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Introduction: Cancer-associated cachexia (CC) is a progressive syndrome characterized by unintentional weight loss, muscle atrophy, fatigue, and poor outcomes that affects most patients with pancreatic ductal adenocarcinoma (PDAC). The ability to identify and classify CC stage along its continuum early in the disease process is challenging but critical for management. Objectives: The main objective of this study was to determine the prevalence of CC stage overall and by sex and race and ethnicity among treatment-naïve PDAC cases using clinical, nutritional, and functional criteria. Secondary objectives included identifying the prevalence and predictors of higher symptom burden, supportive care needs, and quality of life (QoL), and examining their influence on overall survival (OS). Materials and methods: A population-based multi-institutional prospective cohort study of patients with PDAC was conducted between 2018 and 2021 by the Florida Pancreas Collaborative. Leveraging patient-reported data and laboratory values, participants were classified at baseline into four stages [non-cachexia (NCa), pre-cachexia (PCa), cachexia (Ca), and refractory cachexia (RCa)]. Multivariate regression, Kaplan Meier analyses, and Cox regression were conducted to evaluate associations. Results: CC stage was estimated for 309 PDAC cases (156 females, 153 males). The overall prevalence of NCa, PCa, Ca, and RCa was 12.9%, 24.6%, 54.1%, and 8.4%, respectively. CC prevalence across all CC stages was highest for males and racial and ethnic minorities. Criteria differentiated NCa cases from other groups, but did not distinguish PCa from Ca. The most frequently reported symptoms included weight loss, fatigue, pain, anxiety, and depression, with pain significantly worsening over time. The greatest supportive care needs included emotional and physical domains. Males, Black people, and those with RCa had the worst OS. Conclusions: Using clinical, nutritional, and functional criteria, nearly one-quarter of the PDAC cases in our diverse, multi-institutional cohort had PCa and 62.5% had Ca or RCa at the time of diagnosis. The PCa estimate is higher than that reported in prior studies. We recommend these criteria be used to aid in CC classification, monitoring, and management of all incident PDAC cases. Findings also highlight the recommendation for continued emotional support, assistance in alleviating pain, and supportive care needs throughout the PDAC treatment journey.
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Immunotherapy response is associated with the presence of conventional dendritic cells (cDCs). cDC type 1 (cDC1) is critically important for CD8+ T cell activation, cDC type 2 (cDC2) regulates CD4+ T cell responses, and mature regulatory cDCs may dampen T cell responses in the tumor microenvironment (TME). However, we lack a clear understanding of cDC distribution in the human TME, cDC prevalence in metastatic sites, and cDC differences in early- versus late-stage disease. Rapid autopsy specimens of 10 patients with lung adenocarcinoma were evaluated to detect cDCs and immune cells via multiplex immunofluorescence using 18 markers and 42 tumors. First, we found that T cells, cDC1, and cDC2 were confined to stroma, whereas mature regulatory DCs were enriched in tumor, suggesting unique localization-specific functions. Second, lung and lymph node tumors were more enriched in T cells and cDCs than liver tumors, underscoring differences in the TME of metastatic sites. Third, although the proportion of T cells and cDC1 did not differ in different stages, an increase in the proportion of cDC2 and macrophages in late stage suggests potential differences in regulation of T cell responses in different stages. Collectively, these findings provide new, to our knowledge, insights into cDC biology in human cancer that may have important therapeutic implications.
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BACKGROUND: ALK or EGFR inhibitor is an ideal frontline treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring targetable alteration in ALK or EGFR. However, in the real-world setting, frontline treatment may be delayed or not ideal. For such patients, the benefit of initiating ALK or EGFR inhibitor at a later timepoint remains uninvestigated. METHODS: We utilized a nationwide electronic health record-derived, deidentified database collected from diverse oncology practices across the United States to investigate the timeliness of preferred targeted therapy (PTT). Individualized data obtained from patients with stage IV NSCLC at diagnosis treated with PTT from 2018 to 2023 were analyzed. RESULTS: Data from 3250 patients were analyzed: 2640 patients (81%) with EGFR mutation and 610 patients (19%) with ALK rearrangement. The median time to PTT was 7 weeks from diagnosis with 26.4% of patients started PTT within 1 month. Landmark analyses using timepoints ranging from 1 to 12 months after diagnosis showed that at all timepoints, patients who had started on PTT had a significantly better survival than those who had not. In a multivariable analysis, time to PTT ≤ 1 month from diagnosis was an independent predictor of survival: HR 0.74 (95% CI: 0.62-0.89), P = .002. Time to PTT was significantly associated with age, smoking status and genomic class. CONCLUSIONS: In this population-based analysis, an initiation of PTT occurring as late as at least 1 year from diagnosis still resulted in a significant survival benefit, though the magnitude of benefit appeared decreased as time passed.
