Publications by authors named "Andrew M Lowy"

148 Publications

Ki67 Does Not Predict Recurrence for Low Grade Appendiceal Mucinous Neoplasms with Peritoneal Dissemination after Cytoreductive Surgery and HIPEC.

Hum Pathol 2021 Apr 24. Epub 2021 Apr 24.

University of California San Diego. Electronic address:

Introduction: Low-grade appendiceal mucinous neoplasms can disseminate to become low-grade mucinous carcinoma peritonei (LGMCP), which is optimally treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Approximately half of patients with LGMCP recur despite complete cytoreduction, and risk factors for recurrence are poorly understood. We sought to evaluate if Ki67 predicts progression of LGMCP after CRS/HIPEC.

Methods: A retrospective review of a prospectively maintained database was performed to identify patients treated with complete CRS/HIPEC for LGMCP from 2008-2019 with Ki67 assessed. Patient characteristics, histologic data, average and focally high ("hotspot") Ki67 index, progression-free survival (PFS) and overall survival (OS) were analyzed. Ki-67 immunostain was performed on the histologic section with the highest cellularity and architectural complexity.

Results: Forty-four patients with LGMCP (55% male, median age 61) were identified. The median Ki67 score and hotspot Ki67 score was 15% (1-70) and 50% (1-90), respectively. On univariate analysis, average Ki67 and hotspot Ki67 were not predictive of PFS when analyzed as continuous normalized values (HR 1.0, p=0.79 and HR 1.1, p=0.38; respectively) or as categorical values when stratified by the median (HR 0.9, p=0.67 and HR 1.0, p=0.93). This remained true on multivariate analysis when stratified for peritoneal cancer index, CEA, and completeness of cytoreduction score for both normalized Ki67 and hotspot Ki67 (HR 0.9 [95% CI 0.8-1.3], p=0.94 and HR 1.04 [95% CI 0.8-1.3], p=0.73, respectively).

Conclusion: Ki67 failed to predict disease recurrence for patients with LGMCP in this cohort.
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http://dx.doi.org/10.1016/j.humpath.2021.04.007DOI Listing
April 2021

Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2021 Apr 1;19(4):439-457. Epub 2021 Apr 1.

27Huntsman Cancer Institute at the University of Utah.

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.
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http://dx.doi.org/10.6004/jnccn.2021.0017DOI Listing
April 2021

Tumor-penetrating therapy for β5 integrin-rich pancreas cancer.

Nat Commun 2021 03 9;12(1):1541. Epub 2021 Mar 9.

Cancer Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked desmoplasia and drug resistance due, in part, to poor drug delivery to extravascular tumor tissue. Here, we report that carcinoma-associated fibroblasts (CAFs) induce β5 integrin expression in tumor cells in a TGF-β dependent manner, making them an efficient drug delivery target for the tumor-penetrating peptide iRGD. The capacity of iRGD to deliver conjugated and co-injected payloads is markedly suppressed when β5 integrins are knocked out in the tumor cells. Of note, β5 integrin knock-out in tumor cells leads to reduced disease burden and prolonged survival of the mice, demonstrating its contribution to PDAC progression. iRGD significantly potentiates co-injected chemotherapy in KPC mice with high β5 integrin expression and may be a powerful strategy to target an aggressive PDAC subpopulation.
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http://dx.doi.org/10.1038/s41467-021-21858-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943581PMC
March 2021

Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis.

Cancer Cell 2021 May 18;39(5):678-693.e11. Epub 2021 Mar 18.

Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address:

Many cancers, including pancreatic ductal adenocarcinoma (PDAC), depend on autophagy-mediated scavenging and recycling of intracellular macromolecules, suggesting that autophagy blockade should cause tumor starvation and regression. However, until now autophagy-inhibiting monotherapies have not demonstrated potent anti-cancer activity. We now show that autophagy blockade prompts established PDAC to upregulate and utilize an alternative nutrient procurement pathway: macropinocytosis (MP) that allows tumor cells to extract nutrients from extracellular sources and use them for energy generation. The autophagy to MP switch, which may be evolutionarily conserved and not cancer cell restricted, depends on activation of transcription factor NRF2 by the autophagy adaptor p62/SQSTM1. NRF2 activation by oncogenic mutations, hypoxia, and oxidative stress also results in MP upregulation. Inhibition of MP in autophagy-compromised PDAC elicits dramatic metabolic decline and regression of transplanted and autochthonous tumors, suggesting the therapeutic promise of combining autophagy and MP inhibitors in the clinic.
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http://dx.doi.org/10.1016/j.ccell.2021.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119368PMC
May 2021

Clinical Data Prediction Model to Identify Patients With Early-Stage Pancreatic Cancer.

