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1.
Cancer Med ; 10(20): 7233-7241, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34559451

RESUMO

INTRODUCTION: Preoperative autophagy inhibition with hydroxychloroquine (HCQ) in combination with gemcitabine in pancreatic adenocarcinoma (PDAC) has been shown to be safe and effective in inducing a serum biomarker response and increase resection rates in a previous phase I/II clinical trial. We aimed to analyze the long-term outcomes of preoperative HCQ with gemcitabine for this cohort. METHODS: A review of patients enrolled between July 2010 and February 2013 in the completed phase I/II single arm (two doses of fixed-dose gemcitabine (1500 mg/m2 ) in combination with oral hydroxychloroquine administered for 31 consecutive days until the day of surgery for high-risk pancreatic cancer) was undertaken. Progression-free survival (PFS) and overall survival analysis (OS) using Kaplan-Meier estimates were performed. RESULTS: Of 35 patients initially enrolled, 29 patients underwent surgical resection (median age at diagnosis: 62 years, 45% females). Median duration of follow-up was 7.5 years. There was a median 15% decrease in the serum CA19-9 levels following completion of neoadjuvant therapy and 83% of the cohort underwent a pancreaticoduodenectomy, 7 (24%) patients had a concomitant venous resection. On histopathology, 14 (48%) patients had at least a partial treatment response. The median PFS and OS were 11 months (95% Confidence interval [CI]: 7-28) and 31 months (95% CI: 13-47), respectively, while 9 (31%) patients survived beyond 5 years from diagnosis; a rate that compares very favorably with contemporaneous series. CONCLUSION: Compared to historical data, neoadjuvant autophagy inhibition with HCQ plus gemcitabine is associated with encouraging long-term survival for patients with PDAC.

2.
J Surg Oncol ; 124(5): 801-809, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34231222

RESUMO

INTRODUCTION: Neoadjuvant therapy (NAT) is an emerging strategy for operable pancreatic ductal adenocarcinoma (PDAC). While NAT increases multimodal therapy completion, it risks functional decline and treatment dropout. We used decision analysis to determine optimal management of localized PDAC and consider risks faced by elderly patients. METHODS: A Markov cohort decision analysis model evaluated treatment options for a 60-year-old patient with resectable PDAC: (1) upfront pancreaticoduodenectomy or (2) NAT. One-way and probabilistic sensitivity analyses were performed. A subanalysis considered the scenario of a 75-year-old patient. RESULTS: For the base case, NAT offered an incremental survival gain of 4.6 months compared with SF (overall survival: 26.3 vs. 21.7 months). In one-way sensitivity analyses, findings were sensitive to recurrence-free survival for NAT patients undergoing adjuvant, probability of completing NAT, and probability of being resectable at exploration after NAT. On probabilistic analysis, NAT was favored in a majority of trials (97%) with a median survival benefit of 5.1 months. In altering the base case for the 75-year-old scenario, NAT had a survival benefit of 3.8 months. CONCLUSIONS: This analysis demonstrates a significant benefit to NAT in patients with localized PDAC. This benefit persists even in the elderly cohort.


Assuntos
Adenocarcinoma/terapia , Carcinoma Ductal Pancreático/terapia , Técnicas de Apoio para a Decisão , Cadeias de Markov , Terapia Neoadjuvante/mortalidade , Pancreatectomia/mortalidade , Neoplasias Pancreáticas/terapia , Adenocarcinoma/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/patologia , Terapia Combinada , Seguimentos , Humanos , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
3.
Ann Surg Oncol ; 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34224045

