Publications by authors named "Ronald DeMatteo"

444 Publications

The Left Hepatic Bile Duct is not Longer?!

Ann Surg 2021 Apr 7. Epub 2021 Apr 7.

Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1097/SLA.0000000000004900DOI Listing
April 2021

Genetic Determinants of Outcome in Intrahepatic Cholangiocarcinoma.

Hepatology 2021 Mar 25. Epub 2021 Mar 25.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background/aims: Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well-characterized, but their impact on outcome and prognosis remain unknown.

Approach/results: This bi-institutional study of patients with confirmed iCCA (n=412) used targeted next-generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were IDH1 (20%), ARID1A (20%), TP53 (17%), CDKN2A (15%), BAP1 (15%), FGFR2 (15%), PBRM1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions (fus), but neither was associated with outcome. For all patients, TP53 (p<0.0001), KRAS (p=0.0001), and CDKN2A (p<0.0001) alterations predicted worse overall survival (OS). These high-risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n=209), TP53mut (HR=1.82, 95%CI=1.08-3.06, p=0.03) and CDKN2A deletions (del) (HR=3.40, 95%CI=1.95-5.94, p<0.001) independently predicted shorter OS, as did high-risk clinical variables (multifocal liver disease [p<0.001]; regional lymph node metastases [p<0.001]), whereas KRASmut (HR=1.69, 95%CI=0.97-2.93, p=0.06) trended toward statistical significance. The presence of both or neither high-risk clinical or genetic factors represented outcome extremes (median OS=18.3 vs. 74.2 months, p<0.001), with high-risk genetic alterations alone (median OS=38.6 months, 95%CI=28.8-73.5) or high-risk clinical variables alone (median OS=37.0 months, 95%CI=27.6-NA) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high-risk clinical features were notable for limited survival and no benefit of resection over chemotherapy.

Conclusions: TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Since genetic profiling can be integrated into pre-treatment therapeutic decision-making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.
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http://dx.doi.org/10.1002/hep.31829DOI Listing
March 2021

What is the patient experience of surgical care during the coronavirus disease 2019 (COVID-19) pandemic? A mixed-methods study at a single institution.

Surgery 2020 Dec 29. Epub 2020 Dec 29.

Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA.

Background: The coronavirus disease 2019 outbreak has spread worldwide and has resulted in hospital restrictions. The perceived impact of these practices on patients undergoing essential surgeries is less understood.

Methods: Adult (≥18 years) patients who underwent medically necessary surgical procedures spanning multiple surgical specialties from March 23, 2020, to April 24, 2020, during the coronavirus disease 2019 pandemic were identified as eligible for a phone survey. Survey responses were analyzed using a mixed-methods approach involving descriptive statistics and thematic analysis of coded and annotated survey results.

Results: Of the 212 patients who underwent medically necessary surgical procedures during the coronavirus disease 2019 pandemic, the majority of these patients were male (61.3%), White (83.5%), married or with a domestic partner (68.9%), and underwent oncologic procedures (69.3%). Of the 46 patients (21.7%) who completed the survey, the majority of these patients indicated that coronavirus disease 2019 pandemic restrictions had no impact on their inpatient hospital stay and were satisfied with their decision to proceed with surgery. Severity of patient condition (44.4%), the risk/benefit discussion with the surgeon (24.4%), and coronavirus disease 2019 education and testing (19.5%) were the most important factors in proceeding with surgery during the pandemic; 34.4% of patients said their inpatient postoperative course was negatively affected by the lack of visitors.

Conclusion: Medically necessary, time-sensitive surgical procedures, as determined by the surgeon, can be performed during a pandemic with good patient satisfaction provided there is an appropriate discussion between the surgeon and patient about the risks and benefits.
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http://dx.doi.org/10.1016/j.surg.2020.12.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833934PMC
December 2020

Oncogenic KIT Modulates Type I IFN-Mediated Antitumor Immunity in GIST.

Cancer Immunol Res 2021 Mar 1. Epub 2021 Mar 1.

Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

Type I IFNs are implicated in tumor immunogenicity and response to systemic therapy, but their interaction with oncogene signaling is not well understood. Here, we studied oncogenic KIT, which drives gastrointestinal stromal tumor (GIST), the most common sarcoma. Using mouse models of GIST, we found that KIT inhibition reduced type I IFN production and signaling, which downregulated tumor MHC class I expression. Absence of type I IFN signaling increased tumor size, in part due to CD8 T-cell impairment. Oncogenic KIT was required for GIST type I IFN signal transduction via STAT1. In human GIST cell lines and surgical specimens, type I IFN signaling contributed to human lymphocyte antigen class I expression and correlated with tumor immunogenicity. Augmenting the type I IFN response partially compensated for the immunosuppressive effects of KIT inhibition. Thus, KIT signaling contributes to type I IFN signaling, whereas KIT inhibition attenuates tumor immunogenicity and is partly rescued by innate immune stimulation.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0692DOI Listing
March 2021

Proposal of a New Comprehensive Notation for Hepatectomy: The "New World" Terminology.

Ann Surg 2021 Feb 12. Epub 2021 Feb 12.

*Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan †Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA ‡Department of General, Visceral and Transplant Surgery, University Hospital Mainz, Mainz, Germany §Hôpital Paul Brousse, APHP - Université Paris - Saclay, Villejuif, France ¶Department of HPB- and Liver Transplantation Surgery, University College London, Royal Free Hospitals, London, UK ||Department of Surgery & Transplantation, University Hospital Zurich, Zurich, Switzerland **Hepatobiliary Surgery Division, Department of Surgery, IRCCS San Raffaele Hospital, School of Medicine, Milan, Italy ††Department of Hepatobiliary and Digestive Surgery, Rennes University Hospital, Rennes, France ‡‡Section of Transplantation Surgery, Siteman Cancer Center, Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, USA §§Department of Surgery, University of California at San Diego, San Diego, USA ¶¶Department of Surgery, Division of HPB Surgery, Liver Transplant Unit, Italian Hospital of Buenos Aires, Buenos Aires, Argentina ||||Hepato-pancreato-biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China ***Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan †††Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan ‡‡‡Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, USA §§§Department of Surgery, General and Hepatobiliary Surgery, University of Verona, Verona, Italy ¶¶¶Center for Liver Disease and Transplantation, Columbia University Medical Center, New York, USA ||||||HepatoBiliary Surgery & Liver Transplantation, Asan Medical Center, Ulsan University, Seoul, Republic of Korea ****HPB and Transplant Unit, St. James's University Hospital, Leeds, UK ††††Department of General and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany ‡‡‡‡Center for Abdominal Transplantation Weston, Cleveland Clinic Florida, Weston, USA §§§§Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands ¶¶¶¶Department of HPB Surgery and Liver Transplant, Beaujon Hospital, Clichy, France.

