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1.
Ann Surg ; 276(2): 215-221, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-36036988

RESUMO

OBJECTIVE: Predicting R status before surgery for pancreatic cancer (PDAC) patients with upfront surgery and neoadjuvant therapy. SUMMARY BACKGROUND DATA: Negative surgical margins (R0) are a key predictor of long-term outcomes in PDAC. METHODS: Patients undergoing pancreatic resection with curative intent for PDAC were identified. Using the CT scans from the time of diagnosis, the 2019 NCCN borderline resectability criteria were compared to novel criteria: presence of any alteration of the superior mesenteric-portal vein (SMPV) and perivascular stranding of the superior mesenteric artery (SMA). Accuracy of predicting R status was evaluated for both criteria. Patient baseline characteristics, surgical, histopathological parameters, and long-term overall survival (OS) after resection were evaluated. RESULTS: A total of 593 patients undergoing pancreatic resections for PDAC between 2010 and 2018 were identified. Three hundred and twenty-five (54.8%) patients underwent upfront surgery, whereas 268 (45.2%) received neoadjuvant therapy. In upfront resected patients, positive SMA stranding was associated with 56% margin positive resection rates, whereas positive SMA stranding and SMPV alterations together showed a margin positive resection rate of 75%. In contrast to these criteria, the 2019 NCCN borderline criteria failed to predict margin status. In patients undergoing neoadjuvant therapy, only perivascular SMA stranding remained a predictor of margin positive resection, leading to a rate of 33% R+ resections. Perivascular SMA stranding was related to higher clinical T stage (P = 0.003) and clinical N stage (P = 0.043) as well as perineural invasion (P = 0.022). SMA stranding was associated with worse survival in both patients undergoing upfront surgery (36 vs 22 months, P = 0.002) and neoadjuvant therapy (47 vs 34 months, P = 0.050). CONCLUSIONS: The novel criteria were accurate predictors of R status in PDAC patients undergoing upfront resection. After neoadjuvant treatment, likelihood of positive resection margins is approximately halved, and only perivascular SMA stranding remained a predictive factor.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/cirurgia , Humanos , Margens de Excisão , Terapia Neoadjuvante , Pancreatectomia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos , Taxa de Sobrevida
2.
J Natl Cancer Inst ; 2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-35984312

RESUMO

BACKGROUND: Family and other unpaid caregivers play an active role in the recovery of individuals with pancreatic and periampullary cancer after pancreatectomy. However, little is known about caregivers' experiences and how to better support them. METHODS: Caregivers accompanying patients to one-month post-pancreatectomy visits at 3 hospitals completed an electronic survey between November 2018 - February 2020. We examine measures of absenteeism and work productivity loss among the subset of caregivers who reported working-for-pay, and comparatively assess caregiver experiences by employment status. All analyses were performed as 2-sided tests. RESULTS: Of 265 caregivers approached for study participation, 240 (90.6%) enrolled. Caregivers were primarily female (70.8% female, 29.2% male) and spouses (58.3%), or adult children (25.8%) of patients, with a median age of 60 years. Of the 240 caregivers included in the study, 107 (44.6%) worked for pay. Nearly half (44.4%) of working caregivers reported being absent from work due to caregiving amounting to a 14% loss in work hours. While at work, 58.9% of working caregivers reported increased work difficulty due to caregiving. Taken together, an estimated 59.7% loss in work productivity was experienced due to caregiving in the month following pancreatectomy. After adjustment for sociodemographic factors, working (vs non-working) caregivers reported increased financial (OR = 2.32, p = 0.04) and emotional (OR = 1.93, p = 0.04) difficulties, and daily activity restrictions (OR = 1.85, p = 0.048). CONCLUSIONS: Working caregivers of patients with pancreatic and periampullary cancer experience negative impacts on work and productivity, and caregiving-related financial and emotional difficulties may be amplified. This study highlights the need for workplace policies to support unpaid cancer caregiving.

