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BACKGROUND: Vascular complications post-transcatheter aortic valve implantation (TAVI) are common. Recent data regarding predictors of vascular complications are limited, particularly comparing newer plug-based devices versus traditional suture-based vascular closure devices (VCD). AIM: The primary objective was to identify characteristics that predict a higher risk of vascular complications in TAVI patients, as judged by the VARC-3 criteria, specifically comparing risk factors between suture-based vs MANTA device closure. METHODS: Retrospective analysis of patients who underwent TAVI between December 2019 and September 2023 was performed. Logistic regression and propensity score matching was performed to ascertain risk factors for vascular complications post-TAVI. RESULTS: Of the 1763 patients, there were 106 vascular complications (6%). There was a nonsignificant increased complication rate in MANTA vs suture-based device closure (8.3% vs 5.3%, p = 0.064). Among these, the most common complications were VCD failure (23%), pseudoaneurysm (20%) and arterial dissection (19%). Obesity (p = 0.021), anemia (p = 0.039) and MANTA device use (p = 0.027) were predictors of vascular complications. Within the MANTA cohort, novel oral anticoagulant (NOAC) use was predictive of vascular complications (p = 0.002). Among suture-based devices, obesity (p = 0.037) and anaemia (p = 0.017) were significant predictors. A propensity matched analysis derived 90 pairs of patients matched for age, gender, diabetes, peripheral arterial disease, NOAC use, anemia and obesity, identifying an average treatment effect of 0.039 (p = 0.04) when MANTA device closure was performed. CONCLUSION: Vascular complications in TAVI remain common. Identifying predictors such as MANTA device closure, obesity, anemia, and baseline NOAC use will allow for improved risk stratification and appropriate VCD selection in patients undergoing TAVI.
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PURPOSE: Many patients with locoregionally advanced human papillomavirus-negative head and neck squamous cell carcinoma (HNSCC) relapse. ctDNA has the potential to identify minimal residual disease, but its clinical utility for virus-negative HNSCC is not well understood. EXPERIMENTAL DESIGN: We retrospectively evaluated a personalized, commercial ctDNA assay (Signatera, Natera) during clinical care of patients treated for predominantly newly diagnosed human papillomavirus-negative HNSCC. Signatera utilizes 16-plex PCR from matched tumor and blood. Objectives were to understand ctDNA detectability and correlate changes posttreatment with disease outcomes. RESULTS: Testing was successful in 100/116 (86%) patients (median age: 65 years, 68% male, 65% smokers); testing failed in 16 (14%) because of insufficient tissue. Oral cavity (55, 47%) tumors were most common; most had stage III to IV disease (82, 71%), whereas 17 (15%) had distant metastases. Pretreatment, 75/100 patients with successful testing (75%) had detectable ctDNA (range: 0.03-4049.69 mean tumor molecules/mL). No clinical features predicted ctDNA detectability or levels (multivariate analysis). At a median follow-up of 5.1 months (range: 0.2-15.1), 55 (55%) had >1 test result (range: 1-7; 194 samples). Of 55 patients, 17 (31%) remained ctDNA positive after starting treatment. Progression-free survival was significantly worse for patients who were ctDNA positive versus ctDNA negative posttreatment (HR, 7.33; 95% confidence interval, 3.12-17.2; P < 0.001); 1-year overall survival was 89.1% versus 100%, respectively (HR, 7.46; 95% confidence interval, 0.46-119.5; P = 0.155). CONCLUSIONS: Tumor-informed ctDNA testing is feasible in nonviral HNSCC. ctDNA positivity is an indicator of disease progression and associated with inferior survival. Further research is warranted to understand whether ctDNA may be leveraged to guide therapy in HNSCC.
