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Mino-Kenudson, Mari

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Mino-Kenudson

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Mari

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Mino-Kenudson, Mari
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    Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival
    (Public Library of Science, 2017) Pergolini, Ilaria; Morales-Oyarvide, Vicente; Mino-Kenudson, Mari; Honselmann, Kim C.; Rosenbaum, Matthew; Nahar, Sabikun; Kem, Marina; Ferrone, Cristina; Lillemoe, Keith; Bardeesy, Nabeel; Ryan, David; Thayer, Sarah P.; Warshaw, Andrew; Fernandez-Del Castillo, Carlos; Liss, Andrew
    Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice. Fifty-seven tumors were successfully engrafted and even after extensive passaging, the histology of poorly-, moderately-, and well-differentiated tumors was maintained in the PDX models. Moreover, the fibroblast and collagen contents in the stroma of patient tumors were recapitulated in the corresponding PDX models. Analysis of the clinicopathological features of patients revealed xenograft tumor engraftment was associated with lymphovascular invasion (P = 0.001) and worse recurrence-free (median, 7 vs. 16 months, log-rank P = 0.047) and overall survival (median, 13 vs. 21 months, log-rank P = 0.038). Among successful engraftments, median time of growth required for reimplantation into new mice was 151 days. Reflective of the inherent biological diversity between PDX tumors with rapid (<151 days) and slow growth, differences in their growth were maintained during extensive passaging. Rapid growth was additionally associated with lymph node metastasis (P = 0.022). The association of lymphovascular invasion and lymph node metastasis with PDX formation and rapid growth may reflect an underlying biological mechanism that allows these tumors to adapt and grow in a new environment. While the ability of PDX tumors to mimic the cellular and non-cellular features of the parental tumor stroma provides a valuable model to study the interaction of PDAC cells with the tumor microenvironment, the association of successful engraftment with adverse clinicopathological features suggests PDX models over represent more aggressive forms of this disease.
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    Critical role for arginase 2 in obesity-associated pancreatic cancer
    (Nature Publishing Group UK, 2017) Zaytouni, Tamara; Tsai, Pei-Yun; Hitchcock, Daniel S.; DuBois, Cory D.; Freinkman, Elizaveta; Lin, Lin; Morales-Oyarvide, Vicente; Lenehan, Pat; Wolpin, Brian M.; Mino-Kenudson, Mari; Torres, Eduardo M.; Stylopoulos, Nicholas; Clish, Clary B.; Kalaany, Nada
    Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDA remain unknown. Here we show that obesity-driven PDA exhibits accelerated growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. We find that the mitochondrial form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced upon obesity, and silencing or loss of ARG2 markedly suppresses PDA. In vivo infusion of 15N-glutamine in obese mouse models of PDA demonstrates enhanced nitrogen flux into the urea cycle and infusion of 15N-arginine shows that Arg2 loss causes significant ammonia accumulation that results from the shunting of arginine catabolism into alternative nitrogen repositories. Furthermore, analysis of PDA patient tumors indicates that ARG2 levels correlate with body mass index (BMI). The specific dependency of PDA on ARG2 rather than the principal hepatic enzyme ARG1 opens a therapeutic window for obesity-associated pancreatic cancer.