JCO Clin Cancer Inform 2021 Mar;5:279-287

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA.

Purpose: Pancreatic cancer is an aggressive malignancy with patients often experiencing nonspecific symptoms before diagnosis. This study evaluates a machine learning approach to help identify patients with early-stage pancreatic cancer from clinical data within electronic health records (EHRs).

Materials And Methods: From the Optum deidentified EHR data set, we identified early-stage (n = 3,322) and late-stage (n = 25,908) pancreatic cancer cases over 40 years of age diagnosed between 2009 and 2017. Patients with early-stage pancreatic cancer were matched to noncancer controls (1:16 match). We constructed a prediction model using eXtreme Gradient Boosting (XGBoost) to identify early-stage patients on the basis of 18,220 features within the EHR including diagnoses, procedures, information within clinical notes, and medications. Model accuracy was assessed with sensitivity, specificity, positive predictive value, and the area under the curve.

Results: The final predictive model included 582 predictive features from the EHR, including 248 (42.5%) physician note elements, 146 (25.0%) procedure codes, 91 (15.6%) diagnosis codes, 89 (15.3%) medications, and 9 (1.5%) demographic features. The final model area under the curve was 0.84. Choosing a model cut point with a sensitivity of 60% and specificity of 90% would enable early detection of 58% late-stage patients with a median of 24 months before their actual diagnosis.

Conclusion: Prediction models using EHR data show promise in the early detection of pancreatic cancer. Although widespread use of this approach on an unselected population would produce high rates of false-positive tests, this technique may be rapidly impactful if deployed among high-risk patients or paired with other imaging or biomarker screening tools.
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http://dx.doi.org/10.1200/CCI.20.00137DOI Listing
March 2021

Predictors and significance of histologic response to neoadjuvant therapy for gastric cancer.

J Surg Oncol 2021 Mar 18. Epub 2021 Mar 18.

Department of Surgery, University of California San Diego, San Diego, California, USA.

Background: Perioperative therapy is the standard-of-care for locally-advanced gastric cancer but many patients do not respond. There are currently no known factors that predict response to therapy.

Methods: This was a retrospective study aimed to evaluate treatment effect grade (TEG) in patients with locally advanced gastric cancer treated with neoadjuvant therapy and surgery at a single center. Ordinal logistic regression was performed to identify predictors of TEG, scaled from 0 to 3.

Results: Fifty patients were identified. The majority were male (n = 33) and 50% were Hispanic. The most common regimens given were: 5-fluorouracil/leucovorin, oxaliplatin, and docetaxel (n = 23, 46%), epirubicin, cis- or oxaliplatin, and 5-fluorouracil/leucovorin or Xeloda (n = 8, 16%), and 5-fluorouracil/leucovorin and oxaliplatin (n = 9, 18%). Twenty-seven patients (55%) had complete or partial response to therapy (TEG 0-2), and 23 patients (46%) had no response (TEG 3). Of numerous variables analyzed, only race and SRC histology were associated with TEG. TEG was associated with disease free, but not disease specific survival.

Conclusions: In this cohort, 46% of patients had no histologic response to therapy. SRC histology, and possibly race, should be considered in determination of optimal multidisciplinary regimens and in amount of therapy to be given upfront, as patients with SRC histology and those of non-Asian race are less likely to respond to standard regimens.
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http://dx.doi.org/10.1002/jso.26458DOI Listing
March 2021

Macropinocytosis in Cancer-Associated Fibroblasts is Dependent on CaMKK2/ARHGEF2 Signaling and Functions to Support Tumor and Stromal Cell Fitness.