RESUMO

INTRODUCTION: Early recurrence (ER) is a significant challenge for patients with colorectal peritoneal metastases (CRPM) following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS HIPEC). Preoperative risk stratification for ER would improve preoperative decision making. METHODS: We conducted a retrospective study examining patients who underwent CRS HIPEC for CRPM from 2000 to 2018. Optimal definition of ER was determined via minimum p-value approach based on differentiation of post-recurrence survival. Risk factors for ER were assessed in a derivation cohort by uni- and multivariate logistic regression. A predictive score for ER was generated using preoperative variables and validated in an independent cohort. RESULTS: 384 patients were analyzed, 316 (82%) had documented recurrence. Optimal length of post-operative RFS to distinguish ER (n = 144, 46%) vs. late recurrence (LR) (n = 172, 63%) was 8 mos (p<0.01). ER patients had shorter median OS post-CRS-HIPEC (13.6 vs. 39.4 mos, p<0.01). Preoperative BMI (OR 1.88), liver lesions (OR 1.89), progression on chemotherapy (OR 2.14), positive lymph nodes (OR 2.47) and PCI score (16-20: OR 1.7; >20: OR 4.37) were significant predictors of ER (all p<0.05). Using this model, patients were assigned risk scores from 0 to 9. Intermediate (scores 4-6) and high-risk patients (score 7-9) had observed rates of ER of 56% and 79% and overall 2-year survival rates of 27% and 0% respectively. The model showed fair discrimination (AUC 0.72) and good calibration (Hosmer-Lemeshow GOF p = 0.68). CONCLUSIONS: ER predicts markedly worse OS following surgery. Preoperative factors can accurately stratify risk for ER and identify patients in whom CRS-HIPEC for CPRM is futile.

4.
Theranostics ; 11(14): 6668-6681, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093846

RESUMO

Background: Newly emerging cancer immunotherapy has led to significant progress in cancer treatment; however, its efficacy is limited in solid tumors since the majority of them are "cold" tumors. Oncolytic viruses, especially when properly armed, can directly target tumor cells and indirectly modulate the tumor microenvironment (TME), resulting in "hot" tumors. These viruses can be applied as a cancer immunotherapy approach either alone or in combination with other cancer immunotherapies. Cytokines are good candidates to arm oncolytic viruses. IL-23, an IL-12 cytokine family member, plays many roles in cancer immunity. Here, we used oncolytic vaccinia viruses to deliver IL-23 variants into the tumor bed and explored their activity in cancer treatment on multiple tumor models. Methods: Oncolytic vaccinia viruses expressing IL-23 variants were generated by homologue recombination. The characteristics of these viruses were in vitro evaluated by RT-qPCR, ELISA, flow cytometry and cytotoxicity assay. The antitumor effects of these viruses were evaluated on multiple tumor models in vivo and the mechanisms were investigated by RT-qPCR and flow cytometry. Results: IL-23 prolonged viral persistence, probably mediated by up-regulated IL-10. The sustainable IL-23 expression and viral oncolysis elevated the expression of Th1 chemokines and antitumor factors such as IFN-γ, TNF-α, Perforin, IL-2, Granzyme B and activated T cells in the TME, transforming the TME to be more conducive to antitumor immunity. This leads to a systemic antitumor effect which is dependent on CD8+ and CD4+ T cells and IFN-γ. Oncolytic vaccinia viruses could not deliver stable IL-23A to the tumor, attributed to the elevated tristetraprolin which can destabilize the IL-23A mRNA after the viral treatment; whereas vaccinia viruses could deliver membrane-bound IL-23 to elicit a potent antitumor effect which might avoid the possible toxicity normally associated with systemic cytokine exposure. Conclusion: Either secreted or membrane-bound IL-23-armed vaccinia virus can induce potent antitumor effects and IL-23 is a candidate cytokine to arm oncolytic viruses for cancer immunotherapy.


Assuntos
Adenocarcinoma/terapia , Neoplasias do Colo/terapia , Imunoterapia/métodos , Interleucina-23/farmacologia , Vírus Oncolíticos/genética , Microambiente Tumoral/imunologia , Vírus Vaccinia/genética , Adenocarcinoma/imunologia , Adenocarcinoma/virologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Neoplasias do Colo/imunologia , Neoplasias do Colo/virologia , Modelos Animais de Doenças , Feminino , Vetores Genéticos , Granzimas/metabolismo , Humanos , Interferon gama/metabolismo , Interleucina-12/metabolismo , Interleucina-2/metabolismo , Interleucina-23/genética , Interleucina-23/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Vírus Oncolíticos/metabolismo , Perforina/metabolismo , Microambiente Tumoral/genética , Fator de Necrose Tumoral alfa/metabolismo , Vírus Vaccinia/metabolismo
5.
Ann Surg Oncol ; 28(12): 7759-7769, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34027585