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http://dx.doi.org/10.1097/SLA.0000000000004808DOI Listing
February 2021

Cancer-associated fibroblast secretion of PDGFC promotes gastrointestinal stromal tumor growth and metastasis.

Oncogene 2021 Mar 18;40(11):1957-1973. Epub 2021 Feb 18.

Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, CA, USA.

Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.
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http://dx.doi.org/10.1038/s41388-021-01685-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979540PMC
March 2021

Long-term Outcomes After Surgical Resection of Pancreatic Metastases from Renal Clear-Cell Carcinoma.

Ann Surg Oncol 2021 Feb 11. Epub 2021 Feb 11.

Unit of General and Pancreatic Surgery, Department of Surgery and Oncology, University of Verona Hospital Trust, Verona, Italy.

Background: Pancreatic metastases (PM) from renal cell carcinoma (RCC) are uncommon. We herein describe the long-term outcomes associated with pancreatectomy at two academic institutions, with a specific focus on 10-year survival.

Methods: This investigation was limited to patients undergoing pancreatectomy for PM between 2000 and 2008 at the University of Verona and Memorial Sloan Kettering Cancer Center, allowing a potential for 10 years of surveillance. The probabilities of further RCC recurrence and RCC-related death were estimated using a competing risk analysis (method of Fine and Gray) to account for patients who died of other causes during follow-up.

Results: The study population consisted of 69 patients, mostly with isolated metachronous PM (77%). The median interval from nephrectomy to pancreatic metastasectomy was 109 months, whereas the median post-pancreatectomy follow-up was 141 months. The 10-year cumulative incidence of new RCC recurrence was 62.7%. In the adjusted analysis, the relative risk of repeated recurrence was significantly higher in PM synchronous to the primary RCC (sHR = 1.27) and in patients receiving extended pancreatectomy (sHR = 3.05). The 10-year cumulative incidence of disease-specific death was 25.5%. The only variable with an influence on disease-specific death was the recurrence-free interval following metastasectomy (sHR = 0.98). In patients with repeated recurrence, the 10-year cumulative incidence of RCC-related death was 35.4%.

Conclusion: In a selected group of patients followed for a median of 141 months and mostly with isolated metachronous PM, resection was associated with a high possibility of long-term disease control in surgically fit patients with metastases confined to the pancreas.
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http://dx.doi.org/10.1245/s10434-021-09649-wDOI Listing
February 2021

Impact of COVID-19 Restrictions on Demographics and Outcomes of Patients Undergoing Medically Necessary Non-Emergent Surgeries During the Pandemic.

World J Surg 2021 04 28;45(4):946-954. Epub 2021 Jan 28.

Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Background: The COVID-19 pandemic has resulted in large-scale healthcare restrictions to control viral spread, reducing operating room censuses to include only medically necessary surgeries. The impact of restrictions on which patients undergo surgical procedures and their perioperative outcomes is less understood.

Methods: Adult patients who underwent medically necessary surgical procedures at our institution during a restricted operative period due to the COVID-19 pandemic (March 23-April 24, 2020) were compared to patients undergoing procedures during a similar time period in the pre-COVID-19 era (March 25-April 26, 2019). Cardinal matching and differences in means were utilized to analyze perioperative outcomes.

Results: 857 patients had surgery in 2019 (pre-COVID-19) and 212 patients had surgery in 2020 (COVID-19). The COVID-19 era cohort had a higher proportion of patients who were male (61.3% vs. 44.5%, P < 0.0001), were White (83.5% vs. 68.7%, P < 0.001), had private insurance (62.7% vs. 54.3%, p 0.05), were ASA classification 4 (10.9% vs. 3%, P < 0.0001), and underwent oncologic procedures (69.3% vs. 42.7%, P < 0.0001). Following 1:1 cardinal matching, COVID-19 era patients (N = 157) had a decreased likelihood of discharge to a nursing facility (risk difference-8.3, P < 0.0001) and shorter median length of stay (risk difference-0.6, p 0.04) compared to pre-COVID-19 era patients. There was no difference between the two patient cohorts in overall morbidity and 30-day readmission.

Conclusions: COVID-19 restrictions on surgical operations were associated with a change in the racial and insurance demographics in patients undergoing medically necessary surgical procedures but were not associated with worse postoperative morbidity. Further study is necessary to better identify the causes for patient demographic differences.
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http://dx.doi.org/10.1007/s00268-021-05958-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842172PMC
April 2021

The Cost of Quarantine: Projecting the Financial Impact of Canceled Elective Surgery on the Nation's Hospitals.

Ann Surg 2021 05;273(5):844-849

Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania.

Objective: We sought to quantify the financial impact of elective surgery cancellations in the US during COVID-19 and simulate hospitals' recovery times from a single period of surgery cessation.

Background: COVID-19 in the US resulted in cessation of elective surgery-a substantial driver of hospital revenue-and placed patients at risk and hospitals under financial stress. We sought to quantify the financial impact of elective surgery cancellations during the pandemic and simulate hospitals' recovery times.

Methods: Elective surgical cases were abstracted from the Nationwide Inpatient Sample (2016-2017). Time series were utilized to forecast March-May 2020 revenues and demand. Sensitivity analyses were conducted to calculate the time to clear backlog cases and match expected ongoing demand in the post-COVID period. Subset analyses were performed by hospital region and teaching status.