Cancer Discov 2021 Mar 2. Epub 2021 Mar 2.

NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute

Although pancreatic ductal adenocarcinoma (PDAC) cells are exposed to a nutrient-depleted tumor microenvironment, they can acquire nutrients via macropinocytosis, an endocytic form of protein scavenging that functions to support cancer metabolism. Here, we provide evidence that macropinocytosis is operational in the pancreatic tumor stroma. We find that glutamine deficiency triggers macropinocytic uptake in pancreatic cancer-associated fibroblasts (CAFs). Mechanistically, we decipher that stromal macropinocytosis is potentiated via the enhancement of cytosolic Ca2+ and dependent on ARHGEF2 and CaMKK2-AMPK signaling. We elucidate that macropinocytosis has dual function in CAFs - it serves as a source of intracellular amino acids that sustain CAF cell fitness and function, and it provides secreted amino acids that promote tumor cell survival. Importantly, we demonstrate that stromal macropinocytosis supports PDAC tumor growth. These results highlight the functional role of macropinocytosis in the tumor stroma and provide a mechanistic understanding of how nutrient deficiency can control stromal protein scavenging.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0119DOI Listing
March 2021

Phase I Trial of Stereotactic Body Radiation Therapy Dose Escalation in Pancreatic Cancer.

Int J Radiat Oncol Biol Phys 2021 Feb 8. Epub 2021 Feb 8.

University of California San Diego School of Medicine, La Jolla, California; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California. Electronic address:

Purpose: Stereotactic body radiation therapy (SBRT) has demonstrated encouraging local tumor control rates in the treatment of pancreatic cancer, yet we lack prospective clinical trials evaluating dose-escalation strategies among patients treated with 5-fraction SBRT. This phase 1 dose-escalation trial was conducted to determine the maximum tolerated dose of SBRT in patients with pancreatic cancer.

Methods And Materials: Thirty patients with pancreatic cancer were enrolled and treated with 40, 45, or 50 Gy SBRT in 5 fractions with doses determined using a time-to-event continual reassessment method trial design. Systemic therapy was permitted before and after SBRT, but not mandated by the study protocol. Toxicity was the primary study endpoint, and any grade ≥3 acute or late toxicity potentially attributable to SBRT was considered a dose-limiting toxicity. Secondary endpoints included local progression, distant progression, and overall survival.

Results: The median follow up from SBRT was 8.9 months (range, 1.7-62.6 months). Nineteen patients (63%) had locally advanced disease, 3 patients (10%) had metastatic disease, and 8 patients (27%) had medically unresectable disease. Three patients (10%) received 40 Gy, 16 patients (53%) received 45 Gy, and 11 patients (37%) received 50 Gy. Seven patients (23%) experienced grade ≤2 acute toxicity, and 2 patients (6.7%) experienced grade 4 to 5 late toxicity, both of which occurred in the 45 Gy group. Median survival time was 17.1 months from the time of diagnosis and 9.8 months from SBRT. The 1-year cumulative incidence of local progression was 14.2% (95% confidence interval, 4.2%-30%).

Conclusions: This dose-escalation trial evaluated high-dose SBRT delivered in 5 fractions, and overall demonstrated favorable local control and survival, but was associated with nontrivial rates of severe late gastrointestinal toxicity potentially attributable to radiation. Further prospective studies are needed to define the safety and efficacy of high-dose SBRT in patients with pancreatic cancer.
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http://dx.doi.org/10.1016/j.ijrobp.2021.02.008DOI Listing
February 2021

Efficacy of Perioperative Chemotherapy for Resectable Pancreatic Adenocarcinoma: A Phase 2 Randomized Clinical Trial.

JAMA Oncol 2021 Mar;7(3):421-427

Gastrointestinal Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick.

Importance: Clinical outcomes after curative treatment of resectable pancreatic ductal adenocarcinoma (PDA) remain suboptimal. To assess the potential of early control of systemic disease with multiagent perioperative chemotherapy, we conducted a prospective trial.

Objective: To determine 2-year overall survival (OS) using perioperative chemotherapy for resectable PDA.

