Citations

Soft tissue tumors with GLI1 gene fusions or amplifications have been recently described as a unique pathologic entity with an established risk of malignancy. We herein expand these findings by investigating a cohort of 11 head and neck lesions with GLI1 alterations, including 8 from the tongue, for their clinicopathologic and molecular features. The tumors commonly affected males in their 30s (male:female ratio 2.7:1; range: 1 to 65). Tumors showed a multinodular growth pattern, nested architecture separated by a delicate, arborizing vascular network, monotonous round to ovoid nuclei, and clear cytoplasm. Tumor protrusion into vascular spaces was common. Genetic alterations were investigated by fluorescence in situ hybridization and/or targeted RNA sequencing. Seven tumors harbored GLI1 fusions with the following partners: ACTB (n=4), PTCH1 (n=2), or MALAT1 (n=1). The remaining 4 cases showed coamplifications of GLI1 with CDK4 and MDM2 genes. Tumors were commonly positive for S100 protein and CD56. CDK4, MDM2, and STAT6 were positive in GLI1 -amplified tumors. Two of 6 patients with available follow-up (1 each with GLI1 amplification and PTCH1-GLI1 fusion) developed distant metastases. Both tumors showed a high mitotic index and tumor necrosis. The head and neck region, particularly tongue, is a common location for GLI1 -related mesenchymal tumors. Although a morphologic overlap was noted with the previously reported “pericytoma with t(7,12) translocation,” often occurring in the tongue, our findings expand the original findings, to include a more variable immunophenotype, propensity for late distant metastases, and alternative mechanisms of GLI1 oncogenic activation, such as various GLI1 fusion partners or GLI1 coamplifications with MDM2 and CDK4 genes.

Background A major question in patch testing is when to perform the final reading. Our current standard practice is to place patches on day 1, remove them on day 3, and perform readings on days 3 and 5. For certain allergens, another reading is performed sometime from days 7 to 14≥. Objectives The aim of the study was to identify allergens with positive reactions on day 5 that were negative on day 7 or later and allergens with negative reactions on day 5 that were subsequently positive on day 7 or later. Methods We reviewed records of patients who underwent patch testing from January 2007 to December 2016 at Mayo Clinic with readings on day 5 and day 7 or later. Conclusions In total, 131 allergens had positive reactions on day 5 that were negative on day 7 or later, and 58 allergens had negative reactions on day 5 that were positive on day 7 or later. Twenty-five allergens had significantly higher reaction rates on day 5 than day 7 or later. Our standard practice is to perform readings on days 3 and 5 and on days 3, 5, and 7 or later for series containing metals. Readings on days 3, 5, and 7 or later should also be considered for acrylates.

Abstract Background The proportion of tumors of various histologies that may respond to drugs targeted to molecular alterations is unknown. NCI-MATCH, a collaboration between ECOG-ACRIN Cancer Research Group and the National Cancer Institute, was initiated to find efficacy signals by matching patients with refractory malignancies to treatment targeted to potential tumor molecular drivers regardless of cancer histology. Methods Trial development required assumptions about molecular target prevalence, accrual rates, treatment eligibility, and enrollment rates as well as consideration of logistical requirements. Central tumor profiling was performed with an investigational next-generation DNA–targeted sequencing assay of alterations in 143 genes, and protein expression of protein expression of phosphatase and tensin homolog, mutL homolog 1, mutS homolog 2, and RB transcriptional corepressor 1. Treatments were allocated with a validated computational platform (MATCHBOX). A preplanned interim analysis evaluated assumptions and feasibility in this novel trial. Results At interim analysis, accrual was robust, tumor biopsies were safe (<1% severe events), and profiling success was 87.3%. Actionable molecular alteration frequency met expectations, but assignment and enrollment lagged due to histology exclusions and mismatch of resources to demand. To address this lag, we revised estimates of mutation frequencies, increased screening sample size, added treatments, and improved assay throughput and efficiency (93.9% completion and 14-day turnaround). Conclusions The experiences in the design and implementation of the NCI-MATCH trial suggest that profiling from fresh tumor biopsies and assigning treatment can be performed efficiently in a large national network trial. The success of such trials necessitates a broad screening approach and many treatment options easily accessible to patients.