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Marqueurs biologiques tumoraux , ADN tumoral circulant , Tumeurs de la tête et du cou , Carcinome épidermoïde de la tête et du cou , Humains , Mâle , ADN tumoral circulant/sang , ADN tumoral circulant/génétique , Femelle , Carcinome épidermoïde de la tête et du cou/génétique , Carcinome épidermoïde de la tête et du cou/mortalité , Carcinome épidermoïde de la tête et du cou/sang , Carcinome épidermoïde de la tête et du cou/anatomopathologie , Carcinome épidermoïde de la tête et du cou/diagnostic , Carcinome épidermoïde de la tête et du cou/thérapie , Sujet âgé , Adulte d'âge moyen , Marqueurs biologiques tumoraux/génétique , Marqueurs biologiques tumoraux/sang , Études rétrospectives , Tumeurs de la tête et du cou/génétique , Tumeurs de la tête et du cou/thérapie , Tumeurs de la tête et du cou/sang , Tumeurs de la tête et du cou/mortalité , Tumeurs de la tête et du cou/diagnostic , Tumeurs de la tête et du cou/anatomopathologie , Adulte , Sujet âgé de 80 ans ou plus , Médecine de précision/méthodes , Récidive tumorale locale/génétique , Récidive tumorale locale/anatomopathologie , PronosticRÉSUMÉ
Aim: This study addresses the challenge of predicting the response of head and neck squamous cell carcinoma (HNSCC) patients to immunotherapy. Methods: Using DNA methylation cytometry, we analyzed the immune profiles of six HNSCC patients who showed a positive response to immunotherapy over a year without disease progression. Results: There was an initial increase in CD8 T memory cells and natural killer cells during the first four cycles of immunotherapy, which then returned to baseline levels after a year. Baseline CD8 T cell levels were lower in HNSCC immunotherapy responders but became similar to those in healthy subjects after immunotherapy. Conclusion: These findings suggest that monitoring fluctuations in immune profiles could potentially identify biomarkers for immunotherapy response in HNSCC patients.
[Box: see text].
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BACKGROUND: There are limited therapeutic options for patients with recurrent/metastatic anaplastic thyroid carcinoma (ATC), and radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC) refractory to multi-kinase inhibitors. This multi-center trial evaluated sapanisertib, a next generation oral kinase inhibitor of mTOR complexes 1/2, in ATC and RAIR DTC. METHODS: A safety run-in phase I was followed by non-randomized phase II trial in ATC, with an exploratory cohort in RAIR DTC. Primary endpoint was proportion of patients with ATC who were without disease progression at 4 months. Safety and survival outcomes were key secondary endpoints. RESULTS: Forty-six patients (20 ATC; 26 DTC) were enrolled including 40 (18 ATC; 22 DTC) who received recommended phase II dose of 5 mg daily. Eleven percent (2/18, 95% C.I.: 1.4-34.7%) of patients with ATC were progression-free at 4 months, 22.2% (4/18) had stable disease as best response. Enrollment in the ATC cohort stopped early with 18 patients out of proposed 23 due to overall futility. One confirmed partial response (4.5%, 1/22) occurred in RAIR DTC, with stable disease in 63.6% (14/22) patients. Median progression-free survival was 1.6 (95% C.I.: 0.9-2.8) months and 7.8 (2.0-not reached) months in ATC and DTC, respectively. Grade 3 treatment related adverse events occurred in 30% of patients who received the phase II dose, most common being anorexia, nausea, diarrhea, fatigue, skin rash and hyperglycemia. Genomic alterations in the PI3 K/AKT/mTOR pathway were not associated with response or PFS. CONCLUSIONS: Sapanisertib monotherapy did not meet the primary endpoint of this trial (proportion progression-free at 4 months) in ATC, and did not show clinically meaningfully activity. Clinical trials with alternative therapeutic strategies are needed. CLINICAL TRIAL REGISTRATION: NCT02244463.
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BRAF or RAS mutation-induced aberrant activation of the mitogen-activated protein kinase (MAPK) pathway is frequently observed in human cancers. As the key downstream node of MAPK pathway, ERK1/2 is as an important therapeutic target. GDC-0994 (ravoxertinib), an orally bioavailable, highly selective small-molecule inhibitor of ERK1/2, showed acceptable safety and pharmacodynamic profile in a recent phase I clinical trial. In this study, we investigated dependence of the anti-tumor effect of ERK inhibitor GDC-0994 on genetic alterations in the MAPK pathway. The results showed that GDC-0994 sharply inhibited cell proliferation and colony formation and induced remarkable G1 phase cell-cycle arrest in cancer cells harboring BRAF mutation but had little effect on cell behaviors in most RAS mutant or wild-type cell lines. The expression of a large number of genes, particularly the genes in the cell cycle pathway, were significantly changed after GDC-0994 treatment in BRAF mutant cells, while no remarkable expression change of such genes was observed in wild-type cells. Moreover, GDC-0994 selectively inhibited tumor growth in a BRAF mutant xenograft mice model. Our findings demonstrate a BRAF mutation-dependent anti-tumor effect of GDC-0994 and provide a rational strategy for patient selection for ERK1/2 inhibitor treatment.