Results: National revenue loss due to major elective surgery cessation was estimated to be $22.3 billion (B). Recovery to market equilibrium was conserved across strata and influenced by pre- and post-COVID capacity utilization. Median recovery time was 12-22 months across all strata. Lower pre-COVID utilization was associated with fewer months to recovery.

Conclusions: Strategies to mitigate the predicted revenue loss of $22.3B due to major elective surgery cessation will vary with hospital-specific supply-demand equilibrium. If patient demand is slow to return, hospitals should focus on marketing of services; if hospital capacity is constrained, efficient capacity expansion may be beneficial. Finally, rural and urban nonteaching hospitals may face increased financial risk which may exacerbate care disparities.
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http://dx.doi.org/10.1097/SLA.0000000000004766DOI Listing
May 2021

Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment.

JCI Insight 2021 Jan 25;6(2). Epub 2021 Jan 25.

Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strategies for refractory GISTs requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases essential in GISTs. Using multiplexed inhibitor beads and mass spectrometry, we explored the majority of the kinome in GIST specimens from the 3 most common molecular subtypes (KIT mutant, PDGFRA mutant, and succinate dehydrogenase deficient) to identify kinase targets. Kinome profiling with loss-of-function assays identified an important role for G2/M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT mutant and PDGFRA mutant GIST cell lines as well as notable efficacy of MK-1775 as a monotherapy in the engineered PDGFRA mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.
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http://dx.doi.org/10.1172/jci.insight.143474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934848PMC
January 2021

Impact of Primary Tumor Laterality on Adjuvant Hepatic Artery Infusion Pump Chemotherapy in Resected Colon Cancer Liver Metastases: Analysis of 487 Patients.

Ann Surg Oncol 2020 Nov 23. Epub 2020 Nov 23.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Hepatic artery infusion (HAI) chemotherapy is associated with overall survival (OS) in patients with resected colon cancer liver metastases (CLM). The prognostic impact of primary tumor location in CLM following hepatic resection in patients receiving regional HAI is unknown. This study seeks to investigate the prognostic impact of HAI in relation to laterality in this patient population.

Methods: Consecutive patients with resected CLM, with known primary tumor site treated with and without HAI, were reviewed from a prospective institutional database. Correlations between HAI, laterality, other clinicopathological factors, and survival were analyzed, and Cox proportional hazard regression was used to determine whether laterality was an independent prognostic factor.

Results: From 1993 to 2012, 487 patients [182 with right colon cancer (RCC), 305 with left colon cancer (LCC)] were evaluated with a median follow-up of 6.5 years. Fifty-seven percent (n = 275) received adjuvant HAI. Patients with RCC had inferior 5-year OS compared with LCC (56% vs. 67%, P = 0.01). HAI was associated with improved 5-year OS in both RCC (68% vs. 45%; P < 0.01) and LCC (73% vs. 55%; P < 0.01). On multivariable analysis, HAI remained associated with improved OS (HR 0.52; 95% CI 0.39-0.70; P < 0.01) but primary tumor site did not (HR 0.83; 95% CI 0.63-1.11; P = 0.21). Additional significant prognostic factors on multivariable analysis included age, number of tumors, node-positive primary, positive margins, RAS mutation, two-stage hepatectomy, and extrahepatic disease. Cox proportional hazard regression determined no significant interaction between HAI and laterality on OS [parameter estimate (SEM), 0.12 (0.28); P = 0.67].

Conclusions: Our data show an association of adjuvant HAI and increased OS in patients who underwent curative hepatectomy, irrespective of primary tumor location. Laterality should therefore not impact decision-making when offering adjuvant HAI.
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http://dx.doi.org/10.1245/s10434-020-09369-7DOI Listing
November 2020

Surgical Management of Sarcoma Metastatic to Liver.

Surg Oncol Clin N Am 2021 Jan 20;30(1):57-67. Epub 2020 Oct 20.

Department of Surgery, University of Pennsylvania, 3400 Spruce st, Philadelphia, PA 19104, USA.

Sarcomas are rare mesenchymal tumors with a propensity for hematogenous metastasis. Gastrointestinal stromal tumor (GIST) is the most common histologic subtype and the most common source of hepatic metastases. In the case of metastatic GIST, neoadjuvant imatinib can be used as a selection tool for the judicious application of surgery, where treatment-responsive patients who undergo resection to prevent the development of treatment-resistant clones have associated 10-year actuarial survival of 40%. Further advances for many of the non-GIST sarcoma subtypes will depend on the development of improved systemic therapies and evaluation of their activity in subtype or molecularly defined trials.
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http://dx.doi.org/10.1016/j.soc.2020.08.002DOI Listing
January 2021

Prognostic Factors After Neoadjuvant Imatinib for Newly Diagnosed Primary Gastrointestinal Stromal Tumor.

J Gastrointest Surg 2020 Nov 9. Epub 2020 Nov 9.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Introduction: Neoadjuvant imatinib (Neo-IM) therapy may facilitate R0 resection in primary gastrointestinal stromal tumors (GISTs) that are large or in difficult anatomic locations. While response to preoperative tyrosine kinase inhibitors is associated with better outcome in metastatic GIST, little is known about prognostic factors after Neo-IM in primary GIST.

Study Design: Patients with primary GIST with or without synchronous metastases who underwent Neo-IM were retrospectively analyzed from a prospective maintained institutional database for Response Evaluation Criteria in Solid Tumors (RECIST), tumor viability, and mitotic rate. Overall survival (OS) was estimated by Kaplan-Meier and compared by log-rank test. Cox proportionate hazard models were used for univariate and multivariate analysis.

Results: One hundred and fifty patients were treated for a median of 7.1 months (range 0.2-160). By RECIST, partial response, stable disease, and progressive disease were seen in 40%, 51%, and 9%, respectively. By pathologic analysis, ≤ 50% of the tumor was viable in 72%, and the mitotic rate was ≤ 5/50HPF in 74%. On multivariate analysis, RECIST response and tumor viability were not associated with OS, while post-treatment high mitotic rate (hazard ratio (HR) for death 5.3, CI 2.3-12.4), R2 margins (HR 6.0, CI 2.3-15.5), and adjuvant imatinib (HR 0.4, CI 0.2-0.9) were (p < 0.05). Five-year OS was 81 vs. 38% for low vs. high mitotic rate; 81, 59, and 39% for R0, R1, and R2 margins; and 75 vs 61% for adjuvant vs. no adjuvant imatinib therapy (p < 0.05).