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BACKGROUND: While multiple cyst features are evaluated for stratifying pancreatic intraductal papillary mucinous neoplasms (IPMN), cyst size is an important factor that can influence treatment strategies. When magnetic resonance imaging (MRI) is used to evaluate IPMNs, no universally accepted sequence provides optimal size measurements. T2-weighted coronal/axial have been suggested as primary measurement sequences; however, it remains unknown how well these and maximum all-sequence diameter measurements correlate with pathology size. This study aims to compare agreement and bias between IPMN long-axis measurements on seven commonly obtained MRI sequences with pathologic size measurements. METHODS: This retrospective cohort included surgically resected IPMN cases with preoperative MRI exams. Long-axis diameter tumor measurements and the presence of worrisome features and/orhigh-risk stigmata were noted on all seven MRI sequences. MRI size and pathology agreement and MRI inter-observer agreement involved concordance correlation coefficient (CCC) and intraclass correlation coefficient (ICC), respectively. The presence of worrisome features and high-risk stigmata were compared to the tumor grade using kappa analysis. The Bland-Altman analysis assessed the systematic bias between MRI-size and pathology. RESULTS: In 52 patients (age 68 ± 13 years, 22 males), MRI sequences produced mean long-axis tumor measurements from 2.45-2.65 cm. The maximum MRI lesion size had a strong agreement with pathology (CCC = 0.82 (95% CI: 0.71-0.89)). The maximum IPMN size was typically observed on the axial T1 arterial post-contrast and MRCP coronal series and overestimated size versus pathology with bias +0.34 cm. The radiologist interobserver agreement reached ICCs 0.74 to 0.91 on the MRI sequences. CONCLUSION: The maximum MRI IPMN size strongly correlated with but tended to overestimate the length compared to the pathology, potentially related to formalin tissue shrinkage during tissue processing.
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Background: The optimal treatment sequencing for patients with metastatic epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) remains a subject of debate. In the United States, osimertinib is the preferred EGFR tyrosine kinase inhibitor (TKI) in the first-line setting. However, small retrospective studies suggest that alternative EGFR TKI sequencing strategies may produce similar outcomes. This study aimed to compare the outcomes of patients with metastatic NSCLC harboring an EGFR exon 19 deletion or exon 21 L858R mutation treated with osimertinib vs. afatinib as first-line therapy. Methods: This retrospective, single-institution study examined 86 patients with metastatic EGFR-mutant NSCLC treated with either afatinib (n=15) or osimertinib (n=71) in the first-line setting. The primary outcome was progression-free survival (PFS), and secondary endpoints included time on EGFR TKI, overall survival (OS), and the incidence of adverse events (AEs). Results: There was no difference in the PFS (median: 27.9 vs. 29.0 months, P=0.75), OS (P=0.18), and the median time on first-line EGFR TKI (23.9 vs. 15.2 months, P=0.10) between the afatinib and osimertinib groups, respectively. The number of AEs was also similar between the two treatment groups (P=0.17). Conclusions: In this real-world retrospective study, there were no differences in PFS or OS between patients treated with afatinib or osimertinib in the first-line setting. These findings should be further investigated in larger prospective studies.
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Background: Large Cell Neuroendocrine Carcinoma (LCNEC) is a high-grade malignancy with limited treatment options. Despite promising results of immunotherapy in non-small cell and small cell lung cancers, its benefit in LCNEC remains elusive. Methods: We included 24 patients diagnosed with stage IV LCNEC from the Moffitt Cancer Center database who received systemic therapy between January 2016 and May 2021. Group A comprised patients who received first-line CT and ICI (anti-PD-1 or anti-PD-L1 therapy for ICI, n = 11), and Group B received first-line CT only (n = 13). The collected data encompassed overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicities since treatment initiation. Results: Kaplan-Meier survival analysis revealed median OS was 56 weeks (95%CI = 22.2-89.8) and 28 weeks (95% CI=16.3-39.7) in groups A and B, respectively. Log-rank test showed the difference was statistically significant (p=0.029). Median PFS was 32 weeks (95%CI=14.7-49.3) in group A and 20 weeks (95% CI=13.8-26.2) in groups B, but the difference was not statistically significant (p= 0.136). Univariate Cox analysis confirmed that the addition of ICI to CT significantly improved OS in patients with stage IV LCNEC (HR=0.35, 95% CI=0.13-0.95, p = 0.039). The ORR (63.6% vs 45.4%, p= 0.670) and DCR (81.8% vs 63.6%, p= 0.635) tended to be higher in group A than in group B but the difference was not statistically significant. Importantly, the combined treatment demonstrated a satisfactory safety profile, with only two patients reporting grade 2 or higher adverse events. Conclusions: Our results suggest that the combination of immunotherapy with chemotherapy holds potential for improving outcomes in stage IV LCNEC. Despite the retrospective nature and limited sample size of our study, these preliminary findings provide a valuable insight into the potential of immunotherapy in LCNEC treatment and encourage further research through larger, prospective trials.