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OBJECTIVE: To develop and externally validate a prediction model for severe cisplatin associated acute kidney injury (CP-AKI). DESIGN: Multicenter cohort study. SETTING: Six geographically diverse major academic cancer centers across the US. PARTICIPANTS: Adults (≥18 years) receiving their first dose of intravenous cisplatin, 2006-22. MAIN OUTCOME MEASURES: The primary outcome was CP-AKI, defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of intravenous cisplatin. Independent predictors of CP-AKI were identified using a multivariable logistic regression model, which was developed in a derivation cohort and tested in an external validation cohort. For the primary model, continuous variables were examined using restricted cubic splines. A simple risk model was also generated by converting the odds ratios from the primary model into risk points. Finally, a multivariable Cox model was used to examine the association between severity of CP-AKI and 90 day survival. RESULTS: A total of 24 717 adults were included, with 11 766 in the derivation cohort (median age 59 (interquartile range (IQR) 50-67)) and 12 951 in the validation cohort (median age 60 (IQR 50-67)). The incidence of CP-AKI was 5.2% (608/11 766) in the derivation cohort and 3.3% (421/12 951) in the validation cohort. Each of the following factors were independently associated with CP-AKI in the derivation cohort: age, hypertension, diabetes mellitus, serum creatinine level, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose. A simple risk score consisting of nine covariates was shown to predict a higher risk of CP-AKI in a monotonic fashion in both the derivation cohort and the validation cohort. Compared with patients in the lowest risk category, those in the highest risk category showed a 24.00-fold (95% confidence interval (CI) 13.49-fold to 42.78-fold) higher odds of CP-AKI in the derivation cohort and a 17.87-fold (10.56-fold to 29.60-fold) higher odds in the validation cohort. The primary model had a C statistic of 0.75 and showed better discrimination for CP-AKI than previously published models, the C statistics for which ranged from 0.60 to 0.68 (DeLong P<0.001 for each comparison). Greater severity of CP-AKI was monotonically associated with shorter 90 day survival (adjusted hazard ratio 4.63 (95% CI 3.56 to 6.02) for stage 3 CP-AKI versus no CP-AKI). CONCLUSION: This study found that a simple risk score based on readily available variables from patients receiving intravenous cisplatin could predict the risk of severe CP-AKI, the occurrence of which is strongly associated with death.
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Atteinte rénale aigüe , Cisplatine , Adulte , Humains , Adulte d'âge moyen , Cisplatine/effets indésirables , Études de cohortes , Créatinine , Facteurs de risque , Atteinte rénale aigüe/induit chimiquement , Atteinte rénale aigüe/épidémiologie , Appréciation des risques , Études rétrospectivesRÉSUMÉ
BACKGROUND: Primary aldosteronism (PA) has been broadly dichotomized into unilateral and bilateral forms. Adrenal vein sampling (AVS) lateralization indices (LI) ≥2 to 4 are the standard-of-care to recommend unilateral adrenalectomy for presumed unilateral PA. We aimed to assess the rates and characteristics of residual PA after AVS-guided adrenalectomy. METHODS: We conducted an international, retrospective, cohort study of patients with PA from 7 referral centers who underwent unilateral adrenalectomy based on LI≥4 on baseline and/or cosyntropin-stimulated AVS. Aldosterone synthase (CYP11B2) immunohistochemistry and next generation sequencing were performed on available formalin-fixed paraffin-embedded adrenal tissue. RESULTS: The cohort included 283 patients who underwent AVS-guided adrenalectomy, followed for a median of 326 days postoperatively. Lack of PA cure was observed in 16% of consecutive patients, and in 22 patients with lateralized PA on both baseline and cosyntropin-stimulated AVS. Among patients with residual PA postoperatively, 73% had multiple CYP11B2 positive areas within the resected adrenal tissue (versus 23% in those cured), wherein CACNA1D mutations were most prevalent (63% versus 33% in those cured). In adjusted regression models, independent predictors of postoperative residual PA included Black versus White race (odds ratio, 5.10 [95% CI, 1.45-17.86]), AVS lateralization only at baseline (odds ratio, 8.93 [95% CI 3.00-26.32] versus both at baseline and after cosyntropin stimulation), and CT-AVS disagreement (odds ratio, 2.75 [95% CI, 1.20-6.31]). CONCLUSIONS: Multifocal, asymmetrical bilateral PA is relatively common, and it cannot be excluded by robust AVS lateralization. Long-term postoperative monitoring should be routinely pursued, to identify residual PA and afford timely initiation of targeted medical therapy.
