231 results on '"Hawkins WG"'
Search Results
2. Resection of tumors of the neck of the pancreas with venous invasion: the "Whipple at the Splenic Artery (WATSA)" procedure.
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Strasberg SM, Sanchez LA, Hawkins WG, Fields RC, Linehan DC, Strasberg, Steven M, Sanchez, Luis A, Hawkins, William G, Fields, Ryan C, and Linehan, David C
- Abstract
Introduction: Tumors of the neck of the pancreas may involve the superior mesenteric and portal veins as well as the termination of the splenic vein. This presents a difficult problem since the pancreas cannot be transected through the neck as is standard in a Whipple procedure. Here, we present our method of resecting such tumors, which we term "Whipple at the Splenic Artery (WATSA)".Methods: The superior mesenteric and portal veins are isolated below and above the pancreas, respectively. The pancreas and splenic vein are divided just to the right of the point that the splenic artery contacts the superior border of the pancreas. This plane of transection is approximately 2 cm to the left of the pancreatic neck and away from the tumor. The superior mesenteric artery is cleared from the left side of the patient. With the specimen remaining attached only by the superior mesenteric and portal veins, these structures are clamped and divided. Reconstruction is performed with or without a superficial femoral vein graft. The splenic vein is not reconstructed.Results: Ten cases have been performed to date without mortality. We have previously shown that the pattern of venous collateral development following occlusion of the termination of the splenic vein in the manner described is not similar to that of cases of sinistral (left sided) portal hypertension.Discussion: Whipple at the splenic artery (WATSA) is a safe method for resection of tumors of the neck of the pancreas with vein involvement. It should be performed in high-volume pancreatic surgery centers. [ABSTRACT FROM AUTHOR]- Published
- 2012
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3. Long-term results of resection of adenocarcinoma of the body and tail of the pancreas using radical antegrade modular pancreatosplenectomy procedure.
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Mitchem JB, Hamilton N, Gao F, Hawkins WG, Linehan DC, and Strasberg SM
- Published
- 2012
4. ASO Visual Abstract: Plasma Ceramide C24:0/C16:0 Ratio is Associated with Improved Survival in Patients with Pancreatic Ductal Adenocarcinoma.
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Mitchell JD, Panni U, Fergestrom N, Toriola AT, Nywening TM, Goedegebuure SP, Jiang X, Mudd JL, Cao Y, Ippolito J, Fields RC, Hawkins WG, and Peterson LR
- Published
- 2024
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5. Plasma Ceramide C24:0/C16:0 Ratio is Associated with Improved Survival in Patients with Pancreatic Ductal Adenocarcinoma.
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Mitchell JD, Panni U, Fergestrom N, Toriola AT, Nywening TM, Goedegebuure SP, Jiang X, Mudd JL, Cao Y, Ippolito J, Fields RC, Hawkins WG, and Peterson LR
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- Humans, Male, Female, Survival Rate, Aged, Middle Aged, Prognosis, Follow-Up Studies, Pancreatic Neoplasms blood, Pancreatic Neoplasms mortality, Pancreatic Neoplasms pathology, Pancreatic Neoplasms surgery, Carcinoma, Pancreatic Ductal blood, Carcinoma, Pancreatic Ductal mortality, Carcinoma, Pancreatic Ductal surgery, Carcinoma, Pancreatic Ductal pathology, Ceramides blood, Biomarkers, Tumor blood
- Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) has a high fatality rate, with surgery as the only curative treatment. Identification of new biomarkers related to survival may help guide discovery of new pathophysiologic pathways and potential therapeutic targets. As long-chain ceramides have been linked to tumor proliferation, we sought to determine if ceramide levels were prognostic in PDAC., Methods: Patients from two phase I studies of PDAC were followed for all-cause mortality. Ceramide levels (C24:0, C22:0, and C16:0) were quantified before treatment and at study intervals. Multivariable Cox regression models assessed the association of ceramide levels and mortality after adjusting for other univariable predictors, including time-dependent tumor resection. The ability of repeated ceramide measures to discriminate patients at risk for mortality was also assessed using multivariable modeling and the c-statistic., Results: Higher plasma C16:0 concentration was associated with higher all-cause mortality in univariable and multivariable analysis (adjusted hazard ratio [aHR] 1.41, 95% confidence interval [CI] 1.09-1.82; p < 0.01). In contrast, a higher plasma C24:0/C16:0 ratio was associated with lower all-cause mortality in multivariable analysis (aHR 0.69, 95% CI 0.49-0.97; p = 0.032). Discrimination of mortality was significantly improved with the addition of either plasma C16:0 or C24:0/C16:0 levels, with optimal discrimination occurring using repeated measures of the C24:0/C16:0 ratio (c-statistic 0.73 vs. c-statistic 0.66; p < 0.001)., Conclusions: Higher plasma C16:0 and lower C24:0/C16:0 ratios are independently associated with mortality in PDAC and show an ability to improve discrimination of mortality in this deadly disease. Further studies are needed to confirm this association and evaluate this novel pathway for potential therapeutic targets., (© 2024. Society of Surgical Oncology.)
- Published
- 2024
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6. Female-specific pancreatic cancer survival from CT imaging of visceral fat implicates glutathione metabolism in solid tumors.
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Ballard DH, Nguyen GK, Atagu N, Camps G, Salter A, Jaswal S, Naeem M, Ludwig DR, Mellnick VM, Peterson LR, Hawkins WG, Fields RC, Luo J, and Ippolito JE
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- Humans, Female, Male, Retrospective Studies, Middle Aged, Aged, Glutathione metabolism, Sex Factors, Carcinoma, Pancreatic Ductal diagnostic imaging, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal genetics, Adult, Aged, 80 and over, Survival Rate, Intra-Abdominal Fat diagnostic imaging, Intra-Abdominal Fat metabolism, Pancreatic Neoplasms diagnostic imaging, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms genetics, Tomography, X-Ray Computed methods
- Abstract
Rationale and Objectives: To identify if body composition, assessed with preoperative CT-based visceral fat ratio quantification as well as tumor metabolic gene expression, predicts sex-dependent overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC)., Materials and Methods: This was a retrospective analysis of preoperative CT in 98 male and 107 female patients with PDAC. Relative visceral fat (rVFA; visceral fat normalized to total fat) was measured automatically using software and corrected manually. Median and optimized rVFA thresholds were determined according to published methods. Kaplan Meier and log-rank tests were used to estimate OS. Multivariate models were developed to identify interactions between sex, rVFA, and OS. Unsupervised gene expression analysis of PDAC tumors from The Cancer Genome Atlas (TCGA) was performed to identify metabolic pathways with similar survival patterns to rVFA., Results: Optimized preoperative rVFA threshold of 38.9% predicted significantly different OS in females with a median OS of 15 months (above threshold) vs 24 months (below threshold; p = 0.004). No significant threshold was identified in males. This female-specific significance was independent of age, stage, and presence of chronic pancreatitis (p = 0.02). Tumor gene expression analysis identified female-specific stratification from a five-gene signature of glutathione S-transferases. This was observed for PDAC as well as clear cell renal carcinoma and glioblastoma., Conclusion: CT-based assessments of visceral fat can predict pancreatic cancer OS in females. Glutathione S-transferase expression in tumors predicts female-specific OS in a similar fashion., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joseph Ippolito reports the analysis software license was provided by Vital Images Inc., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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7. Cytotoxic sigma-2 ligands trigger cancer cell death via cholesterol-induced-ER-stress.
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Takchi R, Prudner BC, Gong Q, Hagi T, Newcomer KF, Jin LX, Vangveravong S, Van Tine BA, Hawkins WG, and Spitzer D
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- Humans, Animals, Mice, Ligands, Cell Line, Tumor, Cell Death drug effects, Neoplasms metabolism, Neoplasms drug therapy, Neoplasms pathology, Cholesterol metabolism, Receptors, sigma metabolism, Receptors, sigma genetics, Endoplasmic Reticulum Stress drug effects
- Abstract
Sigma-2-ligands (S2L) are characterized by high binding affinities to their cognate sigma-2 receptor, overexpressed in rapidly proliferating tumor cells. As such, S2L were developed as imaging probes (ISO1) or as cancer therapeutics, alone (SV119 [C6], SW43 [C10]) and as delivery vehicles for cytotoxic drug cargoes (C6-Erastin, C10-SMAC). However, the exact mechanism of S2L-induced cytotoxicity remains to be fully elucidated. A series of high-affinity S2L were evaluated regarding their cytotoxicity profiles across cancer cell lines. While C6 and C10 displayed distinct cytotoxicities, C0 and ISO1 were essentially non-toxic. Confocal microscopy and lipidomics analysis in cellular and mouse models revealed that C10 induced increases in intralysosomal free cholesterol and in cholesterol esters, suggestive of unaltered intracellular cholesterol trafficking. Cytotoxicity was caused by cholesterol excess, a phenomenon that contrasts the effects of NPC1 inhibition. RNA-sequencing revealed gene clusters involved in cholesterol homeostasis and ER stress response exclusively by cytotoxic S2L. ER stress markers were confirmed by qPCR and their targeted modulation inhibited or enhanced cytotoxicity of C10 in a predicted manner. Moreover, C10 increased sterol regulatory element-binding protein 2 (SREBP2) and low-density lipoprotein receptor (LDLR), both found to be pro-survival factors activated by ER stress. Furthermore, inhibition of downstream processes of the adaptive response to S2L with simvastatin resulted in synergistic treatment outcomes in combination with C10. Of note, the S2L conjugates retained the ER stress response of the parental ligands, indicative of cholesterol homeostasis being involved in the overall cytotoxicity of the drug conjugates. Based on these findings, we conclude that S2L-mediated cell death is due to free cholesterol accumulation that leads to ER stress. Consequently, the cytotoxic profiles of S2L drug conjugates are proposed to be enhanced via concurrent ER stress inducers or simvastatin, strategies that could be instrumental on the path toward tumor eradication., (© 2024. The Author(s).)
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- 2024
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8. ASO Author Reflections: A Role for Extended VTE Prophylaxis After Neoadjuvant Therapy and Distal Pancreatectomy for Pancreatic Adenocarcinoma.
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Robbins KJ and Hawkins WG
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- Humans, Pancreatectomy, Neoadjuvant Therapy, Pancreatic Neoplasms pathology, Adenocarcinoma surgery, Venous Thromboembolism etiology, Venous Thromboembolism prevention & control
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- 2024
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9. Neoadjuvant Chemotherapy is Associated with Increased Risk of Postoperative DVT After Distal Pancreatectomy for Pancreatic Adenocarcinoma: a NSQIP Analysis.
