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PURPOSE: Most patients with intrahepatic cholangiocarcinoma (IHCC) develop recurrence after resection. Adjuvant capecitabine remains the standard of care for resected IHCC. A combination of gemcitabine, cisplatin, and nab-paclitaxel (GAP) was associated with a 45% response rate and 20% conversion rate among patients with unresectable biliary tract cancers. The aim of this study was to evaluate the feasibility of delivering GAP in the neoadjuvant setting for resectable, high-risk IHCC. METHODS: A multi-institutional, single-arm, phase II trial was conducted for patients with resectable, high-risk IHCC, defined as tumor size > 5 cm, multiple tumors, presence of radiographic major vascular invasion, or lymph node involvement. Patients received preoperative GAP (gemcitabine 800 mg/m2, cisplatin 25 mg/m2, and nab-paclitaxel 100 mg/m2 on days 1 and 8 of a 21-day cycle) for a total of 4 cycles prior to an attempt at curative-intent surgical resection. The primary endpoint was completion of both preoperative chemotherapy and surgical resection. Secondary endpoints were adverse events, radiologic response, recurrence-free survival (RFS), and overall survival (OS). RESULTS: Thirty evaluable patients were enrolled. Median age was 60.5 years. Median follow-up for all patients was 17 months. Ten patients (33%) experienced grade ≥ 3 treatment-related adverse events, the most common being neutropenia and diarrhea; 50% required ≥ 1 dose reduction. The disease control rate was 90% (progressive disease: 10%, partial response: 23%, stable disease: 67%). There was zero treatment-related mortality. Twenty-two patients (73%, 90% CI 57-86; p = 0.008) completed all chemotherapy and surgery. Two patients (9%) who successfully underwent resection had minor postoperative complications. Median length of hospital stay was 4 days. Median RFS was 7.1 months. Median OS for the entire cohort was 24 months and was not reached in patients who underwent surgical resection. CONCLUSION: Neoadjuvant treatment with gemcitabine, cisplatin, and nab-paclitaxel is feasible and safe prior to resection of intrahepatic cholangiocarcinoma and does not adversely impact perioperative outcomes.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Neoplasias Pancreáticas , Humanos , Pessoa de Meia-Idade , Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/etiologia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/cirurgia , Cisplatino , Desoxicitidina , Estudos de Viabilidade , Gencitabina , Terapia Neoadjuvante , Paclitaxel , Neoplasias Pancreáticas/cirurgiaRESUMO
OBJECTIVES: The eighth edition American Joint Committee on Cancer (AJCC) Staging incorporates significant changes to the seventh edition in the staging of oropharyngeal squamous cell carcinomas (OPSCC). An important change was the inclusion of OPSCC associated with the human papilloma virus (HPV). Our goal is to compare the performance of both staging systems for patients with HPV-selected and unselected clinical characteristics for OPSCC. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, 2004-2016, we identified patients with likely HPV-associated OPSCC based on surrogate markers (white males aged <65 years old with squamous cell carcinomas of the tonsil and base of tongue), excluding those who underwent surgery. We re-classified these patients using seventh and eighth edition staging for HPV-selected OPSCC and compared the prediction performance of both staging editions for overall survival (OS) and disease-specific survival (DSS). We performed the same analysis for clinically unselected patients with OPSCC. RESULTS: Our analysis included 9554 patients with a median follow-up of 67 months. Comparing the eighth versus seventh edition for our HPV-selected cohort, clinical staging changed for 92.3% of patients and 10-year OS was 62.2%, 61.2%, 35.3%, and 15.5% for Stage I, II, III, and IV, versus 52.9%, 59.2%, 61.6%, 55.1%, 38.3%, and 15.5% for stage I, II, III, IVA, IVB, and IVC, respectively. A similar pattern was observed for 10-year DSS. The concordance statistics for our HPV-selected cohort were improved for both AJCC 7 (0.6260) and AJCC 8 (0.6846) compared with the unselected cohort, 0.5860 and 0.6457 for AJCC 7 and 8, respectively. CONCLUSION: The overall performance of discrimination improved from AJCC 7 to AJCC 8 for both clinically selected and unselected patients, but more notably for our HPV-selected cohort. Despite the lack of statistically significant differentiation between Stages I and II in AJCC 8 in either groups, markedly improved discrimination was observed between Stages I/II, III, and IV in the HPV-selected cohort.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Idoso , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/patologia , Papillomaviridae , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
