Citations

LBA1 Background: Since 2004, 6 months (m) of oxaliplatin (oxali)-based treatment has been the standard of care as adjuvant therapy for stage III CC. Since oxali is associated with cumulative neurotoxicity, shorter duration of adjuv therapy could spare pts toxicity and lead to substantial saving in health expenditures. Methods: A prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials (SCOT, TOSCA, Alliance/SWOG 80702, IDEA France (GERCOR/PRODIGE), ACHIEVE, HORG) was performed to evaluate the non-inferiority (NI) of 3m compared with 6m (ref) of adjuv FOLFOX/XELOX. The primary endpoint was disease-free survival (DFS), defined as time from enrolment to relapse, 2nd CRC, and death (all causes). NI was to be declared if the 2-sided 95% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.12. NI was examined within regimen and stage subgroups as pre-planned. Results: The analysis included 12,834 pts from 12 countries, accrued from 6/07 to 12/15. Stage distribution: 13% T1-2, 66% T3, 21% T4; 28% N2; 40% received XELOX. G3+ neurotoxicity was higher in the 6m v 3m arm (16 v 3% FOLFOX, 9 v 3% XELOX, p<0.0001). With a median follow-up of 39 mos, 3263 DFS events were observed. Overall, the 3 year DFS rate was 74.6% (3m) and 75.5% (6m), with estimated DFS HR of 1.07 (95%CI, 1.00-1.15). The 3m v 6m DFS HRs were 1.16 (95%CI, 1.06-1.26) and 0.95 (95% CI, 0.85-1.06) for FOLFOX and XELOX treated pts, respectively. The 3m v 6m DFS HRs were 1.01 (95%CI, 0.90-1.12) in T1-3 N1, and 1.12 (95%CI, 1.03-1.23) for T4 or N2 pts. Conclusions: While NI was not established for the overall cohort, NI of 3m v 6m oxali-based adjuv therapy was supported for XELOX. As each IDEA trial treated varying proportions of pts with XELOX (0 to 75%), the regimen interaction likely produced the differential outcomes observed between individual studies. Certain substages (T1-3 N1) also showed NI for 3m v 6m. These data provide a framework for discussions on risks and benefits of individualized adjuv therapy approaches. Support: U10CA180821, U10CA180882, U10CA180888, U10CA180835, INCA, PHRC2009, EME 09/800/34, HTA 14/140/84, CRUK C1348/A15960, JFMC. Clinical trial information: NCT01150045.

BackgroundAlterations in GFER gene have been associated with progressive mitochondrial myopathy, congenital cataracts, hearing loss, developmental delay, lactic acidosis and respiratory chain deficiency in 3 siblings born to consanguineous Moroccan parents by homozygosity mapping and candidate gene approach (OMIM#613076). Next generation sequencing recently confirmed this association by the finding of compound heterozygous variants in 19‐year‐old girl with a strikingly similar phenotype, but this ultra‐rare entity remains however unknown from most of the scientific community.Materials and MethodsWhole exome sequencing was performed as part of a “diagnostic odyssey” for suspected mitochondrial condition in 2 patients, presenting congenital cataracts, progressive encephalomyopathy and hypotrophy and detected unreported compound heterozygous variants in GFER.ResultsThanks to an international data sharing, we found 2 additional patients carrying compound heterozygous variants in GFER. Reverse phenotyping confirmed the phenotypical similarities between the 4 patients. Together with the first literature reports, the review of these 8 cases from 4 unrelated families enables us to better describe this apparently homogeneous disorder, with the clinical and biological stigmata of mitochondrial disease.ConclusionThis report highlights the clinical utility of whole exome sequencing and reverse phenotyping for the diagnosis of ultra‐rare diseases and underlines the importance of a broad data sharing for accurate clinical delineation of previously unrecognized entities.

Targeting three defects with one strategy The neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia are most commonly caused by a mutation in the C9orf72 gene. The mutation is an expanded hexanucleotide repeat in a noncoding region. The expanded repeat produces sense and antisense RNA transcripts, which accumulate in patient cells and appear to sequester RNA-binding proteins. The sense and antisense transcripts are also translated into dipeptide repeat proteins, which are aggregation-prone and accumulate in the brain and spinal cord. Last, loss of function from reduced expression of C9orf72 in neurons and glia could contribute to the disease. Kramer et al. targeted both sense and antisense repeats by blocking a single gene called SPT4 , which mitigated degeneration in human cells by reducing all three types of pathologies. Science , this issue p. 708

Abstract The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.