Conclusions: In primary GIST undergoing Neo-IM therapy, progression was uncommon, but substantial down-sizing occurred in the minority. High tumor mitotic rate and incomplete resection following Neo-IM were associated with poor outcome, while adjuvant imatinib was associated with prolonged survival.
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http://dx.doi.org/10.1007/s11605-020-04843-9DOI Listing
November 2020

Are Volume Pledge Standards Worth the Travel Burden for Major Abdominal Cancer Operations?

Ann Surg 2020 Oct 14. Epub 2020 Oct 14.

Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.

Objective: The study objective is to determine the association between travel distance and surgical volume on outcomes after esophageal, pancreatic, and rectal cancer resections.

Summary Of Background Data: "Take the Volume Pledge" aims to centralize esophagectomies, pancreatectomies, and proctectomies to hospitals meeting minimum volume standards. The impact of travel, and possible care fragmentation, on potential benefits of centralized surgery is not well understood.

Methods: Using the National Cancer Database (2004-2016), patients who underwent esophageal, pancreatic, or rectal resections at far HVH meeting volume standards versus local intermediate (IVH) and low-volume (LVH) hospitals were identified. Perioperative outcomes and 5-year OS were compared.

Results: Of 49,454 patients, 17,544 (34.5%) underwent surgery at far HVH, 11,739 (23.7%) at local IVH, and 20,171 (40.8%) at local LVH. The median (interquartile range) travel distances were 77.1 (51.1-125.4), 13.2 (5.8-27.3), and 7.8 (3.1-15.5) miles to HVH, IVH, and LVH, respectively. By multivariable analysis, LVH was associated with increased 30-day mortality for all resections compared to HVH, but IVH was associated with mortality only for proctectomies [odds ratio 1.90, 95% confidence interval (CI) 1.31-2.75]. Compared to HVH, both IVH (hazard ratio 1.25, 95% CI 1.19-1.31) and LVH (hazard ratio 1.35, 95% CI 1.29-1.42) were associated with decreased 5-year OS.

Conclusions: Compared to far HVH, 30-day mortality was higher for all resections at LVH, but only for proctectomies at IVH. Five-year OS was consistently worse at local LVH and IVH. Improving long-term outcomes at IVH may provide opportunities for greater access to quality cancer care.
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http://dx.doi.org/10.1097/SLA.0000000000004361DOI Listing
October 2020

The V654A second-site KIT mutation increases tumor oncogenesis and STAT activation in a mouse model of gastrointestinal stromal tumor.

Oncogene 2020 12 6;39(49):7153-7165. Epub 2020 Oct 6.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and arises in the gastrointestinal tract. Most GISTs are caused by activating mutations in the KIT receptor tyrosine kinase, such as the exon 11 KIT V559Δ mutation. The small molecule imatinib inhibits KIT and has been a mainstay of therapy in GIST. Unfortunately, imatinib-treated patients typically relapse, most often due to clonal emergence of the resistance-associated KIT V654A mutation. To determine the biologic impact of this second-site mutation in vivo, we created a mouse model with the corresponding V558Δ;V653A Kit double mutation restricted (a) spatially to ETV1 cells, which include the interstitial cells of Cajal (ICCs) from which GISTs presumably originate, and (b) temporally through tamoxifen treatment after birth. This resulted in the first in vivo model of the most common second-site mutation associated with imatinib resistance in GIST and the first in vivo demonstration that cell-autonomous expression of mutant KIT in the ICC lineage leads to GIST. GISTs driven by the V558Δ;V653A Kit double mutation were resistant to imatinib, while cabozantinib was more effective in overcoming resistance than sunitinib. Compared to control mice with a single V558Δ Kit mutation, mice with a double V558Δ; V653A Kit mutation had increased tumor oncogenesis and associated KIT-dependent STAT activation. Our findings demonstrate that the biologic consequences of a second-site mutation in an oncogenic driver may include not only a mechanism for drug resistance, but changes in tumor oncogenic potential and differential activation of signaling pathways.
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http://dx.doi.org/10.1038/s41388-020-01489-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718339PMC
December 2020

Defining postoperative weight change after pancreatectomy: Factors associated with distinct and dynamic weight trajectories.

Surgery 2020 Dec 14;168(6):1041-1047. Epub 2020 Sep 14.

Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. Electronic address:

Background: Weight change offers the simplest indication of a patient's recovery after an operation. There have been no studies that have thoroughly investigated postoperative weight dynamics after pancreatectomy. The aim of this study was to define postoperative weight change after a pancreatectomy and determine factors associated with optimal and poor weight trajectories.

Methods: From 2004 to 2019, 1,090 proximal (65%) and distal (35%) pancreatectomies were performed in patients with adequate data in the medical records. Patient weights were acquired preoperatively and at postoperative months 1, 3, and 12. Optimal (top quartile, weight restoration) and poor (bottom quartile, persistent weight loss) postoperative weight cohorts were identified at 1 year postoperatively.

Results: The median percentage weight change 1 year postpancreatectomy was -6.6% (interquartile range: -1.4% to -12.5%), -7.8% for proximal pancreatectomy, and -4.2% for distal pancreatectomy. For most patients (interquartile range cohort), the median percentage weight change at 1, 3, and 12 months was -6.2%, -7.2%, and -6.6%. The independent factors associated with weight restoration were age <65, nonobesity (body mass index <30kg/m), receiving total parenteral nutrition/total enteral nutrition preoperatively, experiencing preoperative weight loss >10%, distal pancreatectomy, not undergoing vascular resection, and no readmission within 30 days. Conversely, persistent weight loss was associated with American Society of Anesthesiologists classes III to IV, obesity, malignancy, proximal pancreatectomy, blood loss ≥350mL, and experiencing readmission within 30 days. Focusing on pancreatic ductal adenocarcinoma (n = 372) patients, the factors associated with persistent weight loss were obesity, proximal pancreatectomy, and experiencing recurrence within 1 year; however, weight cohorts were not associated with overall survival for pancreatic ductal adenocarcinoma patients.