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We report domain knowledge-based rules for assigning voxels in brain multiparametric MRI (mpMRI) to distinct tissuetypes based on their appearance on Apparent Diffusion Coefficient of water (ADC) maps, T1-weighted unenhanced and contrast-enhanced, T2-weighted, and Fluid-Attenuated Inversion Recovery images. The development dataset comprised mpMRI of 18 participants with preoperative high-grade glioma (HGG), recurrent HGG (rHGG), and brain metastases. External validation was performed on mpMRI of 235 HGG participants in the BraTS 2020 training dataset. The treatment dataset comprised serial mpMRI of 32 participants (total 231 scan dates) in a clinical trial of immunoradiotherapy in rHGG (NCT02313272). Pixel intensity-based rules for segmenting contrast-enhancing tumor (CE), hemorrhage, Fluid, non-enhancing tumor (Edema1), and leukoaraiosis (Edema2) were identified on calibrated, co-registered mpMRI images in the development dataset. On validation, rule-based CE and High FLAIR (Edema1 + Edema2) volumes were significantly correlated with ground truth volumes of enhancing tumor (R = 0.85;p < 0.001) and peritumoral edema (R = 0.87;p < 0.001), respectively. In the treatment dataset, a model combining time-on-treatment and rule-based volumes of CE and intratumoral Fluid was 82.5% accurate for predicting progression within 30 days of the scan date. An explainable decision tree applied to brain mpMRI yields validated, consistent, intratumoral tissuetype volumes suitable for quantitative response assessment in clinical trials of rHGG.
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PURPOSE: We investigated whether a dendritic cell (DC) vaccine transduced with an adenoviral vector encoded with full-length survivin (Ad-S), with mutations neutralizing its antiapoptotic function, could safely generate an immune response and deepen clinical responses when administered before and after autologous stem cell transplant (ASCT) for multiple myeloma. PATIENTS AND METHODS: This phase I first-in-human trial (NCT02851056) evaluated the safety of DC:Ad-S in newly diagnosed multiple myeloma not having achieved complete response with induction, given 7 to 30 days prior to stem cell collection and 20 to 34 days after ASCT. Anti-survivin antibodies and CD4+ and CD8+ specific T cells were quantified. RESULTS: A total of 14 patients were treated and 13 included in the primary efficacy analysis. No serious adverse events were attributed to DC:Ad-S vaccine. Detectable anti-survivin antibodies increased from baseline in 9 of 13 (69%) patients, and 11 of 13 (85%) mounted either a cellular or humoral immune response to survivin. Seven patients had an improved clinical response at day +90, all of whom had mounted an immune response, and 6 of 7 patients remain event-free at a median follow-up of 4.2 years. Estimated progression-free survival at 4 years is 71% (95% confidence interval, 41-88). CONCLUSIONS: Two doses of DC:Ad-S, one given immediately before and another after ASCT, were feasible and safe. A high frequency of vaccine-specific immune responses was seen in combination with durable clinical outcomes, supporting ongoing investigation into the potential of this approach. See related commentary by Dhodapkar, p. 4524.