BACKGROUND: Although many patients with follicular lymphoma (FL) undergo routine radiographic surveillance during their first remission, no consensus exists on the modality, duration, frequency, or need for routine imaging studies. The authors retrospectively examined the effect of surveillance imaging on relapse detection and overall survival (OS) in patients with FL. METHODS: Patients with newly diagnosed FL who had a response to induction therapy were identified from the Lymphoid Malignancies Enterprise Architecture Database (LEAD) at Emory University and from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic. Patients were evaluated for both relapse and method of relapse detection (ie, clinical concerns vs radiologic detection through surveillance imaging in an asymptomatic patient). RESULTS: Of 148 patients in the LEAD cohort, 55 (37%) relapsed, and the majority (n = 35; 64%) of relapses were detected clinically. In the MER cohort, 63 of 177 relapses (54%) were detected clinically. There was no significant difference in OS from the date of diagnosis between the 2 methods of relapse detection in the LEAD (hazard ratio [HR], 0.61; 95% CI, 0.13-2.94; P = .54) and MER (HR, 1.02; 95% CI, 0.47-2.21; P = .96) cohorts. Similarly, there was no significant difference in OS from the date of relapse between the 2 methods of relapse detection in the LEAD (HR, 0.47; 95% CI, 0.10-2.27; P = .35) and MER (HR, 1.02; 95% CI, 0.47-2.21; P = .96) cohorts. CONCLUSIONS: These findings suggest a limited role for routine surveillance imaging in patients with FL who complete front-line therapy. Future studies should evaluate which patients may benefit from a more aggressive surveillance approach and should explore novel methods of relapse detection.
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Linfoma Folicular , Diagnóstico por Imagem , Humanos , Linfoma Folicular/diagnóstico por imagem , Linfoma Folicular/tratamento farmacológico , Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Indução de Remissão , Estudos RetrospectivosRESUMO
Collective invasion, the coordinated movement of cohesive packs of cells, has become recognized as a major mode of metastasis for solid tumors. These packs are phenotypically heterogeneous and include specialized cells that lead the invasive pack and others that follow behind. To better understand how these unique cell types cooperate to facilitate collective invasion, we analyzed transcriptomic sequence variation between leader and follower populations isolated from the H1299 non-small cell lung cancer cell line using an image-guided selection technique. We now identify 14 expressed mutations that are selectively enriched in leader or follower cells, suggesting a novel link between genomic and phenotypic heterogeneity within a collectively invading tumor cell population. Functional characterization of two phenotype-specific candidate mutations showed that ARP3 enhances collective invasion by promoting the leader cell phenotype and that wild-type KDM5B suppresses chain-like cooperative behavior. These results demonstrate an important role for distinct genetic variants in establishing leader and follower phenotypes and highlight the necessity of maintaining a capacity for phenotypic plasticity during collective cancer invasion.
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Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Invasividade Neoplásica/genética , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Heterogeneidade Genética , Genômica , Humanos , Neoplasias Pulmonares/patologia , Microscopia , Invasividade Neoplásica/patologia , RNA-SeqRESUMO
BACKGROUND: Surgery alone is standard-of-care for stage I gastric adenocarcinoma; however, clinicians can offer preoperative therapy for clinical stage I disease with signet ring cell histology, given its presumed aggressive biology. We aimed to assess the validity of this practice. METHODS: The National Cancer Database (2004-2015) was reviewed for patients with clinical stage I signet ring cell gastric adenocarcinoma who underwent treatment with surgery alone, perioperative chemotherapy, neoadjuvant therapy, or adjuvant therapy. Analysis was stratified by preoperative clinical/pathologic stage. Primary outcome was overall survival (OS). RESULTS: Of 1018 patients, median age was 60 years (±14); 53% received surgery alone (n = 542), 5% received perioperative chemotherapy (n = 47), 12% received neoadjuvant therapy (n = 125), and 30% received adjuvant therapy (n = 304). For clinical stage I disease, surgery alone was associated with an improved 5-year OS rate (71%) versus perioperative chemotherapy (58%), neoadjuvant therapy (38%), or adjuvant therapy (52%) [overall p < 0.01]. For pathologic stage I, surgery alone had equivalent or improved survival compared with perioperative, neoadjuvant, and adjuvant therapy (5-year OS: 78% vs. 89% [p = 0.77] vs. 64% [p = 0.04] vs. 84% [p = 0.99]). Adjuvant therapy was associated with improved 5-year OS compared with pretreatment for those patients upstaged (37%) to pathologic stage II/III (55% vs. 36% and 34% vs. 7%; all p < 0.01). CONCLUSIONS: This stage-specific study demonstrates improved survival with surgery alone for clinical stage I signet ring cell gastric adenocarcinoma. Despite 37% of clinical stage I patients being upstaged to pathologic stage II/III, adjuvant therapy offers a favorable rescue strategy, with improved outcomes compared with those treated preoperatively. Surgery alone also affords similar or improved survival for pathologic stage I disease versus multimodality therapy. This study challenges the bias to overtreat stage I signet ring cell gastric adenocarcinoma.