Abstract Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAFV600E mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAFV600E–wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAFV600E–wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. Significance: We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders. Cancer Discov; 6(2); 154–65. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109

Background Recent studies evaluated short-term efficacy and safety of peripheral nerve stimulation (PNS) of the occipital nerves for managing chronic migraine. We present 52-week safety and efficacy results from an open-label extension of a randomized, sham-controlled trial. Methods In this institutional review board-approved, randomized, multicenter, double-blinded study, patients were implanted with a neurostimulation system, randomized to an active or control group for 12 weeks, and received open-label treatment for an additional 40 weeks. Outcomes collected included number of headache days, pain intensity, migraine disability assessment (MIDAS), Zung Pain and Distress (PAD), direct patient reports of headache pain relief, quality of life, satisfaction and adverse events. Statistical tests assessed change from baseline to 52 weeks using paired t-tests. Intent-to-treat (ITT) analyses of all patients ( N = 157) and analyses of only patients who met criteria for intractable chronic migraine (ICM; N = 125) were performed. Results Headache days were significantly reduced by 6.7 (±8.4) days in the ITT population ( p < 0.001) and by 7.7 (±8.7) days in the ICM population ( p < 0.001). The percentages of patients who achieved a 30% and 50% reduction in headache days and/or pain intensity were 59.5% and 47.8%, respectively. MIDAS and Zung PAD scores were significantly reduced for both populations. Excellent or good headache relief was reported by 65.4% of the ITT population and 67.9% of the ICM population. More than half the patients in both cohorts were satisfied with the headache relief provided by the device. A total of 183 device/procedure-related adverse events occurred during the study, of which 18 (8.6%) required hospitalization and 85 (40.7%) required surgical intervention; 70% of patients experienced an adverse event. Conclusion Our results support the 12-month efficacy of PNS of the occipital nerves for headache pain and disability associated with chronic migraine. More emphasis on adverse event mitigation is needed in future research. Trial registration: Clinical trials.gov (NCT00615342).

Abstract Objectives Drug repurposing, which finds new indications for existing drugs, has received great attention recently. The goal of our work is to assess the feasibility of using electronic health records (EHRs) and automated informatics methods to efficiently validate a recent drug repurposing association of metformin with reduced cancer mortality. Methods By linking two large EHRs from Vanderbilt University Medical Center and Mayo Clinic to their tumor registries, we constructed a cohort including 32 415 adults with a cancer diagnosis at Vanderbilt and 79 258 cancer patients at Mayo from 1995 to 2010. Using automated informatics methods, we further identified type 2 diabetes patients within the cancer cohort and determined their drug exposure information, as well as other covariates such as smoking status. We then estimated HRs for all-cause mortality and their associated 95% CIs using stratified Cox proportional hazard models. HRs were estimated according to metformin exposure, adjusted for age at diagnosis, sex, race, body mass index, tobacco use, insulin use, cancer type, and non-cancer Charlson comorbidity index. Results Among all Vanderbilt cancer patients, metformin was associated with a 22% decrease in overall mortality compared to other oral hypoglycemic medications (HR 0.78; 95% CI 0.69 to 0.88) and with a 39% decrease compared to type 2 diabetes patients on insulin only (HR 0.61; 95% CI 0.50 to 0.73). Diabetic patients on metformin also had a 23% improved survival compared with non-diabetic patients (HR 0.77; 95% CI 0.71 to 0.85). These associations were replicated using the Mayo Clinic EHR data. Many site-specific cancers including breast, colorectal, lung, and prostate demonstrated reduced mortality with metformin use in at least one EHR. Conclusions EHR data suggested that the use of metformin was associated with decreased mortality after a cancer diagnosis compared with diabetic and non-diabetic cancer patients not on metformin, indicating its potential as a chemotherapeutic regimen. This study serves as a model for robust and inexpensive validation studies for drug repurposing signals using EHR data.