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Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Survivina , Autoenxertos , Transplante Autólogo , Imunidade , Células Dendríticas , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
BACKGROUND: Randomized clinical trials of novel treatments for solid tumors normally measure disease progression using the Response Evaluation Criteria in Solid Tumors. However, novel, scalable approaches to estimate disease progression using real-world data are needed to advance cancer outcomes research. The purpose of this narrative review is to summarize examples from the existing literature on approaches to estimate real-world disease progression and their relative strengths and limitations, using lung cancer as a case study. METHODS: A narrative literature review was conducted in PubMed to identify articles that used approaches to estimate real-world disease progression in lung cancer patients. Data abstracted included data source, approach used to estimate real-world progression, and comparison to a selected gold standard (if applicable). RESULTS: A total of 40 articles were identified from 2008 to 2022. Five approaches to estimate real-world disease progression were identified including manual abstraction of medical records, natural language processing of clinical notes and/or radiology reports, treatment-based algorithms, changes in tumor volume, and delta radiomics-based approaches. The accuracy of these progression approaches were assessed using different methods, including correlations between real-world endpoints and overall survival for manual abstraction (Spearman rank ρ = 0.61-0.84) and area under the curve for natural language processing approaches (area under the curve = 0.86-0.96). CONCLUSIONS: Real-world disease progression has been measured in several observational studies of lung cancer. However, comparing the accuracy of methods across studies is challenging, in part, because of the lack of a gold standard and the different methods used to evaluate accuracy. Concerted efforts are needed to define a gold standard and quality metrics for real-world data.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/terapia , Avaliação de Resultados em Cuidados de Saúde , Progressão da DoençaRESUMO
Pathway-level survival analysis offers the opportunity to examine molecular pathways and immune signatures that influence patient outcomes. However, available survival analysis algorithms are limited in pathway-level function and lack a streamlined analytical process. Here we present a comprehensive pathway-level survival analysis suite, PATH-SURVEYOR, which includes a Shiny user interface with extensive features for systematic exploration of pathways and covariates in a Cox proportional-hazard model. Moreover, our framework offers an integrative strategy for performing Hazard Ratio ranked Gene Set Enrichment Analysis and pathway clustering. As an example, we applied our tool in a combined cohort of melanoma patients treated with checkpoint inhibition (ICI) and identified several immune populations and biomarkers predictive of ICI efficacy. We also analyzed gene expression data of pediatric acute myeloid leukemia (AML) and performed an inverse association of drug targets with the patient's clinical endpoint. Our analysis derived several drug targets in high-risk KMT2A-fusion-positive patients, which were then validated in AML cell lines in the Genomics of Drug Sensitivity database. Altogether, the tool offers a comprehensive suite for pathway-level survival analysis and a user interface for exploring drug targets, molecular features, and immune populations at different resolutions.
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Leucemia Mieloide Aguda , Melanoma , Criança , Humanos , Reposicionamento de Medicamentos , Oncologia , Melanoma/tratamento farmacológico , Melanoma/genética , Algoritmos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genéticaRESUMO
RATIONALE: Adverse events (AEs) have been shown to have clinical associations, in addition to patient safety assessments of drugs of interest. However, due to their complex content and associated data structure, AE evaluation has been restricted to descriptive statistics and small AE subset for efficacy analysis, limiting the opportunity for global discovery. This study takes a unique approach to utilize AE-associated parameters to derive a set of innovative AE metrics. Comprehensive analysis of the AE-derived biomarkers enhances the chance of discovering new predictive AE biomarkers of clinical outcomes. METHODS: We utilized a set of AE-associated parameters (grade, treatment relatedness, occurrence, frequency, and duration) to derive 24 AE biomarkers. We further innovatively defined early AE biomarkers by landmark analysis at an early time point to assess the predictive value. Statistical methods included the Cox proportional hazards model for progression-free survival (PFS) and overall survival (OS), two-sample t-test for mean difference of AE frequency and duration between disease control (DC: complete response (CR) + partial response (PR) + stable disease (SD)) versus progressive disease (PD), and Pearson correlation analysis for relationship of AE frequency and duration versus treatment duration. Two study cohorts (Cohort A: vorinostat + pembrolizumab, and B: Taminadenant) from two immunotherapy trials in late-stage non-small cell lung cancer were used to test the potential predictiveness of AE-derived biomarkers. Data from over 800 AEs were collected per standard operating procedure in a clinical trial using the Common Terminology Criteria for Adverse Events v5 (CTCAE). Clinical outcomes for statistical analysis included PFS, OS, and DC. RESULTS: An early AE was defined as event occurrence at or prior to day 30 from initial treatment date. The early AEs were then used to calculate the 24 early AE biomarkers to assess overall AE, each toxicity category, and each individual AE. These early AE-derived biomarkers were evaluated for global discovery of clinical association. Both cohorts showed that early AE biomarkers were associated with clinical outcomes. Patients previously experienced with low-grade AEs (including treatment related AEs (TrAE)) had improved PFS, OS, and were associated with DC. The significant early AEs included low-grade TrAE in overall AE, endocrine disorders, hypothyroidism (pembrolizumab's immune-related adverse event (irAE)), and platelet count decreased (vorinostat related TrAE) for Cohort A and low-grade AE in overall AE, gastrointestinal disorders, and nausea for Cohort B. In contrast, patients with early development of high-grade AEs tended to have poorer PFS, OS, and correlated with PD. The associated early AEs included high-grade TrAE in overall AE, gastrointestinal disorders with two members, diarrhea and vomiting, for Cohort A and high-grade AE in overall AE, three toxicity categories, and five related individual AEs for Cohort B. One low-grade TrAE, alanine aminotransferase increased (vorinostat + pembrolizumab related), was an irAE and correlated with worse OS in Cohort A. CONCLUSIONS: The study demonstrated the potential clinical utility of early AE-derived biomarkers in predicting positive and negative clinical outcomes. It could be TrAEs or combination of TrAEs and nonTrAEs from overall AEs, toxicity category AEs, to individual AEs with low-grade event leaning to encouraging effect and high-grade event to undesirable impact. Moreover, the methodology of the AE-derived biomarkers could change current AE analysis practice from a descriptive summary into modern informative statistics. It modernizes AE data analysis by helping clinicians discover novel AE biomarkers to predict clinical outcomes and facilitate the generation of vast clinically meaningful research hypotheses in a new AE content to fulfill the demands of precision medicine.