- Author
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Robbins KJ, Newcomer KF Jr, Barnell EK, Anzelmo MA, Liu J, and Hawkins WG
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- Adult, Humans, Neoadjuvant Therapy adverse effects, Pancreatectomy adverse effects, Quality Improvement, Risk Factors, Postoperative Complications etiology, Postoperative Complications surgery, Venous Thromboembolism etiology, Adenocarcinoma drug therapy, Adenocarcinoma surgery, Adenocarcinoma complications, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms surgery, Pancreatic Neoplasms complications, Venous Thrombosis surgery, Pulmonary Embolism
- Abstract
Background: Venous thromboembolism (VTE) remains a persistent source of postoperative morbidity despite prevention and mitigation efforts. Cancer, surgery, and chemotherapy are known risk factors for VTE. Existing literature suggests that neoadjuvant therapy (NAT) may contribute to increased VTE risk in the postoperative period, but few authors specifically examine this relationship in distal pancreatic adenocarcinoma (PDAC). In this study, we analyze the association of NAT and postoperative VTE in patients who underwent distal pancreatectomy (DP) for PDAC., Patients and Methods: Using the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database, we analyzed the Procedure Targeted files for pancreatectomy from 2014 to 2020. Adults with PDAC who underwent DP were grouped by receipt of NAT. The primary outcome was the rate of deep venous thrombosis (DVT) and the secondary outcome was the rate of pulmonary embolism (PE). We performed univariate and multivariate logistic regression analysis to determine risk factors associated with postoperative DVT., Results: There were 4327 patients with PDAC who underwent DP. Of these, 1414 (32.7%) had NAT. Receipt of NAT was significantly associated with postoperative DVT requiring therapy (3.5% vs. 2.3%, p = 0.02), but was not associated with PE (p = 0.42). On MVA, NAT was associated with a 73% greater chance of developing postoperative DVT [odds ratio (OR) 1.73, 95% CI 1.18-2.55]., Conclusions: Patients who receive NAT prior to DP for PDAC are 73% more likely to develop postoperative DVT compared with upfront resection. As NAT becomes more commonplace, these high-risk patients should be prioritized for guideline-recommended extended duration prophylaxis., (© 2023. Society of Surgical Oncology.)
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- 2024
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10. Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer.
- Author
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Bulle A, Liu P, Seehra K, Bansod S, Chen Y, Zahra K, Somani V, Khawar IA, Chen HP, Dodhiawala PB, Li L, Geng Y, Mo CK, Mahsl J, Ding L, Govindan R, Davies S, Mudd J, Hawkins WG, Fields RC, DeNardo DG, Knoerzer D, Held JM, Grierson PM, Wang-Gillam A, Ruzinova MB, and Lim KH
- Subjects
- Humans, Proto-Oncogene Proteins p21(ras) metabolism, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Mitogen-Activated Protein Kinases metabolism, Cell Line, Tumor, Pancreatic Neoplasms pathology, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal metabolism
- Abstract
Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 dissociates from the protective effect of the RING E3 ligase tripartite motif containing 21, resulting in its degradation. In PDAC patient-derived xenograft (PDX) models, combining ERK and HER inhibitors slows tumour growth and requires cytotoxic chemotherapy to achieve tumour regression. Alternatively, MAPK inhibitors with trastuzumab deruxtecan, an anti-HER2 antibody conjugated with cytotoxic chemotherapy, lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity. Additionally, KRAS inhibitors also activate HER2, supporting testing the combination of KRAS inhibitors and trastuzumab deruxtecan in PDAC. This study identifies a rational and promising therapeutic combination for clinical testing in PDAC patients., (© 2024. The Author(s).)
- Published
- 2024
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11. The novel drug candidate S2/IAPinh improves survival in models of pancreatic and ovarian cancer.
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Hagi T, Vangveravong S, Takchi R, Gong Q, Goedegebuure SP, Tiriac H, Van Tine BA, Powell MA, Hawkins WG, and Spitzer D
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- Humans, Animals, Mice, Female, Apoptosis, Inhibitor of Apoptosis Proteins metabolism, Caspases metabolism, Cell Line, Tumor, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Antineoplastic Agents chemistry, Ovarian Neoplasms drug therapy, Ovarian Neoplasms metabolism
- Abstract
Cancer selective apoptosis remains a therapeutic challenge and off-target toxicity has limited enthusiasm for this target clinically. Sigma-2 ligands (S2) have been shown to enhance the cancer selectivity of small molecule drug candidates by improving internalization. Here, we report the synthesis of a novel drug conjugate, which was created by linking a clinically underperforming SMAC mimetic (second mitochondria-derived activator of caspases; LCL161), an inhibitor (antagonist) of inhibitor of apoptosis proteins (IAPinh) with the sigma-2 ligand SW43, resulting in the new chemical entity S2/IAPinh. Drug potency was assessed via cell viability assays across several pancreatic and ovarian cancer cell lines in comparison with the individual components (S2 and IAPinh) as well as their equimolar mixtures (S2 + IAPinh) both in vitro and in preclinical models of pancreatic and ovarian cancer. Mechanistic studies of S2/IAPinh-mediated cell death were investigated in vitro and in vivo using syngeneic and xenograft mouse models of murine pancreatic and human ovarian cancer, respectively. S2/IAPinh demonstrated markedly improved pharmacological activity in cancer cell lines and primary organoid cultures when compared to the controls. In vivo testing demonstrated a marked reduction in tumor growth rates and increased survival rates when compared to the respective control groups. The predicted mechanism of action of S2/IAPinh was confirmed through assessment of apoptosis pathways and demonstrated strong target degradation (cellular inhibitor of apoptosis proteins-1 [cIAP-1]) and activation of caspases 3 and 8. Taken together, S2/IAPinh demonstrated efficacy in models of pancreatic and ovarian cancer, two challenging malignancies in need of novel treatment concepts. Our data support an in-depth investigation into utilizing S2/IAPinh for the treatment of cancer., (© 2024. The Author(s).)
- Published
- 2024
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12. Intratumoral T-cell receptor repertoire composition predicts overall survival in patients with pancreatic ductal adenocarcinoma.
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Pothuri VS, Hogg GD, Conant L, Borcherding N, James CA, Mudd J, Williams G, Seo YD, Hawkins WG, Pillarisetty VG, DeNardo DG, and Fields RC
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- Humans, T-Lymphocytes, Receptors, Antigen, T-Cell genetics, Biomarkers, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms genetics, Carcinoma, Pancreatic Ductal diagnosis, Carcinoma, Pancreatic Ductal genetics
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is refractory to immune checkpoint inhibitor therapy. However, intratumoral T-cell infiltration correlates with improved overall survival (OS). Herein, we characterized the diversity and antigen specificity of the PDAC T-cell receptor (TCR) repertoire to identify novel immune-relevant biomarkers. Demographic, clinical, and TCR-beta sequencing data were collated from 353 patients across three cohorts that underwent surgical resection for PDAC. TCR diversity was calculated using Shannon Wiener index, Inverse Simpson index, and "True entropy." Patients were clustered by shared repertoire specificity. TCRs predictive of OS were identified and their associated transcriptional states were characterized by single-cell RNAseq. In multivariate Cox regression models controlling for relevant covariates, high intratumoral TCR diversity predicted OS across multiple cohorts. Conversely, in peripheral blood, high abundance of T-cells, but not high diversity, predicted OS. Clustering patients based on TCR specificity revealed a subset of TCRs that predicts OS. Interestingly, these TCR sequences were more likely to encode CD8
+ effector memory and CD4+ T-regulatory (Tregs) T-cells, all with the capacity to recognize beta islet-derived autoantigens. As opposed to T-cell abundance, intratumoral TCR diversity was predictive of OS in multiple PDAC cohorts, and a subset of TCRs enriched in high-diversity patients independently correlated with OS. These findings emphasize the importance of evaluating peripheral and intratumoral TCR repertoires as distinct and relevant biomarkers in PDAC., Competing Interests: N.B. is a consultant for Santa Ana Bio and Omniscope. No potential conflicts of interest were reported by the other authors., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)- Published
- 2024
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13. Area deprivation and rurality impact overall survival and adjuvant therapy administration in patients with pancreatic ductal adenocarcinoma (PDAC).
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Pothuri V, Zárate Rodriguez JG, Kasting C, Leigh N, Hawkins WG, Sanford DE, and Fields RC
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- Humans, Retrospective Studies, Combined Modality Therapy, Pancreatic Neoplasms drug therapy, Carcinoma, Pancreatic Ductal drug therapy
- Abstract
Background: The impact of neighborhood deprivation on outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) is not well-described and represents an area to improve disparities., Methods: We retrospectively queried our prospectively maintained database of patients with PDAC (2014-2022). Patients were grouped by Area Deprivation Index (ADI) and rural-urban commuting area (RUCA) codes. Cox proportional hazards models and logistic regressions were used to investigate effect on overall survival (OS) and adjuvant therapy administration., Results: 536 patients were included. High ADI patients (more disadvantaged, n = 184) were more likely to identify as non-Hispanic Black (17.9% vs. 4.8%, p < 0.01) and were more likely to be from rural areas (49.5% vs. 18.5%, p < 0.01). High ADI was independently associated with decreased OS (HR (95% CI): 1.31 (1.01-1.69), p = 0.04). Urban high ADI patients were 3.5 times more likely to receive adjuvant therapy than rural high ADI patients (OR [95% CI]: 3.48 [1.26-9.61], p = 0.02)., Conclusion: Patients from the most disadvantaged neighborhoods have decreased OS. Access to adjuvant therapy likely contributes to this disparity in rural areas. Investigation into sources of this OS disparity and identification of barriers to adjuvant therapy will be crucial to improve outcomes in underserved patients with PDAC., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2023
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14. Correction: Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: a Phase I Dose Escalation and Expansion Study.
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Wang-Gillam A, Lim KH, McWilliams R, Suresh R, Lockhart AC, Brown A, Breden M, Belle JI, Herndon J, Bogner SJ, Pedersen K, Tan B, Boice N, Acharya A, Abdiannia M, Gao F, Yoon HH, Zhu M, Trikalinos NA, Ratner L, Aranha O, Hawkins WG, Herzog BH, and DeNardo DG
- Published
- 2023
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15. High-dimensional deconstruction of pancreatic cancer identifies tumor microenvironmental and developmental stemness features that predict survival.