3.
Surgery ; 172(4): 1228-1235, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35931556

RESUMO

BACKGROUND: Prognostication in patients undergoing resection for pancreatic ductal adenocarcinoma following neoadjuvant therapy remains challenging. In this study, we aimed to develop and validate a nomogram for the prediction of overall survival of these patients. METHODS: Patients who underwent neoadjuvant therapy followed by surgical resection at the Massachusetts General Hospital were analyzed (training cohort). Patients from Memorial Sloan Kettering were included as a validation cohort. A nomogram to predict overall survival was designed, trained, and subjected to internal (bootstrap) validation. RESULTS: A total of 325 patients were identified from Massachusetts General Hospital. Multivariable Cox regression analysis demonstrated that age (hazard ratio 1.828, 95% confidence interval 1.251-2.246; P = .007), serum carbohydrate antigen 19-9 ≥ 37 U/mL (HR 1.602, 95% confidence interval 1.187-3.258; P = .015), tumor size (hazard ratio 2.278, 95% confidence interval 1.405-4.368; P = .003), nodal status (hazard ratio 1.309, 95% confidence interval 1.108-2.439; P = .032), and R1 tumor resection (hazard ratio 1.481, 95% confidence interval 1.049-2.091; P = .026) were independent factors associated with overall survival. A nomogram that incorporated these significant prognostic factors was established. The calibration plots demonstrated high concordance between predictive nomogram values and actual overall survival for 1-year, 3-year, and 5-year overall survival. The model demonstrated excellent discriminatory power in both the Massachusetts General Hospital and Memorial Sloan Kettering cohorts, with adjusted Harrel's concordance index values of 0.729 and 0.712, respectively. CONCLUSION: In this report, we established and validated a novel nomogram for predicting the survival of patients who underwent neoadjuvant therapy followed by pancreatectomy. This model allows clinicians to better estimate the survival of these specific patients.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carboidratos , Carcinoma Ductal Pancreático/cirurgia , Hospitais Gerais , Humanos , Terapia Neoadjuvante , Nomogramas , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico
4.
Nat Genet ; 54(8): 1178-1191, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35902743

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Molecular stratification in pancreatic cancer remains rudimentary and does not yet inform clinical management or therapeutic development. Here, we construct a high-resolution molecular landscape of the cellular subtypes and spatial communities that compose PDAC using single-nucleus RNA sequencing and whole-transcriptome digital spatial profiling (DSP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment naive. We uncovered recurrent expression programs across malignant cells and fibroblasts, including a newly identified neural-like progenitor malignant cell program that was enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent cohorts. Integrating spatial and cellular profiles revealed three multicellular communities with distinct contributions from malignant, fibroblast and immune subtypes: classical, squamoid-basaloid and treatment enriched. Our refined molecular and cellular taxonomy can provide a framework for stratification in clinical trials and serve as a roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Perfilação da Expressão Gênica , Humanos , Terapia Neoadjuvante , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Prognóstico , Transcriptoma/genética
5.
J Am Coll Surg ; 235(2): 315-330, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35839409

RESUMO

BACKGROUND: Resection of pancreatic neuroendocrine tumors (PNETs) may be associated with adverse perioperative outcomes compared with pancreatic adenocarcinoma given the high-risk nature of soft glands with small pancreatic ducts. The effect of minimally invasive surgery (MIS) pancreatectomy on outcomes of PNETs remains to be examined, which is the aim of this study. STUDY DESIGN: Between 2009 and 2019, 1,023 patients underwent pancreatectomy for PNETs at 4 institutions. Clinicopathologic data and perioperative outcomes of patients who underwent MIS (n = 447) and open resections (n = 576) were compared. RESULTS: Of the 1,023 patients, 51% were male, the mean age was 58, the median tumor size was 2.1 cm, and 73% were grade 1 PNETs. There were 318 (31%) pancreatoduodenectomies (PDs), 541 (53%) distal pancreatectomies (DPs), 80 (7.8%) enucleation (ENs), 72 (7%) central pancreatectomies (CPs), and 12 (1.2%) total pancreatectomies. Almost half of the patients (N = 447, 44%) had MIS operations, of which 230 (51%) were robotic and 217 (49%) were laparoscopic. Compared with open operations, MIS PDs had significantly lower operative blood loss (150 vs 400 mL, p < 0.001) and rate of clinically relevant postoperative pancreatic fistulas (CR-POPFs; 13% vs 27%, p = 0.030), and MIS DPs had a shorter length of stay (5 vs 6 days, p < 0.001). Although MIS DPs and ENs had CR-POPFs comparable with open operations, MIS CPs had a higher CR-POPF rate (45% vs 15%, p = 0.013). After adjusting for pathological differences, MIS pancreatectomy was associated with recurrence-free survival and overall survival comparable with open pancreatectomy. CONCLUSIONS: MIS pancreatectomy for PNETs is associated with improved outcomes or outcomes comparable with open resection.