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Carcinoma de Células em Anel de Sinete , Neoplasias Gástricas , Carcinoma de Células em Anel de Sinete/patologia , Carcinoma de Células em Anel de Sinete/terapia , Quimioterapia Adjuvante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapiaRESUMO
BACKGROUND: Intratumoral heterogeneity is defined by subpopulations with varying genotypes and phenotypes. Specialized, highly invasive leader cells and less invasive follower cells are phenotypically distinct subpopulations that cooperate during collective cancer invasion. Because leader cells are a rare subpopulation that would be missed by bulk sequencing, a novel image-guided genomics platform was used to precisely select this subpopulation. This study identified a novel leader cell mutation signature and tested its ability to predict prognosis in non-small cell lung cancer (NSCLC) patient cohorts. METHODS: Spatiotemporal genomic and cellular analysis was used to isolate and perform RNA sequencing on leader and follower populations from the H1299 NSCLC cell line, and it revealed a leader-specific mutation cluster on chromosome 16q. Genomic data from patients with lung squamous cell carcinoma (LUSC; n = 475) and lung adenocarcinoma (LUAD; n = 501) from The Cancer Genome Atlas were stratified by 16q mutation cluster (16qMC) status (16qMC+ vs 16qMC-) and compared for overall survival (OS), progression-free survival (PFS), and gene set enrichment analysis (GSEA). RESULTS: Poorer OS, poorer PFS, or both were found across all stages and among early-stage patients with 16qMC+ tumors within the LUSC and LUAD cohorts. GSEA revealed 16qMC+ tumors to be enriched for the expression of metastasis- and survival-associated gene sets. CONCLUSIONS: This represents the first leader cell mutation signature identified in patients and has the potential to better stratify high-risk NSCLC and ultimately improve patient outcomes.
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Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem da Célula/genética , Proteínas de Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Cromossomos Humanos Par 16/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Família Multigênica/genética , Mutação/genética , Invasividade Neoplásica/genética , Intervalo Livre de Progressão , Análise de Sequência de RNARESUMO
BACKGROUND: Esophageal adenocarcinoma (AC) and squamous cell carcinoma (SCC) have distinct outcomes, treatment strategies, and response profiles to therapy. Adenosquamous carcinoma (ASC) is thought to behave more aggressively than each of its counterparts. The aim of this study is to determine ifASC is best managed as AC or SCC. METHODS: National Cancer Database (2004-2015) was queried for patients with nonmetastatic esophageal ASC. The analysis was stratified by clinical node-negative (cN0) or clinical node-positive (cN1-3). Treatment was categorized into chemoradiation alone, surgery alone, or preoperative chemoradiation followed by surgery. The primary outcome was 5-year overall survival (OS). RESULTS: Among 352 patients, 43% were cN0 (n = 151), 57% were cN1-3 (n = 201) and 55% had chemoradiation alone (n = 194), 15% surgery alone (n = 53), and 30% preoperative chemoradiation (n = 105). Among patients who had preoperative chemoradiation, 20% had pathologic complete response (n = 17). For either cN0 or cN1-3, Charlson-Deyo Comorbidity Index did not differ among the treatment groups(all p > 0.05). On Kaplan-Meier analysis for cN0, treatment with surgery alone had comparable OS to preoperative chemoradiation (47% vs 34%; P = .5) and each had improved OS compared to chemoradiation alone (30%; P = .02; P = .06). On univariate analysis for cN0, clinical T category was not associated with OS. For cN1-3, however, preoperative chemoradiation was associated with improved OS when compared to chemoradiation alone or surgery alone (27% vs 19% vs 0%; P < .001). This persisted when accounting for age and clinical T category (hazard ratio: 0.45; P < .001). CONCLUSION: Esophageal ASC behaves more like AC in response to chemoradiation and survival based on treatment modality. A complete response to chemoradiation is only 20% unlike what has been shown for SCC, where chemoradiation is an acceptable definitive therapy. Esophageal ASC should be managed more like AC.