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    Comprehensive Microscopy of the Esophagus in Human Patients with Optical Frequency Domain Imaging
    (Elsevier BV, 2008) Suter, Melissa; Vakoc, Benjamin; Yachimski, Patrick S.; Shishkov, Milen; Lauwers, Gregory Y.; Mino-Kenudson, Mari; Bouma, Brett; Nishioka, Norman; Tearney, Guillermo
    Background: Optical coherence tomography (OCT) is a cross-sectional, high-resolution imaging modality that has been shown to accurately differentiate esophageal specialized intestinal metaplasia (SIM) from gastric cardia at the squamocolumnar junction (SCJ) and diagnose high-grade dysplasia and intramucosal carcinoma in patients with SIM. The clinical utility of OCT has been limited, however, by its inability to acquire images over large areas. Objective: The aim of this study was to use recently developed high-speed OCT technology, termed optical frequency domain imaging (OFDI), and a new balloon-centering catheter (2.5 cm diameter) to demonstrate the feasibility of large area, comprehensive optical microscopy of the entire distal esophagus (∼6.0 cm) in patients. Design: A pilot feasibility study. Setting: Massachusetts General Hospital. Patients: Twelve patients undergoing routine EGD. Results: Comprehensive microscopy of the distal esophagus was successfully performed in 10 patients with the OFDI system and balloon catheter. There were no complications resulting from the imaging procedure. Volumetric data sets were acquired in less than 2 minutes. OFDI images at the SCJ showed a variety of microscopic features that were consistent with histopathologic findings, including squamous mucosa, cardia, SIM with and without dysplasia, and esophageal erosion. Limitations: Inability to obtain direct correlation of OFDI data and histopathologic diagnoses. Conclusions: Comprehensive volumetric microscopy of the human distal esophagus was successfully demonstrated with OFDI and a balloon-centering catheter, providing a wealth of detailed information about the structure of the esophageal wall. This technique will support future studies to compare OFDI image information with histopathologic diagnoses.
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    Pancreatic Ductal Adenocarcinoma: Long-Term Survival Does Not Equal Cure
    (Elsevier BV, 2012) Ferrone, Cristina; Pieretti-Vanmarcke, Rafael; Bloom, Jordan; Zheng, Hui; Szymonifka, Jackye; Wargo, Jennifer Ann; Thayer, Sarah P.; Lauwers, Gregory Y.; Deshpande, Vikram; Mino-Kenudson, Mari; Fernandez-Del Castillo, Carlos; Lillemoe, Keith; Warshaw, Andrew
    Background: Pancreatic ductal adenocarcinoma represents 90% of pancreatic cancers and is an important cause of cancer death in the United States. Operative resection remains as the only treatment providing prolonged survival, but even after a curative resection, 5-year survival rates are low. Our aim was to identify the prognostic factors for long-term survival after resection of pancreatic ductal adenocarcinoma related to patients, treatments, and tumor biology. Methods: Retrospective review identified 959 patients who underwent resection of their pancreatic adenocarcinoma between February 1985 and December 2010, of whom 499 were resected before November 2006 and represent the cohort we describe in this study. Patient, tumor, and treatment-related variables were assessed for their associations with 5- and 10-year overall survival. Results: Of the 499 patients, 49% were female and median age was 65 years. The majority of patients had stage IIb disease (60%). Actual 5-year survival after resection of pancreatic adenocarcinoma was 19% (95/499), and actual 10-year survival was 10% (33/329). Significant clinicopathologic factors predicting 5- and 10-year survival were negative margins and negative nodal status. Interestingly, 41% (39/95) of long-term survivors had positive nodes and 24% (23/95) had positive margins. Conclusion: Pancreatic ductal adenocarcinoma demonstrates a very heterogeneous biology, but patients with negative resection margins and node negative cancers are more likely to survive 5 years after resection. However, our series demonstrates that the biology of the cancer rather than simple pathologic factors determine a patient's prognosis.
