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Pancreatic Neoplasms: HELP
Articles by Cristina Rosa Ferrone
Based on 105 articles published since 2010
(Why 105 articles?)
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Between 2010 and 2020, C. Ferrone wrote the following 105 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5
1 Guideline Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. 2017

Tempero, Margaret A / Malafa, Mokenge P / Al-Hawary, Mahmoud / Asbun, Horacio / Bain, Andrew / Behrman, Stephen W / Benson, Al B / Binder, Ellen / Cardin, Dana B / Cha, Charles / Chiorean, E Gabriela / Chung, Vincent / Czito, Brian / Dillhoff, Mary / Dotan, Efrat / Ferrone, Cristina R / Hardacre, Jeffrey / Hawkins, William G / Herman, Joseph / Ko, Andrew H / Komanduri, Srinadh / Koong, Albert / LoConte, Noelle / Lowy, Andrew M / Moravek, Cassadie / Nakakura, Eric K / O'Reilly, Eileen M / Obando, Jorge / Reddy, Sushanth / Scaife, Courtney / Thayer, Sarah / Weekes, Colin D / Wolff, Robert A / Wolpin, Brian M / Burns, Jennifer / Darlow, Susan. · ·J Natl Compr Canc Netw · Pubmed #28784865.

ABSTRACT: Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

2 Editorial FOLFIRINOX: desert, oasis, or mirage? 2015

Ferrone, Cristina R. ·Massachusetts General Hospital, Surgery, Boston, MA, USA, cFERRONE@mgh.harvard.edu. ·Ann Surg Oncol · Pubmed #25490873.

ABSTRACT: -- No abstract --

3 Editorial Lymphadenectomy for pancreatic neuroendocrine tumors: is that the relevant debate? 2014

Ferrone, Cristina R. ·From the Division of General Surgery, Massachusetts General Hospital, Boston, MA. ·Ann Surg · Pubmed #24398923.

ABSTRACT: -- No abstract --

4 Review Status of 5-Year Survivors of the Whipple Procedure for Pancreatic Adenocarcinoma. 2019

Mehtsun, Winta T / Hashimoto, Daniel A / Ferrone, Cristina R. ·Department of Surgery, Massachusetts General Hospital, 15 Parkman Street, WAC 460, Boston, MA 02114, USA. · Department of Surgery, Massachusetts General Hospital, 15 Parkman Street, WAC 460, Boston, MA 02114, USA. Electronic address: cferrone@mgh.harvard.edu. ·Adv Surg · Pubmed #31327451.

ABSTRACT: -- No abstract --

5 Review Treatment of Locally Advanced Pancreatic Ductal Adenocarcinoma. 2016

Loehrer, Andrew P / Kinnier, Christine V / Ferrone, Cristina R. ·Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. · Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. Electronic address: cferrone@partners.org. ·Adv Surg · Pubmed #27520867.

ABSTRACT: -- No abstract --

6 Review Treatment of Locally Advanced Pancreatic Ductal Adenocarcinoma. 2016

Loehrer, Andrew P / Ferrone, Cristina R. ·Department of Surgery, Massachusetts General Hospital, Boston, Mass., USA. ·Dig Surg · Pubmed #27216011.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is increasingly common and a leading cause of cancer-related mortality. Surgery remains the only possibility for cure. Upwards of 40% of patients present with locally advanced PDAC (LA-PDAC), where management strategies continue to evolve. In this review, we highlight current trends in neoadjuvant chemotherapy, surgical resection, and other multimodality approaches for patients with LA-PDAC. Despite promising early results, additional work is needed to more accurately and appropriately tailor treatment for patients with LA-PDAC.

7 Review Spectrum and Classification of Cystic Neoplasms of the Pancreas. 2016

Greer, Jonathan B / Ferrone, Cristina R. ·General Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, GRB-425, Boston, MA 02114, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, Boston, MA 02114, USA. Electronic address: cferrone@mgh.harvard.edu. ·Surg Oncol Clin N Am · Pubmed #27013368.

ABSTRACT: As patients are living longer and axial imaging is more widespread, increasing numbers of cystic neoplasms of the pancreas are found. Intraductal papillary mucinous neoplasms and mucinous cystic neoplasms are the most common. The revised Sendai guidelines provide a safe algorithm for expectant management of certain cystic neoplasms; however, studies are ongoing to identify further subgroups that can be treated nonoperatively. For those patients with high-risk clinical features or symptoms, surgical resection can be performed safely at high-volume pancreatic centers. Accurate diagnosis is critical for accurate decision making.

8 Review Intraductal Papillary Mucinous Neoplasm of the Pancreas: Current State of the Art and Ongoing Controversies. 2016

Fong, Zhi Ven / Ferrone, Cristina R / Lillemoe, Keith D / Fernández-Del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. ·Ann Surg · Pubmed #26727096.

ABSTRACT: With the widespread use and advances in radiographic imaging, Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas are identified with increasing frequency. Although many studies have addressed its biology and treatment, true understanding of its natural history continues to elude us. Its malignant potential places careproviders in a clinical dilemma of balancing the morbidity of pancreatectomy against the risk of malignant transformation while under continuous surveillance. Recently, there have been conflicting data published in the literature, generating more uncertainty in the field. In this article, we critically analyze the contrasting consensus guidelines from the International Association of Pancreatology and the American Gastroenterology Association, and address lingering questions and controversies. We also synthesize newly published data in the context of current standard of care, and provide a comprehensive review and recommendations for the clinical diagnosis, treatment, and follow-up strategy in the management of patients with Intraductal Papillary Mucinous Neoplasms.