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Adenocarcinoma/terapia , Carcinoma Adenoescamoso/terapia , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Carcinoma Adenoescamoso/mortalidade , Carcinoma Adenoescamoso/patologia , Quimiorradioterapia/estatística & dados numéricos , Terapia Combinada , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cuidados Pré-Operatórios , Sistema de Registros , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: For pancreatic adenocarcinoma (PDAC), no studies have established any association between earlier treatment initiation and long-term outcomes. In addition, an optimal type of initial treatment for the localized disease remains ill-defined. METHODS: Patients in the National Cancer Database (2004-2015) with clinical stage I (CS-I) and II (CS-II) PDAC who underwent curative-intent resection were included. Optimal time from diagnosis-to-treatment including neoadjuvant chemotherapy, neoadjuvant chemoradiation, or upfront surgery was assessed. An optimal type of treatment was evaluated. The primary outcome was overall survival (OS). RESULTS: Among 29 167 patients, starting any treatment within 0 to 6 weeks was associated with improved median OS compared with 7 to 12 weeks (21.0 vs 20.1 months; P = .004). This persisted when accounting for sex, race, and Charlson-Deyo score (hazard ratio [HR], 0.94; P = 0.02) and on subset analysis for CS-I (23.5 vs 21.8 months; P = .04) and CS-II (19.4 vs 18.3 months; P = .03). Neoadjuvant chemotherapy was associated with improved OS compared with neoadjuvant chemoradiation (25.6 vs 22.7 months; P < .0001) or US (25.6 vs 20.1 months; P < .0001) even when accounting for sex, race, and Charlson-Deyo score (neoadjuvant chemoradiation: HR, 0.86; P < .001; US: HR, 0.79; P < .001). This improvement persisted in subset analysis with NC compared with neoadjuvant chemoradiation (CS-I: 28.6 vs 25.0 months; CS-II: 25.0 vs 22.9 months; both P < .0001) and to US (CS-I: 28.6 vs 22.9 months; CS-II: 24.7 vs 18.4 months; both P < .0001). On multivariable analysis for each CS-I/CS-II, NC remained associated with 20% improved survival compared with neoadjuvant chemoradiation or upfront surgery. CONCLUSIONS: For PDAC, initiation of therapy within 6 weeks from diagnosis is associated with improved survival, with neoadjuvant chemotherapy associated with the best survival compared with neoadjuvant chemoradiation or upfront surgery.
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Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/terapia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Idoso , Carcinoma Ductal Pancreático/patologia , Quimiorradioterapia Adjuvante/estatística & dados numéricos , Quimioterapia Adjuvante/estatística & dados numéricos , Feminino , Humanos , Masculino , Terapia Neoadjuvante/estatística & dados numéricos , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Sistema de Registros , Procedimentos Cirúrgicos Operatórios/estatística & dados numéricos , Fatores de Tempo , Estados Unidos/epidemiologiaRESUMO
A higher number of donor plasmacytoid dendritic cells (pDCs) is associated with increased survival and reduced graft-versus-host disease (GVHD) in human recipients of unrelated donor bone marrow (BM) grafts, but not granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood grafts. We show that in murine models, donor BM pDCs are associated with increased survival and decreased GVHD compared with G-CSF-mobilized pDCs. To increase the content of pDCs in BM grafts, we studied the effect of FMS-like tyrosine kinase 3 ligand (Flt3L) treatment of murine BM donors on transplantation outcomes. Flt3L treatment (300 µg/kg/day) resulted in a schedule-dependent increase in the content of pDCs in the BM. Mice treated on days -4 and -1 had a >5-fold increase in pDC content without significant changes in numbers of HSCs, T cells, B cells, and natural killer cells in the BM graft. In an MHC-mismatched murine transplant model, recipients of Flt3L-treated T cell-depleted (TCD) BM (TCD F-BM) and cytokine-untreated T cells had increased survival and decreased GVHD scores with fewer Th1 and Th17 polarized T cells post-transplantation compared with recipients of equivalent numbers of untreated donor TCD BM and T cells. Gene array analyses of pDCs from Flt3L-treated human and murine donors showed up-regulation of adaptive immune pathways and immunoregulatory checkpoints compared with pDCs from untreated BM donors. Transplantation of TCD F-BM plus T cells resulted in no loss of the graft-versus-leukemia (GVL) effect compared with grafts from untreated donors in 2 murine GVL models. Thus, Flt3L treatment of BM donors is a novel method for increasing the pDC content in allografts, improving survival, and decreasing GVHD without diminishing the GVL effect.
