Ling Ma, James Brenton, Katherine Bell-McGuinn, Ana Oaknin, Alexandra Leary, Elaina Mann, Heidi Giordano, Mitch Rapon, Iain McNeish, Scott H. Kaufmann. BRCA1 and RAD51C Promoter Hypermethylation Confer Sensitivity to PARP Inhibitors in Patients with Platinum Sensitive Ovarian Carcinoma [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP28.

Abstract High-grade epithelial ovarian carcinomas containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pretreatment and postprogression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in BRCA1, RAD51C, or RAD51D was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations. Significance: Analyses of primary and secondary mutations in RAD51C and RAD51D provide evidence for these primary mutations in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and for combination strategies. Cancer Discov; 7(9); 984–98. ©2017 AACR. See related commentary by Domchek, p. 937. See related article by Quigley et al., p. 999. See related article by Goodall et al., p. 1006. This article is highlighted in the In This Issue feature, p. 920

Altered cortical thickness has been observed in aging and various neurodegenerative disorders. Furthermore, reduced hippocampal volume has been reported in late-life depression. Even mild depressive symptoms are common in the elderly. However, little is known about the structural MRI measures of depressive symptoms in normal cognitive aging. Thus we sought to examine the association between depressive symptoms with cortical thickness and hippocampal volume as measured by brain MRI among community-dwelling participants. We conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging, involving cognitively normal participants ( N = 1,507) aged≥70 years. We observed that depressive symptoms were associated with lower global cortical thickness and lower thickness in specific prefrontal and temporal cortical regions, labeled by FreeSurfer software, version 5.3. As expected, the strength of correlation was very small, given that participants were community-dwelling with only mild depressive symptoms. We did not observe associations between hippocampal volume and depressive symptoms. These findings may provide insight into the structural correlates of mild depressive symptoms in elderly participants.

Chemotherapy‐induced peripheral neuropathy (CIPN) is a common dose‐limiting side effect experienced by patients receiving treatment for cancer. Approximately 30 to 40% of patients treated with neurotoxic chemotherapy will develop CIPN, and there is considerable variability in its severity between patients. It is often sensory‐predominant with pain and can lead to long‐term morbidity in survivors. The prevalence and burden of CIPN late effects will likely increase as cancer survival rates continue to improve. In this review, we discuss the approach to peripheral neuropathy in patients with cancer and address the clinical phenotypes and pathomechanisms of specific neurotoxic chemotherapeutic agents. Ann Neurol 2017;81:772–781

SummaryThe oral proteasome inhibitor ixazomib is approved in the United States, European Union and other countries, in combination with oral lenalidomide and dexamethasone (Rd), for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on the global, randomised, double‐blind, placebo‐controlled Phase III TOURMALINE‐MM1 study of ixazomib‐Rd (IRd) versus placebo‐Rd in patients with relapsed/refractory multiple myeloma. IRd resulted in a significant improvement in progression‐free survival versus placebo‐Rd (median: 20·6 vs. 14·7 months; hazard ratio 0·74). Common toxicities observed more commonly with IRd versus placebo‐Rd were thrombocytopenia, nausea, vomiting, diarrhoea, constipation, rash, peripheral neuropathy, peripheral oedema and back pain; these were generally grade 1/2 in severity except for thrombocytopenia (19% vs. 9% grade 3/4), which appeared manageable and reversible, with no differences between arms in significant bleeding or dose discontinuations. No cumulative toxicities were observed, indicating the potential feasibility of long‐term IRd treatment. Safety data from TOURMALINE‐MM1 are reviewed and guidance for managing clinically relevant adverse events associated with IRd is provided. Most toxicities were manageable with supportive care and dose delays or reductions as needed. Clinicians should be aware of and understand these potential side effects to optimise and prolong patient benefit.

ABSTRACT Serologic evaluation for Zika virus (ZIKV) infection currently includes an initial screen using an anti-ZIKV IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) followed by supplemental testing of specimens with nonnegative results by a plaque reduction neutralization test (PRNT). We compared the performance characteristics of three ELISAs for the detection of IgM class antibodies to ZIKV, including the Centers for Disease Control and Prevention (CDC) Zika MAC-ELISA, the InBios ZIKV Detect MAC-ELISA, and the Euroimmun anti-Zika Virus IgM ELISA. Additionally, we present our initial experiences with ZIKV serologic testing from a national reference laboratory perspective. Using both retrospectively and prospectively collected specimens from patients with possible ZIKV infection, we show that the CDC and InBios MAC-ELISAs perform comparably to each other, with positive agreement, negative agreement, and interrater kappa values ranging from 87.5% to 93.1%, 95.7% to 98.5%, and 0.52 to 0.83, respectively. In contrast, comparison of the Euroimmun ZIKV ELISA to either the CDC or InBios MAC-ELISAs resulted in positive agreement, negative agreement, and interrater kappa values ranging from 17.9% to 42.9%, 91.7% to 98.6%, and 0.10 to 0.39, respectively. Among the 19 prospective samples submitted for PRNT, nine were negative, eight specimens had neutralizing antibodies to a flavivirus (unable to be identified), and one sample each was confirmed for ZIKV or dengue virus infection. This study highlights the ongoing challenges associated with serologic diagnosis of ZIKV infection. Although the availability of a commercial serologic test for ZIKV has greatly expanded the national capacity for such testing, the need to further characterize and improve these assays, particularly with regard to specificity, remains.