Assuntos
Adenocarcinoma , Laparoscopia , Tumores Neuroectodérmicos Primitivos , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Procedimentos Cirúrgicos Robóticos , Adenocarcinoma/cirurgia , Feminino , Humanos , Laparoscopia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos , Tumores Neuroectodérmicos Primitivos/etiologia , Tumores Neuroectodérmicos Primitivos/cirurgia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Pancreatectomia/efeitos adversos , Neoplasias Pancreáticas/patologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Resultado do Tratamento
6.
J Am Coll Surg ; 234(6): 1021-1030, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35703792

RESUMO

BACKGROUND: The 2017 revised International Association of Pancreatology guidelines for management of intraductal papillary mucinous neoplasm (IPMN) describe worrisome features (WF) and high-risk stigmata (HRS), recommending resection in the latter and further work-up and close surveillance for patients with WF. The effect of multiple WF on the likelihood of malignancy has not been evaluated. STUDY DESIGN: Eight hundred ten patients who underwent pancreatic resection for IPMN in 2 tertiary referral centers were identified from prospective institutional databases. Patients were retrospectively categorized into subgroups according to the number of WF or HRS and presence of malignancy, defined as high-grade dysplasia (HGD) or invasive cancer on final pathology. RESULTS: Three hundred seventy-nine (47%) patients had HRS, 370 (46%) had 1 or more WF, and 61 patients (7%) had neither. Malignancy was present in 70% (n = 267) of patients with HRS and in 30% (n = 127) of those with WF. Only 3 of 61 patients without WF/HRS had malignancy, and all only in the form of HGD. The risk of malignancy increased in a stepwise fashion with the number of WF, to 22%, 34%, and 59% with 1, 2, and 3 WF, respectively (p = 0.001), and reached 100% in patients with 4 or more WF. Although the relative risks differed for particular WF, the areas under the curve were not statistically different. CONCLUSION: We confirm that presence of HRS in IPMN is associated with a very high likelihood of malignancy. The presence of a single WF has a malignancy risk of 22%, and additional WF increase this risk significantly. When 3 or more WF are present, the risk is similar to that of HRS.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Intraductais Pancreáticas , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/epidemiologia , Carcinoma Ductal Pancreático/cirurgia , Humanos , Neoplasias Intraductais Pancreáticas/complicações , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Intraductais Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Estudos Retrospectivos
7.
Ann Surg ; 276(3): 522-531, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35758433

RESUMO

INTRODUCTION: The role of parenchyma-sparing resections (PSR) and lymph node dissection in small (<3 cm) nonfunctional pancreatic neuroendocrine tumors (PNET) is unlikely to be studied in a prospective randomized clinical trial. By combining data from 4 high-volume pancreatic centers we compared postoperative and long-term outcomes of patients who underwent PSR with patients who underwent oncologic resections. METHODS: Retrospective review of prospectively collected clinicopathologic data of patients who underwent pancreatectomy between 2000 and 2021 was collected from 4 high-volume institutions. PSR and lymph node-sparing resections (enucleation and central pancreatectomy) were compared to those who underwent oncologic resections with lymphadenectomy (pancreaticoduodenectomy, distal pancreatectomy). Statistical testing was performed using χ 2 test and t test, survival estimates with Kaplan-Meier method and multivariate analysis using Cox proportional hazard model. RESULTS: Of 810 patients with small sporadic nonfunctional PNETs, 121 (14.9%) had enucleations, 100 (12.3%) had central pancreatectomies, and 589 (72.7%) patients underwent oncologic resections. The median age was 59 years and 48.2% were female with a median tumor size of 2.5 cm. After case-control matching for tumor size, 221 patients were selected in each group. Patients with PSR were more likely to undergo minimally invasive operations (32.6% vs 13.6%, P <0.001), had less intraoperative blood loss (358 vs 511 ml, P <0.001) and had shorter operative times (180 vs 330 minutes, P <0.001) than patients undergoing oncologic resections. While the mean number of lymph nodes harvested was lower for PSR (n=1.4 vs n=9.9, P <0.001), the mean number of positive lymph nodes was equivalent to oncologic resections (n=1.1 vs n=0.9, P =0.808). Although the rate of all postoperative complications was similar for PSR and oncologic resections (38.5% vs 48.2%, P =0.090), it was higher for central pancreatectomies (38.5% vs 56.6%, P =0.003). Long-term median disease-free survival (190.5 vs 195.2 months, P =0.506) and overall survival (197.9 vs 192.6 months, P =0.372) were comparable. Of the 810 patients 136 (16.7%) had no lymph nodes resected. These patients experienced less blood loss, shorter operations ( P <0.001), and lower postoperative complication rates as compared to patients who had lymphadenectomies (39.7% vs 56.9%, P =0.008). Median disease-free survival (197.1 vs 191.9 months, P =0.837) and overall survival (200 vs 195.1 months, P =0.827) were similar for patients with no lymph nodes resected and patients with negative lymph nodes (N0) after lymphadenectomy. CONCLUSION: In small <3 cm nonfunctional PNETs, PSRs and lymph node-sparing resections are associated with lower blood loss, shorter operative times, and lower complication rates when compared to oncologic resections, and have similar long-term oncologic outcomes.