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Hyperaldostéronisme , Humains , Hyperaldostéronisme/diagnostic , Hyperaldostéronisme/génétique , Hyperaldostéronisme/chirurgie , Études rétrospectives , Aldostérone , Tétracosactide , Études de cohortes , Cytochrome P-450 CYP11B2 , Glandes surrénales/chirurgie , Glandes surrénales/vascularisation , SurrénalectomieRÉSUMÉ
PURPOSE: RAS mutations occur across the spectrum of thyroid neoplasms, and more tools are needed for better prognostication. The objective of this study was to evaluate how additional genetic events affecting key genes modify prognosis in patients with RAS-mutant thyroid cancers, and specifically differentiated thyroid cancers (DTC). EXPERIMENTAL DESIGN: We performed a clinical-genomic analysis of consecutive patients with DTC, poorly differentiated (PDTC), or anaplastic thyroid cancer (ATC) between January 2014 and December 2021, in whom a custom-targeted next-generation sequencing assay was performed. Patients harboring RAS mutations were included, and we compared their clinical features and outcomes based upon the presence of additional oncogenic alterations. RESULTS: Seventy-eight patients were identified, with 22% (17/78) harboring a driver RAS mutation plus an additional oncogenic alteration. All six (100%) ATCs had an additional mutation. Compared with DTCs harboring a solitary RAS mutation, patients with DTC with RAS and additional mutation(s) were more likely to be classified as American Thyroid Association high-risk of recurrence (77% vs. 12%; P < 0.001) and to have larger primary tumors (4.7 vs. 2.5 cm; P = 0.002) and advanced stage (III or IV) at presentation (67% vs. 3%; P < 0.001). Importantly, over an average 65-month follow-up, DTC-specific-mortality was more than 10-fold higher (20% vs. 1.8%; P = 0.011) when additional mutations were identified. CONCLUSIONS: Identification of key additional mutations in patients with RAS-mutant thyroid cancers confers a more aggressive phenotype, increases mortality risk in DTC, and can explain the diversity of RAS-mutated thyroid neoplasia. These data support genomic profiling of DTCs to inform prognosis and clinical decision-making.
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Adénocarcinome , Carcinome anaplasique de la thyroïde , Tumeurs de la thyroïde , Humains , Tumeurs de la thyroïde/anatomopathologie , Carcinome anaplasique de la thyroïde/génétique , Carcinome anaplasique de la thyroïde/anatomopathologie , Pronostic , Mutation , Protéines proto-oncogènes B-raf/génétiqueRÉSUMÉ
Importance: Circulating tumor tissue-modified viral (TTMV) human papillomavirus (HPV) DNA is a dynamic, clinically relevant biomarker for HPV-positive oropharyngeal squamous cell carcinoma. Reasons for its wide pretreatment interpatient variability are not well understood. Objective: To characterize clinicopathologic factors associated with TTMV HPV DNA. Design, Setting, and Participants: This cross-sectional study included patients evaluated for HPV-positive oropharyngeal squamous cell carcinoma at Dana-Farber Cancer Institute in Boston, Massachusetts, between December 2019 and January 2022 and who were undergoing curative-intent treatment. Exposures: Clinicopathologic characteristics including demographic variables, tumor and nodal staging, HPV genotype, and imaging findings. Main Outcomes and Measures: Pretreatment circulating TTMV HPV DNA from 5 genotypes (16, 18, 31, 33, and 35) assessed using a commercially available