Citations

The Clinical Proteomic Tumor Analysis Consortium (CPTAC) has provided some of the most in-depth analyses of the phenotypes of human tumors ever constructed. Today, the majority of proteomic data analysis is still performed using software housed on desktop computers which limits the number of sequence variants and post-translational modifications that can be considered. The original CPTAC studies limited the search for PTMs to only samples that were chemically enriched for those modified peptides. Similarly, the only sequence variants considered were those with strong evidence at the exon or transcript level. In this multi-institutional collaborative reanalysis, we utilized unbiased protein databases containing millions of human sequence variants in conjunction with hundreds of common post-translational modifications. Using these tools, we identified tens of thousands of high-confidence PTMs and sequence variants. We identified 4132 phosphorylated peptides in nonenriched samples, 93% of which were confirmed in the samples which were chemically enriched for phosphopeptides. In addition, our results also cover 90% of the high-confidence variants reported by the original proteogenomics study, without the need for sample specific next-generation sequencing. Finally, we report fivefold more somatic and germline variants that have an independent evidence at the peptide level, including mutations in ERRB2 and BCAS1. In this reanalysis of CPTAC proteomic data with cloud computing, we present an openly available and searchable web resource of the highest-coverage proteomic profiling of human tumors described to date.

Purpose of review To date, more than 30 antiretroviral drugs have been approved by the Food and Drug Administration for the treatment of HIV infection. As new drugs with better efficacy and safety profile become available for clinical practice, older drugs are either withdrawn from the market or become no longer actively prescribed. We review hepatotoxicity associated with contemporary antiretroviral drugs, with emphasis on data from the past 3 years. Recent findings Although less robust data exists for side effects of contemporary antiretroviral medications recently approved for the management of HIV (i.e., doravirine, ibalizumab, fostemsavir, cabotegravir), the risks of substantial hepatotoxicity appears to be minimal with these agents. Summary Although newer antiretroviral drugs are better tolerated than their earlier counterparts, they are not completely devoid of adverse drug reactions, including hepatotoxicity. Monitoring patients on antiretroviral therapy for treatment-emergent liver injury should continue to be part of routine clinical care.

TPS3616 Background: METamp is a secondary, or co-driving, genetic change in pts with mCRC and acquired resistance to anti-EGFR therapy, which can contribute to disease progression. In EGFR-resistant pts with mCRC and METamp, MET inhibition + an anti-EGFR agent may achieve disease control by targeting emerging MET pathway activation and maintaining EGFR pathway inhibition. Tepotinib is an oral, once-daily, highly selective, potent MET tyrosine kinase inhibitor (TKI), recently approved in the US for NSCLC harboring MET exon 14 skipping. Tepotinib + gefitinib demonstrated improved outcomes in pts with EGFR-mutant METamp NSCLC and acquired EGFR TKI resistance vs chemotherapy (INSIGHT: NCT01982955). In these pts, progression-free survival (PFS) was 16.6 vs 4.2 months (HR = 0.13; 90% CI: 0.04, 0.43) and overall survival (OS) was 37.3 vs 13.1 months (HR = 0.08; 90% CI: 0.01, 0.51). In pts with mCRC and acquired resistance to anti-EGFR antibody therapy due to METamp, tepotinib + anti-EGFR antibody cetuximab may be active and provide an effective therapeutic option. Methods: This Phase II, multicenter, single-arm, open-label study will assess preliminary safety and tolerability, antitumor activity, and explore pharmacokinetic (PK) profiles of tepotinib + cetuximab in pts with RAS/BRAF wild-type left-sided mCRC and acquired resistance to anti-EGFR antibody-targeted therapy due to METamp (NCT04515394). A safety run-in (6–12 pts) will evaluate the recommended Phase II dose of tepotinib to be used in combination with cetuximab (endpoint: dose-limiting toxicities). Enrollment is based on a confirmed advanced left-sided CRC diagnosis ( RAS/BRAF wild-type), documented previous anti-EGFR therapy and acquired resistance on most recent anti-EGFR antibody and METamp confirmed by liquid and/or tissue biopsy. Pts must be ≥18 years old, have ECOG PS of 0/1 and normal organ function. The study will screen sufficient pts to account for setting-specific heterogenecity in reported METamp incidence. Approximately 42 pts are planned to receive study treatment: ̃22 in Cohort A (second-line, outside US) and 20 in Cohort B (≥third-line, US only). Primary endpoint: investigator-assessed objective response (RECIST 1.1). Secondary endpoints are investigator-assessed duration of response (DoR), PFS (RECIST 1.1) and OS, tolerability and safety (NCI-CTCAE v5.0), and cetuximab immunogenicity (measured by antidrug antibody assays at the start and end of treatment). Additional endpoints include assessment of tepotinib and cetuximab PK profiles, and expression of biomarkers of resistance (from blood and/or tissue samples). Retrospective assessment of best overall response, DoR and PFS by an independent review committee may be conducted. No formal statistical hypothesis will be tested in this exploratory study. Clinical trial information: NCT04515394.