Assuntos
Tumores Neuroectodérmicos Primitivos , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroectodérmicos Primitivos/cirurgia , Pancreatectomia/métodos , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Estudos Retrospectivos , Resultado do Tratamento
8.
Am J Med Genet A ; 188(9): 2666-2671, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35612824

RESUMO

We aimed to further characterize pancreatic involvement in tuberous sclerosis complex (TSC), with a focus on management of TSC-associated nonfunctional pancreatic neuroendocrine tumors (PNETs). This was a retrospective chart review of a large cohort of TSC patients. A total of 637 patients with a confirmed diagnosis of TSC were seen at the Herscot Center for Tuberous Sclerosis Complex at Massachusetts General Hospital. Of the 637 total patients with a confirmed diagnosis of TSC, 28 patients were found to have varying pancreatic findings ranging from simple-appearing cysts to well-differentiated PNETs. Thirteen of the 28 patients had PNET confirmed on pathology; 10 of these tumors were resected at Massachusetts General Hospital. None of the patients had serious perioperative or postoperative complications; only one of the patients had a recurrence following resection. As roughly 4.4% of our TSC patient population had pancreatic involvement, surveillance abdominal imaging should include evaluation of the pancreas instead of limiting to a renal protocol. Additionally, given the low risk of complications and recurrence combined with documented risk of metastasis in TSC-associated PNET, TSC patients with pancreatic lesions suspicious for PNETs should be considered as surgical candidates.


Assuntos
Tumores Neuroectodérmicos Primitivos , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Esclerose Tuberosa , Humanos , Tumores Neuroectodérmicos Primitivos/complicações , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Esclerose Tuberosa/complicações , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética
9.
Cancer Discov ; 12(5): 1378-1395, 2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35420673

RESUMO

FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion-positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies. We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion-positive cholangiocarcinoma. SIGNIFICANCE: We demonstrate that feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion-positive cholangiocarcinoma. These studies support the potential of combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma. This article is highlighted in the In This Issue feature, p. 1171.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Receptores ErbB/genética , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo
10.
Ann Surg ; 2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35185121

RESUMO

OBJECTIVE: To compare positron emission tomography (PET)/magnetic resonance imaging (MRI) to the standard of care imaging (SCI) for the diagnosis of peritoneal carcinomatosis (PC) in primary abdominopelvic malignancies. SUMMARY BACKGROUND DATA: Identifying PC impacts prognosis and management of multiple cancer types. METHODS: Adult subjects were prospectively and consecutively enrolled from 4/2019 to 1/2021. Inclusion criteria were: (a) acquisition of whole-body contrast-enhanced (CE) 18F-fluorodeoxyglucose PET/MRI, (b) pathologically confirmed primary abdominopelvic malignancies. Exclusion criteria were: (a) greater than 4 weeks interval between SCI and PET/MRI, (b) unavailable follow-up. SCI consisted of whole-body contrast-enhanced (CE) PET/computed tomography (CT) with diagnostic quality CT, and/or CE-CT of the abdomen and pelvis, and/or CE-MRI of the abdomen±pelvis. If available, pathology or surgical findings served as the reference standard, otherwise, imaging follow-up was used. When SCI and PET/MRI results disagreed, medical records were checked for management changes. Follow-up data were collected until 8/2021. RESULTS: One hundred sixty-four subjects were included, eighty-five (52%) were female, and the median age was 60 years (IQR 50-69). At a subject level, PET/MRI had higher sensitivity (0.97, 95% CI 0.86-1.00) than SCI (0.54, 95% CI 0.37-0.71), p < 0.001, without a difference in specificity, of 0.95 (95% CI 0.90-0.98) for PET/MRI and 0.98 (95% CI 0.93-1.00) for SCI, p = 0.250. PET/MRI and SCI results disagreed in 19 cases. In 5/19 (26%) of the discordant cases, PET/MRI findings consistent with PC missed on SCI led to management changes. CONCLUSIONS: PET/MRI improves detection of PC compared to SCI which frequently changes management.