digital droplet polymerase chain reaction-based assay, considered as either detectable/undetectable or a continuous score (fragments/mL). Results: Among 110 included patients, 96 were men (87%) and 104 were White (95%), with a mean (SD) age of 62.2 (9.4) years. Circulating TTMV HPV DNA was detected in 98 patients (89%), with a median (IQR) score of 315 (47-2686) fragments/mL (range, 0-60â¯061 fragments/mL). Most detectable TTMV HPV DNA was genotype 16 (n = 86 [88%]), while 12 patients (12%) harbored other genotypes. Circulating TTMV HPV DNA detection was most strongly associated with clinical N stage. Although few patients had clinical stage N0 disease, only 4 of these 11 patients (36%) had detectable DNA compared with 94 of 99 patients (95%) with clinical stage N1 to N3 disease (proportion difference, 59%; 95% CI, 30%-87%). Among patients with undetectable TTMV HPV DNA, more than half (7 of 12 [58%]) had clinical stage N0 disease. The TTMV HPV DNA prevalence and score increased with progressively higher clinical nodal stage, diameter of largest lymph node, and higher nodal maximum standardized uptake value on positron emission tomography/computed tomography. In multivariable analysis, clinical nodal stage and nodal maximum standardized uptake value were each strongly associated with TTMV HPV DNA score. Among 27 surgically treated patients, more patients with than without lymphovascular invasion had detectable TTMV HPV DNA (12 of 12 [100%] vs 9 of 15 [60%]). Conclusions and Relevance: In this cross-sectional study, circulating TTMV HPV DNA was statistically significantly associated with nodal disease at HPV-positive OPSCC diagnosis. The few patients with undetectable levels had predominantly clinical stage N0 disease, suggesting assay sensitivity for diagnostic purposes may be lower among patients without cervical lymphadenopathy. Mechanisms underlying this association, and the use of this biomarker for surveillance of patients with undetectable baseline values, warrant further investigation.
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Tumeurs de la tête et du cou , Tumeurs de l'oropharynx , Infections à papillomavirus , Humains , Adulte d'âge moyen , Carcinome épidermoïde de la tête et du cou , Études transversales , Tumeurs de l'oropharynx/thérapie , ADNRÉSUMÉ
Chimeric antigen receptor (CAR) T-cell therapy targeting cluster of differentiation (CD)19 has had a transformative impact on patient outcomes in a subset of patients with relapsed/refractory non-Hodgkin lymphoma. We present a patient with refractory large B-cell lymphoma in complete remission for 2 years following treatment with CD19-targeted CAR T-cell therapy, who presented with 2 weeks of progressive aphasia. Imaging revealed a left occipital brain lesion and biopsy demonstrated features diagnostic of progressive multifocal leukoencephalopathy. Further evaluation revealed severe hypogammaglobulinemia and a low CD4 count. She was treated with pembrolizumab and intravenous immunoglobulin resulting in decreased cerebrospinal fluid viral load without clinical improvement and died 8 weeks after presentation. This case highlights that there is potential for severe opportunistic infections after CAR T-cell therapy, including fatal progressive multifocal leukoencephalopathy. Strategies to enhance post-treatment immune reconstitution are essential to further harness the unique potency of CAR T-cell therapy.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.
