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1.
Cancer Cell ; 40(4): 410-423.e7, 2022 04 11.
Article in English | MEDLINE | ID: mdl-35413272

ABSTRACT

Tumor-infiltrating neoantigen-reactive T cells can mediate regression of metastatic gastrointestinal cancers yet remain poorly characterized. We performed immunological screening against personalized neoantigens in combination with single-cell RNA sequencing on tumor-infiltrating lymphocytes from bile duct and pancreatic cancer patients to characterize the transcriptomic landscape of neoantigen-reactive T cells. We found that most neoantigen-reactive CD8+ T cells displayed an exhausted state with significant CXCL13 and GZMA co-expression compared with non-neoantigen-reactive bystander cells. Most neoantigen-reactive CD4+ T cells from a patient with bile duct cancer also exhibited an exhausted phenotype but with overexpression of HOPX or ADGRG1 while lacking IL7R expression. Thus, neoantigen-reactive T cells infiltrating gastrointestinal cancers harbor distinct transcriptomic signatures, which may provide new opportunities for harnessing these cells for therapy.


Subject(s)
CD8-Positive T-Lymphocytes , Gastrointestinal Neoplasms , Antigens, Neoplasm , Gastrointestinal Neoplasms/genetics , Humans , Lymphocytes, Tumor-Infiltrating , Transcriptome
2.
Pancreas ; 46(7): 898-903, 2017 08.
Article in English | MEDLINE | ID: mdl-28697130

ABSTRACT

OBJECTIVES: Literature addressing the significance of lymph node positivity in the management of nonfunctional pancreatic neuroendocrine tumors (PNETs) is conflicting. METHODS: The National Cancer Data Base was queried for patients who underwent surgical resection of nonfunctional PNETs between 1998 and 2011. Clinical data and overall survival were analyzed using χ and Cox proportional hazards regression. Multiple imputation was used as a comparative analysis because of the high number of patients missing data on tumor grade. RESULTS: Two thousand seven hundred thirty-five patients were identified. The overall incidence of lymph node metastasis was 51%. In the subset of patients with grade 1 tumors less than 1 cm, 24% had positive lymph nodes. Overall median survival for patients with negative lymph nodes was 11 years compared with 8 years for lymph node-positive patients (P < 0.001). On multivariate survival analysis, tumor grade, distant metastases, regional lymph node involvement, positive surgical margins, male sex, and older age were predictive of decreased overall survival. CONCLUSIONS: Lymph node positivity was associated with decreased overall survival. The incidence of lymph node involvement in resected low-grade tumors less than 1 cm is higher than previously reported. Patients selected for resection of PNETs should be offered lymphadenectomy for staging.


Subject(s)
Lymph Nodes/pathology , Neuroendocrine Tumors/surgery , Pancreatectomy/methods , Pancreatic Neoplasms/surgery , Databases, Factual/statistics & numerical data , Female , Humans , Kaplan-Meier Estimate , Lymphatic Metastasis , Male , Middle Aged , Multivariate Analysis , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/pathology
3.
Ann Surg Oncol ; 24(7): 2015-2022, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28299507

ABSTRACT

INTRODUCTION: Current literature addressing the treatment of solid pseudopapillary neoplasms (SPNs) of the pancreas is limited, particularly for patients with distant metastases. We aimed to define predictive indicators of survival in a large series of patients and assess the outcome of patients with distant metastases. METHODS: The National Cancer Database was queried for patients diagnosed with SPNs of the pancreas between 1998 and 2011. Single predictor univariate analyses were performed on variables including demographics, tumor characteristics, and surgery outcomes, and multivariate Cox proportional hazards survival analysis was then completed with backward elimination. RESULTS: Overall, 340 patients were identified: 82% were female, median age was 39 years, and 84% had no comorbidities. Patients undergoing any type of surgical resection experienced long-term survival (85% 8-year survival). Patients undergoing surgical resection (n = 296) had superior survival (hazard ratio [HR] 21 for no surgery, p < 0.0001), as did patients treated at academic centers and those with private insurance (HR 3.9, p = 0.009; HR 4.9, p = 0.007). Sex, age, tumor size, presence of lymph node metastases, positive surgical margins, and presence of distant metastases were not significant predictors of survival in multivariate analysis. Of 24 patients with distant metastases, seven were treated surgically and experienced long-term survival similar to that of patients without metastases treated surgically (HR 2, p = 0.48). CONCLUSION: SPNs of the pancreas are rare neoplasms with excellent overall survival; however, in a low number of patients they metastasize. Of the few patients with metastatic disease selected for resection, most experienced long-term survival.