RESUMO

INTRODUCTION: A positive microscopic margin (R1) following resection of pancreatic ductal adenocarcinoma (PDAC) can occur in up to 80% of patients and is associated with reduced survival and increased recurrence. Our aim was to characterize the impact of neoadjuvant therapy (NAT) on survival and recurrence in patients with PDAC following an R1 resection. METHODS: A retrospective analysis of patients with PDAC who underwent pancreatectomy from 2008 to 2017 was performed. Patients were staged according to the American Joint Committee on Cancer 8th edition and stratified based on resection margin (R0 vs. R1) and treatment sequence (NAT vs. surgery first [SF]). Conditional survival analysis was performed using Cox regression and inverse probability weighted estimates. RESULTS: Among 580 patients, 59% received NAT and 41% underwent SF. On final pathology, the NAT cohort had smaller tumors and less lymph node (LN) positivity (p < 0.05). NAT was not associated with an R1 resection (50%, p = 0.653). Compared with the R1 cohort, the R0 cohort had a higher median overall survival (OS; 39.6 vs. 22.8 months; hazard ratio [HR] 1.6, p < 0.001) and disease-free survival (DFS; 19 vs. 13 months; HR 1.35, p = 0.004). After risk adjustment, NAT was not associated with OS, regardless of margin status (R0, 95% confidence interval [CI] (-)7.31-27.07, p = 0.26; or R1, 95% CI (-)36.99-15.25, p = 0.42). However, NAT was associated with improved DFS in the R1 cohort (95% CI 1.79-11.91, p = 0.008) but not in the R0 cohort (95% CI (-)11.22-10.54, p = 0.95). CONCLUSION: An R0 resection remains an important determinant of overall and disease-free survival, even when NAT is administered. For patients with an R1 resection, receipt of NAT may prolong DFS.

8.
Ann Surg Oncol ; 28(11): 6264-6272, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33748894

RESUMO

INTRODUCTION: Neoadjuvant therapy (NAT) is a growing strategy for patients with resectable pancreatic ductal adenocarcinoma (PDAC). Elderly patients are at increased risk of treatment withdrawal due to functional decline, and the benefit of NAT in this cohort remains to be studied. OBJECTIVE: The objective of this study was to compare outcomes of elderly patients with resectable head PDAC who underwent NAT or a surgery-first (SF) approach. METHODS: All patients 75 years of age and older with radiographically resectable (National Comprehensive Cancer Network criteria) PDAC who underwent pancreaticoduodenectomy at a single institution from 2008 to 2017 were analyzed. Baseline characteristics and perioperative outcomes were compared between the SF and NAT cohorts. Recurrence-free survival and overall survival (OS) were analyzed by treatment strategy. RESULTS: Overall, 158 patients were identified: SF cohort = 90 (57%) and NAT cohort = 68 (43%). Patients in the SF cohort were older (80 vs. 78 years; p = 0.01) but there were no differences in preoperative comorbidities or frailty indices. SF patients had a trend toward higher rates of major complications (38% vs. 24%; p = 0.06) with higher Comprehensive Complication Index totals (20.9 vs. 20; p = 0.03). There were similar rates of adjuvant therapy. NAT was associated with significantly longer OS (24.6 vs. 17.6 months; p = 0.01) in both the intent-to-treat and resected cohorts. On multivariable analysis (MVA), NAT remained an independent predictor of OS (hazard ratio 0.60; p = 0.02). CONCLUSION: NAT is safe and effective for elderly patients with PDAC. This study suggests NAT is associated with fewer complications after surgery, equal rates of adjuvant therapy receipt, and increased OS over a surgery-first approach.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma/cirurgia , Idoso , Carcinoma Ductal Pancreático/cirurgia , Humanos , Terapia Neoadjuvante , Pancreatectomia , Neoplasias Pancreáticas/cirurgia
10.
Front Immunol ; 12: 610042, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679747

RESUMO

Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TIL) achieves durable clinical benefit for patients from whom these cells can be derived in advanced metastatic melanoma but is limited in most solid tumors as a result of immune escape and exclusion. A tumor microenvironment (TME) priming strategy to improve the quantity and quality of TIL represents an important tactic to explore. Oncolytic viruses expressing immune stimulatory cytokines induce a potent inflammatory response that may enhance infiltration and activation of T cells. In this study, we examined the ability of an attenuated oncolytic vaccinia virus expressing IL15/IL15Rα (vvDD-IL15/Rα) to enhance recovery of lavage T cells in peritoneal carcinomatosis (PC). We found that intraperitoneal (IP) vvDD-IL15/Rα treatment of animals bearing PC resulted in a significant increase in cytotoxic function and memory formation in CD8+ T cells in peritoneal fluid. Using tetramers for vaccinia virus B8R antigen and tumor rejection antigen p15E, we found that the expanded population of peritoneal CD8+ T cells are specific for vaccinia or tumor with increased tumor-specificity over time, reinforced with viral clearance. Application of these vvDD-IL15/Rα induced CD8+ T cells in ACT of a lethal model of PC significantly increased survival. In addition, we found in patients with peritoneal metastases from various primary solid tumors that peritoneal T cells could be recovered but were exhausted with infrequent tumor-reactivity. If clinically translatable, vvDD-IL15/Rα in vivo priming would greatly expand the number of patients with advanced metastatic cancers responsive to T cell therapy.