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Storrs EP, Chati P, Usmani A, Sloan I, Krasnick BA, Babbra R, Harris PK, Sachs CM, Qaium F, Chatterjee D, Wetzel C, Goedegebuure SP, Hollander T, Anthony H, Ponce J, Khaliq AM, Badiyan S, Kim H, Denardo DG, Lang GD, Cosgrove ND, Kushnir VM, Early DS, Masood A, Lim KH, Hawkins WG, Ding L, Fields RC, Das KK, and Chaudhuri AA
- Abstract
Numerous cell states are known to comprise the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME). However, the developmental stemness and co-occurrence of these cell states remain poorly defined. Here, we performed single-cell RNA sequencing (scRNA-seq) on a cohort of treatment-naive PDAC time-of-diagnosis endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) samples (n = 25). We then combined these samples with surgical resection (n = 6) and publicly available samples to increase statistical power (n = 80). Following annotation into 25 distinct cell states, cells were scored for developmental stemness, and a customized version of the Ecotyper tool was used to identify communities of co-occurring cell states in bulk RNA-seq samples (n = 268). We discovered a tumor microenvironmental community comprised of aggressive basal-like malignant cells, tumor-promoting SPP1+ macrophages, and myofibroblastic cancer-associated fibroblasts associated with especially poor prognosis. We also found a developmental stemness continuum with implications for survival that is present in both malignant cells and cancer-associated fibroblasts (CAFs). We further demonstrated that high-dimensional analyses predictive of survival are feasible using standard-of-care, time-of-diagnosis EUS-FNB specimens. In summary, we identified tumor microenvironmental and developmental stemness characteristics from a high-dimensional gene expression analysis of PDAC using human tissue specimens, including time-of-diagnosis EUS-FNB samples. These reveal new connections between tumor microenvironmental composition, CAF and malignant cell stemness, and patient survival that could lead to better upfront risk stratification and more personalized upfront clinical decision-making., (© 2023. Nature Publishing Group UK.)
- Published
- 2023
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16. Impact of Prehabilitation on Postoperative Mortality and the Need for Non-Home Discharge in High-Risk Surgical Patients.
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Zarate Rodriguez JG, Cos H, Koenen M, Cook J, Kasting C, Raper L, Guthrie T, Strasberg SM, Hawkins WG, Hammill CW, Fields RC, Chapman WC, Eberlein TJ, Kozower BD, and Sanford DE
- Subjects
- Humans, Risk Assessment, Preoperative Exercise, Retrospective Studies, Quality Improvement, Postoperative Complications epidemiology, Postoperative Complications prevention & control, Patient Discharge
- Abstract
Background: The preoperative period is an important target for interventions (eg Surgical Prehabilitation and Readiness [SPAR]) that can improve postoperative outcomes for older patients with comorbidities., Study Design: To determine whether a preoperative multidisciplinary prehabilitation program (SPAR) reduces postoperative 30-day mortality and the need for non-home discharge in high-risk surgical patients, surgical patients enrolled in a prehabilitation program targeting physical activity, pulmonary function, nutrition, and mindfulness were compared with historical control patients from 1 institution's American College of Surgeons (ACS) NSQIP database. SPAR patients were propensity score-matched 1:3 to pre-SPAR NSQIP patients, and their outcomes were compared. The ACS NSQIP Surgical Risk Calculator was used to compare observed-to-expected ratios for postoperative outcomes., Results: A total of 246 patients were enrolled in SPAR. A 6-month compliance audit revealed that overall patient adherence to the SPAR program was 89%. At the time of analysis, 118 SPAR patients underwent surgery with 30 days of follow-up. Compared with pre-SPAR NSQIP patients (n = 4,028), SPAR patients were significantly older with worse functional status and more comorbidities. Compared with propensity score-matched pre-SPAR NSQIP patients, SPAR patients had significantly decreased 30-day mortality (0% vs 4.1%, p = 0.036) and decreased need for discharge to postacute care facilities (6.5% vs 15.9%, p = 0.014). Similarly, SPAR patients exhibited decreased observed 30-day mortality (observed-to-expected ratio 0.41) and need for discharge to a facility (observed-to-expected ratio 0.56) compared with their expected outcomes using the ACS NSQIP Surgical Risk Calculator., Conclusions: The SPAR program is safe and feasible and may reduce postoperative mortality and the need for discharge to postacute care facilities in high-risk surgical patients., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
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17. Systemic Alterations in Type-2 Conventional Dendritic Cells Lead to Impaired Tumor Immunity in Pancreatic Cancer.
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James CA, Baer JM, Zou C, Panni UY, Knolhoff BL, Hogg GD, Kingston NL, Kang LI, Lander VE, Luo J, Tao Y, Watson MA, Aft R, Fields RC, Hawkins WG, and DeNardo DG
- Subjects
- Humans, Dendritic Cells, Cytokines metabolism, Interleukin-6 metabolism, Pancreatic Neoplasms pathology
- Abstract
Intratumoral T-cell dysfunction is a hallmark of pancreatic tumors, and efforts to improve dendritic cell (DC)-mediated T-cell activation may be critical in treating these immune therapy unresponsive tumors. Recent evidence indicates that mechanisms that induce dysfunction of type 1 conventional DCs (cDC1) in pancreatic adenocarcinomas (PDAC) are drivers of the lack of responsiveness to checkpoint immunotherapy. However, the impact of PDAC on systemic type 2 cDC2 development and function has not been well studied. Herein, we report the analysis of 3 cohorts, totaling 106 samples, of human blood and bone marrow (BM) from patients with PDAC for changes in cDCs. We found that circulating cDC2s and their progenitors were significantly decreased in the blood of patients with PDAC, and repressed numbers of cDC2s were associated with poor prognosis. Serum cytokine analyses identified IL6 as significantly elevated in patients with PDAC and negatively correlated with cDC numbers. In vitro, IL6 impaired the differentiation of cDC1s and cDC2s from BM progenitors. Single-cell RNA sequencing analysis of human cDC progenitors in the BM and blood of patients with PDAC showed an upregulation of the IL6/STAT3 pathway and a corresponding impairment of antigen processing and presentation. These results suggested that cDC2s were systemically suppressed by inflammatory cytokines, which was linked to impaired antitumor immunity., (©2023 American Association for Cancer Research.)
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- 2023
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18. Induction of cancer neoantigens facilitates development of clinically relevant models for the study of pancreatic cancer immunobiology.
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Panni UY, Chen MY, Zhang F, Cullinan DR, Li L, James CA, Zhang X, Rogers S, Alarcon A, Baer JM, Zhang D, Gao F, Miller CA, Gong Q, Lim KH, DeNardo DG, Goedegebuure SP, Gillanders WE, and Hawkins WG
- Subjects
- Humans, Antigens, Neoplasm, CD8-Positive T-Lymphocytes, Immunotherapy, Pancreatic Neoplasms therapy, Carcinoma, Pancreatic Ductal therapy
- Abstract
Neoantigen burden and CD8 T cell infiltrate are associated with clinical outcome in pancreatic ductal adenocarcinoma (PDAC). A shortcoming of many genetic models of PDAC is the lack of neoantigen burden and limited T cell infiltrate. The goal of the present study was to develop clinically relevant models of PDAC by inducing cancer neoantigens in KP2, a cell line derived from the KPC model of PDAC. KP2 was treated with oxaliplatin and olaparib (OXPARPi), and a resistant cell line was subsequently cloned to generate multiple genetically distinct cell lines (KP2-OXPARPi clones). Clones A and E are sensitive to immune checkpoint inhibition (ICI), exhibit relatively high T cell infiltration, and have significant upregulation of genes involved in antigen presentation, T cell differentiation, and chemokine signaling pathways. Clone B is resistant to ICI and is similar to the parental KP2 cell line in terms of relatively low T cell infiltration and no upregulation of genes involved in the pathways noted above. Tumor/normal exome sequencing and in silico neoantigen prediction confirms successful generation of cancer neoantigens in the KP2-OXPARPi clones and the relative lack of cancer neoantigens in the parental KP2 cell line. Neoantigen vaccine experiments demonstrate that a subset of candidate neoantigens are immunogenic and neoantigen synthetic long peptide vaccines can restrain Clone E tumor growth. Compared to existing models, the KP2-OXPARPi clones better capture the diverse immunobiology of human PDAC and may serve as models for future investigations in cancer immunotherapies and strategies targeting cancer neoantigens in PDAC., (© 2023. The Author(s).)
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- 2023
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19. NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023.
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Benson AB, D'Angelica MI, Abrams T, Abbott DE, Ahmed A, Anaya DA, Anders R, Are C, Bachini M, Binder D, Borad M, Bowlus C, Brown D, Burgoyne A, Castellanos J, Chahal P, Cloyd J, Covey AM, Glazer ES, Hawkins WG, Iyer R, Jacob R, Jennings L, Kelley RK, Kim R, Levine M, Palta M, Park JO, Raman S, Reddy S, Ronnekleiv-Kelly S, Sahai V, Singh G, Stein S, Turk A, Vauthey JN, Venook AP, Yopp A, McMillian N, Schonfeld R, and Hochstetler C
- Subjects
- Humans, Bile Ducts, Intrahepatic, Biliary Tract Neoplasms diagnosis, Biliary Tract Neoplasms therapy, Gallbladder Neoplasms diagnosis, Gallbladder Neoplasms therapy, Cholangiocarcinoma diagnosis, Cholangiocarcinoma therapy, Liver Neoplasms diagnosis, Liver Neoplasms therapy, Bile Duct Neoplasms
- Abstract
In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.
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- 2023
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20. Ampullary Adenocarcinoma, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.
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Chiorean EG, Chiaro MD, Tempero MA, Malafa MP, Benson AB, Cardin DB, Christensen JA, Chung V, Czito B, Dillhoff M, Donahue TR, Dotan E, Fountzilas C, Glazer ES, Hardacre J, Hawkins WG, Klute K, Ko AH, Kunstman JW, LoConte N, Lowy AM, Masood A, Moravek C, Nakakura EK, Narang AK, Nardo L, Obando J, Polanco PM, Reddy S, Reyngold M, Scaife C, Shen J, Truty MJ, Vollmer C, Wolff RA, Wolpin BM, Rn BM, Lubin S, and Darlow SD
- Subjects
- Humans, Pancreatic Neoplasms, Ampulla of Vater, Common Bile Duct Neoplasms diagnosis, Common Bile Duct Neoplasms therapy, Duodenal Neoplasms diagnosis, Duodenal Neoplasms therapy, Adenocarcinoma diagnosis, Adenocarcinoma therapy
- Abstract
Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.
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- 2023
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21. Stromal and therapy-induced macrophage proliferation promotes PDAC progression and susceptibility to innate immunotherapy.
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Zuo C, Baer JM, Knolhoff BL, Belle JI, Liu X, Alarcon De La Lastra A, Fu C, Hogg GD, Kingston NL, Breden MA, Dodhiawala PB, Zhou DC, Lander VE, James CA, Ding L, Lim KH, Fields RC, Hawkins WG, Weber JD, Zhao G, and DeNardo DG
- Subjects
- Animals, Mice, Humans, Macrophages metabolism, Immunotherapy, Cell Proliferation, Tumor Microenvironment, Cell Line, Tumor, Pancreatic Neoplasms metabolism, Carcinoma, Pancreatic Ductal metabolism
- Abstract
Tumor-associated macrophages (TAMs) are abundant in pancreatic ductal adenocarcinomas (PDACs). While TAMs are known to proliferate in cancer tissues, the impact of this on macrophage phenotype and disease progression is poorly understood. We showed that in PDAC, proliferation of TAMs could be driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. CSF1 induced high levels of p21 in macrophages, which regulated both TAM proliferation and phenotype. TAMs in human and mouse PDACs with high levels of p21 had more inflammatory and immunosuppressive phenotypes. p21 expression in TAMs was induced by both stromal interaction and/or chemotherapy treatment. Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo drove tumor progression. Serendipitously, the same p21-driven pathways that drive tumor progression also drove response to CD40 agonist. These data suggest that stromal or therapy-induced regulation of cell cycle machinery can regulate both macrophage-mediated immune suppression and susceptibility to innate immunotherapy., (© 2023 Zuo et al.)