Design, Setting, And Participants: This was a randomized phase 2 trial of perioperative chemotherapy with a pick-the-winner design. It was conducted across the National Clinical Trials Network, including academic and community centers all across the US. Eligibility required patients with Zubrod Performance Score of 0 or 1, confirmed tissue diagnosis of PDA, and resectable disease per Intergroup criteria.

Interventions: Perioperative (12 weeks preoperative, 12 weeks postoperative) chemotherapy with either fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX, arm 1) or gemcitabine/nab-paclitaxel (arm 2).

Main Outcomes And Measures: The primary outcome was 2-year overall survival (OS), using a pick-the-winner design; for 100 eligible patients, accrual up to 150 patients was planned to account for cases deemed ineligible at central radiology review.

Results: From 2015 to 2018, 147 patients were enrolled; 43 patients (29%) had ineligible disease, beyond resectability criteria, at central radiology review. There were 102 eligible and evaluable patients, 55 in arm 1 and 47 in arm 2, of whom the median (range) age was 66 (44-76) and 64 (46-76) years, respectively; 36 patients (65%) in arm 1 and 24 (51%) in arm 2 were men. In arm 1, 34 (62%) had Zubrod Performance Score of 0, while in arm 2, 31 (66%) did; and 44 (80%) in arm 1 and 39 (83%) in arm 2 had head tumors. Of 102 patients, 84% and 85% completed preoperative chemotherapy, 73% and 70% underwent resection, and 49% and 40% completed all treatment. Adverse events were expected hematologic toxic effects, fatigue, and gastrointestinal toxicities. Two-year OS was 47% (95% CI, 31%-61%) for arm 1 and 48% (95% CI, 31%-63%) for arm 2; median OS was 23.2 months (95% CI, 17.6-45.9 months) and 23.6 months (95% CI, 17.8-31.7 months). Neither arm's 2-year OS estimate was significantly higher than the a priori threshold of 40%. Median disease-free survival after resection was 10.9 months in arm 1 and 14.2 months in arm 2.

Conclusions And Relevance: This phase 2 randomized clinical trial did not demonstrate an improved OS with perioperative chemotherapy, compared with historical data from adjuvant trials in resectable pancreatic cancer. Two-year OS was 47% with mFOLFIRINOX and 48% with gemcitabine/nab-paclitaxel for all eligible patients starting treatment for resectable PDA. The trial also demonstrated adequate safety and high resectability rates with perioperative chemotherapy, and challenges in quality control for resectability criteria.

Trial Registration: ClinicalTrials.gov Identifier: NCT02562716.
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http://dx.doi.org/10.1001/jamaoncol.2020.7328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821078PMC
March 2021

A MET Targeting Antibody-Drug Conjugate Overcomes Gemcitabine Resistance in Pancreatic Cancer.

Clin Cancer Res 2021 Apr 15;27(7):2100-2110. Epub 2021 Jan 15.

Division of Surgical Oncology, Department of Surgery, Moores Cancer Center, University of California San Diego, La Jolla, California.

Purpose: Pancreatic cancer is an aggressive disease associated with a poor 5-year overall survival. Most patients are ineligible for surgery due to late diagnosis and are treated primarily with chemotherapy with very limited success. Pancreatic cancer is relatively insensitive to chemotherapy due to multiple factors, including reduced bioavailability of drugs to tumor cells. One strategy to improve drug efficacy with reduced toxicity is the development of antibody-drug conjugates (ADC), which have now been used successfully to treat both solid and liquid tumors. Here, we evaluate the efficacy of TR1801-ADC, a newly developed ADC composed of a MET antibody conjugated to the highly potent pyrrolobenzodiazepine toxin-linker, tesirine.

Experimental Design: We first evaluated MET expression and subcellular localization in pancreatic cancer cell lines, human tumors, and patient-derived xenografts (PDX). We then tested TR1801-ADC efficacy in pancreatic cancer cell lines. Preclinical evaluation of TR1801-ADC efficacy was conducted on PDXs selected on the basis of their MET expression level.

Results: We show that MET is highly expressed and located at the plasma membrane of pancreatic cancer cells. We found that TR1801-ADC induces a specific cytotoxicity in pancreatic cancer cell lines and a profound tumor growth inhibition, even in a gemcitabine-resistant tumor. We also noted synergism between TR1801-ADC and gemcitabine and an improved response to the combination .