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PURPOSE: Patients with locoregional recurrence of squamous cell carcinoma of the head and neck (SCCHN) have relatively poor outcomes; therefore, stereotactic body radiation therapy (SBRT) has been investigated for this patient population. We performed a phase 1 clinical trial to establish a maximum tolerated dose of SBRT with concurrent cisplatin in previously irradiated locoregional SCCHN. METHODS AND MATERIALS: Patients with recurrent SCCHN who had previously undergone radiation therapy to doses ≥45 Gy to the area of recurrence ≥6 months before enrollment and who were not surgical candidates or refused surgery were eligible. SBRT was delivered every other day for 5 fractions. Starting dose level was 6 Gy × 5 fractions, followed by 7 Gy × 5 fractions and 8 Gy × 5 fractions. Chemotherapy consisted of cisplatin given before every SBRT fraction at a dose of 15 mg/m2. Patients were monitored for dose-limiting toxicities (DLT) that occurred within 3 months from the start of SBRT. Secondary endpoints included locoregional failure, distant metastasis, and overall survival. RESULTS: Twenty patients were enrolled, with 18 patients evaluable for endpoints. One patient at dose level 1 (30 Gy) died of unknown causes 2 weeks following completion of treatment. Therefore, an additional 3 patients were accrued to the 30-Gy dose level, with no further DLTs observed. Three patients were then accrued at dose level 2 (35 Gy) and 9 patients at dose level 3 (40 Gy) without DLTs. At a median follow-up of 9.5 months, cumulative incidence of locoregional failure at 2 years was 61% (95% confidence interval [CI], 12%-66%), cumulative incidence of distant metastasis was 11% (95% CI, 74%-100%) at 2 years, and overall survival was 22% (95% CI, 9%-53%) at 2 years. CONCLUSIONS: Concurrent cisplatin and reirradiation with an SBRT dose of ≤40 Gy was safe and feasible in patients with locoregionally recurrent or second primary SCCHN.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Radiocirurgia , Reirradiação , Humanos , Cisplatino , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos , Reirradiação/efeitos adversos , Neoplasias de Cabeça e Pescoço/radioterapia , Recidiva Local de Neoplasia/radioterapia , Carcinoma de Células Escamosas/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Pathway-level survival analysis offers the opportunity to examine molecular pathways and immune signatures that influence patient outcomes. However, available survival analysis algorithms are limited in pathway-level function and lack a streamlined analytical process. Here we present a comprehensive pathway-level survival analysis suite, DRPPM-PATH-SURVEIOR, which includes a Shiny user interface with extensive features for systematic exploration of pathways and covariates in a Cox proportional-hazard model. Moreover, our framework offers an integrative strategy for performing Hazard Ratio ranked Gene Set Enrichment Analysis (GSEA) and pathway clustering. As an example, we applied our tool in a combined cohort of melanoma patients treated with checkpoint inhibition (ICI) and identified several immune populations and biomarkers predictive of ICI efficacy. We also analyzed gene expression data of pediatric acute myeloid leukemia (AML) and performed an inverse association of drug targets with the patient's clinical endpoint. Our analysis derived several drug targets in high-risk KMT2A-fusion-positive patients, which were then validated in AML cell lines in the Genomics of Drug Sensitivity database. Altogether, the tool offers a comprehensive suite for pathway-level survival analysis and a user interface for exploring drug targets, molecular features, and immune populations at different resolutions.