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- 2023
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22. Comments on "Challenging Orthodoxy: Beyond the Critical View of Safety".
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Strasberg SM, Brunt LM, Fields RC, Alseidi A, and Hawkins WG
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- 2023
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23. Postoperative Proton Pump Inhibitors are associated with a significantly higher rate of delayed gastric emptying after pancreatoduodenectomy.
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Panni U, Srivastava R, Bewley A, Williams GA, Fields RC, Sanford DE, Hawkins WG, Leigh N, and Hammill CW
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- Humans, Proton Pump Inhibitors adverse effects, Pancreaticoduodenectomy adverse effects, Retrospective Studies, Postoperative Complications etiology, Gastric Emptying, Gastroparesis etiology, Gastroparesis prevention & control, Peptic Ulcer chemically induced
- Abstract
Background: Proton pump inhibitors (PPIs) are effective in reducing marginal ulcers after pancreatoduodenectomy. However, their impact on perioperative complications has not been defined., Methods: We retrospectively analyzed the effect of postoperative PPIs on 90-day perioperative outcomes in all patients who underwent pancreatoduodenectomy at our institution from April 2017 to December 2020., Results: 284 patients were included; 206 (72.5%) received perioperative PPIs, 78 (27.5%) did not. The two cohorts were similar in demographics and operative variables. Postoperatively, the PPI cohort had significantly higher rates of overall complications (74.3% vs. 53.8%) and delayed gastric emptying (28.6% vs. 11.5%), p < 0.05. However, no differences in infectious complications, postoperative pancreatic fistula, or anastomotic leaks were seen. On multivariate analysis, PPI was independently associated with a higher risk of overall complications (OR 2.46, CI 1.33-4.54) and delayed gastric emptying (OR 2.73, CI 1.26-5.91), p = 0.011. Four patients developed marginal ulcers within 90-days postoperatively; all were in the group who received PPIs., Conclusion: Postoperative proton pump inhibitor use was associated with a significantly higher rate of overall complications and delayed gastric emptying after pancreatoduodenectomy., Competing Interests: Conflict of interest None to declare., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)
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- 2023
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24. Correction to: Comments on "Challenging Orthodoxy: Beyond the Critical View of Safety".
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Strasberg SM, Brunt LM, Fields RC, Alseidi A, and Hawkins WG
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- 2023
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25. Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study.
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Park LK, Lim KH, Volkman J, Abdiannia M, Johnston H, Nigogosyan Z, Siegel MJ, McGill JB, McKee AM, Salam M, Zhang RM, Ma D, Popuri K, Chow VTY, Beg MF, Hawkins WG, Peterson LR, and Ippolito JE
- Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC's excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear., Methods: We performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma chemistries for measuring metabolism and tumor burden were also analyzed., Results: Of 23 patients who were screened, 15 enrolled. One expired (due to complications from underlying disease), 2 dropped out (did not tolerate GnP chemotherapy) during the first 4 weeks, and 12 completed. There were no unexpected or serious adverse events with dapagliflozin. One patient was told to discontinue dapagliflozin after 6 weeks due to elevated ketones, although there were no clinical signs of ketoacidosis. Dapagliflozin compliance was 99.4%. Plasma glucagon increased significantly. Although abdominal muscle and fat volumes decreased; increased muscle-to-fat ratio correlated with better therapeutic response. After 8 weeks of treatment in the study, partial response (PR) to therapy was seen in 2 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. After dapagliflozin discontinuation (and chemotherapy continuation), an additional 7 patients developed the progressive disease in the subsequent scans measured by increased lesion size as well as the development of new lesions. Quantitative imaging assessment was supported by plasma CA19-9 tumor marker measurements., Conclusions: Dapagliflozin is well-tolerated and was associated with high compliance in patients with advanced, inoperable PDAC. Overall favorable changes in tumor response and plasma biomarkers suggest it may have efficacy against PDAC, warranting further investigation., (© 2023. The Author(s).)
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- 2023
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26. How Biomarkers of Response to Chemotherapy Might Change Patient Management.
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Hawkins WG, Hammill CW, and Ballentine SJ
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- Humans, Biomarkers, Biomarkers, Tumor
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- 2023
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27. MR-Guided Radiation Therapy With Concurrent Gemcitabine/Nab-Paclitaxel Chemotherapy in Inoperable Pancreatic Cancer: A TITE-CRM Phase I Trial.
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Kim H, Olsen JR, Green OL, Chin RI, Hawkins WG, Fields RC, Hammill C, Doyle MB, Chapman W, Suresh R, Tan B, Pedersen K, Jansen B, DeWees TA, Lu E, Henke LE, Badiyan S, Parikh PJ, Roach MC, Wang-Gillam A, and Lim KH
- Subjects
- Humans, Albumins, Antineoplastic Combined Chemotherapy Protocols adverse effects, Gemcitabine, Paclitaxel, Adenocarcinoma radiotherapy, Adenocarcinoma drug therapy, Pancreatic Neoplasms radiotherapy, Pancreatic Neoplasms drug therapy
- Abstract
Purpose: Ablative radiation therapy for borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) may limit concurrent chemotherapy dosing and usually is only safely deliverable to tumors distant from gastrointestinal organs. Magnetic resonance guided radiation therapy may safely permit radiation and chemotherapy dose escalation., Methods and Materials: We conducted a single-arm phase I study to determine the maximum tolerated dose of ablative hypofractionated radiation with full-dose gemcitabine/nab-paclitaxel in patients with BR/LA-PDAC. Patients were treated with gemcitabine/nab-paclitaxel (1000/125 mg/m
2 ) x 1c then concurrent gemcitabine/nab-paclitaxel and radiation. Gemcitabine/nab-paclitaxel and radiation doses were escalated per time-to-event continual reassessment method from 40 to 45 Gy 25 fxs with chemotherapy (600-800/75 mg/m2 ) to 60 to 67.5 Gy/15 fractions and concurrent gemcitabine/nab-paclitaxel (1000/100 mg/m2 ). The primary endpoint was maximum tolerated dose of radiation as defined by 60-day dose limiting toxicity (DLT). DLT was treatment-related G5, G4 hematologic, or G3 gastrointestinal requiring hospitalization >3 days. Secondary endpoints included resection rates, local progression free survival (LPFS), distant metastasis free survival (DMFS), and overall survival (OS)., Results: Thirty patients enrolled (March 2015-February 2019), with 26 evaluable patients (2 progressed before radiation, 1 was determined ineligible for radiation during planning, 1 withdrew consent). One DLT was observed. The DLT rate was 14.1% (3.3%-24.9%) with a maximum tolerated dose of gemcitabine/nab-paclitaxel (1000/100 mg/m2 ) and 67.5 Gy/15 fractions. At a median follow-up of 40.6 months for living patients the median OS was 14.5 months (95% confidence interval [CI], 10.9-28.2 months). The median OS for patients with Eastern Collaborative Oncology Group 0 and carbohydrate antigen 19-9 <90 were 34.1 (95% CI, 13.6-54.1) and 43.0 (95% CI, 8.0-not reached) months, respectively. Two-year LPFS and DMFS were 85% (95% CI, 63%-94%) and 57% (95% CI, 34%-73%), respectively., Conclusions: Full-dose gemcitabine/nab-paclitaxel with ablative magnetic resonance guided radiation therapy dosing is safe in patients with BR/LA-PDAC, with promising LPFS and DMFS., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2023
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28. 4,300 steps per day prior to surgery are associated with improved outcomes after pancreatectomy.
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Cos H, Zárate Rodríguez JG, Srivastava R, Bewley A, Raper L, Li D, Dai R, Williams GA, Fields RC, Hawkins WG, Lu C, Sanford DE, and Hammill CW
- Subjects
- Humans, Risk Factors, Pancreatectomy adverse effects, Postoperative Complications etiology
- Abstract
Background: Decreased preoperative physical fitness and low physical activity have been associated with preoperative functional reserve and surgical complications. We sought to evaluate daily step count as a measure of physical activity and its relationship with post-pancreatectomy outcomes., Methods: Patients undergoing pancreatectomy were given a remote telemonitoring device to measure their preoperative levels of physical activity. Patient activity, demographics, and perioperative outcomes were collected and compared in univariate and multivariate logistic regression analysis., Results: 73 patients were included. 45 (61.6%) patients developed complications, with 17 (23.3%) of those patients developing severe complications. These patients walked 3437.8 (SD 1976.7) average daily steps, compared to 5918.8 (SD 2851.1) in patients without severe complications (p < 0.001). In logistic regression analysis, patients who walked less than 4274.5 steps had significantly higher odds of severe complications (OR = 7.5 (CI 2.1, 26.8), p = 0.002)., Conclusion: Average daily steps below 4274.5 before surgery are associated with severe complications after pancreatectomy. Preoperative physical activity levels may represent a modifiable target for prehabilitation protocols., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2023
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29. Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study.
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Wang-Gillam A, Lim KH, McWilliams R, Suresh R, Lockhart AC, Brown A, Breden M, Belle JI, Herndon J, Bogner SJ, Pedersen K, Tan B, Boice N, Acharya A, Abdiannia M, Gao F, Yoon HH, Zhu M, Trikalinos NA, Ratner L, Aranha O, Hawkins WG, Herzog BH, and DeNardo DG
- Subjects
- Animals, Mice, Gemcitabine, Deoxycytidine, Albumins, Paclitaxel, Antineoplastic Combined Chemotherapy Protocols adverse effects, Pancreatic Neoplasms, Pancreatic Neoplasms pathology, Adenocarcinoma pathology
- Abstract
Purpose: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a tolerable safety profile., Patients and Methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a recommended phase II dose (RP2D). In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had stable disease (SD) after at least 4 months of standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and posttreatment tumor biopsies were performed to evaluate tumor immunity., Results: The triple drug combination was well-tolerated, with no dose-limiting toxicities. Among 20 treated patients with refractory PDAC, the disease control rate (DCR) was 80%, with one partial response (PR) and 15 SDs, and the median progression-free survival (PFS) and overall survival (OS) were 3.6 and 7.8 months, respectively. Among 10 evaluable patients in the maintenance cohort, DCR was 70% with one PR and six SDs. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS on study treatment were 5.0 and 8.3 months, respectively., Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy, and showed biomarker activity in infiltrative T lymphocytes. Efficacy of this strategy may require incorporation of more potent chemotherapy in future studies., (©2022 American Association for Cancer Research.)