9 Review Intraductal papillary mucinous neoplasms: does a family history of pancreatic cancer matter? 2012

Nehra, Deepika / Oyarvide, Vicente Morales / Mino-Kenudson, Mari / Thayer, Sarah P / Ferrone, Cristina R / Wargo, Jennifer A / Muzikansky, Alona / Finkelstein, Dianne / Warshaw, Andrew L / Castillo, Carlos Fernández-del. ·Department of Surgery, Massachusetts General Hospital, Boston MA, USA. ·Pancreatology · Pubmed #22898638.

ABSTRACT: BACKGROUND/OBJECTIVES: The purpose of this study is to compare surgically resected intraductal papillary mucinous neoplasms (IPMNs) in patients with and without a family history of pancreatic cancer to gain insight into differences that may suggest the need for differential management. METHODS: A retrospective review of patients who underwent resection of an IPMN at the Massachusetts General Hospital (1990-2011) was conducted. Three hundred and twenty-four patients of whom 45 (13.9%) had a family history of pancreatic cancer were identified. Patients with (PFH) and without (NFH) a family history of pancreatic cancer were compared. RESULTS: There were no differences in demographic characteristics between groups. Extra-pancreatic malignancies diagnosed prior to the IPMN were more common in those with a PFH (35.6% vs 20.1%, p = 0.03). There were no differences in IPMN characteristics between groups including no difference in the presence of invasive disease (p = 0.55). Concurrent pancreatic ductal adenocarcinomas were more common in those with a PFH (11.1% vs 2.9%, p = 0.02). The survival in the PFH group was marginally lower than the NFH group, a difference found to be attributable to the higher prevalence of extra-pancreatic malignancies. CONCLUSION: Characteristics of surgically resected IPMNs are not different between patients with and without a family history of pancreatic cancer. Most importantly, the incidence of invasive disease is not different, suggesting that these lesions may not be more aggressive when they occur in the presence of a family history of pancreatic cancer.

10 Clinical Trial Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial. 2019

Murphy, Janet E / Wo, Jennifer Y / Ryan, David P / Clark, Jeffrey W / Jiang, Wenqing / Yeap, Beow Y / Drapek, Lorraine C / Ly, Leilana / Baglini, Christian V / Blaszkowsky, Lawrence S / Ferrone, Cristina R / Parikh, Aparna R / Weekes, Colin D / Nipp, Ryan D / Kwak, Eunice L / Allen, Jill N / Corcoran, Ryan B / Ting, David T / Faris, Jason E / Zhu, Andrew X / Goyal, Lipika / Berger, David L / Qadan, Motaz / Lillemoe, Keith D / Talele, Nilesh / Jain, Rakesh K / DeLaney, Thomas F / Duda, Dan G / Boucher, Yves / Fernández-Del Castillo, Carlos / Hong, Theodore S. ·Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ·JAMA Oncol · Pubmed #31145418.

ABSTRACT: Importance: Patients with locally advanced pancreatic cancer have historically poor outcomes. Evaluation of a total neoadjuvant approach is warranted. Objective: To evaluate the margin-negative (R0) resection rate of neoadjuvant FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy for locally advanced pancreatic cancer. Design, Setting, and Participants: A single-arm phase 2 clinical trial was conducted at a large academic hospital from August 22, 2013, to May 22, 2018, among 49 patients with previously untreated locally advanced unresectable pancreatic cancer as determined by multidisciplinary review. Patients had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 17.1 months (range, 5.0-53.7) among 27 patients still alive at study completion. Interventions: Patients received FOLFIRINOX and losartan for 8 cycles. Patients with radiographically resectable tumor after chemotherapy received short-course chemoradiotherapy (5 GyE × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy (50.4 Gy with a vascular boost to 58.8 Gy) with fluorouracil or capecitabine. Main Outcomes and Measures: R0 resection rate. Results: Of the 49 patients (26 women and 23 men; median age 63 years [range, 42-78 years]), 39 completed 8 cycles of FOLFIRINOX and losartan; 10 patients had fewer than 8 cycles due to progression (5 patients), losartan intolerance (3 patients), and toxicity (2 patients). Seven patients (16%) had short-course chemoradiotherapy while 38 (84%) had long-course chemoradiotherapy. Forty-two (86%) patients underwent attempted surgery, with R0 resection achieved in 34 of 49 patients (69%; 95% CI, 55%-82%). Overall median progression-free survival was 17.5 months (95% CI: 13.9-22.7) and median overall survival was 31.4 months (95% CI, 18.1-38.5). Among patients who underwent resection, median progression-free survival was 21.3 months (95% CI, 16.6-28.2), and median overall survival was 33.0 months (95% CI, 31.4 to not reached). Conclusions and Relevance: Total neoadjuvant therapy with FOLFIRINOX, losartan, and chemoradiotherapy provides downstaging of locally advanced pancreatic ductal adenocarcinoma and is associated with an R0 resection rate of 61%. Trial Registration: ClinicalTrials.gov identifier: NCT01821729.

11 Clinical Trial Total Neoadjuvant Therapy With FOLFIRINOX Followed by Individualized Chemoradiotherapy for Borderline Resectable Pancreatic Adenocarcinoma: A Phase 2 Clinical Trial. 2018

Murphy, Janet E / Wo, Jennifer Y / Ryan, David P / Jiang, Wenqing / Yeap, Beow Y / Drapek, Lorraine C / Blaszkowsky, Lawrence S / Kwak, Eunice L / Allen, Jill N / Clark, Jeffrey W / Faris, Jason E / Zhu, Andrew X / Goyal, Lipika / Lillemoe, Keith D / DeLaney, Thomas F / Fernández-Del Castillo, Carlos / Ferrone, Cristina R / Hong, Theodore S. ·Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston. ·JAMA Oncol · Pubmed #29800971.