11.
J Geriatr Oncol ; 13(4): 410-415, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35074322

RESUMO

BACKGROUND: Older adults with gastrointestinal cancers undergoing surgery often experience poor outcomes, such as prolonged postoperative hospital length of stay (LOS), intensive care unit (ICU) use, hospital readmissions, and complications. Involvement of geriatricians in the care of older adults with cancer can improve outcomes. We conducted a randomized trial of a perioperative geriatric intervention (PERI-OP) in older patients with gastrointestinal cancer undergoing surgery. METHODS: From 9/2016-4/2019, we randomly assigned patients age ≥ 65 with gastrointestinal cancer planning to undergo surgical resection to receive PERI-OP or usual care. Patients assigned to PERI-OP met with a geriatrician preoperatively in the outpatient setting and postoperatively as an inpatient consultant. The primary outcome was postoperative hospital LOS. Secondary outcomes included postoperative ICU use, 90-day hospital readmission rates, and complication rates. We conducted intention-to-treat (ITT) and per-protocol (PP) analyses. RESULTS: ITT analyses included 137/160 patients who underwent surgery (usual care = 68/78, intervention = 69/82). PP analyses included the 68 usual care patients and the 30/69 intervention patients who received the preoperative and postoperative intervention components. ITT analyses demonstrated no significant differences between intervention and usual care in postoperative hospital LOS (7.23 vs 8.21 days, P = 0.374), ICU use (23.2% vs 32.4%, P = 0.257), 90-day hospital readmission rates (21.7% vs 25.0%, P = 0.690), or complication rates (17.4% vs 20.6%, P = 0.668). In PP analyses, intervention patients had shorter postoperative hospital LOS (5.90 vs 8.21 days, P = 0.024), but differences in ICU use (13.3% vs 32.4%, P = 0.081), 90-day hospital readmission rates (16.7% vs 25.0%, P = 0.439), and complication rates (6.7% vs 20.6%, P = 0.137) remained non-significant. CONCLUSIONS: In this randomized trial, PERI-OP did not have a significant impact on postoperative hospital LOS, ICU use, hospital readmissions, or complications. However, the subgroup who received PERI-OP as planned experienced encouraging results. Future studies of PERI-OP should include efforts, such as telehealth, to ensure the intervention is delivered as planned.


Assuntos
Neoplasias , Readmissão do Paciente , Idoso , Humanos , Tempo de Internação , Neoplasias/complicações , Neoplasias/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia
12.
Ann Surg ; 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-35081574

RESUMO

OBJECTIVES: To identify factors associated with concordance between World Health Organization (WHO) grade on cytological analysis (c-grade) and histopathological analysis (h-grade) of surgical specimen in patients with PanNETs and examine trends in utilization and accuracy of EUS-FNA in preoperatively predicting grade. BACKGROUND: WHO grading system is prognostic in pancreatic neuroendocrine tumors (PanNETs). The concordance between c-grade and h-grade is reported to be between 60% and 80%. METHODS: A multicenter retrospective study was performed on patients undergoing resection for PanNETs at four high-volume centers. Patients with functional or syndrome-associated tumors, and those receiving neoadjuvant therapy were excluded. Factors associated with concordance between c-grade and h-grade and trends of utilization of EUS-FNA were assessed. RESULTS: Of 1,336 patients included, 682 (51.1%) underwent EUS-FNA; 567 (83.1%) were diagnostic of PanNETs and WHO-grade was reported for 293 (51.7%) patients. The concordance between c-grade and h-grade was 78.2% with moderate inter-rater agreement (Kc=0.48,p<0.001). Significantly higher rates of concordance were observed in patients with smaller tumors (<2 vs. ≥2 cm, 88.9% vs. 72.7%,p=0.001). Highest concordance (97.9%) was observed in patients with small tumors undergoing assessment between 2015-2019 with near-perfect inter-rater agreement (Kc=0.88,p<0.001)An increase in the utilization of EUS-FNA (46.7% to 62.1%) was observed over the last 2 decades (p<0.001). EUS-FNA was more frequently diagnostic of PanNETs (p<0.001), and WHO-grade was more frequently reported (<0.001). However, concordance between c-grade and h-grade did not change significantly (p=0.056). CONCLUSION: Recently, a trend towards increasing utilization and improved diagnostic accuracy of EUS-FNA has been observed in PanNETs. Concordance between c-grade and h-grade is associated with tumor size with near-perfect agreement when assessing PanNETs >2 cm in size.