Conclusions: Together, these results suggest the promise of agents such as TR1801-ADC as a novel approach to the treatment of pancreatic cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3210DOI Listing
April 2021

A Multi-institutional Study of Peritoneal Recurrence Following Resection of Low-grade Appendiceal Mucinous Neoplasms.

Ann Surg Oncol 2021 Jan 7. Epub 2021 Jan 7.

Department of Surgery, University of California San Diego, La Jolla, CA, USA.

Background: Peritoneal dissemination of low-grade appendiceal mucinous neoplasms (LAMNs), sometimes referred to as pseudomyxoma peritonei, can result in significant morbidity and mortality. Little is known about the natural history of localized (non-disseminated) LAMNs.

Objective: The goal of this study was to evaluate the risk of peritoneal recurrence in patients with localized LAMNs.

Methods: We performed a multi-institutional retrospective review of patients with pathologically confirmed localized LAMNs. Baseline characteristics, pathology, and follow-up data were collected. The primary endpoint was the rate of peritoneal recurrence.

Results: We identified 217 patients with localized LAMNs. Median age was 59 years (11-95) and 131 (60%) patients were female. Surgical management included appendectomy for 124 (57.1%) patients, appendectomy with partial cecectomy for 26 (12.0%) patients, and colectomy for 67 (30.9%) patients. Pathology revealed perforation in 46 patients (37.7% of 122 patients with perforation status mentioned in the report), extra-appendiceal acellular mucin (EAM) in 49 (22.6%) patients, and extra-appendiceal neoplastic cells (EAC) in 13 (6.0%) patients. Median follow-up was 51.1 months (0-271). Seven (3.2%) patients developed a peritoneal recurrence, with a median time to recurrence of 14.4 months (2.5-47.0). Seven (15.2%) patients with histologic evidence of perforation had recurrence, versus no patients (0%) without perforation (p < 0.001); five (10.2%) patients with EAM versus two (1.2%) patients without EAM (p = 0.007), and one (7.7%) patient with EAC versus six (2.9%) patients without EAC (p = 0.355) had recurrence.

Conclusions: This multi-institutional study represents the largest reported series of patients with localized LAMNs. In the absence of perforation or extra-appendiceal mucin or cells, recurrence was extremely rare; however, patients with any of these pathologic findings require careful follow-up.
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http://dx.doi.org/10.1245/s10434-020-09499-yDOI Listing
January 2021

Preoperative bevacizumab does not increase complications following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

PLoS One 2020 3;15(12):e0243252. Epub 2020 Dec 3.

Division of Surgical Oncology, Department of Surgery, University of California, San Diego, La Jolla, California, United States of America.

Background: Preoperative bevacizumab has been reported to increase postoperative complication risk following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). We sought to review our experience with preoperative bevacizumab in patients undergoing CRS/HIPEC for peritoneal surface malignancy.

Methods: This is a retrospective review of patients who received neoadjuvant systemic therapy with or without bevacizumab prior to CRS/HIPEC at a high-volume academic center from 2007-2018.

Results: Of 499 patients, a total of 88 patients received neoadjuvant chemotherapy alone (n = 34) or in combination with bevacizumab (n = 54) within 3 months prior to CRS/HIPEC. No differences existed in 60-day major morbidity (17.6 vs. 16.7%, p = 0.81) or 60-day mortality (0 vs. 0%) between the two cohorts, and neoadjuvant bevacizumab was not associated with increased odds of overall complications (OR 0.86, 95% CI 0.35-2.09, p = 0.73) or major morbidity (OR 0.86, 95% CI 0.24-3.00, p = 0.81). Stratifying patients by primary tumor origin and post-operative complications did not reveal any significant differences between the two treatment groups. In addition, progression-free survival (PFS) and overall survival (OS) were similar in both cohorts.

Conclusions: Preoperative bevacizumab is not associated with increased morbidity or mortality following CRS/HIPEC. Neoadjuvant therapy employing this biologic agent is safe and should not be a deterrent for aggressive cytoreduction with curative intent.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243252PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714141PMC
January 2021

Prognostic Utility of Pre- and Postoperative Circulating Tumor DNA Liquid Biopsies in Patients with Peritoneal Metastases.