ABSTRACT: Importance: Patients with borderline-resectable pancreatic ductal adenocarcinoma have historically poor outcomes with surgery followed by adjuvant chemotherapy. Evaluation of a total neoadjuvant approach with highly active therapy is warranted. Objective: To evaluate the margin-negative (R0) resection rate in borderline-resectable pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX (fluorouracil, irinotecan, and oxaliplatin) therapy and individualized chemoradiotherapy. Design, Setting, and Participants: A single-arm, phase 2 clinical trial was conducted at a large academic hospital with expertise in pancreatic surgery from August 3, 2012, through August 31, 2016, among 48 patients with newly diagnosed, previously untreated, localized pancreatic cancer determined to be borderline resectable by multidisciplinary review, who had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 18.0 months among the 30 patients still alive at study completion. Interventions: Patients received FOLFIRINOX for 8 cycles. Upon restaging, patients with resolution of vascular involvement received short-course chemoradiotherapy (5 Gy × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy with fluorouracil or capecitabine. Main Outcomes and Measures: The primary outcome was R0 resection rate; secondary outcomes were median progression-free survival (PFS) and median overall survival (OS). Results: Of the 48 eligible patients, 27 were men and 21 were women, with a median age of 62 years (range, 46-74 years). Of the 43 patients who planned to receive 8 preoperative cycles of chemotherapy, 34 (79%) were able to complete all cycles. Twenty-seven patients (56%) had short-course chemoradiotherapy, while 17 patients (35%) had long-course chemoradiotherapy. R0 resection was achieved in 31 of the 48 eligible patients (65%; 95% CI, 49%-78%). Among the 32 patients who underwent resection, the R0 resection rate was 97% (n = 31). Median PFS among all eligible patients was 14.7 months (95% CI, 10.5 to not reached), with 2-year PFS of 43%; median OS was 37.7 months (95% CI, 19.4 to not reached), with 2-year OS of 56%. Among patients who underwent resection, median PFS was 48.6 months (95% CI, 14.4 to not reached) and median OS has not been reached, with a 2-year PFS of 55% and a 2-year OS of 72%. Conclusions and Relevance: Preoperative FOLFIRINOX followed by individualized chemoradiotherapy in borderline resectable pancreatic cancer results in high rates of R0 resection and prolonged median PFS and median OS, supporting ongoing phase 3 trials. Trial Registration: ClinicalTrials.gov Identifier: NCT01591733.

12 Clinical Trial A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. 2014

Hong, Theodore S / Ryan, David P / Borger, Darrell R / Blaszkowsky, Lawrence S / Yeap, Beow Y / Ancukiewicz, Marek / Deshpande, Vikram / Shinagare, Shweta / Wo, Jennifer Y / Boucher, Yves / Wadlow, Raymond C / Kwak, Eunice L / Allen, Jill N / Clark, Jeffrey W / Zhu, Andrew X / Ferrone, Cristina R / Mamon, Harvey J / Adams, Judith / Winrich, Barbara / Grillo, Tarin / Jain, Rakesh K / DeLaney, Thomas F / Fernandez-del Castillo, Carlos / Duda, Dan G. ·Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: tshong1@partners.org. · Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts. ·Int J Radiat Oncol Biol Phys · Pubmed #24867540.

ABSTRACT: PURPOSE: To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS AND MATERIALS: Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥ 3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood. RESULTS: The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05). CONCLUSIONS: This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS(G12D) status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.

13 Clinical Trial Phase I study of neoadjuvant accelerated short course radiation therapy with photons and capecitabine for resectable pancreatic cancer. 2014

Wo, Jennifer Y / Mamon, Harvey J / Ferrone, Cristina R / Ryan, David P / Blaszkowsky, Lawrence S / Kwak, Eunice L / Tseng, Yolanda D / Napolitano, Brian N / Ancukiewicz, Marek / Swanson, Richard S / Lillemoe, Keith D / Fernandez-del Castillo, Carlos / Hong, Theodore S. ·Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United States. Electronic address: jwo@partners.org. · Department of Radiation Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States. · Department of General Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States. · Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United States. · Harvard Radiation Oncology Program, Boston, United States. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United States. · Department of General Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States. ·Radiother Oncol · Pubmed #24231241.

ABSTRACT: PURPOSE: In this phase I study, we sought to determine the feasibility and tolerability of neoadjuvant short course radiotherapy (SC-CRT) delivered with photon RT with concurrent capecitabine for resectable pancreatic adenocarcinoma. MATERIALS AND METHODS: Ten patients with localized, resectable pancreatic adenocarcinoma were enrolled from December 2009 to August 2011. In dose level I, patients received 3 Gy × 10. In dose level 2, patients received 5 Gy × 5 (every other day). In dose level 3, patients received 5 Gy × 5 (consecutive days). Capecitabine was given during weeks 1 and 2. Surgery was performed 1-3 weeks after completion of chemotherapy. RESULTS: With an intended accrual of 12 patients, the study was closed early due to unexpected intraoperative complications. Compared to the companion phase I proton study, patients treated with photons had increased intraoperative RT fibrosis reported by surgeons (27% vs. 63%). Among those undergoing a Whipple resection, increased RT fibrosis translated to an increased mean OR time of 69 min. Dosimetric comparison revealed significantly increased low dose exposure to organs at risk for patients treated with photon RT. CONCLUSIONS: This phase I experience evaluating the tolerability of neoadjuvant SC-CRT with photon RT closed early due to unexpected intraoperative complications.

14 Article Variation in long-term oncologic outcomes by type of cancer center accreditation: An analysis of a SEER-Medicare population with pancreatic cancer. 2020

Fong, Zhi Ven / Chang, David C / Hur, Chin / Jin, Ginger / Tramontano, Angela / Sell, Naomi M / Warshaw, Andrew L / Fernandez-Del Castillo, Carlos / Ferrone, Cristina R / Lillemoe, Keith D / Qadan, Motaz. ·Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. · Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA, USA. · Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. Electronic address: mqadan@mgh.harvard.edu. ·Am J Surg · Pubmed #32265013.