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Adjuvantes Imunológicos/uso terapêutico , Transplante de Medula Óssea/métodos , Células Dendríticas/imunologia , Proteínas de Membrana/uso terapêutico , Transplante Homólogo/métodos , Adjuvantes Imunológicos/farmacologia , Animais , Humanos , Masculino , Proteínas de Membrana/farmacologia , Camundongos , Doadores de TecidosRESUMO
PURPOSE: Gliosarcoma is a histologic variant of glioblastoma (GBM), and like GBM carries a poor prognosis. Median survival is less than one (1) year with less than 5% of patients alive after 5 years. Although there is no cure, standard treatment includes surgery, radiation and chemotherapy. While very similar to GBM, gliosarcoma exhibits several distinct differences, morphologically and molecularly. Therefore, we report a comprehensive analysis of DNA copy number changes in gliosarcoma using a cytogenomic DNA copy number (CN) microarray (OncoScan®). METHODS: Cytogenomic DNA copy number microarray (OncoScan®) was performed on 18 cases of gliosarcoma. MetaCore™ enrichment was applied to the array results to detect associated molecular pathways. RESULTS: The most frequent alteration was copy number loss, comprising 57% of total copy number changes. The number of losses far exceeded the number of amplifications (***, < 0.001) and loss of heterozygosity events (***, < 0.001). Amplifications were infrequent (4.6%), particularly for EGFR. Chromosomes 9 and 10 had the highest number of losses; a large portion of which correlated to CDKN2A/B loss. Copy number gains were the second most common alteration (26.2%), with the majority occurring on chromosome 7. MetaCore™ enrichment detected notable pathways for copy number gains including: HOXA, Rho family of GTPases, and EGFR; copy number loss including: WNT, NF-kß, and CDKN2A; and copy number loss of heterozygosity including: WNT and p53. CONCLUSIONS: The pathways and copy number alterations detected in this study may represent key drivers in gliosarcoma oncogenesis and may provide a starting point toward targeted oncologic analysis with therapeutic potential.
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Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA , Genômica/métodos , Gliossarcoma/genética , Recidiva Local de Neoplasia/genética , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , Adulto , Idoso , Feminino , Seguimentos , Gliossarcoma/patologia , Gliossarcoma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
PURPOSE: Pediatric brain cancer medulloblastoma (MB) standard-of-care results in numerous comorbidities. MB is comprised of distinct molecular subgroups. Group 3 molecular subgroup patients have the highest relapse rates and after standard-of-care have a 20% survival. Group 3 tumors have high expression of GABRA5, which codes for the α5 subunit of the γ-aminobutyric acid type A receptor (GABAAR). We are advancing a therapeutic approach for group 3 based on GABAAR modulation using benzodiazepine-derivatives. METHODS: We performed analysis of GABR and MYC expression in MB tumors and used molecular, cell biological, and whole-cell electrophysiology approaches to establish presence of a functional 'druggable' GABAAR in group 3 cells. RESULTS: Analysis of expression of 763 MB tumors reveals that group 3 tumors share high subgroup-specific and correlative expression of GABR genes, which code for GABAAR subunits α5, ß3 and γ2 and 3. There are ~ 1000 functional α5-GABAARs per group 3 patient-derived cell that mediate a basal chloride-anion efflux of 2 × 109 ions/s. Benzodiazepines, designed to prefer α5-GABAAR, impair group 3 cell viability by enhancing chloride-anion efflux with subtle changes in their structure having significant impact on potency. A potent, non-toxic benzodiazepine ('KRM-II-08') binds to the α5-GABAAR (0.8 µM EC50) enhancing a chloride-anion efflux that induces mitochondrial membrane depolarization and in response, TP53 upregulation and p53, constitutively phosphorylated at S392, cytoplasmic localization. This correlates with pro-apoptotic Bcl-2-associated death promoter protein localization. CONCLUSION: GABRA5 expression can serve as a diagnostic biomarker for group 3 tumors, while α5-GABAAR is a therapeutic target for benzodiazepine binding, enhancing an ion imbalance that induces apoptosis.