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    Comprehensive Imaging of Gastroesophageal Biopsy Samples by Spectrally Encoded Confocal Microscopy
    (Elsevier BV, 2010) Kang, Dongkyun; Suter, Melissa; Boudoux, Caroline; Yoo, Hongki; Yachimski, Patrick S.; Puricelli, William P.; Nishioka, Norman; Mino-Kenudson, Mari; Lauwers, Gregory Y.; Bouma, Brett; Tearney, Guillermo
    Background: Spectrally encoded confocal microscopy (SECM) is a high-speed reflectance confocal microscopy technique that has the potential to be used for acquiring comprehensive images of the entire distal esophagus endoscopically with subcellular resolution. Objective: The goal of this study was to demonstrate large-area SECM in upper GI tissues and to determine whether the images contain microstructural information that is useful for pathologic diagnosis. Design: A feasibility study. Setting: Gastrointestinal Unit, Massachusetts General Hospital. Patients: Fifty biopsy samples from 36 patients undergoing routine EGD were imaged by SECM, in their entirety, immediately after their removal. Results: The microstructure seen in the SECM images was similar to that seen by histopathology. Gastric cardia mucosa was clearly differentiated from squamous mucosa. Gastric fundic/body type mucosa showed more tightly packed glands than gastric cardia mucosa. Fundic gland polyps showed cystically dilated glands lined with cuboidal epithelium. The presence of intraepithelial eosinophils was detected with the cells demonstrating a characteristic bilobed nucleus. Specialized intestinal metaplasia was identified by columnar epithelium and the presence of goblet cells. Barrett's esophagus (BE) with dysplasia was differentiated from specialized intestinal metaplasia by the loss of nuclear polarity and disorganized glandular architecture. Limitations: Ex vivo, descriptive study. Conclusions: Large-area SECM images of gastroesophageal biopsy samples enabled the visualization of both subcellular and architectural features of various upper GI mucosal types and were similar to the corresponding histopathologic slides. These results suggest that the development of an endoscopic SECM probe is merited.
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    Identifying Intestinal Metaplasia at the Squamocolumnar Junction by Using Optical Coherence Tomography
    (Elsevier BV, 2007) Evans, John A.; Bouma, Brett; Bressner, Jason; Shishkov, Milen; Lauwers, Gregory Y.; Mino-Kenudson, Mari; Nishioka, Norman; Tearney, Guillermo
    Background: Optical coherence tomography (OCT) is an optical imaging method that produces high-resolution cross-sectional images of the esophagus. The accuracy of OCT for differentiating tissue types at the squamocolumnar junction (SCJ) has not been established. Objective: The purpose of this study was to identify and validate OCT image criteria for distinguishing metaplastic from nonmetaplastic tissue at the SCJ. Design: A total of 196 biopsy-correlated OCT images of the SCJ were acquired from 113 patients undergoing upper endoscopy. A pathologist blinded to the OCT results reviewed each pathology specimen and determined the presence of the following histopathology: gastric cardia, squamous mucosa, pancreatic metaplasia, and intestinal metaplasia. An algorithm for diagnosing specialized intestinal metaplasia (SIM) was created by reviewing a training set of 40 biopsy-correlated OCT images. Two blinded investigators prospectively tested the algorithm on a validation set of 123 images. Results: OCT images of squamous mucosa were characterized by a layered appearance without epithelial glands; gastric cardia, by vertical pit and gland structure, a well-defined epithelial surface reflectivity, and relatively poor image penetration; and SIM by an irregular architecture and good image penetration. The OCT criteria were 85% sensitive and 95% specific for SIM when applied retrospectively to the training set. When applied to the validation set, the algorithm was 81% sensitive for both OCT readers and 66% and 57% specific for diagnosing SIM. The interobserver agreement was good (κ = 0.53). Conclusions: OCT imaging can identify SIM at the SCJ with an accuracy similar to that of endoscopy.
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    Alpha-CTLA-4 mAb-associated Panenteritis: A Histologic and Immunohistochemical Analysis
    (Ovid Technologies (Wolters Kluwer Health), 2008) Oble, Darryl A.; Mino-Kenudson, Mari; Goldsmith, Jeffrey; Hodi, Frank; Seliem, Rania M.; Dranoff, Glenn; Mihm, Martin; Hasserjian, Robert; Lauwers, Gregory Y.