ABSTRACT: BACKGROUND: Cancer center accreditation is designed to identify centers that provide high-quality cancer care. This also guides patients and referring physicians towards centers of excellence for specialized care. We sought to examine if cancer center accreditation was associated with improved long-term oncologic outcomes in patients with pancreatic adenocarcinoma. METHODS: Using the SEER-Medicare database, we identified patients who underwent pancreatectomy for pancreatic adenocarcinoma from 1996 to 2013. Hospitals were categorized into three groups: National Cancer Institute-designated (NCI-designated) centers, Commission on Cancer (CoC)-accredited centers, and "non-accredited" (NA) centers. Multilevel mixed-effects models were used to calculate adjusted examined lymph nodes, disease-specific survival (DSS), and overall survival (OS). RESULTS: We identified 5,118 patients who underwent pancreatectomy at 632 hospitals (41.0% NA, 49.6% CoC, 9.4% NCI). NCI-designated centers had a greater median number of lymph nodes examined compared with CoC-accredited or NA centers (14 vs. 10 vs. 11.0 nodes, respectively; p < 0.001). Patients treated at NCI centers had a higher 5-year DSS compared to those treated at CoC or NA centers (31.2% vs. 23.6% vs. 23.0%, respectively; p < 0.001). Finally, patients treated at NCI centers had a higher 5-year OS compared to those treated at CoC or NA centers (23.5% vs. 18.9% vs. 17.9%, respectively; p < 0.001). The associations held true when adjusted analyses were performed. CONCLUSION: Patients with resected pancreatic cancer treated at NCI-designated centers were associated with improved long-term oncologic outcomes. There was no difference between CoC-accredited centers compared with NA centers. Meticulous validation of accreditation is warranted globally prior to implementation.

15 Article Clinical staging in pancreatic adenocarcinoma underestimates extent of disease. 2020

Chawla, Akhil / Wo, Jennifer / Castillo, Carlos Fernandez-Del / Ferrone, Cristina R / Ryan, David P / Hong, Theodore S / Blaszkowsky, Lawrence S / Lillemoe, Keith D / Qadan, Motaz. ·Division of Surgical Oncology, Department of Surgery, Northwestern Medicine Regional Medical Group, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Vernon Cancer Center, Newton-Wellesley Hospital, 2014 Washington Street, Newton, MA, 02462, USA. · Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Vernon Cancer Center, Newton-Wellesley Hospital, 2014 Washington Street, Newton, MA, 02462, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Vernon Cancer Center, Newton-Wellesley Hospital, 2014 Washington Street, Newton, MA, 02462, USA. Electronic address: mqadan@mgh.harvard.edu. ·Pancreatology · Pubmed #32222341.

ABSTRACT: BACKGROUND/OBJECTIVES: We sought to identify the reliability of AJCC clinical staging was in comparison to pathologic staging in surgically resected patients with pancreatic cancer. METHODS: We used the National Cancer Database Pancreas from 2004 to 2016 and evaluated patients who underwent resection for PDAC with all documented components of clinical and pathologic stage. We first evaluated the distribution of overall clinical stage and pathologic stage and then evaluated for stage migration by assessing the number of patients who shifted from a clinical stage group to a respective pathologic stage group. To further characterize the migratory pattern, we assessed the distribution of clinical and pathologic T-stage and N-stage. RESULTS: In our cohort of 28,338 patients who underwent resection for PDAC, AJCC clinical staging did not reliably predict pathologic stage. Stage migration after resection was responsible for discrepancies between the distribution of overall clinical stage and pathologic stage. The predominant migration was from patients with clinical stage I disease to pathologic stage II disease. Most patients with clinical T1 and T2 disease were upstaged to pathologic T3 disease and over half of patients with clinical N0 disease were upstaged to pathologic N1 disease after resection. DISCUSSION: Clinical staging appears to overrepresent early T1, T2, and N0 disease, and underrepresent T3 and N1 disease.

16 Article Diabetes mellitus is associated with unfavorable pathologic features, increased postoperative mortality, and worse long-term survival in resected pancreatic cancer. 2020

Hank, Thomas / Sandini, Marta / Qadan, Motaz / Weniger, Maximilian / Ciprani, Debora / Li, Annie / Ferrone, Cristina R / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-Del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: CFernandez@mgh.harvard.edu. ·Pancreatology · Pubmed #31706821.

ABSTRACT: BACKGROUND: The risk of pancreatic ductal adenocarcinoma (PDAC) is increased in patients with diabetes mellitus (DM), particularly in those with new-onset DM. However, the impact of DM on outcomes following pancreatic surgery is not fully understood. We sought to explore the effects of DM on post-resection outcomes in patients undergoing either upfront resection or following neoadjuvant treatment (NAT). METHODS: Resections for PDAC between 2007 and 2016 were identified from a prospectively-maintained database. Data on demographics, pathology, and perioperative outcomes were compared between patients with or without DM. Survival analysis was performed using Kaplan-Meier curves and adjusted for confounders by a Cox-proportional hazards model. RESULTS: 662 patients were identified, of whom 277 (41.8%) had DM. Diabetics were more likely to be male, had higher BMI, and higher ASA-scores. At pathology, DM was associated with larger tumors (30 vs. 26 mm; p = 0.041), higher rates of lymph-node involvement (69% vs. 59%; p = 0.031) and perineural invasion (88% vs. 82%; p = 0.026). Despite having similar rates of complications, diabetics experienced higher 30-day mortality (3.2% vs. 0.8%; p = 0.019). Median overall survival was worse in diabetic patients (18 vs. 34 months; p < 0.001); this effect was more pronounced in patients with NAT (18 vs. 54 months; p < 0.001). At multivariate analysis, DM was confirmed as an independent predictor of post-resection survival. CONCLUSION: DM is a common comorbidity in PDAC and is associated with unfavorable pathology, as well as worse postoperative and oncologic outcomes. The blunted effect on survival is more pronounced in patients who undergo resection following NAT.