Conclusion: These data define weight kinetics after pancreatectomy. Ultimately, postoperative weight trajectories appear to be largely predetermined but may be mitigated by limiting readmissions and complications. Clinicians should use these data to identify patients who continue to lose weight between the first and third month postoperatively with a high suspicion for the requirement of nutritional monitoring or other interventions.
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http://dx.doi.org/10.1016/j.surg.2020.07.056DOI Listing
December 2020

A contemporary analysis of palliative procedures in aborted pancreatoduodenectomy: Morbidity, mortality, and impact on future therapy.

Surgery 2020 Dec 1;168(6):1026-1031. Epub 2020 Sep 1.

Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA.

Background: Periampullary malignancies are often unresectable tumors that frequently cause biliary or duodenal obstruction. Advances in endoscopic and percutaneous options have lessened the need for operative palliation. Nevertheless, many patients are still found to be unresectable at the time of exploration, making palliative bypass a consideration. Several prior studies have examined the morbidity of operative palliation, but many were conducted over lengthy time periods, and few have examined the impact of these procedures on future therapy. This study is a contemporary analysis of the short- and long-term outcomes of palliative bypass procedures for unresectable periampullary malignancies at a single high-volume institution.

Methods: We identified a contemporary cohort of patients in whom a pancreatoduodenectomy was planned for periampullary malignancy but instead underwent an aborted procedure. Patients were divided into 5 procedure groups: laparoscopy only, laparotomy with or without cholecystectomy, gastrointestinal bypass, biliary bypass, and double bypass (gastrointestinal and biliary). Data regarding the patient cohort, procedures, morbidity/mortality, and the interval to initiation of systemic therapy were collected prospectively and reviewed retrospectively.

Results: Between July 2011 and November 2018, 128 out of 615 (17%) patients had an aborted pancreatoduodenectomy; 113 out of 128 patients had pancreatic adenocarcinoma, and 86 (67.1%) had duodenal or biliary obstruction at the time of operation. Patients who underwent laparoscopy only (n = 34) had no operative complications and a 90-day mortality of 6%; 88% of these patients went on to receive systemic therapy (median 21 days postprocedure). Double bypass was associated with a far lesser complication rate than in prior studies; 17% of patients had some complication(s), but only 9% had a severe complication. The 90-day all-cause mortality was 13%, and only 71% of these patients went on to receive systemic therapy (median 47 days postprocedure). Notably, 27 out of 34 (79%) of patients who underwent laparoscopy alone needed additional procedures for local obstruction, whereas only 5 out of 42 (12%) double bypass patients needed additional interventions. Median survival for the entire cohort was 10.3 months.

Conclusion: Palliative procedures in this cohort had a far lesser complication rate than that of historical series. Palliative procedures, however, delayed systemic therapy, and a fair number of patients never received additional treatments. Palliative procedures markedly decreased the need for future interventions. Intraoperative decisions regarding palliative procedures must incorporate the functional status and motivations of the patient; these procedures are increasingly safe but may still affect survival.
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http://dx.doi.org/10.1016/j.surg.2020.06.041DOI Listing
December 2020

Do microscopic surgical margins matter for primary gastric gastrointestinal stromal tumor?

Surgery 2021 02 27;169(2):419-425. Epub 2020 Aug 27.

Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA.

Background: Although tumor size and mitotic rate are established prognostic factors for worse survival in patients undergoing surgical resection for gastric gastrointestinal stromal tumors, the impact of microscopic margins, or R1 resection, is not completely established.

Methods: Patients who received no neoadjuvant therapy and underwent surgical resection for stage I to III gastric gastrointestinal stromal tumors were identified from the 2010 to 2013 National Cancer Database and divided into 2 cohorts, R0 and R1 resections. Cox proportional hazards ratio and Kaplan Meier survival estimates were utilized to analyze 5-y overall survival.

Results: Of 2,084 patients, those with R1 resection (57, 2.7%) were more likely to have tumors >10 cm (28.1% vs 11.9%, odds ratio 3.51, P = .017) and stage III disease (26.3% vs 11.2%, odds ratio 2.26, P = .047). Although margin status was associated with higher risk tumors, it was not associated with receipt of adjuvant therapy. After multivariate Cox regression, R1 and R0 patients did not have a difference in 5-y overall survival (82.5% vs 88.6%, hazards ratio 1.26, P = .49). When stratified by stage of disease, there remained no difference in survival across all stages when comparing R1 and R0 patients.

Conclusion: Positive microscopic margins are uncommon but do not appear to impact survival outcomes in patients with resected localized gastric gastrointestinal stromal tumors.
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http://dx.doi.org/10.1016/j.surg.2020.07.018DOI Listing
February 2021

Choices of Therapeutic Strategies for Colorectal Liver Metastases Among Expert Liver Surgeons: A Throw of the Dice?

Ann Surg 2020 11;272(5):715-722

Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland.

Objective: To test the degree of agreement in selecting therapeutic options for patients suffering from colorectal liver metastasis (CRLM) among surgical experts around the globe.

Summary/background: Only few areas in medicine have seen so many novel therapeutic options over the past decades as for liver tumors. Significant variations may therefore exist regarding the choices of treatment, even among experts, which may confuse both the medical community and patients.

Methods: Ten cases of CRLM with different levels of complexity were presented to 43 expert liver surgeons from 23 countries and 4 continents. Experts were defined as experienced surgeons with academic contributions to the field of liver tumors. Experts provided information on their medical education and current practice in liver surgery and transplantation. Using an online platform, they chose their strategy in treating each case from defined multiple choices with added comments. Inter-rater agreement among experts and cases was calculated using free-marginal multirater kappa methodology. A similar, but adjusted survey was presented to 60 general surgeons from Asia, Europe, and North America to test their attitude in treating or referring complex patients to expert centers.