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COVID-19/complications , SARS-CoV-2 , Maladie aigüe , COVID-19/épidémiologie , COVID-19/ethnologie , COVID-19/thérapie , Maladies cardiovasculaires/épidémiologie , Maladies cardiovasculaires/thérapie , Humains , Défense du patient , Syndrome , Syndrome de réponse inflammatoire généralisée/épidémiologie , Syndrome de réponse inflammatoire généralisée/thérapie , Thromboembolisme veineux/épidémiologie , Thromboembolisme veineux/prévention et contrôleRÉSUMÉ
Importance: Despite approximately 40% of patients having Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores of at least 2 in the real world, most landmark clinical trials that led to the use of pembrolizumab as standard of care in advanced non-small cell lung cancer (NSCLC) excluded this group. Objective: To evaluate whether an ECOG PS score of at least 2 at the start of therapy is associated with progression-free survival (PFS) and overall survival (OS) in advanced NSCLC treated with pembrolizumab monotherapy. Design, Setting, and Participants: This cohort study included all consecutive patients with advanced NSCLC who underwent treatment with palliative pembrolizumab monotherapy from February 2016 to October 2019 at a single academic cancer center, with data censoring on January 15, 2020. Exposures: ECOG PS score at start of therapy, with 0 and 1 indicating fully active or restricted in strenuous activity and scores of 2 and higher indicating increasing disability. Main Outcomes and Measures: PFS and OS, measured from initiation of pembrolizumab monotherapy. Results: Of 74 patients (median [range] age, 68.5 [33-87] years; 36 [48.7%] women; 53 [71.6%] White individuals) with median follow-up of 19.5 (95% CI, 13.4-27.8) months, 45 (60.8%) had an ECOG PS of 0 or 1, while 29 (39.2%) had an ECOG PS of at least 2. There were no significant differences in the baseline characteristics, except in age. Compared with patients with PS scores of 0 or 1, those with PS scores of at least 2 had significantly lower disease control rates (38 [88.4%] vs 15 [53.6%]; P = .002), shorter median PFS (7.9 [95% CI, 4.6-15.4] months vs 2.3 [95% CI, 1.8-4.8] months; P = .004), and shorter median OS (23.2 [14.0 vs 35.7] months vs 4.1 [95% CI, 2.1-6.9] months; P < .001). Among those potentially eligible for subsequent cancer-directed therapy beyond pembrolizumab monotherapy, patients in the group with PS scores of at least 2 were less likely to receive it than those with PS scores of 0 or 1 (2 [8.3%] vs 14 [45.2%]; P = .003). Multivariable adjustment for baseline characteristics confirmed ECOG PS of at least 2 as an independent risk factor for worse PFS (HR, 2.02; 95% CI, 1.09-3.74; P = .03) and worse OS (HR, 2.87; 95% CI, 1.40-5.89; P = .004). Conclusions and Relevance: In this cohort study, having an ECOG PS score of at least 2 was associated with poorer prognosis for treatment of advanced NSCLC with palliative pembrolizumab monotherapy. Further prospective studies are needed to evaluate more objective and consistent measures of functional status to facilitate identification of patients with borderline performance status who may achieve durable clinical benefit from treatment with pembrolizumab monotherapy.
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Anticorps monoclonaux humanisés/usage thérapeutique , Antinéoplasiques immunologiques/usage thérapeutique , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , État fonctionnel , Tumeurs du poumon/traitement médicamenteux , Tumeurs de la surrénale/traitement médicamenteux , Tumeurs de la surrénale/secondaire , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Tumeurs osseuses/traitement médicamenteux , Tumeurs osseuses/secondaire , Tumeurs du cerveau/traitement médicamenteux , Tumeurs du cerveau/secondaire , Carcinome pulmonaire non à petites cellules/anatomopathologie , Carcinome pulmonaire non à petites cellules/physiopathologie , Carcinome pulmonaire non à petites cellules/secondaire , Études de cohortes , Prise de décision partagée , Femelle , Humains , Tumeurs du foie/traitement médicamenteux , Tumeurs du foie/secondaire , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/physiopathologie , Métastase lymphatique , Mâle , Adulte d'âge moyen , Métastase tumorale , Soins palliatifs , Tumeurs de la plèvre/traitement médicamenteux , Tumeurs de la plèvre/secondaire , Pronostic , Survie sans progression , Taux de survieRÉSUMÉ
While p53 is the most highly mutated and perhaps best studied tumor suppressor protein related to cancer, it remains refractory to targeted therapeutic strategies. In this issue of the JCI, Tan and colleagues investigated the mechanistic basis of the mutant p53 secretome in preclinical models of lung adenocarcinoma. The authors uncovered miR-34a as a regulator of a conventional protein secretion axis, which is mediated by three proteins: the Golgi reassembly and stacking protein 55 kDa (GRASP55), basic leucine zipper nuclear factor 1, and myosin IIA. Inhibition of GRASP55 in TP53-deficient lung adenocarcinoma suppressed protumorigenic secretion of osteopontin/secreted phosphoprotein 1 and insulin-like growth factor binding protein 2 and reduced tumor growth and metastases in mice as well as in patient-derived xenografts. These results provide a therapeutic opportunity to target downstream effects of p53 loss.