Assuntos
Vetores Genéticos/efeitos adversos , Imunoterapia Adotiva , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Vírus Oncolíticos/imunologia , Neoplasias Peritoneais/terapia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Vetores Genéticos/genética , Humanos , Imunofenotipagem , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Interleucina-15/metabolismo , Subunidade alfa de Receptor de Interleucina-15/metabolismo , Camundongos , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos/genética , Neoplasias Peritoneais/secundário , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Ann Surg Oncol ; 28(7): 3522-3531, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33687614

RESUMO

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS HIPEC) can offer significant survival advantage for select patients with colorectal peritoneal metastases (CRPM). Low socioeconomic status (SES) is implicated in disparities in access to care. We analyze the impact of SES on postoperative outcomes and survival at a high-volume tertiary CRS HIPEC center. PATIENTS AND METHODS: We conducted a retrospective cohort study examining patients who underwent CRS HIPEC for CRPM from 2000 to 2018. Patients were grouped according to SES. Baseline characteristics, perioperative outcomes, and survival were examined between groups. RESULTS: A total of 226 patients were analyzed, 107 (47%) low-SES and 119 (53%) high-SES patients. High-SES patients were younger (52 vs. 58 years, p = 0.01) and more likely to be White (95.0% vs. 91.6%, p = 0.06) and privately insured (83% vs. 57%, p < 0.001). They traveled significantly further for treatment and had lower burden of comorbidities and frailty (p = 0.01). Low-SES patients more often presented with synchronous peritoneal metastases (48% vs. 35%, p = 0.05). Following CRS HIPEC, low-SES patients had longer length of stay and higher burden of postoperative complications, 90-day readmission, and 30-day mortality. Median overall survival following CRS HIPEC was worse for low-SES patients (17.8 vs. 32.4 months, p = 0.02). This disparity persisted on multivariate survival analysis (low SES: HR = 1.46, p = 0.03). CONCLUSIONS: Despite improving therapies for CRPM, low-SES patients remain at a significant disadvantage. Even patients who overcome barriers to care experience worse short- and long-term outcomes. Improving access and addressing these disparities is crucial to ensure equitable outcomes and improve patient care.


Assuntos
Neoplasias Colorretais , Hipertermia Induzida , Neoplasias Peritoneais , Neoplasias Colorretais/terapia , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Humanos , Neoplasias Peritoneais/terapia , Estudos Retrospectivos , Classe Social , Taxa de Sobrevida
12.
Cancer Immunol Immunother ; 70(9): 2467-2481, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33538860

RESUMO

In this study, we aimed to apply the cytokine IL-36γ to cancer immunotherapy by constructing new oncolytic vaccinia viruses (OV) expressing interleukin-36γ (IL-36γ-OVs), leveraging unique synergism between OV and IL-36γ's ability to promote antitumor adaptive immunity and modulate tumor microenvironment (TME). IL-36γ-OV had dramatic therapeutic efficacies in multiple murine tumor models, frequently leading to complete cancer eradication in large fractions of mice. Mechanistically, IL-36-γ-armed OV induced infiltration of lymphocytes and dendritic cells, decreased myeloid-derived suppressor cells and M2-like tumor-associated macrophages, and T cell differentiation into effector cells. Further study showed that IL-36γ-OV increased the number of tumor antigen-specific CD4+ and CD8+ T cells and the therapeutic efficacy depended on both CD8+ and CD4+ T cells. These results demonstrate that these IL36γ-armed OVs exert potent therapeutic efficacy mainly though antitumor immunity and they may hold great potential to advance treatment in human cancer patients.