Results: Thirty-eight (88%) experts completed the evaluation. Most of them are in leading positions (92%) with a median clinical experience of 25 years. Agreement on therapeutic strategies among them was none to minimal in more than half of the cases with kappa varying from 0.00 to 0.39. Many general surgeons may not refer the complex cases to expert centers, including in Europe, where they also engage in complex liver surgeries.

Conclusions: Considerable inconsistencies of decision-making exist among expert surgeons when choosing a therapeutic strategy for CRLM. This might confuse both patients and referring physicians and indicate that an international high-level consensus statements and widely accepted guidelines are needed.
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http://dx.doi.org/10.1097/SLA.0000000000004331DOI Listing
November 2020

Adjuvant Hepatic Artery Infusion Chemotherapy is Associated With Improved Survival Regardless of KRAS Mutation Status in Patients With Resected Colorectal Liver Metastases: A Retrospective Analysis of 674 Patients.

Ann Surg 2020 08;272(2):352-356

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.

Objective: To investigate the impact of adjuvant hepatic artery infusion (HAI) in relation to KRAS mutational status in patients with resected colorectal cancer liver metastases (CRLM).

Background: Patients with KRAS-mutated CRLM have worse outcomes after resection. Adjuvant HAI chemotherapy improves overall survival after liver resection.

Methods: Patients with resected CRLM treated at MSKCC with and without adjuvant HAI who had available KRAS status (wild-type, WT; mutated, MUT) were reviewed from a prospectively maintained institutional database. Correlations between KRAS status, adjuvant HAI, clinical factors, and outcomes were analyzed. Cox proportional hazard model was used to adjust for confounders.

Results: Between 1993 and 2012, 674 patients (418 KRAS-WT, 256 MUT) with a median follow up of 6.5 years after resection were evaluated. Fifty-four percent received adjuvant HAI. Tumor characteristics (synchronous disease, number of lesions, clinical-risk score, 2-stage hepatectomy) were significantly worse in the HAI group; however, there were more patients with resected extrahepatic metastases in the no-HAI group. In KRAS-WT tumors, 5-year survival was 78% for patients treated with HAI versus 57% for patients without HAI [hazard ratio (HR) 0.51, P < 0.001]. In KRAS-MUT tumors, 5-year survival was 59% for patients treated with HAI versus 40% for patients without HAI (HR 0.56, P < 0.001). On multivariate analysis, HAI remained associated with improved OS (HR 0.53, P < 0.002) independent of KRAS status and other clinicopathologic factors.

Conclusion: Adjuvant HAI after resection of CRLM is independently associated with improved outcomes regardless of KRAS mutational status. Adjuvant HAI may mitigate the worse outcomes seen in patients with resectable KRAS-MUT CRLM.
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http://dx.doi.org/10.1097/SLA.0000000000003248DOI Listing
August 2020

Benchmarking Accomplishments of Leaders in American Surgery and Justification for Enhancing Diversity and Inclusion.

Ann Surg 2020 12;272(6):897-903

Department of Surgery, University of Alabama-Birmingham (UAB), Birmingham, Alabama.

Objective: To comprehensively assess the level of achievement and demographics of national surgical society presidents.

Background: Data on the accomplishments needed to rise to positions of national surgical leadership is scarce and merit alone does not always yield such opportunities. Recognizing the shortcomings of sex and ethnic diversity within academic surgical leadership, the American College of Surgeon (ACS), American Surgical Association (ASA), Association of Women Surgeons (AWS), and the Society of Black Academic Surgeons (SBAS) partnered to address these challenges by performing a comprehensive assessment of their presidents over the last 16 years.

Methods: ACS, ASA, AWS, and SBAS presidents' CVs, at the time of their presidential term, were assessed for demographics and scholastic achievements. Regression analyses controlling for age were performed to determine relative differences across societies.

Results: A total of 62 of the 64 presidents' CVs were received and assessed (97% response rate). There was a large discrepancy in the average age in years of ACS (70) and ASA (66) presidents compared to the AWS (51) and SBAS (53) presidents. For the ACS and ASA cohort, 87% were male and 83% were White, collectively. After controlling for age (52), the AWS and SBAS presidents' scholastic achievements were comparable to the ACS (and ASA) cohort in 9 and 12 of the 15 accessed metrics, respectively.

Conclusion: The ACS and ASA presidents' CVs displayed unsurpassed scholastic achievement, and although not equivalent, both the AWS and the SBAS presidents had comparable attainment. These findings further substantiate that women and ethnic minority surgeons are deserving of additional national leadership consideration as organized medicine pursues a more diverse and reflective physician workforce.
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http://dx.doi.org/10.1097/SLA.0000000000004151DOI Listing
December 2020

Can We Coach Resilience? An Evaluation of Professional Resilience Coaching as a Well-Being Initiative for Surgical Interns.

J Surg Educ 2020 Nov - Dec;77(6):1481-1489. Epub 2020 May 20.

Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Electronic address:

Objective: The purpose of this study was to evaluate the use of a professionally trained, resilience coach for surgical interns.

Design: Mixed-methods study with pre- and postcoaching quantitative surveys measuring burnout and resilience factors and semistructured interviews.

Setting: General, Vascular, Cardiac, Plastic, and Urologic Surgery residencies at a tertiary academic center.

Participants: Categorical and preliminary interns (N = 25) participated in a year-long, 8-session resilience coaching program for the academic year 2018 to 2019.

Results: Program participants included 17 (68%) men and 8 (32%) women. The precoaching survey administered to interns before the start of the program identified 60% at risk of burnout as measured by the Abbreviated Maslach Burnout Inventory. The mean (standard deviation) Brief Resilience Scale score was 3.8 (0.8), with a trend toward a higher score (greater resilience) among men compared to women (4.1 [0.7] vs 3.4 [1.0], p = 0.10). Following the completion of the coaching program, the mean (standard deviation) Brief Resilience Scale score increased significantly from 3.8 [0.8] to 4.2 [0.7] p = 0.002). There were no changes in other parameters measuring burnout, satisfaction with life, or positive/negative affect. In semistructured interviews (N = 16/25 participants), most interns believed the coaching experience provided useful skills, but expressed concern about the durability of a 1-year intervention. Additionally, leadership-driven wellness at work, including optimizing team dynamics and purpose-driven engagement, were emphasized.