AbstractOur prior studies identified the prognostic significance of quantifying cPCs by multiparametric flow cytometry (MFC) in newly diagnosed multiple myeloma (NDMM) patients. We evaluated if a similar quantification of cPCs could add prognostic value to the current R‐ISS classification of 556 consecutive NDMM patients seen at the Mayo Clinic, Rochester from 2009 to 2017. Those patients that had ≥5 cPCs/μL and either R‐ISS stage I or stage II disease were re‐classified as R‐ISS IIB stage for the purposes of this study. The median time to next therapy (TTNT) and overall survival (OS) for patients with ≥5 cPCs/μL at diagnosis was as follows: R‐ISS I (N = 110) ‐ 40 months and not reached; R‐ISS II (N = 69) ‐ 30 and 72 months; R‐ISS IIB (N = 96) ‐ 21 and 45 months and R‐ISS III (N = 281) ‐ 20 and 47 months respectively. Finally, ≥ 5 cPCs/μL retained its adverse prognostic significance in a multivariable model for TTNT and OS. Hence, quantifying cPCs by MFC can potentially enhance the R‐ISS classification of a subset of NDMM patients with stage I and II disease by identifying those patients with a worse than expected survival outcome.

Background: Knowledge regarding the burden and predictors of hypoglycemia among older adults with type 1 diabetes (T1D) is limited. Methods: We analyzed baseline data from the Wireless Innovations for Seniors with Diabetes Mellitus (WISDM) study, which enrolled participants at 22 sites in the United States. Eligibility included clinical diagnosis of T1D, age ≥60 years, no real-time continuous glucose monitoring (CGM) use in prior three months, and HbA1c <10.0%. Blinded CGM data from 203 participants with at least 240 hours were included in the analyses. Results: Median age of the cohort was 68 years (52% female, 93% non-Hispanic white, and 53% used insulin pumps). Mean HbA1c was 7.5%. Median time spent in the glucose range <70 mg/dL was 5.0% (72 min/day) and <54 mg/dL was 1.6% (24 min/day). Among all factors analyzed, only reduced hypoglycemia awareness was associated with greater time spent <54 mg/dL (median time of 2.7% vs 1.3% [39 vs 19 minutes per day] for reduced awareness vs aware/uncertain, respectively, P = .03). Participants spent a mean 56% of total time in target glucose range of 70-180 mg/dL and 37% of time above 180 mg/dL. Conclusions: Over half of older T1D participants spent at least an hour a day with glucose levels <70 mg/dL. Those with reduced hypoglycemia awareness spent over twice as much time than those without in a serious hypoglycemia range (glucose levels <54 mg/dL). Interventions to reduce exposure to clinically significant hypoglycemia and increase time in range are urgently needed in this age group.

Abstract Purpose: Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization. Experimental Design: PDXs were established from glioblastoma, IDH-wildtype (n = 93), glioblastoma, IDH-mutant (n = 2), diffuse midline glioma, H3 K27M-mutant (n = 1), and both primary (n = 60) and recurrent (n = 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES, n = 83), RNA-sequencing (n = 68), and genome-wide methylation profiling (n = 76). WES data from 24 patient tumors was compared with derivative models. Results: PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show characteristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of TERT, EGFR, PTEN, TP53, BRAF, and IDH1, most at frequencies comparable with human glioblastoma. However, PDGFRA amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes. MGMT promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including EGFR amplification. However, in four patient–PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection. Conclusions: Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.