Assuntos
Imunidade Adaptativa , Terapia Genética , Vetores Genéticos/genética , Interleucina-1/genética , Neoplasias/imunologia , Neoplasias/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Citotoxicidade Imunológica , Modelos Animais de Doenças , Expressão Gênica , Engenharia Genética , Vetores Genéticos/administração & dosagem , Humanos , Melanoma Experimental , Camundongos , Imagem Molecular , Neoplasias/diagnóstico , Neoplasias/genética , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Ann Surg Oncol ; 28(5): 2438-2446, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33523364

RESUMO

AIMS: National studies have demonstrated disparities in the treatment and survival of pancreatic cancer patients based on socioeconomic status (SES). This study aimed to identify specific differences in perioperative management and outcomes based on patient SES and to study the role of a multidisciplinary clinic (MDC) in mitigating any variations. METHODS: The study analyzed patients undergoing pancreaticoduodenectomy for pancreatic ductal adenocarcinoma in a large hospital system. The patients were categorized into groups of high and low SES and whether they were managed by the authors' pancreatic cancer MDC or not. The study compared differences in disease characteristics, receipt of multimodality therapy, perioperative outcomes, and recurrence-free and overall survival. RESULTS: Of the 162 low-SES patients and 119 high-SES patients, 54% were managed in the MDC. Outside the MDC, low-SES patients were less likely to receive neoadjuvant chemotherapy and had less minimally invasive surgery, a longer OR time, less enhanced recovery participation, and more major complications (p < 0.05). No SES disparities were observed among the MDC patients. Despite similar tumor characteristics, the low-SES patients had inferior median overall survival (21 vs 32 months; p = 0.005), but the MDC appeared to eliminate this disparity. Low SES correlated with inferior survival for the non-MDC patients (17 vs 32 months; p < 0.001), but not for the MDC patients (24 vs 25 months; p = 0.33). These findings persisted in the multivariable analysis. CONCLUSION: A pancreatic cancer MDC standardizes treatment decisions, eliminates disparities in surgical outcomes, and improves survival for low-SES patients.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/cirurgia , Disparidades em Assistência à Saúde , Humanos , Recidiva Local de Neoplasia , Pancreatectomia , Neoplasias Pancreáticas/cirurgia , Classe Social
14.
Ann Surg Oncol ; 28(5): 2715-2727, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33575873

RESUMO

Thoracic malignancies are associated with high mortality rates. Conventional therapy for many of the patients with thoracic malignancies is obviated by a high incidence of locoregional recurrence and distant metastasis. Fortunately, developments in immunotherapy provide effective strategies for both local and systemic treatments that have rapidly advanced during the last decade. One promising approach to cancer immunotherapy is to use oncolytic viruses, which have the advantages of relatively high tumor specificity, selective replication-mediated oncolysis, enhanced antigen presentation, and potential for delivery of immunogenic payloads such as cytokines, with subsequent elicitation of effective antitumor immunity. Several oncolytic viruses including adenovirus, coxsackievirus B3, herpes virus, measles virus, reovirus, and vaccinia virus have been developed and applied to thoracic cancers in preclinical murine studies and clinical trials. This review discusses the current state of oncolytic virotherapy in lung cancer, esophageal cancer, and metastatic malignant pleural effusions and considers its potential as an emergent therapeutic for these patients.


Assuntos
Terapia Viral Oncolítica , Vírus Oncolíticos , Derrame Pleural Maligno , Animais , Humanos , Imunoterapia , Camundongos , Recidiva Local de Neoplasia
15.
Ann Surg Oncol ; 28(8): 4637-4646, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33400000