13.
Pancreatology ; 22(2): 264-269, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35000863

RESUMO

BACKGROUND: The ABO blood type has been associated with risk of development of several malignancies, including pancreatic cancer. Data regarding IPMN is equivocal. To investigate this further, we analyzed the association between the ABO blood group and the presence of malignancy in a large cohort of resected IPMN and its influence in survival. METHODS: 819 patients who underwent pancreatic resection for IPMN in the Massachusetts General Hospital (MGH) and Cambridge University Hospitals NHS Foundation Trust (CUH) from January 1993 to December 2020 were identified from prospective institutional databases. Pathological characteristics and blood type were correlated. RESULTS: The distribution of blood types A, B, AB and O was 384 (47%), 92 (11%), 44 (5%) and 299 (37%), respectively. This blood type distribution was different than the reference population of the MGH and the CUH, which is 55% non-O blood group, and 45% type O. There was a significant predominance of non-O blood types when compared with O-blood type in patients with malignant IPMN (i.e. patients with high-grade dysplasia and invasive cancer) (67% vs 33%, OR 1.31 95%CI: 0.98-1.75, p = 0.069). The association was stronger for IPMN with invasive cancer (OR 1.43 95%CI: 1.01-2.02, p = 0.039). Blood group did not influence survival. CONCLUSION: Non-O blood type is associated with need for resection in IPMN and with presence of invasive carcinoma.


Assuntos
Adenocarcinoma Mucinoso , Carcinoma Ductal Pancreático , Neoplasias Intraductais Pancreáticas , Neoplasias Pancreáticas , Sistema ABO de Grupos Sanguíneos , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/cirurgia , Carcinoma Ductal Pancreático/patologia , Humanos , Invasividade Neoplásica/patologia , Neoplasias Intraductais Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Estudos Retrospectivos
14.
Cancer Discov ; 12(3): 812-835, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34848557

RESUMO

Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate-dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate-mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell-autonomous inactivation of TET2 DNA demethylase. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon γ (IFNγ) expression and promotes TET2-dependent induction of IFNγ response genes in tumor cells. CD8+ T-cell depletion or tumor cell-specific ablation of TET2 or IFNγ receptor 1 causes treatment resistance. Whereas immune-checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFNγ-TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy. SIGNIFICANCE: Mutant IDH1 inhibition stimulates cytotoxic T-cell function and derepression of the DNA demethylating enzyme TET2, which is required for tumor cells to respond to IFNγ. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies. See related commentary by Zhu and Kwong, p. 604. This article is highlighted in the In This Issue feature, p. 587.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Dioxigenases , Animais , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos/metabolismo , Antígeno CTLA-4/genética , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Humanos , Interferon gama/genética , Isocitrato Desidrogenase , Camundongos , Mutação
15.
Ann Surg ; 275(2): 391-397, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32649455

RESUMO

OBJECTIVE: To build a prognostic score for patients with primary chemotherapy undergoing surgery for pancreatic cancer based on pathological parameters and preoperative Carbohydrate antigen 19-9 (CA19-9) levels. BACKGROUND: Prognostic stratification after primary chemotherapy for pancreatic cancer is challenging and prediction models, such as the AJCC staging system, lack validation in the setting of preoperative chemotherapy. METHODS: Patients with primary chemotherapy resected at the Massachusetts General Hospital between 2007 and 2017 were analyzed. Tumor characteristics independently associated with overall survival were identified and weighted by Cox-proportional regression. The pancreatic neoadjuvant Massachusetts-score (PANAMA-score) was computed from these variables and its performance assessed by Harrel concordance index and area under the receiving characteristics curves analysis. Comparisons were made with the AJCC staging system and external validation was performed in an independent cohort with primary chemotherapy from Heidelberg, Germany. RESULTS: A total of 216 patients constituted the training cohort. The multivariate analysis demonstrated tumor size, number of positive lymph-nodes, R-status, and high CA19-9 to be independently associated with overall survival. Kaplan-Meier analysis according to low, intermediate, and high PANAMA-score showed good discriminatory power of the new metrics (P < 0.001). The median overall survival for the three risk-groups was 45, 27, and 12 months, respectively. External validation in 258 patients confirmed the prognostic ability of the score and demonstrated better accuracy compared with the AJCC staging system. CONCLUSION: The proposed PANAMA-score, based on independent predictors of postresection survival, including pathologic variables and CA19-9, not only provides better discrimination compared to the AJCC staging system, but also identifies patients at high-risk for early death.


