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Introduction: Up to 20% of EGFR-mutated NSCLC cases harbor uncommon EGFR mutations, including atypical exon 19 and compound mutations. Relatively little is known about the efficacy of osimertinib in these cases. Methods: Patients treated with first-line osimertinib for NSCLC with rare EGFR exon 19 (non E746_A750del) or compound mutations were included. Response assessment and time to progression were determined using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Kaplan-Meier analyses were used to estimate progression-free survival (PFS), time to treatment discontinuation (TTD), and overall survival (OS). Results: Thirty-seven patients with NSCLC harboring an atypical EGFR exon 19 mutation or compound mutation were treated with first-line osimertinib at Johns Hopkins from 2016 to 2021. Overall response rate (ORR) was 76% and median PFS, TTD, and OS were 13 months (95% confidence interval [CI]: 10-15), 22 months (95% CI: 17-32) and 36 months (95% CI, 29-48), respectively. Among atypical exon 19 mutations (n = 25), ORR was 80%, median PFS was 12 months (95% CI: 10-15), median TTD was 19 months (95% CI: 17-38), and median OS was 48 months (95% CI: 25-not reached). Compound mutations (n = 12) had an ORR of 67%, median PFS of 14 months (95% CI: 5-22), median TTD of 26 months (95% CI: 5-36), and median OS of 36 months (95% CI: 20-46). Twelve patients (32%) continued first-line osimertinib after local therapy for oligoprogression. Conclusions: Osimertinib exhibited favorable outcomes for rare EGFR exon 19 and compound mutations. The heterogeneity in outcomes among these groups of tumors with similar mutations underscores the need for continued reporting and further study of outcomes among rare variants to optimize management for each patient.
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As novel therapeutic regimens continue to lead to increased survival of patients with lung cancer, it is imperative to remain mindful of the accompanying increase in the incidence of new primary malignancies. Although the most common secondary malignancies in patients with lung cancer have historically included colon, rectal, esophageal, and thyroid cancers, we report here two rare cases of new primary hepatocellular carcinomas in patients receiving immune checkpoint inhibitor therapy for NSCLC. In both cases, the diagnosis of hepatocellular carcinoma, rather than assuming a hepatic metastasis, was crucial for determining the appropriate approach for treatment. These cases thus underscore the importance of appropriate diagnostics to ensure that the proper therapeutics are chosen and present important considerations for the lung cancer community going forward.
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PURPOSE: Lymphopenia is associated with poor survival outcomes in head and neck squamous cell carcinoma (HNSCC), yet there is no consensus on whether we should limit lymphopenia risks during treatment. To fully elucidate the prognostic role of baseline versus treatment-related lymphopenia, a robust analysis is necessary to investigate the relative importance of various lymphopenia metrics (LMs) in predicting survival outcomes. METHODS: In this prospective cohort study, 363 patients were eligible for analysis (patients with newly diagnosed, nonmetastatic HNSCC treated with neck radiation with or without chemotherapy in 2015-2019). Data were acquired on 28 covariates: seven baseline, five disease, seven treatment, and nine LMs, including static and time-varying features for absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio, and immature granulocytes (IGs). IGs were included, given their hypothesized role in inhibiting lymphocyte function. Overall, there were 4.0% missing data. Median follow-up was 2.9 years. We developed a model (POTOMAC) to predict survival outcomes using a random survival forest (RSF) procedure. RSF uses an ensemble approach to reduce the risk of overfitting and provides internal validation of the model using data that are not used in model development. The ability to predict survival risk was assessed using the AUC for the predicted risk score. RESULTS: POTOMAC predicted 2-year survival with AUCs at 0.78 for overall survival (primary end point) and 0.73 for progression-free survival (secondary end point). Top modifiable risk factors included radiation dose and max ALC decrease. Top baseline risk factors included age, Charlson Comorbidity Index, Karnofsky Performance Score, and baseline IGs. Top-ranking LMs had superior prognostic performance when compared with human papillomavirus status, chemotherapy type, and dose (up to 2, 8, and 65 times higher in variable importance score). CONCLUSION: POTOMAC provides important insights into potential approaches to reduce mortality in patients with HNSCC treated by chemoradiation but needs to be validated in future studies.
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Neoplasias de Cabeça e Pescoço , Linfopenia , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Estudos Prospectivos , Linfopenia/etiologia , Linfopenia/diagnóstico , Contagem de Linfócitos , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Cabeça e Pescoço/complicaçõesRESUMO
The endoplasmic reticulum (ER) carries out essential and conserved cellular functions, which depend on the maintenance of its structure and subcellular distribution. Here, we report developmentally regulated changes in ER morphology and composition during budding yeast meiosis, a conserved differentiation program that gives rise to gametes. A subset of the cortical ER collapses away from the plasma membrane at anaphase II, thus separating into a spatially distinct compartment. This programmed collapse depends on the transcription factor Ndt80, conserved ER membrane structuring proteins Lnp1 and reticulons, and the actin cytoskeleton. A subset of ER is retained at the mother cell plasma membrane and excluded from gamete cells via the action of ER-plasma membrane tethering proteins. ER remodeling is coupled to ER degradation by selective autophagy, which relies on ER collapse and is regulated by timed expression of the autophagy receptor Atg40. Thus, developmentally programmed changes in ER morphology determine the selective degradation or inheritance of ER subdomains by gametes.
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Retículo Endoplasmático/metabolismo , Padrões de Herança/genética , Meiose , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismo , Citoesqueleto de Actina/metabolismo , Autofagia , Membrana Celular/metabolismo , Imageamento Tridimensional , Mutação/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Imagem com Lapso de TempoRESUMO
Cellular stress responses often require transcription-based activation of gene expression to promote cellular adaptation. Whether general mechanisms exist for stress-responsive gene downregulation is less clear. A recently defined mechanism enables both up- and downregulation of protein levels for distinct gene sets by the same transcription factor via coordinated induction of canonical mRNAs and long undecoded transcript isoforms (LUTIs). We analyzed parallel gene expression datasets to determine whether this mechanism contributes to the conserved Hac1-driven branch of the unfolded protein response (UPRER), indeed observing Hac1-dependent protein downregulation accompanying the upregulation of ER-related proteins that typifies UPRER activation. Proteins downregulated by Hac1-driven LUTIs include those with electron transport chain (ETC) function. Abrogated ETC function improves the fitness of UPRER-activated cells, suggesting functional importance to this regulation. We conclude that the UPRER drives large-scale proteome remodeling, including coordinated up- and downregulation of distinct protein classes, which is partly mediated by Hac1-induced LUTIs.