    Monoclonal antibodies (mAbs) against the cytotoxic T lymphocyte antigen-4 (CTLA-4) molecule are used as an adjuvant to experimental tumor immunization protocols in the treatment of malignant melanomas and ovarian cancers. Aside from noted early therapeutic successes, a spectrum of adverse effects, including severe gastroenteritis, has been reported. We report herein our observations of 5 patients who developed severe gastrointestinal toxicity affecting the gastric, small intestinal, and colonic mucosa. The endoscopic findings were variable, ranging from normal to diffusely erythematous and ulcerated mucosa. The constant histologic findings included a lymphoplasmacytic expansion of the lamina propria with increase in intraepithelial lymphocytes. Increased epithelial apoptosis was also a distinctive feature. Cryptitis and glandular inflammation were observed in the colon, ileum, and stomach, whereas villous blunting was present in the ileal and duodenal mucosa. Immunohistochemical analysis revealed a marked increase of all T-cell subsets (CD3+, CD4+, and CD8+) and of CD4CD25 regulatory T cells. We conclude that the panenteritis associated with injection of alpha-CTLA-4 mAbs demonstrates histology resembling autoimmune enteropathy. Furthermore, although the pathogenesis of immune dysregulation after the infusion of alpha-CTLA-4 mAbs remains unclear, we suspect that the increased number of regulatory T cells in the gastrointestinal mucosa may play a role in the pathogenicity.
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    Prognostic relevance of morphological types of intraductal papillary mucinous neoplasms of the pancreas
    (BMJ, 2010) Furukawa, Toru; Hatori, Takashi; Fujita, I.; Yamamoto, M.; Kobayashi, M.; Ohike, N.; Morohoshi, T.; Egawa, S.; Unno, M.; Takao, S.; Osako, M.; Yonezawa, S.; Mino-Kenudson, Mari; Lauwers, Gregory Y.; Yamaguchi, H.; Ban, S.; Shimizu, M.
    Objective: The clinicopathological significance of four morphological types of intraductal papillary mucinous neoplasms of the pancreas (IPMNs; gastric, intestinal, pancreatobiliary and oncocytic) was assessed. Design Retrospective multicentre analysis of 283 surgically resected IPMNs. Results: Of the 283 IPMNs, 139 were of the gastric type, 101 were intestinal, 19 were pancreatobiliary and 24 were oncocytic. These types were significantly associated with clinicopathological factors including sex (p=0.0032), age (p=0.00924), ectatic duct size (p=0.0245), detection of mural nodules (p=4.09×10−6), histological grade (p<2.20×10−16), macroscopic types with differential involvement of the pancreatic duct system (p=3.91×10−5), invasive phenotypes (p=3.34×10−12), stage (p<2.20×10−16) and recurrence (p=0.00574). Kaplan–Meier analysis showed significant differences in patient survival by morphological type (p=5.24×10−6). Survival rates at 5 and 10 years, respectively, were 0.937 (95% CI 0.892 to 0.984) for patients with gastric-type IPMNs; 0.886 (95% CI 0.813 to 0.965) and 0.685 (95% CI 0.553 to 0.849) for those with intestinal-type IPMNs; 0.839 (95% CI 0.684 to 1.000) and 0.734 (95% CI 0.526 to 1.000) for those with oncocytic-type IPMNs; and 0.520 (95% CI 0.298 to 0.909) and undetermined for those with pancreatobiliary-type IPMNs. Analysis by the Cox proportional hazards model comparing prognostic risks determined by stage and the morphological and macroscopic types indicated that staging was the most significant predictor of survival (p=3.68×10−8) followed by the morphological type (p=0.0435). Furthermore, the morphological type remained a significant predictor in a subcohort of invasive cases (p=0.0089). Conclusion: In this multicentre retrospective analysis, the morphological type of IPMN appears to be an independent predictor of patient prognosis.