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- 2022
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30. Combination TIGIT/PD-1 blockade enhances the efficacy of neoantigen vaccines in a model of pancreatic cancer.
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Peng H, Li L, Zuo C, Chen MY, Zhang X, Myers NB, Hogg GD, DeNardo DG, Goedegebuure SP, Hawkins WG, and Gillanders WE
- Subjects
- Humans, Mice, Animals, Programmed Cell Death 1 Receptor, Antigens, Neoplasm, Peptides therapeutic use, Receptors, Immunologic therapeutic use, Pancreatic Neoplasms, Pancreatic Neoplasms genetics, Carcinoma, Pancreatic Ductal genetics, Cancer Vaccines
- Abstract
Background: Cancer neoantigens are important targets of cancer immunotherapy and neoantigen vaccines are currently in development in pancreatic ductal adenocarcinoma (PDAC) and other cancer types. Immune regulatory mechanisms in pancreatic cancer may limit the efficacy of neoantigen vaccines. Targeting immune checkpoint signaling pathways in PDAC may improve the efficacy of neoantigen vaccines., Methods: We used KPC4580P, an established model of PDAC, to test whether neoantigen vaccines can generate therapeutic efficacy against PDAC. We focused on two immunogenic neoantigens associated with genetic alterations in the CAR12 and CDK12 genes. We tested a neoantigen vaccine comprised of two 20-mer synthetic long peptides and poly IC, a Toll-like receptor (TLR) agonist. We investigated the ability of neoantigen vaccine alone, or in combination with PD-1 and TIGIT signaling blockade to impact tumor growth. We also assessed the impact of TIGIT signaling on T cell responses in human PDAC., Results: Neoantigen vaccines induce neoantigen-specific T cell responses in tumor-bearing mice and slow KPC4580P tumor growth. However, KPC4580P tumors express high levels of PD-L1 and the TIGIT ligand, CD155. A subset of neoantigen-specific T cells in KPC4580P tumors are dysfunctional, and express high levels of TIGIT. PD-1 and TIGIT signaling blockade in vivo reverses T cell dysfunction and enhances neoantigen vaccine-induced T cell responses and tumor regression. In human translational studies, TIGIT signaling blockade in vitro enhances neoantigen-specific T cell function following vaccination., Conclusions: Taken together, preclinical and human translational studies support testing neoantigen vaccines in combination with therapies targeting the PD-1 and TIGIT signaling pathways in patients with PDAC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Peng, Li, Zuo, Chen, Zhang, Myers, Hogg, DeNardo, Goedegebuure, Hawkins and Gillanders.)
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- 2022
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31. Qualitative imaging features of pancreatic neuroendocrine neoplasms predict histopathologic characteristics including tumor grade and patient outcome.
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Yano M, Shetty AS, Williams GA, Lancia S, Trikalinos NA, Hammill CW, Hawkins WG, Salter A, and Chatterjee D
- Subjects
- Humans, Retrospective Studies, Fibrosis, Pancreatic Neoplasms pathology
- Abstract
Objectives: To identify PanNEN imaging features associated with tumor grade and aggressive histopathological features., Methods: Associations between histopathological and imaging features of resected PanNEN were retrospectively tested. Histopathologic features included WHO grade, lymphovascular invasion (LVI), growth pattern (infiltrative, circumscribed), and intratumoral fibrosis (mature, immature). Imaging features included size, degree/uniformity of enhancement, progressive enhancement, contour, infiltrative appearance (infiltrative
im ), calcifications, cystic components, tumor thrombus, vascular occlusion (VO), duct dilatation, and atrophy. Multinomial logistic regression analyses evaluated the magnitude of associations. Association of variables with outcome was assessed using Cox-proportional hazards regression., Results: 133 patients were included. 3 imaging features (infiltrativeim , ill-defined contour [contourill ], and VO) were associated with all histopathologic parameters and poor outcome. Increase in grade increased odds of contourill by 15.6 times (p = 0.0001, 95% CI 3.8-64.4). PanNEN with VO were 51.1 times (p = 0.0002, 6.5-398.6) more likely to demonstrate LVI. For PanNEN with contourill , infiltrative growth pattern was 51.3 times (p < 0.0001, 9.1-288.4), and fibrosis was 14 times (p = 0.0065, 2.1-93.7) more likely. Contourill was associated with decreased recurrence-free survival (p = 0.0003, HR 18.29, 3.83-87.3) and VO (p = 0.0004, HR6.08, 2.22-16.68) with decreased overall survival., Conclusions: Infiltrativeim , contourill , and VO on imaging are associated with higher grade/histopathological parameters linked to tumor aggression, and poor outcome., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2022
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32. Cause and outcome of aborting a difficult laparoscopic cholecystectomy due to severe inflammation: a study of operative notes.
- Author
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Panni UY, Williams GA, Hammill CW, Sanford DE, Hawkins WG, and Strasberg SM
- Subjects
- Cholecystectomy methods, Humans, Inflammation etiology, Retrospective Studies, Cholecystectomy, Laparoscopic methods, Cholecystitis complications, Cholecystitis surgery, Cholecystitis, Acute surgery
- Abstract
Background: Upon encountering a difficult cholecystectomy in which, after a reasonable trial of dissection, anatomical identification has not been attained due to severe inflammation, and the risk of additional dissection is deemed to be hazardous, "bail-out" strategies are encouraged safety valves. One strategy is to abort the cholecystectomy and refer the patient to a HPB center for further management., Methods: A retrospective review was conducted of cholecystectomies performed by HPB surgeons at our center between 2005 and 2019. We identified 63 patients who had an aborted cholecystectomy because of acute or chronic cholecystitis and were referred for additional care. Of these, operative notes and other clinical records were available for 43 patients who were included in this study., Results: 42 cholecystectomies (98%) were started laparoscopically. 25 patients (58%) had chronic cholecystitis, and 18 (42%) had acute cholecystitis. 40 cases (93%) fell into the highest level of difficulty on the Nassar scale (Grade 4). Procedures were aborted at the following stages of dissection: in 10 patients (23%), none of the gallbladder was identified; in another 11 (26%), only the dome of gallbladder was identified; the body of the gallbladder was exposed in 13 (30%); and dissection of the hepatocystic triangle was attempted unsuccessfully in 9 (21%). Following referral to our center, 30 patients (70%) were managed with total cholecystectomy while in 13 cases (30%), subtotal cholecystectomy was performed., Conclusion: Aborting cholecystectomy and referring the patient to an HPB center is rarely needed but is an effective bail-out strategy for general surgeons encountering highly difficult operative conditions due to inflammation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
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33. Oligometastatic Rectal Adenocarcinoma Treated With Short-Course Radiation Therapy and Chemotherapy With Nonoperative Intent of the Primary for Locoregional Complete Responders.
- Author
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Schiff JP, Chin RI, Roy A, Mahapatra L, Stowe HB, Andruska N, Huang Y, Mutch M, Fields RC, Hawkins WG, Doyle M, Chapman W, Tan B, Henke LE, Badiyan SN, DeSelm C, Samson PP, Pedersen K, and Kim H
- Subjects
- Humans, Neoadjuvant Therapy methods, Neoplasm Recurrence, Local pathology, Rectum pathology, Retrospective Studies, Salvage Therapy, Adenocarcinoma radiotherapy, Rectal Neoplasms pathology
- Abstract
Purpose: Nonoperative management with short-course radiation therapy (SCRT) as a component of definitive therapy for oligometastatic rectal cancer has not been previously reported. This single-institution retrospective analysis evaluates treatment with SCRT in combination with chemotherapy (SCRT-CTX) with nonoperative intent for patients with a locoregional clinical complete response (cCR)., Methods and Materials: Thirty-six patients with newly diagnosed oligometastatic rectal cancer were treated with SCRT-CTX between January 1, 2018, and May 31, 2020. Digital rectal examination, endoscopy, and imaging (computed tomography or magnetic resonance imaging) were used to determine cCR. Medically operable patients without cCR underwent surgical resection of the primary rectal tumor. Patients with cCR who experienced a local failure received salvage surgery. Rates of hospitalization related to primary tumor disease and pelvic symptoms were reviewed. Overall survival (OS) and progression free survival were evaluated., Results: Seventeen percent (6/36) of patients achieved cCR after SCRT-CTX. Eleven percent (4) of patients experienced a local failure. OS for all patients was 83% (71%-96%) at 12 months and 57% (41%-80%) at 24 months. Progression free survival for all patients was 56% (41%-74%) at 12 months and 10% (3.1%-35%) at 24 months. On multivariate analysis, having received more than 4 months of chemotherapy (hazard ratio = 0.21; 95% confidence interval, 0.06-0.71; P = .01) and definitive treatment of metastatic site (hazard ratio = 0.17; 95% confidence interval, 0.05-0.66; P = .01) predicted for improved OS. The number of patients requiring hospitalization due to obstruction (8/36, 22%), rectal bleeding (5/36, 14%), or need for permanent ostomy placement (5/36, 14%) was low, and there was a decrease in endorsement of obstructive symptoms and rectal bleeding after completion of SCRT-CTX., Conclusions: SCRT-CTX with nonoperative intent for patients with a locoregional cCR may be a reasonable treatment option for patients with newly diagnosed oligometastatic rectal adenocarcinoma and demonstrates excellent control of pelvic disease and symptoms. Increased duration of chemotherapy within the treatment paradigm may improve oncologic outcomes., (Copyright © 2022 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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34. Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer.
- Author
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Cui Zhou D, Jayasinghe RG, Chen S, Herndon JM, Iglesia MD, Navale P, Wendl MC, Caravan W, Sato K, Storrs E, Mo CK, Liu J, Southard-Smith AN, Wu Y, Naser Al Deen N, Baer JM, Fulton RS, Wyczalkowski MA, Liu R, Fronick CC, Fulton LA, Shinkle A, Thammavong L, Zhu H, Sun H, Wang LB, Li Y, Zuo C, McMichael JF, Davies SR, Appelbaum EL, Robbins KJ, Chasnoff SE, Yang X, Reeb AN, Oh C, Serasanambati M, Lal P, Varghese R, Mashl JR, Ponce J, Terekhanova NV, Yao L, Wang F, Chen L, Schnaubelt M, Lu RJ, Schwarz JK, Puram SV, Kim AH, Song SK, Shoghi KI, Lau KS, Ju T, Chen K, Chatterjee D, Hawkins WG, Zhang H, Achilefu S, Chheda MG, Oh ST, Gillanders WE, Chen F, DeNardo DG, Fields RC, and Ding L
- Subjects
- Cell Transformation, Neoplastic genetics, Humans, Pancreas metabolism, Tumor Microenvironment genetics, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal metabolism, Pancreatic Neoplasms metabolism
- Abstract
Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease., (© 2022. The Author(s).)