Assuntos
Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Idoso , Antígeno CA-19-9/sangue , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidade , Período Pré-Operatório , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
16.
Surgery ; 171(5): 1379-1387, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34774289

RESUMO

BACKGROUND: Pathological treatment effect of resected pancreatic adenocarcinoma after neoadjuvant therapy has prognostic implications. The impact for patients who received chemotherapy alone or chemoradiotherapy is not well defined. METHODS: Patients with localized pancreatic adenocarcinoma who had pancreatectomy after neoadjuvant therapy at 3 centers from 2011 to 2017 were retrospectively analyzed. The chemotherapy and chemoradiotherapy groups were evaluated separately. RESULTS: Of 525 patients, 148 received neoadjuvant chemotherapy and 377 received chemoradiotherapy. The chemoradiotherapy group had a better treatment effect (score 0: 10%, score 1: 30%, score 2: 42%, and score 3: 18%) than the chemotherapy group (score 0: 2%, score 1: 8%, score 2: 35%, and score 3: 55%) (P < .001). Median overall survival was similar between the 2 groups (25.8 vs 26.4 months). Median overall survival for score 0/1, 2, or 3 was 72.2, 38.5, and 20.0 months in the chemotherapy group and 37.9, 24.5, and 19.0 months in the chemoradiotherapy group. Score 2 in the chemotherapy group was associated with better overall survival compared to score 3 (adjusted hazard ratio: 0.49, P = .005), whereas only combined score 0/1 reached significance over score 2 for the chemoradiotherapy group (hazard ratio: 0.63, P = .006). CONCLUSION: The prognostic significance of pathological treatment effect for localized pancreatic adenocarcinoma differs for patients receiving neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Humanos , Terapia Neoadjuvante , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos
17.
Ann Surg ; 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34954756

RESUMO

OBJECTIVE: To identify disparities in access to NAT for PDAC at the prehospital and intrahospital phases of care. SUMMARY OF BACKGROUND DATA: Delivery of NAT in PDAC is susceptible to disparities in access. There are limited data that accurately locate the etiology of disparities at the prehospital and intrahospital phases of care. METHODS: Retrospective cohort of patients ≥18 years old with clinical stage I-II PDAC from the 2010-2016 National Cancer Database. Multiple logistic regression was used to assess 2 sequential outcomes: (1) access to an NAT facility (prehospital phase) and (2) receipt of NAT at an NAT facility (intrahospital phase). RESULTS: A total of 36,208 patients were included for analysis in the prehospital phase of care. Higher education, longer travel distances, being treated at academic/research or integrated network cancer programs, and more recent year of diagnosis were independently associated with receipt of treatment at an NAT facility.All patients treated at NAT facilities (31,099) were included for the second analysis. Higher education level and receiving care at an academic/research facility were independently associated with increased receipt of NAT. Non-Black racial minorities (including American Indian, Asian, Pacific Islanders), being Hispanic, being uninsured, and having Medicaid insurance were associated with decreased receipt of NAT at NAT facilities. CONCLUSIONS: Non-Black racial minorities and Hispanic patients were less likely to receive NAT at NAT facilities compared to White and non-Hispanic patients, respectively. Discrepancies in administration of NAT while being treated at NAT facilities exist and warrant urgent further investigation.