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Benzodiazepinas/farmacologia , Neoplasias Cerebelares/patologia , Meduloblastoma/patologia , Receptores de GABA-A/química , Regulação Alostérica , Morte Celular/efeitos dos fármacos , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/metabolismo , Perfilação da Expressão Gênica , Humanos , Meduloblastoma/tratamento farmacológico , Meduloblastoma/metabolismo , Receptores de GABA-A/metabolismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoAssuntos
Colangiocarcinoma , Neoplasias Pancreáticas , Humanos , Gencitabina , Cisplatino/uso terapêutico , Terapia Neoadjuvante , Estudos de Viabilidade , Albuminas , Paclitaxel , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Current surgical assessment tools are subjective and nonscalable. Objective performance indicators, calculated from robotic systems data, provide automated data regarding surgeon movements and robotic arm kinematics. We identified objective performance indicators that significantly differed among expert and trainee surgeons during specific steps of robotic right colectomy. METHODS: Endoscopic videos were annotated to delineate surgical steps during robotic right colectomies. Objective performance indicators were compared during mesenteric dissection, ascending colon mobilization, hepatic flexure mobilization, and bowel preparation for transection. RESULTS: Twenty-five robotic right colectomy procedures (461 total surgical steps) performed by 2 experts and 8 trainees were analyzed. Experts exhibited faster camera acceleration and jerk during all steps, as well as faster dominant and nondominant arm acceleration and dominant arm jerk during all steps except distal bowel preparation. During mesenteric dissection, experts used faster camera and dominant arm velocity. During medial-to-lateral ascending colon mobilization, experts used less-dominant wrist yaw and pitch, faster nondominant arm velocity, shorter dominant arm path length, and shorter moving times for camera, dominant arm, and nondominant arm. During lateral-to-medial ascending colon mobilization, experts had faster dominant and nondominant arm velocity and third-arm acceleration. During hepatic flexure mobilization, experts exhibited more camera movements, greater velocity for camera, dominant and nondominant arms, and faster third-arm acceleration. During distal bowel preparation, experts used greater dominant wrist articulation, faster camera velocity, and longer nondominant arm path length. During proximal bowel preparation, experts demonstrated faster nondominant arm velocity. CONCLUSION: Objective performance indicators can differentiate experts from trainees during distinct steps of robotic right colectomy. These automated, objective and scalable metrics can provide personalized feedback for trainees.
RESUMO
BACKGROUND: Surgical workflow assessments offer insight regarding procedure variability. We utilised an objective method to evaluate workflow during robotic proctectomy (RP). METHODS: We annotated 31 RPs and used Spearman's correlation to measure the correlation of step time and step visit frequency with console time (CT) and total operative time (TOT). RESULTS: Strong correlations were seen with CT and step times for inferior mesenteric vein dissection and ligation (ρ = 0.60, ρ = 0.60), lateral-to-medial splenic flexure mobilisation (SFM) (ρ = 0.63), left rectal dissection (ρ = 0.64) and mesorectal division (ρ = 0.71). CT correlated strongly with medial-to-lateral (ρ = 0.75) and supracolic SFM visit frequency (ρ = 0.65). TOT correlated strongly with initial exposure time (ρ = 0.60), and medial-to-lateral (ρ = 0.67) and supracolic SFM visit frequency (ρ = 0.65). CONCLUSION: This study correlates surgical steps with CT and TOT through standardised annotation, providing an objective approach to quantify workflow.
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Protectomia , Procedimentos Cirúrgicos Robóticos , Humanos , Fluxo de Trabalho , Dissecação , Duração da CirurgiaRESUMO
OBJECTIVES: Progression of PCNSL remains a challenge with salvage therapies, including the risk of substantial morbidity and mortality. We report patterns of first tumor progression to inform opportunities for improvement. METHODS: This is an institutional retrospective review from 2002 to 2021 of 95 consecutive patients with pathologically confirmed PCNSL, of whom 29 experienced progressive disease. Kaplan-Meier method, log-rank test, and Cox proportional hazard models are used to characterize associations of patient, tumor, and treatment variables with LC, PFS, and patterns of first failure. RESULTS: Most patients were below 65 years old (62%) with KPS >70 (64%) and negative CSF cytology (70%). In 70 patients with MRIs, the median tumor volume was 12.6 mL (range: 0.5 to 67.8 mL). After a median follow-up of 11 months, 1-year PFS was 48% and 1-year LC was 80%. Of the 29 patients with progression, 24% were distant only, 17% were distant and local, and 59% were local only. On MVA, LC was associated with age (HR: 1.08/y, P =0.02), KPS (HR: 0.10, P =0.02), completion of >6 cycles of HD-MTX (HR: 0.10, P <0.01), and use of intrathecal chemotherapy (HR: 0.03, P <0.01). On UVA, local only first failure trended to be increased with >14 mL tumors (OR: 5.06, P =0.08) with 1-year LC 83% (<14 mL) versus 64% (>14mL). There were no significant associations with LC and WBRT ( P =0.37), Rituximab ( P =0.12), or attempted gross total resection ( P =0.72). CONCLUSIONS: Our findings reaffirm the importance of systemic and intrathecal therapies for local control in PCNSL. However, bulky tumors trend to fail locally, warranting further investigation about the role of local therapies or systemic therapy intensification.