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- 2022
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35. Increased Morbidity and Mortality After Hepatectomy for Colorectal Liver Metastases in Frail Patients is Largely Driven by Worse Outcomes After Minor Hepatectomy: It's Not "Just a Wedge".
- Author
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Leigh N, Williams GA, Strasberg SM, Fields RC, Hawkins WG, Hammill CW, and Sanford DE
- Subjects
- Hepatectomy, Humans, Length of Stay, Morbidity, Postoperative Complications etiology, Retrospective Studies, Risk Factors, Colorectal Neoplasms complications, Colorectal Neoplasms surgery, Frailty complications, Liver Neoplasms complications, Liver Neoplasms surgery
- Abstract
Background: Frailty is associated with postoperative mortality, but its significance after hepatectomy for colorectal liver metastases (CRLM) is poorly defined. This study evaluated the impact of frailty after hepatectomy for CRLM., Methods: The study identified 8477 patients in National Surgical Quality Improvement Program databases from 2014 to 2019 and stratified them by frailty score using the risk analysis index as very frail (>90th percentile), frail (75th-90th percentile), or non-frail (< 75th percentile). Multivariate regression models determined the impact of frailty on perioperative outcomes, including by the extent of hepatectomy., Results: The procedures performed were 2752 major hepatectomies (left hepatectomy, right hepatectomy, trisectionectomy) and 5725 minor hepatectomies (≤2 segments) for 870 (10.3%) very frail, 1680 (19.8%) frail, and 5927 (69.9%) non-frail patients. Postoperatively, the very frail and frail patients experienced more complications (very frail [41.8%], frail [35.1%], non-frail [31.0%]), which resulted in a longer hospital stay (very-frail [5.7 days], frail [5.8 days], non-frail [5.1 days]), a higher 30-day mortality (very-frail [2.2%], frail [1.3%], non-frail [0.5%]), and more discharges to a facility (very frail [6.8%], frail [3.7%], non-frail [2.6%]) (p < 0.05) although they underwent similarly extensive (major vs. minor) hepatectomies. In the multivariate analysis, frailty was independently associated with complications (very-frail [odds ratio {OR}, 1.70], frail [OR, 1.25]) and 30-day mortality (very-frail [OR, 4.24], frail [OR, 2.41]) (p < 0.05). After minor hepatectomy, the very frail and frail patients had significantly higher rates of complications and 30-day mortality than the non-frail patients, and in the multivariate analysis, frailty was independently associated with complications (very frail [OR, 1.97], frail [OR, 1.27]) and 30-day mortality (very frail [OR, 6.76], frail [OR, 3.47]) (p < 0.05) after minor hepatectomy., Conclusions: Frailty predicted significantly poorer outcomes after hepatectomy for CRLM, even after only a minor hepatectomy., (© 2022. Society of Surgical Oncology.)
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- 2022
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36. Improved outcomes with minimally invasive pancreaticoduodenectomy in patients with dilated pancreatic ducts: a prospective study.
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Cos H, LeCompte MT, Srinivasa S, Zarate Rodriguez J, Woolsey CA, Williams G, Patel S, Khan A, Fields RC, Majella Doyle MB, Chapman WC, Strasberg SM, Hawkins WG, Hammill CW, and Sanford DE
- Subjects
- Humans, Pancreatic Ducts surgery, Pancreaticoduodenectomy adverse effects, Postoperative Complications epidemiology, Postoperative Complications etiology, Postoperative Complications surgery, Prospective Studies, Retrospective Studies, Laparoscopy adverse effects, Pancreatic Neoplasms surgery
- Abstract
Background: Little is known about what factors predict better outcomes for patients who undergo minimally invasive pancreaticoduodenectomy (MIPD) versus open pancreaticoduodenectomy (OPD). We hypothesized that patients with dilated pancreatic ducts have improved postoperative outcomes with MIPD compared to OPD., Methods: All patients undergoing pancreaticoduodenectomy were prospectively followed over a time period of 47 months, and perioperative and pathologic covariates and outcomes were compared. Ideal outcome after PD was defined as follows: (1) no complications, (2) postoperative length of stay < 7 days, and (3) negative (R0) margins on pathology. Patients with dilated pancreatic ducts (≥ 3 mm) who underwent MIPD were 1:3 propensity score-matched to patients with dilated ducts who underwent OPD and outcomes compared. Likewise, patients with non-dilated pancreatic ducts (< 3 mm) who underwent MIPD were 1:3 propensity score-matched to patients with non-dilated ducts who underwent OPD and outcomes were compared., Results: 371 patients underwent PD-74 (19.9%) MIPD and 297 (80.1%) underwent OPD. Overall, patients who underwent MIPD had significantly less intraoperative blood loss. After 1:3 propensity score matching, patients with dilated pancreatic ducts who underwent MIPD (n = 45) had significantly lower overall complication and 90-day readmission rates compared to matched OPD patients (n = 135) with dilated ducts. Patients with dilated duct who underwent MIPD were more likely to have an ideal outcome than patients with OPD (29 vs 15%, p = 0.035). There were no significant differences in postoperative outcomes among propensity score-matched patients with non-dilated pancreatic ducts who underwent MIPD (n = 29) compared to matched patients undergoing OPD (n = 87) with non-dilated ducts., Conclusions: MIPD is safe with comparable perioperative outcomes to OPD. Patients with pancreatic ducts ≥ 3 mm appear to derive the most benefit from MIPD in terms of fewer complications, lower readmission rates, and higher likelihood of ideal outcome., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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37. Oncogenic Kras-Mediated Cytokine CCL15 Regulates Pancreatic Cancer Cell Migration and Invasion through ROS.
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Messex JK, Adams KLA, Hawkins WG, DeNardo D, Bardeesy N, Billadeau DD, and Liou GY
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is well known for its high death rate due to prompt cancer metastasis caused by cancer cell migration and invasion within the early stages of its development. Here, we reveal a new function of cytokine CCL15, namely the upregulation of PDAC cell migration and invasion. We showed increased levels of CCL15 transcripts and protein expressions in human PDAC tissue samples, as well as in cultured cell lines. Furthermore, PDAC cells also expressed CCL15 receptors, including CCR1 and CCR3. Murine PDAC cell lines and tissues strengthened this finding. The manipulation of CCL15 in metastatic Panc-1 cells through CCL15 knockdown or CCL15 neutralization decreased Panc-1 cell motility and invasiveness. In addition, treating non-metastatic BxPC-3 cells with recombinant CCL15 accelerated the cell migration of BxPC-3. A reduction in the levels of reactive oxygen species (ROS) by either N-Acetyl-L-Cysteine treatment or p22phox knockdown led to a decrease in Panc-1 cell migration and a reversed effect on recombinant CCL15-promoted BxPC-3 cell movement. Importantly, the knockdown of oncogenic Kras in Panc-1 cells abolished CCL15 protein expression and impeded cell migration without affecting PDAC cell growth. Altogether, our work elucidates an additional molecular pathway of oncogenic Kras to promote PDAC metastasis through the upregulation of cell migration and invasion by the Kras downstream CCL15, a lesser-known cytokine within the cancer research field.
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- 2022
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38. Clinical classification of symptomatic heterotopic pancreas of the stomach and duodenum: A case series and systematic literature review.
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LeCompte MT, Mason B, Robbins KJ, Yano M, Chatterjee D, Fields RC, Strasberg SM, and Hawkins WG
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- Duodenum pathology, Gastrointestinal Hemorrhage complications, Humans, Pancreas pathology, Pancreas surgery, Choristoma pathology, Gastric Outlet Obstruction etiology, Pancreatitis complications, Upper Gastrointestinal Tract pathology
- Abstract
Background: Heterotopic pancreas (HP) is an aberrant anatomic malformation that occurs most commonly in the upper gastrointestinal tract. While the majority of heterotopic pancreatic lesions are asymptomatic, many manifest severe clinical symptoms which require surgical or endoscopic intervention. Understanding of the clinical manifestations and symptoms of HP is limited due to the lack of large volume studies in the literature. The purpose of this study is to review symptomatic cases at a single center and compare these to a systematic review of the literature in order to characterize common clinical manifestations and treatment of this disease., Aim: To classify the common clinical manifestations of heterotopic pancreas., Methods: A retrospective review was conducted of pathologic samples containing heterotopic pancreas from 2000-2018. Review was limited to HP of the upper gastrointestinal tract due to the frequency of presentation in this location. Symptomatic patients were identified from review of the medical records and clinical symptoms were tabulated. These were compared to a systematic review of the literature utilizing PubMed and Embase searches for papers pertaining to heterotopic pancreas. Publications describing symptomatic presentation of HP were selected for review. Information including demographics, symptoms, presentation and treatment were compiled and analyzed., Results: Twenty-nine patient were identified with HP at a single center, with six of these identified has having clinical symptoms. Clinical manifestations included, gastrointestinal bleeding, gastric ulceration with/without perforation, pancreatitis, and gastric outlet obstruction. Systemic review of the literature yielded 232 publications detailing symptomatic cases with only 20 studies describing ten or more patients. Single and multi-patient studies were combined to form a cohort of 934 symptomatic patients. The majority of patients presented with abdominal pain (67%) combined with one of the following clinical categories: (1) Dyspepsia, ( n = 445, 48%); (2) Pancreatitis ( n = 260, 28%); (3) Gastrointestinal bleeding ( n = 80, 9%); and (4) Gastric outlet obstruction ( n = 80, 9%). The majority of cases ( n = 832, 90%) underwent surgical or endoscopic resection with 85% reporting resolution or improvement in their symptoms., Conclusion: Heterotopic pancreas can cause significant clinical symptoms in the upper gastrointestinal tract. Better understanding and classification of this disease may result in more accurate identification and treatment of this malformation., Competing Interests: Conflict-of-interest statement: The authors of this study have no related conflicts of interest to disclose., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)
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- 2022
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39. The targeted SMAC mimetic SW IV-134 augments platinum-based chemotherapy in pre-clinical models of ovarian cancer.