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Adénocarcinome pulmonaire , Tumeurs du poumon , microARN , Adénocarcinome pulmonaire/traitement médicamenteux , Adénocarcinome pulmonaire/génétique , Animaux , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Souris , Protéine p53 suppresseur de tumeur/génétique , Protéines suppresseurs de tumeursRÉSUMÉ
Objective: Transposition of great arteries is a common cyanotic heart defect. Balloon atrial septostomy aims to improve circulatory mixing and oxygenation. Previous studies have combined infants with intact ventricular septum and those with ventricular septal defect. Additionally, the septostomy was performed much later after birth. The objectives were to ascertain any correlation between the atrial septal defect size and oxygenation, before and after septostomy, as well the change in parameters pre-post procedure. Methods: We performed an audit of the last 10 years of clinical and echocardiographic data (2010-2020) for infants with transposition of great arteries with intact ventricular septum. A pediatric cardiologist, masked to clinical data, reviewed the images. Results: Our study of 25 infants with transposition of great arteries with intact ventricular septum noted that the procedure was performed at a median [interquartile range (IQR)] of 3 (2, 4) hours after birth. Prostaglandin was administered to the majority of infants [20/25 (80%)]. While significant increases in partial pressure of oxygen (24±5 vs 40±6 mmHg, p<0.001) and preductal oxygen saturations (67%±18% vs 81%±11%, p=0.003) were noted, and while the atrial septal defect increased in size from 1.8±0.6 vs 4.8±0.7 mm (p<0.001), no correlation was noted between atrial septal defect size and oxygen saturations. Conclusions: In our study of infants with transposition of great arteries and intact ventricular septum managed with balloon atrial septostomy, no correlation was noted between the atrial septal defect size and oxygen saturations. Pulmonary vascular resistance and pulmonary blood flow may be important physiological variables determining oxygenation.
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Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.
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Immunothérapie , Protéines tumorales , Tumeurs expérimentales , Récepteur-1 de mort cellulaire programmée , RNA-Seq , Analyse sur cellule unique , Sphéroïdes de cellules , Animaux , Lignée cellulaire tumorale , Souris , Protéines tumorales/génétique , Protéines tumorales/immunologie , Tumeurs expérimentales/génétique , Tumeurs expérimentales/immunologie , Tumeurs expérimentales/thérapie , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Récepteur-1 de mort cellulaire programmée/génétique , Récepteur-1 de mort cellulaire programmée/immunologie , Sphéroïdes de cellules/immunologie , Sphéroïdes de cellules/anatomopathologieRÉSUMÉ
BACKGROUND: Besides modeling/simulation-based analysis, no post-approval studies have evaluated the optimal administration frequency of pembrolizumab in non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We performed a multicenter retrospective cohort study to evaluate the association between survival outcomes and treatment extensions/delays of pembrolizumab-based regimens in patients with advanced NSCLC. Those who had received at least 4 cycles in routine practice were divided into 2 groups: nonstandard (Non-Std, ≥ 2 cycles at intervals > 3 weeks + 3 days) and standard (Std, all cycles every 3 weeks or 1 cycle > 3 weeks + 3 days). RESULTS: Among 150 patients, 92 (61%) were eligible for the study (Non-Std, 27; Std, 65). The reasons for patients with extensions/delays in the Non-Std group included: immune-related adverse events (irAEs) (33%), non-irAE-related medical issues (26%), and patient-physician preference (41%). The Non-Std group was more likely to have a higher programmed death-ligand 1 tumor proportion score, a higher number of treatment cycles, and pembrolizumab monotherapy. Univariate and 6-month landmark analyses showed longer median overall survival and progression-free survival in the Non-Std group compared with the Std group. After multivariable adjustment for confounding factors, there was no significant difference in overall survival (hazard ratio, 1.2; 95% confidence interval, 0.3-4.8; P = .824) or progression-free survival (hazard ratio, 2.6; 95% confidence interval, 0.7-9.6; P = .157) between the 2 groups. CONCLUSION: Our study shows that a significant proportion of patients with advanced NSCLC receive pembrolizumab-based regimens with extended intervals or delays in routine clinical practice and with similar outcomes to those receiving treatment at label-specified 3-week intervals. Given the durability of benefit seen and the potential for cost reduction and decreased infusion frequency in these patients, this requires validation in prospective trials.