19.
Am J Surg Pathol ; 45(10): 1314-1323, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34334689

RESUMO

Inflammatory pseudotumor is a term used to designate inflammation-rich tumefactive lesions. Following the exclusion of specific entities such as IgG4-related disease and other neoplastic entities previously included in this entity, the majority of hepatic pseudotumors show a prominent fibrohistiocytic inflammatory reaction and have been previously categorized as fibrohistiocytic variant of hepatic pseudotumor (FHVHPT). The goal of this study was to examine the clinical, radiologic, histologic, and etiologic aspects of this entity. After excluding neoplastic diseases, we identified 30 patients with FHVHPT from 3 institutions between 2009 and 2019. We extracted demographic and clinical data, liver function tests as well as culture results and radiologic information. Hematoxylin and eosin-stained slides were reviewed for pattern of inflammation as well as its cellular composition. Immunohistochemistry for IgG4 and IgG was performed in all cases. The mean age of the 30 lesions characterized as FHVHPT was 56 years (range: 23 to 79 y). Nineteen patients showed solitary lesions; 11 were multiple. The mean size of the lesion was 3.8 cm (range: 1 to 7.5 cm). On imaging, a neoplastic process or metastasis was the leading diagnostic consideration (n=15, 50%). The most common symptom was abdominal pain (n=14/30); 8 patients presented with symptoms compatible with an infectious process, including fever. The inflammatory infiltrate was dominated by lymphocytes and plasma cells, and in most cases, a prominent histiocytic infiltrate (22/30). Neutrophils were identified in 12 cases, with microabscess noted in 8. Storiform pattern of fibrosis was seen in 14/30 cases; obliterative phlebitis was not identified. Culture identified a microorganism in 4 of 9 cases evaluated. The mean IgG4 count was 9.3 per HPF (range: 0 to 51) with 9 of the 26 (35%) biopsies showing >10 IgG4 positive plasma cells per HPF. The mean IgG4 to IgG ratio was 8% (range: 8% to 46%). A hepatectomy was performed in 4 cases. On broad spectrum antibiotics (n=14) the lesions either resolved or decreased in size. Eight patients did not receive specific therapy, nevertheless, the lesion(s) resolved spontaneously in 6 cases, remained stable or decreased in size in 2 cases. Notably, none of these patients showed evidence of a hepatic recurrence. FHVHPT, a tumefactive lesion that mimics hepatic neoplasia, is histologically characterized by a fibrohistiocytic infiltrate. In the majority of patients FHVHPT represents the organizing phase of hepatic abscess and can be successfully managed with antibiotic therapy.


Assuntos
Antibacterianos/uso terapêutico , Granuloma de Células Plasmáticas/tratamento farmacológico , Abscesso Hepático/tratamento farmacológico , Fígado/efeitos dos fármacos , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Granuloma de Células Plasmáticas/diagnóstico por imagem , Granuloma de Células Plasmáticas/microbiologia , Granuloma de Células Plasmáticas/patologia , Humanos , Fígado/patologia , Abscesso Hepático/diagnóstico por imagem , Abscesso Hepático/microbiologia , Abscesso Hepático/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
20.
Ann Surg ; 274(5): 721-728, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34353988

RESUMO

OBJECTIVE: The aim of this study was to evaluate whether neoadjuvant therapy (NAT) critically influenced microscopically complete resection (R0) rates and long-term outcomes for patients with pancreatic ductal adenocarcinoma who underwent pancreatoduodenectomy (PD) with portomesenteric vein resection (PVR) from a diverse, world-wide group of high-volume centers. SUMMARY OF BACKGROUND DATA: Limited size studies suggest that NAT improves R0 rates and overall survival compared to upfront surgery in R/BR-PDAC patients. METHODS: This multicenter study analyzed consecutive patients with R/BR-PDAC who underwent PD with PVR in 23 high-volume centers from 2009 to 2018. RESULTS: Data from 1192 patients with PD and PVR were collected and analyzed. The median age was 68 [interquartile range (IQR) 60-73] years and 52% were males. Some 186 (15.6%) and 131 (10.9%) patients received neoadjuvant chemotherapy (NAC) alone and neoadjuvant chemoradiotherapy, respectively. The R0/R1/R2 rates were 57%, 39.3%, and 3.2% in patients who received NAT compared to 46.6%, 49.9%, and 3.5% in patients who did not, respectively (P =0.004). The 1-, 3-, and 5-year OS in patients receiving NAT was 79%, 41%, and 29%, while for those that did not it was 73%, 29%, and 18%, respectively (P <0.001). Multivariable analysis showed no administration of NAT, high tumor grade, lymphovascular invasion, R1/R2 resection, no adjuvant chemotherapy, occurrence of Clavien-Dindo grade 3 or higher postoperative complications within 90 days, preoperative diabetes mellitus, male sex and portal vein involvement were negative independent predictive factors for OS. CONCLUSION: Patients with PDAC of the pancreatic head expected to undergo venous reconstruction should routinely be considered for NAT.


Assuntos
Veias Mesentéricas/cirurgia , Pâncreas/irrigação sanguínea , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/métodos , Veia Porta/cirurgia , Procedimentos Cirúrgicos Vasculares/métodos , Idoso , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Pâncreas/cirurgia , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo
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