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BACKGROUND/AIM: Grading pancreatic neuroendocrine neoplasms (PNENs) via mitotic rate and Ki-67 index score is complicated by interobserver variability. Differentially expressed miRNAs (DEMs) are useful for predicting tumour progression and may be useful for grading. PATIENTS AND METHODS: Twelve PNENs were selected. Four patients had grade (G) 1 pancreatic neuroendocrine tumours (PNETs); 4 had G2 PNETs; and 4 had G3 PNENs (2 PNETs and 2 pancreatic neuroendocrine carcinomas). Samples were profiled using the miRNA NanoString Assay. RESULTS: There were 6 statistically significant DEMs between different grades of PNENs. MiR1285-5p was the sole miRNA differentially expressed (p=0.03) between G1 and G2 PNETs. Six statistically significant DEMs (miR135a-5p, miR200a-3p, miR3151-5p, miR-345-5p, miR548d-5p and miR9-5p) (p<0.05) were identified between G1 PNETs and G3 PNENs. Finally, 5 DEMs (miR155-5p, miR15b-5p, miR222-3p, miR548d-5p and miR9-5p) (p<0.05) were identified between G2 PNETs and G3 PNENs. CONCLUSION: The identified miRNA candidates are concordant with their patterns of dysregulation in other tumour types. The reliability of these DEMs as discriminators of PNEN grades support further investigations using larger patient populations.
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MicroRNAs , Tumores Neuroectodérmicos Primitivos , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Pembrolizumab monotherapy or pembrolizumab plus chemotherapy has become an important frontline treatment for advanced non-small cell lung cancer (NSCLC). To date, it remains unclear how the coronavirus disease 2019 (COVID-19) pandemic impacted the treatment outcome. METHODS: A quasi-experimental study was conducted based on a real-world database, comparing pandemic with pre-pandemic patient cohorts. The pandemic cohort consisted of patients who initiated treatment from March to July 2020, with follow-up through March 2021. The pre-pandemic cohort consisted of those initiating treatment between March and July 2019.The outcome was overall real-world survival. Multivariable Cox-proportional hazard models were constructed. RESULTS: Analyses included data from 2090 patients: 998 in the pandemic cohort and 1092 in the pre-pandemic cohort. Baseline characteristics were comparable, with 33% of patients having PD-L1 expression level ≥50% and 29% of patients receiving pembrolizumab monotherapy. Among those treated with pembrolizumab monotherapy (N = 613), there was a differential impact of the pandemic on survival by PD-L1 expression levels (p-interaction = 0.02). For those with PD-L1 level < 50%, survival was better in the pandemic cohort than the pre-pandemic cohort: hazard ratio (HR) 0.64 (95% CI: 0.43-0.97, p = 0.03). However, for those with PD-L1 level ≥ 50%, survival was not better in the pandemic cohort: HR 1.17 (95% CI: 0.85-1.61, p = 0.34). We found no statistically significant impact of the pandemic on survival among patients treated with pembrolizumab plus chemotherapy. CONCLUSIONS: The COVID-19 pandemic was associated with an increase in survival among patients with lower PD-L1 expression who were treated with pembrolizumab monotherapy. This finding suggests an increased efficacy of immunotherapy due to viral exposure in this population.
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Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions to pancreatic ductal adenocarcinoma that are challenging to manage due to limited imaging, cytologic, and molecular markers that accurately classify lesions, grade of dysplasia, or focus of invasion preoperatively. The objective of this pilot study was to determine the frequency and type of DNA mutations in a cohort of surgically resected, pathologically confirmed IPMN, and to determine if concordant mutations are detectable in paired pretreatment plasma samples. Formalin-fixed paraffin-embedded (FFPE) tissue from 46 surgically resected IPMNs (31 low-grade, 15 high-grade) and paired plasma from a subset of 15 IPMN cases (10 low-grade, 5 high-grade) were subjected to targeted mutation analysis using a QIAseq Targeted DNA Custom Panel. Common driver mutations were detected in FFPE from 44 of 46 (95.6%) IPMN cases spanning all grades; the most common DNA mutations included: KRAS (80%), RNF43 (24%), and GNAS (43%). Of note, we observed a significant increase in the frequency of RNF43 mutations from low-grade to high-grade IPMNs associated or concomitant with invasive carcinoma (trend test, P = 0.01). Among the subset of cases with paired plasma, driver mutations identified in the IPMNs were not detected in circulation. Overall, our results indicate that mutational burden for IPMNs is a common occurrence, even in low-grade IPMNs. Furthermore, although blood-based biopsies are an attractive, noninvasive method for detecting somatic DNA mutations, the QIAseq panel was not sensitive enough to detect driver mutations that existed in IPMN tissue using paired plasma in the volume we were able to retrieve for this retrospective study.