PURPOSETo estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized.METHODSWe analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes.RESULTSWe found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10−76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10−3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10−3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10−2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10−3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer.CONCLUSIONThese results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

AbstractAimEosinophilic fasciitis (EF) is a rare, fibrosing disorder of skin and subcutaneous tissue. This study was undertaken to describe its clinical and laboratory features and identify prognostic factors associated with outcome.MethodsWe conducted a retrospective review of all EF patients evaluated at our institution from 1 January1997 to 30 December 2016. Kaplan‐Meier methods were used to determine treatment response rates over time. Potential associations between baseline characteristics and complete response were examined using Cox models adjusted for age and sex. Time‐dependent covariates were used to examine treatment effects.ResultsWe identified 89 EF patients, with a female‐to‐male ratio of 1:1. Clinical features included groove sign in 26 (29%), peau d'orange/dimpling in 22 (25%), inflammatory arthritis in 9 (10%) and muscle weakness in 9 (10%). Aldolase was elevated in 11/36 (31%). Complete response rate was 60% (95% confidence interval [CI]: 35‐75) at 3 years. Diagnostic delay was inversely associated with treatment response (hazards ratio: 0.84 per 1 month increase; 95% CI: 0.73‐0.98). No baseline characteristics correlated with treatment response, but a trend toward positive association of elevated aldolase, hypergammaglobulinemia and presence of hematologic disorders was noted. Methotrexate was the most commonly used immunosuppressant in 79%, hydroxychloroquine in 45%, mycophenolate mofetil in 18% and azathioprine in 8%. No single immunosuppressant agent was associated with a superior response during treatment.ConclusionsEF is characterized by relatively high response rates. Consensus diagnostic criteria, standardized management algorithms, and large prospective multi‐center cohorts are needed to develop an evidence‐directed approach to this challenging condition.

Background: Thyroid immune-related adverse events (IRAEs) have been reported more frequently with programmed cell death protein-1 (PD-1) inhibitors than cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors, but there is limited data describing endocrinopathies from programmed cell death protein–ligand 1 (PD-L1) inhibitors. This study characterizes thyroid IRAEs in cancer patients treated with PD-L1 inhibitors and examines the impact on overall survival. Methods: This is a retrospective cohort study of cancer patients treated with atezolizumab and avelumab at the Mayo Clinic, Rochester, Minnesota, from June 1, 2016 to January 30, 2018, and followed for a median of 10.1 months. Thyroid IRAEs were characterized as new onset hypothyroidism, thyrotoxicosis, and worsening of pre-existing hypothyroidism. Results: Of 91 patients treated with a PD-L1 inhibitor, 19 (21%) developed new onset thyroid dysfunction, of whom 14 presented with hypothyroidism and 5 with thyrotoxicosis (3 progressed to hypothyroidism and 2 returned to euthyroidism), and 4 (4%) had worsening of pre-existing hypothyroidism. Thyroid IRAEs occurred after a median of two doses (6 weeks), 48% required thyroid hormone replacement, and none required steroids or discontinuation of immunotherapy. Two out of four patients with thyroid peroxidase (TPO) antibody >9 IU/mL at baseline developed thyroid IRAEs. Median TPO antibody titer was not different between those with and without thyroid IRAEs but was higher in those with overt than those with subclinical hypothyroidism (5 vs. 0.3 IU/mL, p = 0.003) and those prescribed thyroid hormone replacement as compared with observation (5.5 vs. 0.3, p = 0.008). Diffusely increased thyroid 18-fluorodeoxyglucose ( 18 FDG) uptake on positron emission tomography (PET) scan occurred in 71% with thyroid IRAE as compared with 6% without thyroid IRAEs ( p = 0.001). Patients who developed thyroid IRAEs had longer overall survival ( p = 0.027) and lower mortality (hazard ratio 0.49 [95% CI 0.25–0.99], p = 0.034) after adjusting for potential confounders. Conclusions: PD-L1 inhibitors lead to immune-mediated thyroiditis, the most frequent endocrine IRAE. In most cases, management is supportive without requiring steroids or discontinuation of immunotherapy. Diffusely increased thyroid 18 FDG uptake on PET scan may predict the occurrence of thyroiditis, whereas TPO antibodies may help identify its severity. Thyroiditis may be a biomarker for antitumor immune response, highlighting the need to further characterize its underlying mechanism.