17 Article Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors. 2019

Cejas, Paloma / Drier, Yotam / Dreijerink, Koen M A / Brosens, Lodewijk A A / Deshpande, Vikram / Epstein, Charles B / Conemans, Elfi B / Morsink, Folkert H M / Graham, Mindy K / Valk, Gerlof D / Vriens, Menno R / Castillo, Carlos Fernandez-Del / Ferrone, Cristina R / Adar, Tomer / Bowden, Michaela / Whitton, Holly J / Da Silva, Annacarolina / Font-Tello, Alba / Long, Henry W / Gaskell, Elizabeth / Shoresh, Noam / Heaphy, Christopher M / Sicinska, Ewa / Kulke, Matthew H / Chung, Daniel C / Bernstein, Bradley E / Shivdasani, Ramesh A. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. · Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. · Translational Oncology Laboratory, Hospital La Paz Institute for Health Research, Madrid, Spain. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. yotam.drier@mail.huji.ac.il. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. yotam.drier@mail.huji.ac.il. · Lautenberg Center for Immunology and Cancer Research, Hebrew University, Faculty of Medicine, Jerusalem, Israel. yotam.drier@mail.huji.ac.il. · Department of Endocrine Oncology, UMC Utrecht Cancer Center, Utrecht, the Netherlands. · Department of Internal Medicine, Amsterdam UMC, Amsterdam, the Netherlands. · Department of Pathology, UMC Utrecht Cancer Center, Utrecht, the Netherlands. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. · Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgical Oncology, UMC Utrecht Cancer Center, Utrecht, the Netherlands. · Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Department of Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. · Departments of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. bernstein.bradley@mgh.harvard.edu. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. bernstein.bradley@mgh.harvard.edu. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. ramesh_shivdasani@dfci.harvard.edu. · Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. ramesh_shivdasani@dfci.harvard.edu. · Departments of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. ramesh_shivdasani@dfci.harvard.edu. ·Nat Med · Pubmed #31263286.

ABSTRACT: Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered 'non-functional'

18 Article Cross Validation of the Monoclonal Antibody Das-1 in Identification of High-Risk Mucinous Pancreatic Cystic Lesions. 2019

Das, Koushik K / Geng, Xin / Brown, Jeffrey W / Morales-Oyarvide, Vicente / Huynh, Tiffany / Pergolini, Ilaria / Pitman, Martha B / Ferrone, Cristina / Al Efishat, Mohammad / Haviland, Dana / Thompson, Elizabeth / Wolfgang, Christopher / Lennon, Anne Marie / Allen, Peter / Lillemoe, Keith D / Fields, Ryan C / Hawkins, William G / Liu, Jingxia / Castillo, Carlos Fernandez-Del / Das, Kiron M / Mino-Kenudson, Mari. ·Division of Gastroenterology, Washington University, St Louis, Missouri. Electronic address: k.das@wustl.edu. · Division of Gastroenterology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey. · Division of Gastroenterology, Washington University, St Louis, Missouri. · Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts. · Deparment of Pathology, Massachusetts General Hospital, Boston, Massachusetts. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland. · Department of Surgery Johns Hopkins School of Medicine, Baltimore, Maryland. · Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, Maryland. · Department of Surgery, Washington University, St Louis, Missouri. · Deparment of Pathology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: mminokenudson@partners.org. ·Gastroenterology · Pubmed #31175863.

ABSTRACT: BACKGROUND & AIMS: Although pancreatic cystic lesions (PCLs) are frequently and incidentally detected, it is a challenge to determine their risk of malignancy. In immunohistochemical and enzyme-linked immunosorbent assay (ELISA) analyses of tissue and cyst fluid from pancreatic intraductal papillary mucinous neoplasms, the monoclonal antibody Das-1 identifies those at risk for malignancy with high levels of specificity and sensitivity. We aimed to validate the ability of Das-1 to identify high-risk PCLs in comparison to clinical guidelines and clinical features, using samples from a multicenter cohort. METHODS: We obtained cyst fluid samples of 169 PCLs (90 intraductal papillary mucinous neoplasms, 43 mucinous cystic neoplasms, and 36 non-mucinous cysts) from patients undergoing surgery at 4 tertiary referral centers (January 2010 through June 2017). Histology findings from surgical samples, analyzed independently and centrally re-reviewed in a blinded manner, were used as the reference standard. High-risk PCLs were those with invasive carcinomas, high-grade dysplasia, or intestinal-type intraductal papillary mucinous neoplasms with intermediate-grade dysplasia. An ELISA with Das-1 was performed in parallel using banked cyst fluid samples. We evaluated the biomarker's performance, generated area under the curve values, and conducted multivariate logistic regression using clinical and pathology features. RESULTS: The ELISA for Das-1 identified high-risk PCLs with 88% sensitivity, 99% specificity, and 95% accuracy, at a cutoff optical density value of 0.104. In 10-fold cross-validation analysis with 100 replications, Das-1 identified high-risk PCLs with 88% sensitivity and 98% specificity. The Sendai, Fukuoka, and American Gastroenterological Association guideline criteria identified high-risk PCLs with 46%, 52%, and 74% accuracy (P for comparison to Das-1 ELISA <.001). When we controlled for Das-1 in multivariate regression, main pancreatic duct dilation >5 mm (odds ratio, 14.98; 95% confidence interval, 2.63-108; P < .0012), main pancreatic duct dilation ≥1 cm (odds ratio, 47.9; 95% confidence interval, 6.39-490; P < .0001), and jaundice (odds ratio, 6.16; 95% confidence interval, 1.08-36.7; P = .0397) were significantly associated with high-risk PCLs. CONCLUSIONS: We validated the ability of an ELISA with the monoclonal antibody Das-1 to detect PCLs at risk for malignancy with high levels of sensitivity and specificity. This biomarker might be used in conjunction with clinical guidelines to identify patients at risk for malignancy.