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Binder PS, Hashim YM, Cripe J, Buchanan T, Zamorano A, Vangveravong S, Mutch DG, Hawkins WG, Powell MA, and Spitzer D
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- Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Humans, Mice, Mice, Inbred C57BL, Antineoplastic Agents therapeutic use, Azabicyclo Compounds therapeutic use, Carcinoma, Ovarian Epithelial drug therapy, Cisplatin therapeutic use, Oligopeptides therapeutic use, Ovarian Neoplasms drug therapy
- Abstract
Background: Ovarian cancer is initially responsive to frontline chemotherapy. Unfortunately, it often recurs and becomes resistant to available therapies and the survival rate for advanced and recurrent ovarian cancer is unacceptably low. We thus hypothesized that it would be possible to achieve more durable treatment responses by combining cisplatin chemotherapy with SW IV-134, a cancer-targeted peptide mimetic and inducer of cell death. SW IV-134 is a recently developed small molecule conjugate linking a sigma-2 ligand with a peptide analog (mimetic) of the intrinsic death pathway activator SMAC (second-mitochondria activator of caspases). The sigma-2 receptor is overexpressed in ovarian cancer and the sigma-2 ligand portion of the conjugate facilitates cancer selectivity. The effector portion of the conjugate is expected to synergize with cisplatin chemotherapy and the cancer selectivity is expected to reduce putative off-target toxicities., Methods: Ovarian cancer cell lines were treated with cisplatin alone, SW IV-134 alone and a combination of the two drugs. Treatment efficacy was determined using luminescent cell viability assays. Caspase-3/7, - 8 and - 9 activities were measured as complementary indicators of death pathway activation. Syngeneic mouse models and patient-derived xenograft (PDX) models of human ovarian cancer were studied for response to SW IV-134 and cisplatin monotherapy as well as combination therapy. Efficacy of the therapy was measured by tumor growth rate and survival as the primary readouts. Potential drug related toxicities were assessed at necropsy., Results: The combination treatment was consistently superior in multiple cell lines when compared to the single agents in vitro. The expected mechanism of tumor cell death, such as caspase activation, was confirmed using luminescent and flow cytometry-based assay systems. Combination therapy proved to be superior in both syngeneic and PDX-based murine models of ovarian cancer. Most notably, combination therapy resulted in a complete resolution of established tumors in all study animals in a patient-derived xenograft model of ovarian cancer., Conclusions: The addition of SW IV-134 in combination with cisplatin chemotherapy represents a promising treatment option that warrants further pre-clinical development and evaluation as a therapy for women with advanced ovarian cancer., (© 2022. The Author(s).)
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- 2022
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40. Development of a Prognostic Nomogram and Nomogram Software Application Tool to Predict Overall Survival and Disease-Free Survival After Curative-Intent Gastrectomy for Gastric Cancer.
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Spolverato G, Capelli G, Lorenzoni G, Gregori D, Squires MH, Poultsides GA, Fields RC, Bloomston MP, Weber SM, Votanopoulos KI, Acher AW, Jin LX, Hawkins WG, Schmidt CR, Kooby DA, Worhunsky DJ, Saunders ND, Levine EA, Cho CS, Maithel SK, Pucciarelli S, and Pawlik TM
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- Bayes Theorem, Disease-Free Survival, Gastrectomy, Humans, Prognosis, Retrospective Studies, Software, Nomograms, Stomach Neoplasms surgery
- Abstract
Background: We sought to derive and validate a prediction model of survival and recurrence among Western patients undergoing resection of gastric cancer., Methods: Patients who underwent curative-intent surgery for gastric cancer at seven US institutions and a major Italian center from 2000 to 2020 were included. Variables included in the multivariable Cox models were identified using an automated model selection procedure based on an algorithm. Best models were selected using the Bayesian information criterion (BIC). The performance of the models was internally cross-validated via the bootstrap resampling procedure. Discrimination was evaluated using the Harrell's Concordance Index and accuracy was evaluated using calibration plots. Nomograms were made available as online tools., Results: Overall, 895 patients met inclusion criteria. Age (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.17-1.84), presence of preoperative comorbidities (HR 1.66, 95% CI 1.14-2.41), lymph node ratio (LNR; HR 1.72, 95% CI 1.42-2.01), and lymphovascular invasion (HR 1.81, 95% CI 1.33-2.45) were associated with overall survival (OS; all p < 0.01), whereas tumor location (HR 1.93, 95% CI 1.23-3.02), T category (Tis-T1 vs. T3: HR 0.31, 95% CI 0.14-0.66), LNR (HR 1.82, 95% CI 1.45-2.28), and lymphovascular invasion (HR 1.49; 95% CI 1.01-2.22) were associated with disease-free survival (DFS; all p < 0.05) The models demonstrated good discrimination on internal validation relative to OS (C-index 0.70) and DFS (C-index 0.74)., Conclusions: A web-based nomograms to predict OS and DFS among gastric cancer patients following resection demonstrated good accuracy and discrimination and good performance on internal validation., (© 2021. Society of Surgical Oncology.)
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- 2022
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41. Enhanced recovery pathway after open pancreaticoduodenectomy reduces postoperative length of hospital stay without reducing composite length of stay.
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Takchi R, Cos H, Williams GA, Woolsey C, Hammill CW, Fields RC, Strasberg SM, Hawkins WG, and Sanford DE
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- Anastomosis, Surgical, Humans, Length of Stay, Postoperative Complications etiology, Postoperative Complications prevention & control, Retrospective Studies, Pancreatectomy adverse effects, Pancreaticoduodenectomy adverse effects, Pancreaticoduodenectomy methods
- Abstract
Background/purpose: There is no data regarding the impact of enhanced recovery pathways (ERP) on composite length of stay (CLOS) after procedures with increased risk of morbidity and mortality, such as pancreaticoduodenectomy., Methods: Patients undergoing open pancreaticoduodenectomy before and after implementation of ERP were prospectively followed for 90 days after surgery and complications were severity graded using the Modified Accordion Grading System. A retrospective analysis of patient outcomes were compared before and after instituting ERP. 1:1 propensity score matching was used to compare ERP patient outcomes to those of matched pre-ERP patients. CLOS is defined as postoperative length of hospital stay (PLOS) plus readmission length of hospital stay within 90 days after surgery., Results: 494 patients underwent open pancreaticoduodenectomy - 359 pre-ERP and 135 ERP. In a 1:1 propensity-score-matched analysis of 110 matched pairs, ERP patients had significantly decreased superficial surgical site infections (5.5% vs 15.5% p = 0.015) and significantly increased rates of urinary retention (29.1% vs 7.3% p < 0.0001) compared to matched pre-ERP patients. However, overall complication rate and 90-day readmission rate were not significantly different between matched groups. Propensity score-matched ERP patients had significantly decreased PLOS (7 days vs 8 days p = 0.046) compared to matched pre-ERP patients, but CLOS was not significantly different (9 days vs 9.5 days p = 0.615)., Conclusion: ERP may reduce PLOS but might not impact the total postoperative time spent in the hospital (i.e. CLOS) within 90 days after pancreaticoduodenectomy., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)
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- 2022
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42. Neoadjuvant FOLFIRINOX Therapy Is Associated with Increased Effector T Cells and Reduced Suppressor Cells in Patients with Pancreatic Cancer.
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Peng H, James CA, Cullinan DR, Hogg GD, Mudd JL, Zuo C, Takchi R, Caldwell KE, Liu J, DeNardo DG, Fields RC, Gillanders WE, Goedegebuure SP, and Hawkins WG
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, CD8-Positive T-Lymphocytes, Fluorouracil therapeutic use, Humans, Irinotecan, Leucovorin therapeutic use, Leukocytes, Mononuclear, Oxaliplatin, Neoadjuvant Therapy, Pancreatic Neoplasms drug therapy
- Abstract
Purpose: FOLFIRINOX has demonstrated promising results for patients with pancreatic ductal adenocarcinoma (PDAC). Chemotherapy-induced immunogenic cell death can prime antitumor immune responses. We therefore performed high-dimensional profiling of immune cell subsets in peripheral blood to evaluate the impact of FOLFIRINOX on the immune system., Experimental Design: Peripheral blood mononuclear cells (PBMC) were obtained from treatment-naïve ( n = 20) and FOLFIRINOX-treated patients ( n = 19) with primary PDAC tumors at the time of resection. PBMCs were characterized by 36 markers using mass cytometry by time of flight (CyTOF)., Results: Compared with treatment-naïve patients, FOLFIRINOX-treated patients showed distinct immune profiles, including significantly decreased inflammatory monocytes and regulatory T cells (Treg), increased Th1 cells, and decreased Th2 cells. Notably, both monocytes and Treg expressed high levels of immune suppression-associated CD39, and the total CD39
+ cell population was significantly lower in FOLFIRINOX-treated patients compared with untreated patients. Cellular alterations observed in responders to FOLFIRINOX included a significantly decreased frequency of Treg, an increased frequency of total CD8 T cells, and an increased frequency of CD27- Tbet+ effector/effector memory subsets of CD4 and CD8 T cells., Conclusions: Our study reveals that neoadjuvant chemotherapy with FOLFIRINOX enhances effector T cells and downregulates suppressor cells. These data indicate that FOLFIRINOX neoadjuvant therapy may improve immune therapy and clinical outcome in patients with PDAC., (©2021 The Authors; Published by the American Association for Cancer Research.)- Published
- 2021
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43. Inability to manage non-severe complications on an outpatient basis increases non-white patient readmission rates after pancreaticoduodenectomy: A large metropolitan tertiary care center experience.
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Zarate Rodriguez JG, Cos H, Williams GA, Woolsey CA, Fields RC, Strasberg SM, Doyle MB, Khan AS, Chapman WC, Hammill CW, Hawkins WG, and Sanford DE
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- Female, Humans, Male, Middle Aged, Pancreaticoduodenectomy statistics & numerical data, Risk Factors, Ambulatory Care statistics & numerical data, Healthcare Disparities statistics & numerical data, Hospitals, Urban statistics & numerical data, Pancreaticoduodenectomy adverse effects, Patient Readmission statistics & numerical data, Racial Groups statistics & numerical data, Tertiary Care Centers statistics & numerical data
- Abstract
Background: Pancreaticoduodenectomy (PD) has a high rate of readmission, and racial disparities in care could be an important contributor., Methods: Patients undergoing PD were prospectively followed, and their complications graded using the Modified Accordion Grading System (MAGS). Patient factors and perioperative outcomes for patients with and without postoperative readmission were compared in univariate and multivariate analysis by severity., Results: 837 patients underwent PD, the overall 90-day readmission rate was 27.5%. Non-white race was independently associated with readmission (OR 1.83, p = 0.007). 51.3% of readmissions were for non-severe complications (MAGS <3). Non-white race was independently associated with MAGS non-severe readmission (OR 2.13, p = 0.006), but not MAGS severe readmission., Conclusions: Non-white patients are more likely to be readmitted, particularly for non-severe complications. Follow up protocols should be tailored to address race disparities in the rates of readmission as readmission for less severe complications could potentially be avoidable., (Copyright © 2021. Published by Elsevier Inc.)
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- 2021
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44. In silico epitope prediction analyses highlight the potential for distracting antigen immunodominance with allogeneic cancer vaccines.