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Neoplasias do Sistema Nervoso Central , Falha de Tratamento , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Neoplasias do Sistema Nervoso Central/terapia , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/mortalidade , Adulto , Progressão da Doença , Idoso de 80 Anos ou mais , Terapia de SalvaçãoRESUMO
Importance: Intensity-modulated radiation therapy (IMRT) reirradiation of nonmetastatic recurrent or second primary head and neck squamous cell carcinoma (HNSCC) results in poor progression-free survival (PFS) and overall survival (OS). Objective: To investigate the tolerability, PFS, OS, and patient-reported outcomes with nivolumab (approved standard of care for patients with HNSCC) during and after IMRT reirradiation. Design, Setting, and Participants: In this multicenter nonrandomized phase 2 single-arm trial, the treatment outcomes of patients with recurrent or second primary HNSCC who satisfied recursive partitioning analysis class 1 and 2 definitions were evaluated. Between July 11, 2018, and August 12, 2021, 62 patients were consented and screened. Data were evaluated between June and December 2023. Intervention: Sixty- to 66-Gy IMRT in 30 to 33 daily fractions over 6 to 6.5 weeks with nivolumab, 240 mg, intravenously 2 weeks prior and every 2 weeks for 5 cycles during IMRT, then nivolumab, 480 mg, intravenously every 4 weeks for a total nivolumab duration of 52 weeks. Main Outcomes and Measures: The primary end point was PFS. Secondary end points included OS, incidence, and types of toxic effects, including long-term treatment-related toxic effects, patient-reported outcomes, and correlatives of tissue and blood biomarkers. Results: A total of 62 patients were screened, and 51 were evaluable (median [range] age was 62 [56-67] years; 42 [82%] were male; 6 [12%] had p16+ disease; 38 [75%] had salvage surgery; and 36 [71%.] had neck dissection). With a median follow-up of 24.5 months (95% CI, 19.0-25.0), the estimated 1-year PFS was 61.7% (95% CI, 49.2%-77.4%), rejecting the null hypothesis of 1-year PFS rate of less than 43.8% with 1-arm log-rank test P = .002 within a 1-year timeframe. The most common treatment-related grade 3 or higher adverse event (6 [12%]) was lymphopenia with 2 patients (4%) and 1 patient each (2%) exhibiting colitis, diarrhea, myositis, nausea, mucositis, and myasthenia gravis. Functional Assessment of Cancer Therapy-General and Functional Assessment of Cancer Therapy-Head and Neck Questionnaire quality of life scores remained stable and consistent across all time points. A hypothesis-generating trend favoring worsening PFS and OS in patients with an increase in blood PD1+, KI67+, and CD4+ T cells was observed. Conclusions and Relevance: This multicenter nonrandomized phase 2 trial of IMRT reirradiation therapy and nivolumab suggested a promising improvement in PFS over historical controls. The treatment was well tolerated and deserves further evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT03521570.
Assuntos
Neoplasias de Cabeça e Pescoço , Recidiva Local de Neoplasia , Nivolumabe , Radioterapia de Intensidade Modulada , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Nivolumabe/uso terapêutico , Nivolumabe/efeitos adversos , Masculino , Feminino , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Radioterapia de Intensidade Modulada/métodos , Radioterapia de Intensidade Modulada/efeitos adversos , Pessoa de Meia-Idade , Idoso , Recidiva Local de Neoplasia/radioterapia , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Cabeça e Pescoço/mortalidade , Reirradiação/métodos , Reirradiação/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Segunda Neoplasia Primária , Intervalo Livre de Progressão , AdultoRESUMO
Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.