RESUMO

BACKGROUND: Peritoneal metastases portend poor prognosis in the setting of standard chemotherapy. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) improves outcomes, but relapse is common. We report a phase II trial evaluating the safety and efficacy of adjuvant αDC1 vaccination with chemokine modulation (CKM) after CRS/HIPEC. METHODS: Patients undergoing CRS/HIPEC for appendiceal cancer, colorectal cancer, or peritoneal mesothelioma were enrolled. In addition to standard adjuvant chemotherapy, patients received intranodal and intradermal injections of autologous tumor-loaded αDC1 vaccine. After each vaccine booster, patients received CKM over 4 days, consisting of celecoxib, interferon (IFN)-α, and rintatolimod. RESULTS: Forty-six patients underwent CRS/HIPEC followed by αDC1 treatment, including 24 appendiceal primaries, 20 colorectal, and 2 mesotheliomas. DC maturation was successful, with 97% expressing HLA-DR and CD86. Tumor cell recovery from peritoneal tumors was challenging, resulting in only 17% of patients receiving the target dose of αDC1. The αDC1 and CKM regimen was well tolerated. CKM successfully modulated serum inflammatory cytokine and chemokine levels. Median progression-free survival (PFS) for appendiceal primaries was 50.4, 34.2, and 8.9 months for grade 1, 2, and 3 tumors, respectively, while median PFS for colorectal cancer was 20.5 and 8.9 months for moderately and poorly differentiated tumors, respectively. CONCLUSIONS: Adjuvant autologous tumor antigen-loaded αDC1 vaccine and CKM is well tolerated. The mucinous nature of peritoneal metastases limits the feasibility of obtaining adequate autologous tumor cells. The improvement in median PFS did not meet our predefined thresholds, leading us to conclude that αDC1 vaccination is not appropriate for patients undergoing CRS/HIPEC for peritoneal metastases.


Assuntos
Neoplasias Colorretais , Hipertermia Induzida , Neoplasias Peritoneais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Celecoxib/uso terapêutico , Neoplasias Colorretais/terapia , Procedimentos Cirúrgicos de Citorredução , Células Dendríticas , Humanos , Quimioterapia Intraperitoneal Hipertérmica , Interferon-alfa/uso terapêutico , Recidiva Local de Neoplasia , Neoplasias Peritoneais/tratamento farmacológico , Poli I-C , Poli U
16.
Ann Surg Oncol ; 28(7): 3800-3807, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33386547

RESUMO

BACKGROUND: Despite controversy regarding the role of neoadjuvant chemotherapy (NAC) in pancreatic adenocarcinoma, nearly half of resected patients do not receive chemotherapy postoperatively. This study aimed to examine whether use of NAC compensates for omission of adjuvant chemotherapy (AC) for resected pancreatic adenocarcinoma. METHODS: Adults with resected stages 1 to 3 pancreatic adenocarcinoma were enrolled from the National Cancer Database NCDB (2006-2016). Overall survival (OS) analyses were used to examine the impact of NAC on those who did not receive AC. RESULTS: The study analyzed a national cohort of 56,286 patients: 30% without chemotherapy, 11% with NAC, 54% with AC, and 5% with NAC plus AC. Use of NAC increased by more than 400% from 2006 to 2016, whereas the rates for omission of chemotherapy remained unchanged. The OS rates were similar between the patients who received NAC and those who received AC (hazard ratio, 0.97; p = 0.21). Among the patients who did not receive AC, NAC was associated with improved OS (26.7 vs. 18.4 months; p < 0.0001). The patients who did not receive AC but underwent NAC had a median OS comparable with the OS of those who received AC alone (26.9 vs. 24.7 months). In the adjusted analysis, the use of NAC for those without AC was significantly associated with improved OS (estimate, - 0.24; p < 0.0001). CONCLUSIONS: Although data are limited regarding the survival benefit derived from neoadjuvant versus adjuvant chemotherapy in pancreatic adenocarcinoma, nearly half of patients do not receive adjuvant chemotherapy. This study demonstrates that the use of NAC lessens the survival disadvantage caused by omission of AC. Despite controversy, NAC may be considered for pancreatic adenocarcinoma patients given the high likelihood that adjuvant chemotherapy will be omitted.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adulto , Quimioterapia Adjuvante , Humanos , Terapia Neoadjuvante , Neoplasias Pancreáticas/tratamento farmacológico , Modelos de Riscos Proporcionais
17.
Ann Surg Oncol ; 28(9): 5287-5296, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33486643