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James CA, Ronning P, Cullinan D, Cotto KC, Barnell EK, Campbell KM, Skidmore ZL, Sanford DE, Goedegebuure SP, Gillanders WE, Griffith OL, Hawkins WG, and Griffith M
- Subjects
- Humans, Epitopes, Antigens, Neoplasm genetics, Cancer Vaccines, Neoplasms therapy, Hematopoietic Stem Cell Transplantation
- Abstract
Allogeneic cancer vaccines are designed to induce antitumor immune responses with the goal of impacting tumor growth. Typical allogeneic cancer vaccines are produced by expansion of established cancer cell lines, transfection with vectors encoding immunostimulatory cytokines, and lethal irradiation. More than 100 clinical trials have investigated the clinical benefit of allogeneic cancer vaccines in various cancer types. Results show limited therapeutic benefit in clinical trials and currently there are no FDA approved allogeneic cancer vaccines. We used recently developed bioinformatics tools including the pVAC-seq suite of software tools to analyze DNA/RNA sequencing data from the TCGA to examine the repertoire of antigens presented by a typical allogeneic cancer vaccine, and to simulate allogeneic cancer vaccine clinical trials. Specifically, for each simulated clinical trial we modeled the repertoire of antigens presented by allogeneic cancer vaccines consisting of three hypothetical cancer cell lines to 30 patients with the same cancer type. Simulations were repeated ten times for each cancer type. Each tumor sample in the vaccine and the vaccine recipient was subjected to HLA typing, differential expression analyses for tumor associated antigens (TAAs), germline variant calling, and neoantigen prediction. These analyses provided a robust, quantitative comparison between potentially beneficial TAAs and neoantigens versus distracting antigens present in the allogeneic cancer vaccines. We observe that distracting antigens greatly outnumber shared TAAs and neoantigens, providing one potential explanation for the lack of observed responses to allogeneic cancer vaccines. This analysis provides additional rationale for the redirection of efforts towards a personalized cancer vaccine approach., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest.
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- 2021
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45. Less is more in the difficult gallbladder: recent evolution of subtotal cholecystectomy in a single HPB unit.
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LeCompte MT, Robbins KJ, Williams GA, Sanford DE, Hammill CW, Fields RC, Hawkins WG, and Strasberg SM
- Subjects
- Cholecystectomy, Humans, Reoperation, Retrospective Studies, Cholecystectomy, Laparoscopic, Gallbladder diagnostic imaging, Gallbladder surgery
- Abstract
Introduction: Subtotal cholecystectomy (SC) is a technique to manage the difficult gallbladder and avoid hazardous dissection and biliary injury. Until recently it was used infrequently. However, because of reduced exposure to open total cholecystectomy in resident training, we recently adopted subtotal cholecystectomy as the bail-out procedure of choice for resident teaching. This study reports our experience and outcomes with subtotal cholecystectomy in the years immediately preceding adoption and since adoption., Methods: A retrospective analysis was conducted of patients undergoing SC from July 2010 to June 2019. Outcomes, including bile leak, reoperation and need for additional procedures, were analyzed. Complications were graded by the Modified Accordion Grading Scale (MAGS)., Results: 1571 cholecystectomies were performed of which 71 were SC. Subtotal cholecystectomy patients had several indicators of difficulty including prior attempted cholecystectomy and previous cholecystostomy tube insertion. The most common indication for SC was marked inflammation in the hepatocystic triangle (51%). As our experience increased, fewer patients required open conversion to accomplish SC and SC was completed laparoscopically, usually subtotal fenestrating cholecystectomy (SFC). Most patients (85%) had a drain placed and 28% were discharged with a drain. The highest MAGS complication observed was grade 3 (11 patients, 15%). Six patients had a bile leak from the cystic duct resolved by ERCP. At mean follow-up of about 1 year no patient returned with recurrent symptoms., Conclusions: Subtotal fenestrating cholecystectomy is a useful technique to avoid biliary injury in the difficult gallbladder and can be performed with very satisfactory rates of bile fistula, ERCP, and reoperation.
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- 2021
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46. Elucidating the Efficacy of Pancreatectomy for Renal Cell Metastases Remains Problematic.
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Leigh N and Hawkins WG
- Subjects
- Humans, Pancreatectomy, Carcinoma, Renal Cell surgery, Kidney Neoplasms surgery, Pancreatic Neoplasms surgery
- Published
- 2021
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47. Care Fragmentation and Mortality in Readmission after Surgery for Hepatopancreatobiliary and Gastric Cancer: A Patient-Level and Hospital-Level Analysis of the Healthcare Cost and Utilization Project Administrative Database.
- Author
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Brauer DG, Wu N, Keller MR, Humble SA, Fields RC, Hammill CW, Hawkins WG, Colditz GA, and Sanford DE
- Subjects
- Aged, Chemotherapy, Adjuvant economics, Chemotherapy, Adjuvant statistics & numerical data, Continuity of Patient Care economics, Continuity of Patient Care statistics & numerical data, Databases, Factual statistics & numerical data, Digestive System Neoplasms economics, Digestive System Neoplasms mortality, Digestive System Surgical Procedures economics, Digestive System Surgical Procedures statistics & numerical data, Female, Health Care Costs statistics & numerical data, Hospital Mortality, Humans, Male, Middle Aged, Patient Acceptance of Health Care statistics & numerical data, Patient Readmission economics, Postoperative Complications economics, Postoperative Complications etiology, Radiotherapy, Adjuvant economics, Radiotherapy, Adjuvant statistics & numerical data, Retrospective Studies, Risk Assessment statistics & numerical data, Risk Factors, Tertiary Care Centers economics, Tertiary Care Centers organization & administration, Tertiary Care Centers statistics & numerical data, Time Factors, Continuity of Patient Care organization & administration, Digestive System Neoplasms therapy, Digestive System Surgical Procedures adverse effects, Patient Readmission statistics & numerical data, Postoperative Complications epidemiology
- Abstract
Background: Hepatopancreatobiliary (HPB) and gastric oncologic operations are frequently performed at referral centers. Postoperatively, many patients experience care fragmentation, including readmission to "outside hospitals" (OSH), which is associated with increased mortality. Little is known about patient-level and hospital-level variables associated with this mortality difference., Study Design: Patients undergoing HPB or gastric oncologic surgery were identified from select states within the Healthcare Cost and Utilization Project database (2006-2014). Follow-up was 90 days after discharge. Analyses used Kruskal-Wallis test, Youden index, and multilevel modeling at the hospital level., Results: There were 7,536 patients readmitted within 90 days of HPB or gastric oncologic surgery to 636 hospitals; 28% of readmissions (n = 2,123) were to an OSH, where 90-day readmission mortality was significantly higher: 8.0% vs 5.4% (p < 0.01). Patients readmitted to an OSH lived farther from the index surgical hospital (median 24 miles vs 10 miles; p < 0.01) and were readmitted later (median 25 days after discharge vs 12; p < 0.01). These variables were not associated with readmission mortality. Surgical complications managed at an OSH were associated with greater readmission mortality: 8.4% vs 5.7% (p < 0.01). Hospitals with <100 annual HPB and gastric operations for benign or malignant indications had higher readmission mortality (6.4% vs 4.7%, p = 0.01), although this was not significant after risk-adjustment (p = 0.226)., Conclusions: For readmissions after HPB and gastric oncologic surgery, travel distance and timing are major determinants of care fragmentation. However, these variables are not associated with mortality, nor is annual hospital surgical volume after risk-adjustment. This information could be used to determine safe sites of care for readmissions after HPB and gastric surgery. Further analysis is needed to explore the relationship between complications, the site of care, and readmission mortality., (Copyright © 2021 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)
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- 2021
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48. Re-defining a high volume center for pancreaticoduodenectomy.
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Panni RZ, Panni UY, Liu J, Williams GA, Fields RC, Sanford DE, Hawkins WG, and Hammill CW
- Subjects
- Anastomosis, Surgical, Databases, Factual, Hospital Mortality, Hospitals, High-Volume, Humans, Logistic Models, Pancreatectomy, Pancreaticoduodenectomy adverse effects
- Abstract
Background: The purpose of this study was to re-evaluate the previously utilized definitions of high volume center for pancreaticoduodenectomy to determine/establish an objective, evidence based threshold of hospital volume associated with improvement in perioperative mortality., Methods: Patients who underwent pancreaticoduodenectomy were identified using the National Cancer Database from 2004 to 2015. The relationship between hospital volume and 90-day mortality was assessed using a logistic regression model. Receiver Operator Characteristic analysis was performed and Youden's statistic was utilized to calculate the optimal cut offs., Results: 42,402 patients underwent elective Pancreaticoduodenectomy at 1238 unique hospitals. A logistic regression was performed which showed a significant inverse linear association between institutional volume and overall 90 day mortality. The maximum improvement in 90 day mortality is seen if the average annual hospital volume was greater than 9 (OR = 0.647 (0.595-0.702), p < 0.0001). When analysis is limited to hospitals that performed >9 cases per year, the maximum improvement in 90 day mortality was noticed at 36 cases per year (OR = 0.458 (0.399-0.525), p < 0.0001)., Conclusions: Based on our results, we recommend defining low, medium, and high volume centers for pancreaticoduodenectomy as hospitals with average annual volume less than 9, 9 to 35, and more than 35 cases per year, respectively., (Copyright © 2020. Published by Elsevier Ltd.)
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- 2021
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49. Hepatobiliary Cancers, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.
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Benson AB, D'Angelica MI, Abbott DE, Anaya DA, Anders R, Are C, Bachini M, Borad M, Brown D, Burgoyne A, Chahal P, Chang DT, Cloyd J, Covey AM, Glazer ES, Goyal L, Hawkins WG, Iyer R, Jacob R, Kelley RK, Kim R, Levine M, Palta M, Park JO, Raman S, Reddy S, Sahai V, Schefter T, Singh G, Stein S, Vauthey JN, Venook AP, Yopp A, McMillian NR, Hochstetler C, and Darlow SD
- Subjects
- Humans, Sorafenib therapeutic use, Carcinoma, Hepatocellular diagnosis, Carcinoma, Hepatocellular therapy, Liver Neoplasms diagnosis, Liver Neoplasms therapy
- Abstract
The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.
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- 2021
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50. Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.
- Author
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Tempero MA, Malafa MP, Al-Hawary M, Behrman SW, Benson AB, Cardin DB, Chiorean EG, Chung V, Czito B, Del Chiaro M, Dillhoff M, Donahue TR, Dotan E, Ferrone CR, Fountzilas C, Hardacre J, Hawkins WG, Klute K, Ko AH, Kunstman JW, LoConte N, Lowy AM, Moravek C, Nakakura EK, Narang AK, Obando J, Polanco PM, Reddy S, Reyngold M, Scaife C, Shen J, Vollmer C, Wolff RA, Wolpin BM, Lynn B, and George GV
- Subjects
- Humans, Adenocarcinoma diagnosis, Adenocarcinoma therapy, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms therapy
- Abstract
Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients' advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.
- Published
- 2021
- Full Text
- View/download PDF
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