Assuntos
Hidrazinas , Neoplasias Renais , Triazóis , Tumor de Wilms , Humanos , Proteína Exportina 1 , Transporte Ativo do Núcleo Celular , Carioferinas/genética , Carioferinas/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Linhagem Celular Tumoral , Apoptose , Recidiva Local de Neoplasia , Doxorrubicina/farmacologia , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Proteínas de Ciclo Celular/metabolismoRESUMO
INTRODUCTION: Tobacco cessation is a critical but challenging intervention for cancer patients. Our National Cancer Institute-designated Comprehensive Cancer Center instituted a tobacco cessation program in 2019. This manuscript reports on the first 2 years of our experience. METHODS: Patients were referred to the program by their care team, and a certified tobacco treatment specialist contacted patients remotely and provided behavioral therapy and coordinated pharmacotherapy. We retrospectively captured data from patients with a cancer diagnosis referred to the tobacco cessation program. Univariate and multivariable logistic regression analyses with the backward elimination approach were performed to determine factors associated with patient acceptance of referral to the tobacco cessation program. Tobacco cessation rates after referral to the program were also captured. RESULTS: Between July 2019 and August 2021, 194 patients were referred to the tobacco cessation program. Of the 194 patients referred, 93 agreed to enroll in the tobacco cessation program (47.9%), of which 84 requested pharmacotherapy (90.3%). Twenty-four were able to cease tobacco use (25.8%). Only 7 patients out of the 101 patients (6.9%) who declined cessation services were successful (p < 0.001). On univariate logistic regression, race (p = 0.027) and marital status (p = 0.020) were associated with referral acceptance. On multivariable analysis, single patients (odds ratio [OR] = 0.33) and Caucasian patients (OR = 0.43) were less likely to accept a referral. CONCLUSIONS: Access to tobacco cessation services is a critical component of comprehensive cancer care. Our experience highlights the need to understand patient-specific factors associated with engagement with a tobacco cessation program during cancer treatment. The use of pharmacotherapy is also a critical component of successful tobacco cessation.
Assuntos
Neoplasias , Abandono do Hábito de Fumar , Abandono do Uso de Tabaco , Estados Unidos/epidemiologia , Humanos , National Cancer Institute (U.S.) , Estudos Retrospectivos , Razão de Chances , Neoplasias/epidemiologia , Neoplasias/terapiaRESUMO
Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening malignancy that arises in the setting of immunosuppression (IS) after solid organ transplant. IS regimens containing belatacept have been associated with an increased risk of PTLD in Epstein-Barr virus (EBV)-seronegative renal transplant recipients, and the use of belatacept is contraindicated in this population. However, the impact of belatacept-based regimens on PTLD risk and outcomes in EBV-seropositive renal transplant recipients is less well characterized. Methods: A case-control study was conducted to investigate how combinatorial IS regimens impact the risk of PTLD and survival outcomes in renal transplant recipients at a large transplant center between 2010 and 2019. In total, 17 cases of PTLD were identified and matched 1:2 to controls without PTLD by age, sex, and transplanted organ(s). We compared baseline clinical characteristics, examined changes in IS regimen, viral loads, and renal function over time, and evaluated time-to-event analyses, including graft rejection and survival. Results: Cases of PTLD largely resembled matched controls in terms of baseline characteristics, although expected differences in EBV serostatus trended toward significance (42.9% of PTLD cases were donor-positive/recipient-negative vs. 8.3% controls, p = 0.063). PTLD cases were not more likely to have received belatacept than controls. Belatacept was not associated with graft rejection or failure, re-transplant, hospitalization, or decreased survival. Conclusions: Belatacept was not associated with an increased risk of PTLD, and was not associated with decreased survival in either PTLD cases or in the entire cohort. Our case-control study supports the concept that belatacept remains a safe and effective option for IS in EBV-seropositive renal transplant patients.
RESUMO
BACKGROUND: Black women are 40% more likely to die of breast cancer compared to White women. Inadequate representation of Black patients in clinical trials may contribute to health care inequity. We aimed to assess breast cancer clinical outcomes in Non-Hispanic Black (Black) versus Non-Hispanic White (White) women with metastatic breast cancer (MBC) enrolled on investigator-initiated clinical trials at Winship Cancer Institute at Emory University, given the significant number of patients from underrepresented minority groups seen at Winship. MATERIALS AND METHODS: Black and White women with MBC on investigator-initiated trials at Emory between 2009 and 2019 were retrospectively evaluated. Univariate analyses and multiple logistic regression models were used to assess clinical response and treatment toxicities. Differences in overall survival between groups was assessed using quantile analysis. RESULTS: Sixty-two women with MBC were included (66% White vs. 34% Black). Black patients had less clinical benefit from the trial therapy as only 57% had partial response or stable disease as best response compared to 78% of White women (P = .09). Quantile analysis showed significant difference in mean survival between Whites and Blacks by the end of follow up (64 vs. 38 months). There were no significant differences in toxicities between groups. CONCLUSION: Participation rates of Black women with MBC on investigator-initiated clinical trials at an urban cancer center were higher compared to key national trials. Black women had worse treatment response and survival. These results reinforce the need for assessment of tumor differences by ancestry and continued improvement in minority representation on clinical trials.