Subject(s)
Carcinoma, Papillary/secondary , Pancreatectomy/mortality , Pancreatic Neoplasms/pathology , Adult , Carcinoma, Papillary/surgery , Female , Follow-Up Studies , Humans , Male , Neoplasm Invasiveness , Neoplasm Metastasis , Pancreatic Neoplasms/surgery , Prospective Studies , Survival Rate , Treatment Outcome , Tumor Burden
4.
HPB (Oxford) ; 19(6): 508-514, 2017 06.
Article in English | MEDLINE | ID: mdl-28233672

ABSTRACT

BACKGROUND: Fistula Risk Score (FRS) is a previously developed tool to assess the risk of clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreatoduodenectomy (PD). METHODS: Prospectively collected databases from 4 university affiliated and non-affiliated HPB centers in United States and Canada were used. The influence of individual baseline characteristics, FRS and FRS group on CR-POPF was assessed in univariate and multivariate analyses. FRS calculator performance was assessed using a C-statistic. RESULTS: 444 patients were identified. Pathology, soft pancreas texture and pancreatic duct size were associated with CR-POPF rates (p < 0.001 for each); EBL was not (p = 0.067). The negligible risk group consisted of 50 (11.3%) patients, low risk of 118 (26.6%), moderate 234 (52.7%) and high risk group of 42 (9.5%) patients. The overall rate of CR-POPF was 20%. Of the patients in the negligible risk group, 2% developed CR-POPF, 13.6% of the low risk, 23.1% moderate and 42.9% in the high risk group (p < 0.001). Overall C-statistic was 0.719. CONCLUSION: FRS is robust and able to stratify the risk of developing CR-POPF following PD in diverse North American academic and non-academic institutions. The FRS should be used in research and to guide clinical management of patients post PD in these institutions.


Subject(s)
Decision Support Techniques , Gastroenterology , Pancreatic Fistula/etiology , Pancreaticoduodenectomy/adverse effects , Canada , Chi-Square Distribution , Clinical Decision-Making , Databases, Factual , Gastroenterology/standards , Humans , Logistic Models , Multivariate Analysis , Pancreatic Fistula/diagnosis , Pancreaticoduodenectomy/standards , Predictive Value of Tests , Reproducibility of Results , Retrospective Studies , Risk Assessment , Risk Factors , United States
5.
Am J Surg ; 211(5): 871-6, 2016 May.
Article in English | MEDLINE | ID: mdl-27046794

ABSTRACT

BACKGROUND: Preoperative risk stratification for postoperative pancreatic fistula in patients undergoing distal pancreatectomy is needed. METHODS: Risk factors for postoperative pancreatic fistula in 220 consecutive patients undergoing distal pancreatectomy at 2 major institutions were recorded retrospectively. Gland density was measured on noncontrast computed tomography scans (n = 101), and histologic scoring of fat infiltration and fibrosis was performed by a pathologist (n = 120). RESULTS: Forty-two patients (21%) developed a clinically significant pancreatic fistula within 90 days of surgery. Fat infiltration was significantly associated with gland density (P = .0013), but density did not predict pancreatic fistula (P = .5). Recursive partitioning resulted in a decision tree that predicted fistula in this cohort with a misclassification rate less than 15% using gland fibrosis (histology), density (HU), margin thickness (cm), and pathologic diagnosis. CONCLUSIONS: This multicenter study shows that no single perioperative factor reliably predicts postoperative pancreatic fistula after distal pancreatectomy. A decision tree was constructed for risk stratification.


Subject(s)
Pancreas/pathology , Pancreatectomy/adverse effects , Pancreatic Fistula/etiology , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/surgery , Tomography, X-Ray Computed/methods , Adult , Aged , Biopsy, Needle , Cohort Studies , Female , Humans , Immunohistochemistry , Male , Middle Aged , Pancreas/surgery , Pancreatectomy/methods , Pancreatic Fistula/physiopathology , Pancreatic Fistula/surgery , Pancreatic Neoplasms/mortality , Postoperative Complications/diagnosis , Postoperative Complications/surgery , Predictive Value of Tests , Preoperative Care/methods , Prognosis , ROC Curve , Retrospective Studies , Risk Adjustment , Survival Rate , Treatment Outcome
6.
HPB (Oxford) ; 18(1): 21-8, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26776847

ABSTRACT

BACKGROUND: Total pancreatectomy is infrequently performed for pancreatic cancer. Perceived operative mortality and questionable survival benefit deter many surgeons. Clinical outcomes, described in single-center series, remain largely unknown. METHODS: The National Cancer Database was queried for cases of pancreatic ductal adenocarcinoma undergoing total pancreatectomy (1998-2011). Univariate survival analyses were performed for 21 variables: demographic (8), tumor characteristics (5), surgery outcomes (6), and adjuvant therapy (2). The Log-rank test of differences in Kaplan-Meier survival curves was used for categorical variables. Variables with p < 0.05 were included in a multivariate analysis. Cox proportional hazards regression was used to analyze continuous variables and multivariate models. RESULTS: 2582 patients with staging and survival data made up the study population. 30-day mortality was 5.5%. Median overall survival was 15 months, with 1, 3, and 5-year survival rates of 60%, 22%, and 13%, respectively. Age, facility type, tumor size and grade, lymph node positivity, margin positivity, and adjuvant therapy significantly impacted survival in multivariate analysis. CONCLUSION: Although total pancreatectomy is a reasonable option for selected patients with pancreatic ductal adenocarcinoma, survival of the entire group is limited. Operative mortality is improved from prior reports. Greater survival benefits were seen in younger patients with smaller, node negative tumors resected with negative margins in academic research centers.