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Neoplasias Císticas, Mucinosas e Serosas , Neoplasias Intraductais Pancreáticas , Neoplasias Pancreáticas , Humanos , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Intraductais Pancreáticas/patologia , Projetos Piloto , Estudos Retrospectivos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , MutaçãoRESUMO
Molecular epidemiology evidence indicates racial and ethnic differences in the aggressiveness and survival of breast cancer. Hispanics/Latinas (H/Ls) and non-Hispanic Black women (NHB) are at higher risk of breast cancer (BC)-related death relative to non-Hispanic white (NHW) women in part because they are diagnosed with hormone receptor-negative (HR) subtype and at higher stages. Since the cell cycle is one of the most commonly deregulated cellular processes in cancer, we propose that the mitotic kinases TTK (or Mps1), TBK1, and Nek2 could be novel targets to prevent breast cancer progression among NHBs and H/Ls. In this study, we calculated levels of TTK, p-TBK1, epithelial (E-cadherin), mesenchymal (Vimentin), and proliferation (Ki67) markers through immunohistochemical (IHC) staining of breast cancer tissue microarrays (TMAs) that includes samples from 6 regions in the Southeast of the United States and Puerto Rico -regions enriched with NHB and H/L breast cancer patients. IHC analysis showed that TTK, Ki67, and Vimentin were significantly expressed in triple-negative (TNBC) tumors relative to other subtypes, while E-cadherin showed decreased expression. TTK correlated with all of the clinical variables but p-TBK1 did not correlate with any of them. TCGA analysis revealed that the mRNA levels of multiple mitotic kinases, including TTK, Nek2, Plk1, Bub1, and Aurora kinases A and B, and transcription factors that are known to control the expression of these kinases (e.g. FoxM1 and E2F1-3) were upregulated in NHBs versus NHWs and correlated with higher aneuploidy indexes in NHB, suggesting that these mitotic kinases may be future novel targets for breast cancer treatment in NHB women.
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Mounting evidence suggests that chronic stress and subsequent distress can promote ovarian cancer progression. These altered psychological states have been linked to sustained release of stress hormones, activation of the ß-adrenergic receptors in ovarian cancer cells, and induction of pro-tumoral signaling pathways. In addition, data suggest that chronic stress promotes an inflammatory landscape highlighted by increased infiltration of tumor-associated macrophages into the ovarian tumor microenvironment (TME). In ovarian cancer, ascites is a unique TME comprised of tumor, and immune cells, which secrete pro-tumoral cytokines and chemokines that modulate tumor-associated immunity. However, our knowledge about how stress hormones impact the ascites TME remains limited. We hypothesized that the ascites harbors measurable levels of stress hormones, and accumulation of these in the ascites generates a pro-tumorigenic, inflammatory, and immunosuppressive TME. We evaluated ascites samples from 49 patients with high grade serous ovarian cancer (HGSOC) and quantified cortisol and stress hormones metabolites, metanephrine (MN), and normetanephrine (NMN) in all samples. We also measured 38 individual cytokines in the ascites, including several pro-inflammatory cytokines, such as IL-6, which were positively correlated to MN or NMN levels of those samples. Conversely, we found cortisol levels were negatively correlated to several pro-inflammatory cytokines. As T-cells are integral to the TME and our analyses identified cytokines in the ascites known to modulate T-cell function, we characterized ascites-derived T-cells and assessed the impact of stress hormones on the T-cell phenotype. Our data show an altered CD4+/CD8+ T-cell ratio and a heterogeneous expression of exhaustion markers in T-cells from the ascites, while ascites-derived CD8+ T-cells exposed to epinephrine had decreased co-expression CD38 and Granzyme B. To extend these findings to animal models, we subjected ovarian cancer-bearing mice to daily restraint stress, which resulted in increased tumor growth in two models. Congruent with our human analyses, we detected corticosterone, MN, and NMN in the ascites from tumor-bearing mice, and these stress hormones correlated with several inflammatory cytokines. Moreover, daily restraint stress leads to increased CD4+PD-1+/CD8+PD-1+ T-cell ratio in the ovarian tumor microenvironment. Overall, these data highlight a role of stress hormones in the ascites TME as a driver of tumor-associated inflammation, T-cell suppression, and disease progression.