19 Article Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer. 2019

Ligorio, Matteo / Sil, Srinjoy / Malagon-Lopez, Jose / Nieman, Linda T / Misale, Sandra / Di Pilato, Mauro / Ebright, Richard Y / Karabacak, Murat N / Kulkarni, Anupriya S / Liu, Ann / Vincent Jordan, Nicole / Franses, Joseph W / Philipp, Julia / Kreuzer, Johannes / Desai, Niyati / Arora, Kshitij S / Rajurkar, Mihir / Horwitz, Elad / Neyaz, Azfar / Tai, Eric / Magnus, Neelima K C / Vo, Kevin D / Yashaswini, Chittampalli N / Marangoni, Francesco / Boukhali, Myriam / Fatherree, Jackson P / Damon, Leah J / Xega, Kristina / Desai, Rushil / Choz, Melissa / Bersani, Francesca / Langenbucher, Adam / Thapar, Vishal / Morris, Robert / Wellner, Ulrich F / Schilling, Oliver / Lawrence, Michael S / Liss, Andrew S / Rivera, Miguel N / Deshpande, Vikram / Benes, Cyril H / Maheswaran, Shyamala / Haber, Daniel A / Fernandez-Del-Castillo, Carlos / Ferrone, Cristina R / Haas, Wilhelm / Aryee, Martin J / Ting, David T. ·Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. · Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. · Clinic of Surgery, UKSH Campus Lübeck, Germany. · Institute of Pathology, University Medical Center Freiburg, Germany. · Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: aryee.martin@mgh.harvard.edu. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: dting1@mgh.harvard.edu. ·Cell · Pubmed #31155233.

ABSTRACT: Single-cell technologies have described heterogeneity across tissues, but the spatial distribution and forces that drive single-cell phenotypes have not been well defined. Combining single-cell RNA and protein analytics in studying the role of stromal cancer-associated fibroblasts (CAFs) in modulating heterogeneity in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) model systems, we have identified significant single-cell population shifts toward invasive epithelial-to-mesenchymal transition (EMT) and proliferative (PRO) phenotypes linked with mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling. Using high-content digital imaging of RNA in situ hybridization in 195 PDAC tumors, we quantified these EMT and PRO subpopulations in 319,626 individual cancer cells that can be classified within the context of distinct tumor gland "units." Tumor gland typing provided an additional layer of intratumoral heterogeneity that was associated with differences in stromal abundance and clinical outcomes. This demonstrates the impact of the stroma in shaping tumor architecture by altering inherent patterns of tumor glands in human PDAC.

20 Article Autoimmune Pancreatitis Type 2: Diagnostic Utility of PD-L1 Immunohistochemistry. 2019

Gupta, Rajib / Neyaz, Azfar / Chougule, Abhijit / Akita, Masayuki / Zen, Yoh / Forcione, David / Castillo, Carlos Fernandez-Del / Ferrone, Cristina R / Deshpande, Vikram. ·Department of Pathology, Upstate Medical University, Syracuse, NY. · Departments of Pathology. · Department of Diagnostic Pathology, Kobe University, Kobe, Japan. · Institute of Liver Studies, King's College Hospital and King's College London, London, UK. · Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Surgery. ·Am J Surg Pathol · Pubmed #31135488.

ABSTRACT: BACKGROUND: Autoimmune pancreatitis (AIP) encompasses a heterogenous disease group that includes IgG4-related type 1 AIP and non-IgG4-related type 2 AIP. Clinically and on imaging, type 2 AIP mimics type 1 AIP, other forms of chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC); therefore, discriminatory markers may aid proper diagnosis. Herein, we examine the expression of PD-L1 and indoleamine 2,3-dioxygenase (IDO1) as a diagnostic tool to distinguish type 2 AIP from other forms of pancreatitis and PDAC. DESIGN: We evaluated 35 pancreatectomy specimens diagnosed with type 2 AIP and potential mimics of this disease including type 1 AIP (n=14), chronic pancreatitis-not otherwise specified (n=10), groove pancreatitis (n=14), and PDAC (n=278). We scored inflammatory infiltrates, fibrosis and atrophy and performed immunohistochemical staining for PD-L1 and IDO1. We validated our findings on a series of endoscopic ultrasound-guided biopsies from patients with suspected type 2 AIP and inflammatory and neoplastic mimics of this disease (n=37). RESULTS: The mean age of patients with type 2 AIP was 50 years with a F:M ratio of 1.2:1. Patients with type 2 AIP showed pancreatic ductal staining for PD-L1 and IDO1 in 69% (24/35) and 60% (15/25) of cases, respectively. PD-L1 reactivity was noted in 3% of patients with other forms of chronic pancreatitis and 3% of PDACs; notably, peritumoral ducts and acini were negative. Eight of 9 endoscopic ultrasound-guided biopsies with pancreatic ductal epithelium from patients with type 2 AIP were positive for PD-L1, while the inflammatory and neoplastic mimics were negative. Collectively, the sensitivity and specificity of PD-L1 as a marker of type 2 AIP was 70% and 99%, respectively. CONCLUSIONS: Ductal PD-L1 reactivity has the potential to distinguish type 2 AIP from other forms of pancreatitis and PDAC.

21 Article Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells. 2019

Du, Hongwei / Hirabayashi, Koichi / Ahn, Sarah / Kren, Nancy Porterfield / Montgomery, Stephanie Ann / Wang, Xinhui / Tiruthani, Karthik / Mirlekar, Bhalchandra / Michaud, Daniel / Greene, Kevin / Herrera, Silvia Gabriela / Xu, Yang / Sun, Chuang / Chen, Yuhui / Ma, Xingcong / Ferrone, Cristina Rosa / Pylayeva-Gupta, Yuliya / Yeh, Jen Jen / Liu, Rihe / Savoldo, Barbara / Ferrone, Soldano / Dotti, Gianpietro. ·Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA. · Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Surgery, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA. · Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: gdotti@med.unc.edu. ·Cancer Cell · Pubmed #30753824.