RESUMO

BACKGROUND: Ninety-day hospital readmission rates following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) range from 20 to 40%. OBJECTIVE: The aim of this study was to develop and validate a simple score to predict readmissions following CRS/HIPEC. STUDY DESIGN: Using a prospectively maintained database, we retrospectively reviewed clinicopathologic, perioperative, and day-of-discharge data for patients undergoing CRS/HIPEC for peritoneal surface malignancies between 2010 and 2018. In-hospital mortalities and discharges to hospice were excluded. Multivariate logistic regression was utilized to identify predictors of unplanned readmission, with three-quarters of the sample randomly selected as the derivation cohort and one-quarter as the validation cohort. Using regression coefficient-based scoring methods, we developed a weighted 7-factor, 10-point predictive score for risk of readmission. RESULTS: Overall, 1068 eligible discharges were analyzed; 379 patients were readmitted within 90 days (35.5%). Seven factors were associated with readmission: stoma creation, Peritoneal Cancer Index score ≥ 15, hyponatremia, in-hospital major complication, preoperative chemotherapy, anemia, and discharge to nursing home. In the validation cohort, 25 patients (9.2%) were categorized as high risk for readmission, with a predicted rate of readmission of 69.3% and an observed rate of 76.0%. The score had fair discrimination (area under the curve 0.70) and good calibration (Hosmer-Lemeshow goodness-of-fit p-value of 0.77). CONCLUSION: Our proposed risk score, easily obtainable on day of discharge, distinguishes patients at high risk for readmission over 90 days following CRS/HIPEC. This score has the potential to target high-risk individuals for intensive follow-up and other interventions.


Assuntos
Procedimentos Cirúrgicos de Citorredução , Hipertermia Induzida , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Humanos , Hipertermia Induzida/efeitos adversos , Readmissão do Paciente , Estudos Retrospectivos , Fatores de Risco
19.
Cancer Gene Ther ; 28(1-2): 98-111, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32632271

RESUMO

Adoptive cell therapy (ACT) using tumor-specific tumor-infiltrating lymphocytes (TILs) has demonstrated success in patients where tumor-antigen specific TILs can be harvested from the tumor, expanded, and re-infused in combination with a preparatory regimen and IL2. One major issue for non-immunogenic tumors has been that the isolated TILs lack tumor specificity and thus possess limited in vivo therapeutic function. An oncolytic virus (OV) mediates an immunogenic cell death for cancer cells, leading to elicitation and dramatic enhancement of tumor-specific TILs. We hypothesized that the tumor-specific TILs elicited and promoted by an OV would be a great source for ACT for solid cancer. In this study, we show that a local injection of oncolytic poxvirus in MC38 tumor with low immunogenicity in C57BL/6 mice, led to elicitation and accumulation of tumor-specific TILs in the tumor tissue. Our analyses indicated that IL2-armed OV-elicited TILs contain lower quantities of exhausted PD-1hiTim-3+ CD8+ T cells and regulatory T cells. The isolated TILs from IL2-expressing OV-treated tumor tissue retained high tumor specificity after expansion ex vivo. These TILs resulted in significant tumor regression and improved survival after adoptive transfer in mice with established MC38 tumor. Our study showcases the feasibility of using an OV to induce tumor-reactive TILs that can be expanded for ACT.

20.
Ann Surg ; 273(5): 966-972, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31851003

RESUMO

OBJECTIVES: This study aims to present the outcomes of our decade-long experience of robotic pancreatoduodenectomy and provide insights into successful program implementation. BACKGROUND: Despite significant improvement in mortality over the past 30 years, morbidity following open pancreatoduodenectomy remains high. We implemented a minimally invasive pancreatic surgery program based on the robotic platform as one potential method of improving outcomes for this operation. METHODS: A retrospective review of a prospectively maintained institutional database was performed to identify patients who underwent robotic pancreatoduodenectomy (RPD) between 2008 and 2017 at the University of Pittsburgh. RESULTS: In total, 500 consecutive RPDs were included. Operative time, conversion to open, blood loss, and clinically relevant postoperative pancreatic fistula improved early in the experience and have remained low despite increasing complexity of case selection as reflected by increasing number of patients with pancreatic cancer, vascular resections, and higher Charlson Comorbidity scores (all P<0.05). Operating room time plateaued after 240 cases at a median time of 391 minutes (interquartile rang 340-477). Major complications (Clavien >2) occurred in less than 24%, clinically relevant postoperative pancreatic fistula in 7.8%, 30- and 90-day mortality were 1.4% and 3.1% respectively, and median length of stay was 8 days. Outcomes were not impacted by integration of trainees or expansion of selection criteria. CONCLUSIONS: Structured implementation of robotic pancreatoduodenectomy can be associated with excellent outcomes. In the largest series of RPD, we establish benchmarks for the surgical community to consider when adopting this approach.


Assuntos
Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/estatística & dados numéricos , Procedimentos Cirúrgicos Robóticos/estatística & dados numéricos , Idoso , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento
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