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BACKGROUND: Merkel cell carcinoma is among the most aggressive and lethal of primary skin cancers, with a high rate of distant metastasis. Anti-programmed death receptor 1 (anti-PD-1) and programmed death ligand 1 (PD-L1) monotherapy is currently standard of care for unresectable, recurrent, or metastatic Merkel cell carcinoma. We assessed treatment with combined nivolumab plus ipilimumab, with or without stereotactic body radiotherapy (SBRT) in patients with advanced Merkel cell carcinoma as a first-line therapy or following previous treatment with anti-PD-1 and PD-L1 monotherapy. METHODS: In this randomised, open label, phase 2 trial, we randomly assigned adults from two cancer sites in the USA (one in Florida and one in Ohio) to group A (combined nivolumab and ipilimumab) or group B (combined nivolumab and ipilimumab plus SBRT) in a 1:1 ratio. Eligible patients were aged at least 18 years with histologically proven advanced stage (unresectable, recurrent, or stage IV) Merkel cell carcinoma, a minimum of two tumour lesions measureable by CT, MRI or clinical exam, and tumour tissue available for exploratory biomarker analysis. Patients were stratified by previous immune-checkpoint inhibitor (ICI) status to receive nivolumab 240 mg intravenously every 2 weeks plus ipilimumab 1 mg/kg intravenously every 6 weeks (group A) or the same schedule of combined nivolumab and ipilimumab with the addition of SBRT to at least one tumour site (24 Gy in three fractions at week 2; group B). Patients had to have at least two measurable sites of disease so one non-irradiated site could be followed for response. The primary endpoint was objective response rate (ORR) in all randomly assigned patients who received at least one dose of combined nivolumab and ipilimumab. ORR was defined as the proportion of patients with a complete response or partial response per immune-related Response Evaluation Criteria in Solid Tumours. Response was assessed every 12 weeks. Safety was assessed in all patients. This trial is registered with ClinicalTrials.gov, NCT03071406. FINDINGS: 50 patients (25 in both group A and group B) were enrolled between March 14, 2017, and Dec 21, 2021, including 24 ICI-naive patients (13 [52%] of 25 group A patients and 11 [44%] of 25 group B patients]) and 26 patients with previous ICI (12 [48%] of 25 group A patients and 14 [56%] of 25 group B patients]). One patient in group B did not receive SBRT due to concerns about excess toxicity. Median follow-up was 14·6 months (IQR 9·1-26·5). Two patients in group B were excluded from the analysis of the primary endpoint because the target lesions were irradiated and so the patients were deemed non-evaluable. Of the ICI-naive patients, 22 (100%) of 22 (95% CI 82-100) had an objective response, including nine (41% [95% CI 21-63]) with complete response. Of the patients who had previously had ICI exposure, eight (31%) of 26 patients (95% CI 15-52) had an objective response and four (15% [5-36]) had a complete response. No significant differences in ORR were observed between groups A (18 [72%] of 25 patients) and B (12 [52%] of 23 patients; p=0·26). Grade 3 or 4 treatment-related adverse events were observed in 10 (40%) of 25 patients in group A and 8 (32%) of 25 patients in group B. INTERPRETATION: First-line combined nivolumab and ipilimumab in patients with advanced Merkel cell carcinoma showed a high ORR with durable responses and an expected safety profile. Combined nivolumab and ipilimumab also showed clinical benefit in patients with previous anti-PD-1 and PD-L1 treatment. Addition of SBRT did not improve efficacy of combined nivolumab and ipilimumab. The combination of nivolumab and ipilimumab represents a new first-line and salvage therapeutic option for advanced Merkel cell carcinoma. FUNDING: Bristol Myers Squibb Rare Population Malignancy Program.
Assuntos
Carcinoma de Célula de Merkel , Radiocirurgia , Neoplasias Cutâneas , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Biomarcadores , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/radioterapia , Humanos , Inibidores de Checkpoint Imunológico , Ipilimumab , Nivolumabe , Receptores de Morte Celular , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/radioterapiaRESUMO
BACKGROUND: Given the growing interest in using microRNAs (miRNAs) as biomarkers of early disease, establishment of robust protocols and platforms for miRNA quantification in biological fluids is critical. OBJECTIVE: The goal of this multi-center pilot study was to evaluate the reproducibility of NanoString nCounter™ technology when analyzing the abundance of miRNAs in plasma and cystic fluid from patients with pancreatic lesions. METHODS: Using sample triplicates analyzed across three study sites, we assessed potential sources of variability (RNA isolation, sample processing/ligation, hybridization, and lot-to-lot variability) that may contribute to suboptimal reproducibility of miRNA abundance when using nCounter™, and evaluated expression of positive and negative controls, housekeeping genes, spike-in genes, and miRNAs. RESULTS: Positive controls showed a high correlation across samples from each site (median correlation coefficient, r> 0.9). Most negative control probes had expression levels below background. Housekeeping and spike-in genes each showed a similar distribution of expression and comparable pairwise correlation coefficients of replicate samples across sites. A total of 804 miRNAs showed a similar distribution of pairwise correlation coefficients between replicate samples (p= 0.93). After normalization and selecting miRNAs with expression levels above zero in 80% of samples, 55 miRNAs were identified; heatmap and principal component analysis revealed similar expression patterns and clustering in replicate samples. CONCLUSIONS: Findings from this pilot investigation suggest the nCounter platform can yield reproducible results across study sites. This study underscores the importance of implementing quality control procedures when designing multi-center evaluations of miRNA abundance.