Conclusions: About 60% of new interns at our institution were at risk of burnout. The coaching program was viewed positively and was effective in improving resilience. While this intervention was a useful first step, it should be incorporated into a longitudinal wellness program for the duration of surgical training.
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http://dx.doi.org/10.1016/j.jsurg.2020.04.014DOI Listing
May 2020

Invasive central venous monitoring during hepatic resection: unnecessary for most patients.

HPB (Oxford) 2020 Dec 23;22(12):1732-1737. Epub 2020 Apr 23.

Memorial Sloan Kettering Cancer Center, 1275 York Avenue, 10065, New York, NY, USA.

Background: Low central venous pressure (LCVP) anesthesia reduces blood loss during hepatic resection and historically has required a central venous catheter (CVC) for intra-operative monitoring. The aim of this study was to assess the effect of an evolution of practice to CVP monitoring without CVC on the perioperative outcomes after liver resection.

Methods: A retrospective study of partial hepatectomy patients from 2007 to 2016 who were over 18 years of age was performed.

Results: Of 3903 patients having partial hepatectomy, 2445 (62%) met inclusion criteria, and 404 (16%) had a CVC. Overall morbidity (33% non-CVC vs 38% CVC P = 0.076), major morbidity (16% vs 20% P = 0.067), and infective complications (superficial wound infection) 3% vs 4% P = 0.429; deep wound infection (5% vs 6% P = 0.720) did not differ between the two groups. In multivariate analysis, superficial wound infection, deep wound infection, and major complications were not associated with the presence of a CVC. All-cause mortality at 90 days was associated with CVC presence (OR 3.45, CI 1.74-6.85, P = 0.001) and age (OR 1.05, CI 1.02-1.08, P < 0.001).

Conclusion: Since the adoption of non-invasive CVP monitoring, there has been no increase in adverse peri-operative outcomes.
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http://dx.doi.org/10.1016/j.hpb.2020.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581625PMC
December 2020

Extended Experience with a Dynamic, Data-Driven Selective Drain Management Protocol in Pancreaticoduodenectomy: Progressive Risk Stratification for Better Practice.

J Am Coll Surg 2020 05 17;230(5):809-818.e1. Epub 2020 Feb 17.

Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA. Electronic address:

Background: Intraoperative drain use for pancreaticoduodenectomy has been practiced in an unconditional, binary manner (placement/no placement). Alternatively, dynamic drain management has been introduced, incorporating the Fistula Risk Score (FRS) and drain fluid amylase (DFA) analysis, to mitigate clinically relevant postoperative pancreatic fistula (CR-POPF).

Study Design: An extended experience with dynamic drain management was used at a single institution for 400 consecutive pancreaticoduodenectomies (2014 to 2019). This protocol consists of the following: drains omitted for negligible/low-risk FRS (0 to 2) and drains placed for moderate/high-risk FRS (3 to 10) with early (postoperative day [POD] 3) removal if POD1 DFA ≤5,000 U/L. Adherence to this protocol was prospectively annotated and outcomes were retrospectively analyzed.

Results: The overall CR-POPF rate was 8.7%, with none occurring in the negligible/low-risk cases. Moderate/high-risk patients manifested an 11.9% CR-POPF rate (n = 35 of 293), which was lower on-protocol (9.5% vs 21%; p = 0.014). After drain placement, POD1 DFA ≥5,000 U/L was a better predictor of CR-POPF than FRS (odds ratio 14.7; 95% CI, 4.3 to 50.3). For POD1 DFA ≤5,000 U/L, early drain removal was associated with fewer CR-POPFs (2.8% vs 23.5%; p < 0.001), and substantiated by multivariable analysis (odds ratio 0.09; 95% CI, 0.03 to 0.28). Surgeon adherence was inversely related to CR-POPF rate (R = 0.846).

Conclusions: This extended experience validates a dynamic drain management protocol, providing a model for better drain management and individualized patient care after pancreaticoduodenectomy. This study confirms that drains can be safely omitted from negligible/low-risk patients, and moderate/high-risk patients benefit from early drain removal.
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http://dx.doi.org/10.1016/j.jamcollsurg.2020.01.028DOI Listing
May 2020

ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity.

Nature 2020 03 19;579(7797):130-135. Epub 2020 Feb 19.

Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues. Although ILC2s are found in cancers of these tissues, their roles in cancer immunity and immunotherapy are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumour immunity. Interleukin-33 (IL33) activates tumour ILC2s (TILC2s) and CD8 T cells in orthotopic pancreatic tumours but not heterotopic skin tumours in mice to restrict pancreas-specific tumour growth. Resting and activated TILC2s express the inhibitory checkpoint receptor PD-1. Antibody-mediated PD-1 blockade relieves ILC2 cell-intrinsic PD-1 inhibition to expand TILC2s, augment anti-tumour immunity, and enhance tumour control, identifying activated TILC2s as targets of anti-PD-1 immunotherapy. Finally, both PD-1 TILC2s and PD-1 T cells are present in most human PDACs. Our results identify ILC2s as anti-cancer immune cells for PDAC immunotherapy. More broadly, ILC2s emerge as tissue-specific enhancers of cancer immunity that amplify the efficacy of anti-PD-1 immunotherapy. As ILC2s and T cells co-exist in human cancers and share stimulatory and inhibitory pathways, immunotherapeutic strategies to collectively target anti-cancer ILC2s and T cells may be broadly applicable.
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http://dx.doi.org/10.1038/s41586-020-2015-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060130PMC
March 2020

Opioid Use Disorder is Associated With Complications and Increased Length of Stay After Major Abdominal Surgery.

Ann Surg 2019 Nov 27. Epub 2019 Nov 27.

Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Objective: The objective of this study was to determine the impact of opioid use disorder (OUD) on perioperative outcomes after major upper abdominal surgeries.

Summary Of Background Data: OUD, defined as dependence/abuse, is a national health epidemic. Its impact on outcomes after major abdominal surgery has not been well characterized.