ABSTRACT: The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3.CAR-Ts, and superior antitumor activity when targeting tumor cells that constitutively expressed PD-L1. We took advantage of the cross-reactivity of the B7-H3.CAR with murine B7-H3, and found that B7-H3.CAR-Ts significantly controlled tumor growth in a syngeneic tumor model without evident toxicity. These findings support the clinical development of B7-H3.CAR-Ts.

22 Article Quasimesenchymal phenotype predicts systemic metastasis in pancreatic ductal adenocarcinoma. 2019

Mahadevan, Krishnan K / Arora, Kshitij S / Amzallag, Arnaud / Williams, Erik / Kulkarni, Anupriya S / Fernandez-Del Castillo, Carlos / Lillemoe, Keith D / Bardeesy, Nabeel / Hong, Theodore S / Ferrone, Cristina R / Ting, David T / Deshpande, Vikram. ·Department of Pathology, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston, MA, USA. · Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston, MA, USA. · Department of Medicine, Division of Oncology, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston, MA, USA. · Department of Surgery, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston, MA, USA. · Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston, MA, USA. · Department of Pathology, Massachusetts General Hospital, Boston, MA and Harvard Medical School, Boston, MA, USA. vikramdirdeshpande@gmail.com. ·Mod Pathol · Pubmed #30683911.

ABSTRACT: Metastasis following surgical resection is a leading cause of mortality in pancreatic ductal adenocarcinoma. Epithelial-mesenchymal transition is thought to play an important role in metastasis, although its clinical relevance in metastasis remains uncertain. We evaluated a panel of RNA in-situ hybridization probes for epithelial-mesenchymal transition-related genes expressed in circulating tumor cells. We assessed the predictive value of this panel for metastasis in pancreatic ductal adenocarcinoma and, to determine if the phenotype is generalizable between cancers, in colonic adenocarcinoma. One hundred fifty-eight pancreatic ductal adenocarcinomas and 205 colonic adenocarcinomas were classified as epithelial or quasimesenchymal phenotype using dual colorimetric RNA-in-situ hybridization. SMAD4 expression on pancreatic ductal adenocarcinomas was assessed by immunohistochemistry. Pancreatic ductal adenocarcinomas with quasimesenchymal phenotype had a significantly shorter disease-specific survival (P = 0.031) and metastasis-free survival (P = 0.0001) than those with an epithelial phenotype. Pancreatic ductal adenocarcinomas with SMAD4 loss also had lower disease-specific survival (P = 0.041) and metastasis-free survival (P = 0.001) than those with intact SMAD4. However, the quasimesenchymal phenotype proved a more robust predictor of metastases-area under the curve for quasimesenchymal = 0.8; SMAD4 = 0.6. The quasimesenchymal phenotype also predicted metastasis-free survival (P = 0.004) in colonic adenocarcinoma. Epithelial-mesenchymal transition defined two phenotypes with distinct metastatic capabilities-epithelial phenotype tumors with predominantly organ-confined disease and quasimesenchymal phenotype with high risk of metastatic disease in two epithelial malignancies. Collectively, this work validates the relevance of epithelial-mesenchymal transition in human gastrointestinal tumors.

23 Article Neoadjuvant FOLFIRINOX for Patients with Borderline Resectable or Locally Advanced Pancreatic Cancer: Results of a Decision Analysis. 2019

Choi, Jin G / Nipp, Ryan D / Tramontano, Angela / Ali, Ayman / Zhan, Tiannan / Pandharipande, Pari / Dowling, Emily C / Ferrone, Cristina R / Hong, Theodore S / Schrag, Deborah / Fernandez-Del Castillo, Carlos / Ryan, David P / Kong, Chung Yin / Hur, Chin. ·Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. · Institute for Technology Assessment, Massachusetts General Hospital, Boston, Massachusetts, USA. · Health Innovations Research and Evaluations Unit, Columbia University Medical Center, New York, NY, USA. · Department of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA rnipp@mgh.harvard.edu. · Harvard Medical School, Boston, Massachusetts, USA. · Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Department of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA. · Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA. ·Oncologist · Pubmed #30559125.

ABSTRACT: BACKGROUND: The effectiveness and cost-effectiveness of using neoadjuvant FOLFIRINOX (nFOLFIRINOX) for patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC) are unknown. Our objective was to determine whether nFOLFIRINOX is more effective or cost-effective for patients with BR/LA PDAC compared with upfront resection surgery and adjuvant gemcitabine plus capecitabine (GEM/CAPE) or gemcitabine monotherapy (GEM). MATERIALS AND METHODS: We performed a decision-analysis to assess the value of nFOLFIRINOX versus GEM/CAPE or GEM using a mathematical simulation model. Model transition probabilities were estimated using published and institutional clinical data. Model outcomes included overall and disease-free survival, quality-adjusted life-years (QALYs), cost in U.S. dollars, and cost-effectiveness expressed as an incremental cost-effectiveness ratio. Deterministic and probabilistic sensitivity analyses explored the uncertainty of model assumptions. RESULTS: Model results found median overall survival (34.5/28.0/22.0 months) and disease-free survival (15.0/14.0/13.0 months) were better for nFOLFIRINOX compared with GEM/CAPE and GEM. nFOLFIRINOX was the optimal strategy on an efficiency frontier, resulting in an additional 0.35 life-years, or 0.30 QALYs, at a cost of $46,200/QALY gained compared with GEM/CAPE. Sensitivity analysis found that cancer recurrence and complete resection rates most affected model results, but were otherwise robust. Probabilistic sensitivity analyses found that nFOLFIRINOX was cost-effective 92.4% of the time at a willingness-to-pay threshold of $100,000/QALY. CONCLUSION: Our modeling analysis suggests that nFOLFIRINOX is preferable to upfront surgery for patients with BR/LA PDAC from both an effectiveness and cost-effectiveness standpoint. Additional clinical data that further define the long-term effectiveness of nFOLFIRINOX are needed to confirm our results. IMPLICATIONS FOR PRACTICE: Increasingly, neoadjuvant FOLFIRINOX has been used for borderline resectable and locally advanced pancreatic cancer with the goal of rendering them resectable and decreasing risk of recurrence. Despite many efforts to show the benefits of neoadjuvant over adjuvant therapies, clinical evidence to guide this decision is largely lacking. Decision-analytic modeling can provide a methodologic platform that integrates the best available data to quantitatively explore clinical decisions by simulating a hypothetical clinical trial. This modeling analysis suggests that neoadjuvant FOLFIRINOX is preferable to upfront surgery and adjuvant therapies by various outcome metrics including quality-adjusted life years, overall survival, and incremental cost-effectiveness ratio.