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    Mucinous Cystic Neoplasm of the Pancreas is Not an Aggressive Entity
    (Ovid Technologies (Wolters Kluwer Health), 2008) Crippa, Stefano; Salvia, Roberto; Warshaw, Andrew; Domínguez, Ismael; Bassi, Claudio; Falconi, Massimo; Thayer, Sarah P.; Zamboni, Giuseppe; Lauwers, Gregory Y.; Mino-Kenudson, Mari; Capelli, Paola; Pederzoli, Paolo; Castillo, Carlos Fernández-del
    Objective: Mucinous cystic neoplasms (MCNs) of the pancreas have often been confused with intraductal papillary mucinous neoplasms. We evaluated the clinicopathologic characteristics, prevalence of cancer, and prognosis of a large series of well-characterized MCNs in 2 tertiary centers. Methods: Analysis of 163 patients with resected MCNs, defined by the presence of ovarian stroma and lack of communication with the main pancreatic duct. Results: MCNs were seen mostly in women (95%) and in the distal pancreas (97%); 25% were incidentally discovered. Symptomatic patients typically had mild abdominal pain, but 9% presented with acute pancreatitis. One hundred eighteen patients (72%) had adenoma, 17 (10.5%) borderline tumors, 9 (5.5%) in situ carcinoma, and 19 (12%) invasive carcinoma. Patients with invasive carcinoma were significantly older than those with noninvasive neoplasms (55 vs. 44 years, P = 0.01). Findings associated with malignancy were presence of nodules (P = 0.0001) and diameter ≥60 mm (P = 0.0001). All neoplasms with cancer were either ≥40 mm in size or had nodules. There was no operative mortality and postoperative morbidity was 49%. Median follow-up was 57 months (range, 4 –233); only patients with invasive carcinoma had recurrence. The 5-year disease-specific survival for noninvasive MCNs was 100%, and for those with invasive cancer, 57%. Conclusions: This series, the largest with MCNs defined by ovarian stroma, shows a prevalence of cancer of only 17.5%. Patients with invasive carcinoma are older, suggesting progression from adenoma to carcinoma. Although resection should be considered for all cases, in low-risk MCNs (≤4 cm/no nodules), nonradical resections are appropriate.
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    Cyclooxygenase-2 expression in esophageal epithelium before and after photodynamic therapy for Barrett’s esophagus with high-grade dysplasia or intramucosal carcinoma
    (Springer Nature, 2011) Yachimski, Patrick; Mino-Kenudson, Mari; Sherwood, Margaret E.; Puricelli, William P.; Nishioka, Norman; Lauwers, Gregory Y.
    Cyclooxygenase-2 expression is upregulated in Barrett’s esophagus and esophageal adenocarcinoma. Photodynamic therapy using porfimer sodium can result in ablation of dysplasia and intramucosal carcinoma, eradication of Barrett’s esophagus, and restitution of squamous epithelium. The aim of this study was to determine the effect of photodynamic therapy on cyclooxygenase-2 expression in esophageal epithelium. Paired pre- and post-photodynamic therapy biopsy samples from the same anatomical levels of 20 individuals who had undergone photodynamic therapy for Barrett’s esophagus with high-grade dysplasia and/or intramucosal carcinoma were immunostained using a cyclooxygenase-2 monoclonal antibody. Cyclooxygenase-2 expression was graded in squamous epithelium, Barrett’s esophagus, and neoplasia (if present) as follows: grade 0 (no staining), grade 1 (staining in 1–10% of cells), grade 2 (staining in 11–90% of cells), and grade 3 (staining in >90% of cells). Pre-photodynamic therapy median cyclooxygenase-2 expression was grade 2 (range 1–3) in neoplastic foci and grade 1 (range 1–3) in nondysplastic Barrett’s esophagus (P = 0.0009 for pairwise comparison). With the exception of a few cells staining in the basal epithelial layers, median cyclooxygenase-2 expression was graded as 0 (similar to controls) in both pre-photodynamic therapy squamous epithelium and post-photodynamic therapy neosquamous epithelium. This was significantly lower when compared to either neoplastic foci (P < 0.0001) or nondysplastic Barrett’s esophagus (P < 0.0001) pre-photodynamic therapy. Notably, in four patients with post-photodynamic therapy recurrent neoplasia, cyclooxygenase-2 expression returned to elevated levels. Cyclooxygenase-2 expression is elevated in Barrett’s esophagus with high-grade dysplasia or intramucosal carcinoma prior to photodynamic therapy. Following successful photodynamic therapy, cyclooxygenase-2 expression in neosquamous epithelium returns to a low baseline level similar to that observed in native esophageal squamous epithelium. Post-photodynamic therapy neoplastic recurrence is associated with elevated cyclooxygenase-2 expression. Prospective studies should determine whether cyclooxygenase inhibitors have a role as adjuvant therapy to prevent recurrence of Barrett’s esophagus following endoscopic therapy.