Methods: Patients who underwent elective esophagectomy, total/partial gastrectomy, major hepatectomy, and pancreatectomy were identified using the National Inpatient Sample (2003-2015). Propensity score matching by baseline characteristics was performed for patients with and without OUD. Outcomes measured were in-hospital complications, mortality, length of stay (LOS), and discharge disposition.

Results: Of 376,467 patients, 1096 (0.3%) had OUD. Patients with OUD were younger (mean 53 vs 61 years, P < 0.001) and more often male (55.1% vs 53.2%, P < 0.001), black (15.0% vs 7.6%, P < 0.001), Medicaid beneficiaries (22.0% vs 6.4%, P < 0.001), and in the lowest income quartile (32.6% vs 21.3%, P < 0.001). They also had a higher rate of alcohol (17.2% vs 2.8%, P < 0.001) and nonopioid drug (2.2% vs 0.2%, P = 0.023) dependence/abuse. After matching (N = 1077 OUD, N = 2164 no OUD), OUD was associated with a higher complication rate (52.9% vs 37.3%, P < 0.001), including increased pain [odds ratio (OR) 3.5, P < 0.001], delirium (OR 3.0, P = 0.004), and pulmonary complications (OR 2.0, P = 0.006). Additionally, OUD was associated with increased LOS (mean 12.4 vs 10.6 days, P = 0.015) and nonroutine discharge (OR 1.6, P < 0.001). In-hospital mortality did not differ (OR 2.4, P = 0.10).

Conclusion: Patients with OUD more frequently experienced complications and increased LOS. Close postoperative monitoring may mitigate adverse outcomes.
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http://dx.doi.org/10.1097/SLA.0000000000003697DOI Listing
November 2019

Defining the Safety Profile for Performing Pancreatoduodenectomy in the Setting of Hyperbilirubinemia.

Ann Surg Oncol 2020 May 5;27(5):1595-1605. Epub 2019 Nov 5.

Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Background: Hyperbilirubinemia is commonly observed in patients requiring pancreatoduodenectomy (PD). Thus far, literature regarding the danger of operating in the setting of hyperbilirubinemia is equivocal. What remains undefined is at what specific level of bilirubin there is an adverse safety profile for undergoing PD. The aim of this study is to identify the optimal safety profile of patients with hyperbilirubinemia undergoing PD.

Patients And Methods: The present work analyzed 803 PDs from 2004 to 2018. A generalized additive model was used to determine cutoff values of total serum bilirubin (TB) that were associated with increases in adverse outcomes, including 90-day mortality. Subgroup comparisons and biliary stent-specific analyses were performed for patients with TB below and above the cutoff.

Results: TB of 13 mg/dL was associated with an increase in 90-day mortality (P = 0.043) and was the dominant risk factor on multivariate logistic regression [odds ratio (OR) 8.193, P = 0.001]. Increased TB levels were also associated with reoperations, number of complications per patient, and length of stay. Patients with TB greater than or equal to 13 mg/dL (TB ≥ 13) who received successful biliary decompression through stenting had less combined death and serious morbidity (P = 0.048).

Conclusions: Preoperative TB ≥ 13 mg/dL was associated with increased 90-day mortality after PD. Reducing a TB ≥ 13 is generally recommended before proceeding to surgery.
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http://dx.doi.org/10.1245/s10434-019-08044-wDOI Listing
May 2020

Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial.

JAMA Oncol 2019 Oct 31. Epub 2019 Oct 31.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients.

Objective: To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC.

Design, Setting, And Participants: A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded.

Interventions: Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin.

Main Outcomes And Measures: The primary outcome was progression-free survival (PFS) of 80% at 6 months.

Results: For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4).

Conclusions And Relevance: Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.
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http://dx.doi.org/10.1001/jamaoncol.2019.3718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824231PMC
October 2019

Lending a hand for laparoscopic distal pancreatectomy: the optimal approach?

HPB (Oxford) 2020 05 7;22(5):690-701. Epub 2019 Oct 7.

Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA, USA. Electronic address:

Background: Both minimally invasive surgery (MIS) and open approaches for distal pancreatectomy are acceptable. MIS options include total laparoscopic/robotic (TLR) and hand-assist laparoscopy (HAL). When considering safety profile and specimen quality, the optimal approach is unknown.

Methods: Patients who underwent distal pancreatectomy from 2010-2018 at two major academic institutions were included. Converted procedures were categorized into final approach. Ninety-day perioperative/pathologic outcomes of MIS and open were compared. Subset analyses between TLR vs HAL and HAL vs open were performed. Intent-to-treat analysis was performed.

Results: Among 1006 patients, resection was performed by MIS in 35% (n = 352), open in 65% (n = 654). MIS had similar patient comorbidity profile as open but had increased operative time (183 vs 162 min; p < 0.01), lower estimated-blood-loss (EBL; 131 vs 341 mL; p < 0.01), fewer intraoperative blood transfusions (1.4 vs 5%; p < 0.01), shorter LOS (5.2 vs 7.2 days; p < 0.01). Tumor size was smaller (3.2 vs 4.4 cm; p < 0.01) with lower lymph node (LN) yield (14 vs 16; p < 0.01). When comparing HAL (n = 109) to TLR (n = 243), despite increased prior abdominal operations (60 vs 43%; p = 0.008), HAL had shorter operative time (167 vs 191 min; p < 0.01), similar length-of-stay (LOS; 5.4 vs 5.1 days; p = 0.27), and readmission rate (15 vs 13%; p = 0.47). When comparing HAL to open, the advantages of TLR approach persisted including lower EBL (171 vs 342 mL; p < 0.01), and shorter LOS (5.4 vs 7.2 days; p < 0.01). Although HAL had smaller tumors, it had a similar LN yield (16 vs 16; p = 0.80), and higher R0-rate (97 vs 83%; p < 0.01).

Conclusion: Hand-assist laparoscopy is safe and feasible for distal pancreatectomy as operative time, complication profile, lymph node yield, and R0-rates are similar to open procedures, while maintaining the associated the advantages of a total laparoscopic/robotic approach with reduced blood loss and shorter length-of-stay.
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http://dx.doi.org/10.1016/j.hpb.2019.09.007DOI Listing
May 2020