Contemporary antiretroviral agents afford enhanced potency and safety for patients living with HIV. Newer antiretroviral drugs are often better tolerated than those initially approved in the early stages of the HIV epidemic. While the safety profile has improved, adverse drug reactions still occur. We have segregated the antiretroviral agents used in contemporary practice into class groupings based on their mechanism of antiviral activity (non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, and entry inhibitors) while providing a review and discussion of the hepatoxicity seen in the most relevant clinical literature published to date. Clinical literature for individual agents is discussed and agent comparisons afforded within each group in tabular format. Our review will provide a summative overview of the incidence and medications associated with hepatic adverse reactions linked to the use of contemporary antiretroviral drugs.

Antiretroviral (ARV) therapy in people living with HIV (PLWH) and end-stage renal disease (ESRD) on hemodialysis (HD) is complicated, requiring renally adjusted nucleoside reverse transcriptase inhibitors (NRTIs) and daily administration of non-renally eliminated agents. Recent data in PLWH with ESRD on HD demonstrate maintenance of viral suppression (82% with viral loads (VLs) <50 copies/mL) and favorable safety/tolerability profiles after ARV simplification with a fixed dose combination single tablet [elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF)]. Extrapolation of these data to all F/TAF formulations would allow ARV simplification to most PLWH with ESRD receiving HD. The objective of this retrospective study was to identify if ARV-experienced PLWH with ESRD on HD receiving renally adjusted NRTIs may be simplified to once daily ARV formulations without adverse effects while maintaining viral suppression. This single-center retrospective analysis assessed virologic control (3–12 months) and ARV tolerability post-regimen simplification (primarily NRTI once-daily dose adjustment) in PLWH with ESRD on thrice weekly HD receiving human immunodeficiency virus (HIV) care in an ambulatory clinic. Seventeen PLWH with ESRD on HD were included after documented ARV simplification. At 12 months, 12 patients (71%) remained undetectable (HIV VL <50 copies/mL) with two additional maintaining viral suppression (<200 copies/mL). One patient remained undetectable at month eight but became non-adherent with viral rebound. Two patients did not complete the 6- and 12-month evaluation after documented nonadherence ( N = 1) and an adverse effect (pruritus) ( N = 1). At 12 months, virologic suppression and tolerability resulted after a simplified ARV regimen including once daily F/TAF was initiated in PLWH with ESRD on thrice weekly HD with a reduction in pill burden.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

Although Epstein–Barr virus (EBV) is hypothesized to be a prerequisite for multiple sclerosis (MS), up to 15% of children with a diagnosis of MS were reported to be EBV‐seronegative. When re‐evaluating 25 EBV‐seronegative children out of 189 pediatric patients with a diagnosis of clinically isolated syndrome/MS, we found anti–myelin oligodendrocyte glycoprotein (MOG) antibody in 11 of 25 (44%) EBV‐seronegative but only 9 of 164 (5.5%,p < 0.001) EBV‐seropositive patients. After critical review, MS remained a plausible diagnosis in only 4 of 14 EBV‐seronegative/MOG antibody–negative patients. In children with an MS‐like presentation, EBV seronegativity should alert clinicians to consider diagnoses other than MS, especially MOG‐antibody disease. ANN NEUROL 2021;89:1234–1239