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Anticorps monoclonaux humanisés/administration et posologie , Antinéoplasiques immunologiques/administration et posologie , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Tumeurs du poumon/traitement médicamenteux , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Carcinome pulmonaire non à petites cellules/anatomopathologie , Études de cohortes , Calendrier d'administration des médicaments , Femelle , Humains , Tumeurs du poumon/anatomopathologie , Mâle , Adulte d'âge moyen , Survie sans progression , Études rétrospectives , Taux de survie , Facteurs temps , Résultat thérapeutiqueRÉSUMÉ
The optimal management of advanced non-small cell lung cancer (NSCLC) with noncanonical epidermal growth factor receptor (EGFR) mutations (i.e., exon 19 deletion and exon 21 L858R) is constrained by the heterogeneous behavior of individual uncommon mutations and limited prospective clinical data in this setting. Despite encouraging results with osimertinib from a recently published phase II trial from South Korea, afatinib remains the only currently approved drug for patients with tumors harboring uncommon EGFR mutations (i.e., S768I, L861Q, and/or G719X). When used at the standard dose of 40 mg daily, afatinib is associated with significant rates of treatment-related adverse events, leading to frequent dose reductions and treatment discontinuations. We report a case of a woman with advanced NSCLC harboring EGFR-G719A mutation treated with afatinib (at an off-label pulse dose strategy that merits further evaluation in prospective studies) with sustained partial response for 20 months with manageable expected toxicities. Subsequent disease progression was mediated by off-target pan-EGFR inhibitor (including osimertinib)-resistant KRAS mutation and not by acquisition of EGFR-T790M. We further present the current state of evidence in the literature behind use of first-, second-, and third-generation tyrosine kinase inhibitors and summarize the evolving spectrum of activity ascribed to osimertinib (and newer EGFR inhibitors with a more favorable therapeutic window and intracranial penetration) in this population of patients with advanced NSCLC and uncommon EGFR mutations. KEY POINTS: Uncommon EGFR mutations characterize a heterogeneous group of patients with advanced non-small cell lung cancer (NSCLC). Afatinib is the only currently U.S. Food and Drug Administration-approved drug for management of advanced NSCLC with uncommon EGFR mutations (S768I, L861Q, and/or G719X). Afatinib treatment at 40 mg daily is associated with high rates of adverse events and dose reductions; alternative strategies including pulse intermittent dosing should be evaluated prospectively. Osimertinib (with favorable safety profile and intracranial penetration) has shown promising results in this population in a phase II trial from South Korea; additional trials are ongoing.
Sujet(s)
Carcinome pulmonaire non à petites cellules , Tumeurs du poumon , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/génétique , Récepteurs ErbB/génétique , Femelle , Humains , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Mutation , Études prospectives , Inhibiteurs de protéines kinases/effets indésirables , République de CoréeRÉSUMÉ
ROS1-rearranged (also known as ROS1 fusion-positive) non-small-cell lung cancer is an uncommon but distinct molecular subgroup seen in approximately 1-2% of cases. Oncogene addiction due to constitutive ROS1 tyrosine kinase activation has allowed development of molecularly targeted therapies with remarkable anti-tumor activity. Both crizotinib and entrectinib, multitargeted tyrosine kinase inhibitors (TKIs) have now received approval by the FDA for treatment of patients with advanced ROS1-rearranged lung cancers; however, the clinical efficacy and safety of these drugs have been derived from expansion cohorts of single-arm phase I or basket clinical trials with relatively small populations of this clinically and molecularly distinct subgroup. Both drugs lead to high objective response rates (approximately 70-80%) and have manageable side effects, although only entrectinib has potent intracranial efficacy. Lorlatinib is an oral brain-penetrant ALK/ROS1 TKI with activity in both TKI-naïve and some crizotinib-resistant settings (albeit with limited potency against the crizotinib/entrectinib-resistant ROS1-G2032R mutation). We describe cases of advanced ROS1-rearranged lung cancer receiving crizotinib, entrectinib, and/or lorlatinib in first and later line treatment settings to dissect the current state of evidence supporting management decisions for these patients. The next generation ROS1 TKIs (repotrectinib and DS-6051b), owing to their broad activity against kinase mutations including ROS1-G2032R in preclinical studies, hold promise to transform the current treatment paradigm and permit even further gains with regards to long-term outcomes in this subset of patients.