24 Article Major Complications Independently Increase Long-Term Mortality After Pancreatoduodenectomy for Cancer. 2019

Sandini, M / Ruscic, K J / Ferrone, C R / Qadan, M / Eikermann, M / Warshaw, A L / Lillemoe, K D / Castillo, Carlos Fernández-Del. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 15 Parkman ST, Boston, MA, 02114-02115, USA. · Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 15 Parkman ST, Boston, MA, 02114-02115, USA. cfernandez@mgh.harvard.edu. ·J Gastrointest Surg · Pubmed #30225794.

ABSTRACT: BACKGROUND: Postoperative major morbidity has been associated with worse survival gastrointestinal tumors. This association remains controversial in pancreatic cancer (PC). We analyzed whether major complications after surgical resection affect long-term survival. METHODS: Records of all PC patients resected from 2007 to 2015 were reviewed. Major morbidity was defined as any grade-3 or higher 30-day complications, per the Clavien-Dindo Classification. Patients who died within 90 days after surgery were excluded from survival analysis. RESULTS: Of 616 patients, 81.7% underwent pancreatoduodenectomy (PD) and 18.3% distal pancreatectomy (DP). Major complications occurred in 19.1% after PD and 15.9% after DP. In patients who survived > 90 days, the likelihood of receiving adjuvant treatment was 43.9% if major complications had occurred, vs. 68.5% if not (p < 0.001), and those who received it started the treatment median 10 days later compared with uncomplicated patients (median 60 days (50-72) vs. 50 days (41-61), p = 0.001). By univariate analysis, in addition to the conventional pathology-related prognostic determinants and the receipt of adjuvant treatment, major complications worsened long-term survival after PD (median OS 26 months vs. 15, p = 0.008). A difference was also seen after DP, but it did not reach statistical significance, likely related to the small sample size (median OS 33 months vs. 18, p = 0.189). At multivariate analysis for PD, major postoperative complications remained independently associated with worse survival [HR 1.37, 95%CI (1.01-1.86)]. CONCLUSIONS: Major surgical complications after pancreaticoduodenectomy are associated with worse long-term survival in pancreatic cancer. This effect is independent of the receipt of adjuvant treatment.

25 Article Number of Examined Lymph Nodes and Nodal Status Assessment in Distal Pancreatectomy for Body/Tail Ductal Adenocarcinoma. 2019

Malleo, Giuseppe / Maggino, Laura / Ferrone, Cristina R / Marchegiani, Giovanni / Mino-Kenudson, Mari / Capelli, Paola / Rusev, Borislav / Lillemoe, Keith D / Bassi, Claudio / Fernàndez-Del Castillo, Carlos / Salvia, Roberto. ·Unit of General and Pancreatic Surgery, Department of Surgery and Oncology, University of Verona Hospital Trust, Verona, Italy. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Department of Pathology and Diagnostics, University of Verona Hospital Trust, Verona, Italy. · ARC-Net Research Center, University of Verona, Verona, Italy. ·Ann Surg · Pubmed #29672406.

ABSTRACT: OBJECTIVE: First, to assess the impact of the number of examined lymph nodes (ELNs) on staging and survival after distal pancreatectomy (DP) for pancreatic adenocarcinoma (PDAC). Second, to identify the minimum number of ELNs (MNELNs) ensuring an accurate detection of nodal involvement. Third, to reappraise the role of lymph node (LN) parameters, including N-status and lymph node ratio (LNR). BACKGROUND: In contrast with pancreatoduodenectomy, information on LN staging and the MNELN required in DP is lacking. METHODS: Patients undergoing DP for PDAC at 2 academic hospitals from 2000 through 2013 were retrospectively analyzed. The eighth edition of the American Joint Committee on Cancer staging system was used. The MNELN was estimated using the binomial probability law. Survival analyses were performed separately for node-negative and node-positive patients using univariable and multivariable models. RESULTS: The study population consisted of 240 patients. The median number of ELN was 21, significantly lower in node-negative patients as compared with node-positive patients (18.5 vs 24.0; P = 0.001). The proportion of node-positive patients increased with increasing numbers of ELNs, whereas LNR showed an inverse trend. The estimated MNELN was 20. The number of ELN (≥ or <20) was an independent prognostic factor only in node-negative patients [odds ratio (OR) 3.23 for ELN <20), suggesting a stage migration effect. In node-positive patients, N2-class, but not LNR, was a significant predictor of survival at multivariable analysis (OR 1.68). CONCLUSION: The number of ELN affects nodal staging in body/tail PDAC. At least 20 LNs are required for correct staging. N-status is superior to LNR in predicting survival of node-positive patients.

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