Subject(s)
Carcinoma, Pancreatic Ductal/surgery , Pancreatectomy/methods , Pancreatic Neoplasms/surgery , Academic Medical Centers , Adult , Age Factors , Aged , Aged, 80 and over , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/secondary , Databases, Factual , Female , Humans , Kaplan-Meier Estimate , Lymphatic Metastasis , Male , Middle Aged , Multivariate Analysis , Neoplasm Staging , Pancreatectomy/adverse effects , Pancreatectomy/mortality , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Patient Selection , Proportional Hazards Models , Retrospective Studies , Risk Factors , Time Factors , Treatment Outcome , Tumor Burden , United States
7.
HPB (Oxford) ; 18(1): 79-87, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26776855

ABSTRACT

INTRODUCTION: Routine lymphadenectomy in the surgical treatment of intrahepatic cholangiocarcinoma (ICC) is not routinely performed. We aim to define predictive indicators of survival in patients with positive lymph nodes. METHODS: The National Cancer Data Base (NCDB) was queried for patients who underwent major hepatectomy for ICC between 1998 and 2011. Clinical and pathologic data were assessed using uni- and multi-variate analyses. A sub-analysis was performed on the 160 patients with positive lymph nodes. RESULTS: Of 849 patients with lymph node data, 57% had at least one lymph node examined. Median survival for lymph node negative patients was 37 months versus 15 months for lymph node positive patients. In lymph node positive patients, poorer survival was associated with not receiving chemotherapy (HR 1.83, p = 0.003), tumor size > 5 cm (p = 0.029), and older age (p < 0.0001). Lymph node positive patients age less than 45 had a median survival of 27 months. CONCLUSIONS: Overall survival in patients with lymph node metastases from ICC is poor. Adjuvant therapy was associated with a longer survival in lymph node positive patients, although prospective data are needed. Routine lymphadenectomy should be strongly considered to provide prognostic information and guidance for adjuvant therapy.


Subject(s)
Bile Duct Neoplasms/surgery , Cholangiocarcinoma/surgery , Hepatectomy , Lymph Node Excision , Lymph Nodes/surgery , Adult , Aged , Bile Duct Neoplasms/mortality , Bile Duct Neoplasms/pathology , Cholangiocarcinoma/mortality , Cholangiocarcinoma/secondary , Databases, Factual , Female , Hepatectomy/adverse effects , Hepatectomy/mortality , Humans , Kaplan-Meier Estimate , Lymph Node Excision/adverse effects , Lymph Node Excision/mortality , Lymph Nodes/pathology , Lymphatic Metastasis , Male , Middle Aged , Multivariate Analysis , Proportional Hazards Models , Risk Factors , Time Factors , Treatment Outcome , United States
8.
HPB (Oxford) ; 17(5): 454-60, 2015 May.
Article in English | MEDLINE | ID: mdl-25580988

ABSTRACT

INTRODUCTION: With technological advances, questions arise regarding how to best fit newer treatment modalities, such as transarterial therapies, into the treatment algorithm for patients with hepatocellular carcinoma (HCC). METHODS: Between 2005 and 2011, 128 patients initially treated with transarterial radioembolization or chemoembolization using drug-eluting beads were identified. The response was graded retrospectively. Toxicity was measured 1, 3, and 6 months after the first and last treatments. RESULTS: Sixty-five patients (53%) were advanced stage. Twenty patients (16%) had an initial complete response, but with additional treatments, this was increased to 46 (36%). Patients with a complete response as their best response to treatment had a median survival [95% confidence interval (CI)] of 5.77 (2.58, upper limit not yet reached) years, significantly longer than those whose best response was a partial response, 1.22 (0.84, 2.06) years and those with stable disease as their best response, 0.34 (0.29, 0.67) years. Repeated treatments did not increase toxicity. DISCUSSION: This retrospective review of patients treated for intermediate and advanced stage HCC revealed a significant survival advantage in patients who achieved a complete response. These data support use of a multi-modality approach to intermediate and advanced stage HCC, combining liver-directed treatments as necessary to achieve a complete response.


Subject(s)
Carcinoma, Hepatocellular/therapy , Combined Modality Therapy/methods , Liver Neoplasms/therapy , Carcinoma, Hepatocellular/mortality , Chemoembolization, Therapeutic/methods , Female , Humans , Kaplan-Meier Estimate , Liver Neoplasms/mortality , Male , Middle Aged , Retrospective Studies , Survival Rate/trends , Treatment Outcome , United States/epidemiology
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