Ann Surg Oncol 2020 Sep 6;27(9):3259-3267. Epub 2020 Aug 6.

Center for Personalized Cancer Therapy, University of California, San Diego, La Jolla, CA, USA.

Background: Circulating tumor DNA (ctDNA) is a promising technology for treatment selection, prognostication, and surveillance after definitive therapy. Its use in the perioperative setting for patients with metastatic disease has not been well studied. We characterize perioperative plasma ctDNA and its association with progression-free survival (PFS) in patients undergoing surgery for peritoneal metastases.

Patients And Methods: We recruited 71 patients undergoing surgery for peritoneal metastases and evaluated their plasma with a targeted 73-gene ctDNA next-generation sequencing test before and after surgery. The association between perioperative ctDNA, as well as other patient factors, and PFS was evaluated by Cox regression.

Results: ctDNA was detectable in 28 patients (39.4%) preoperatively and in 37 patients (52.1%) postoperatively. Patients with high ctDNA [maximum somatic variant allele fraction (MSVAF) > 0.25%] had worse PFS than those with low MSVAF (< 0.25%) in both the pre- and postoperative settings (median 4.8 vs. 19.3 months, p < 0.001, and 9.2 vs.15.0 months, p = 0.049, respectively; log-rank test). On multivariate analysis, high-grade histology [hazard ratio (HR) 3.42, p = 0.001], incomplete resection (HR 2.35, p = 0.010), and high preoperative MSVAF (HR 3.04, p = 0.001) were associated with worse PFS. Patients with new postoperative alterations in the context of preoperative alteration(s) also had a significantly shorter PFS compared with other groups (HR 4.28, p < 0.001).

Conclusions: High levels of perioperative ctDNA and new postoperative ctDNA alterations in the context of preoperative alterations predict worse outcomes in patients undergoing resection for peritoneal metastases. This may highlight a role for longitudinal ctDNA surveillance in this population.
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http://dx.doi.org/10.1245/s10434-020-08331-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470602PMC
September 2020

Surgical Outcome Results From SWOG S1505: A Randomized Clinical Trial of mFOLFIRINOX Versus Gemcitabine/Nab-paclitaxel for Perioperative Treatment of Resectable Pancreatic Ductal Adenocarcinoma.

Ann Surg 2020 09;272(3):481-486

Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.

Objective: The optimal neoadjuvant therapy for resectable pancreatic ductal adenocarcinoma (PDA) and the impact on surgical outcomes remains unclear.

Methods: S1505 (NCT02562716) was a randomized phase II study of perioperative chemotherapy with mFOLFIRINOX (Arm 1) or gemcitabine/nab-paclitaxel (Arm 2). Measured parameters included resection rate, margin positivity, pathologic response, and toxicity.

Results: Between 2015 and 2018, 147 patients were randomized. Of these, 44 (30%) were deemed ineligible (43 by central review). Of the 103 eligible patients, 77 (76%) completed preoperative therapy and underwent surgery; reasons patients did not undergo surgery included toxicity related to preoperative therapy (n = 9), progression (n = 9), or other (n = 7). Of the 77, 73 (95%) underwent successful resection; 21 (29%) required vascular reconstruction, 62 (85%) had negative (R0) margins, and 24 (33%) had a complete or major pathologic response to therapy. The grade 3-5 postoperative complication rate was 16%. Of the 73 patients completing surgery, 57 (78%) started and 46 (63%) completed postoperative therapy. This study represents the first prospective trial evaluating modern systemic therapy delivered in a neoadjuvant/perioperative format for resectable PDA.

Conclusions: We have demonstrated: (1) Based on the high percentage of enrolled, but ineligible patients, it is clear that adherence to strict definitions of resectable PDA is challenging; (2) Patients can tolerate modern systemic therapy and undergo successful surgical resection without prohibitive perioperative complications; (3) Completion of adjuvant therapy in the perioperative format is difficult; (4) Major pathologic response rate of 33% is encouraging.
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http://dx.doi.org/10.1097/SLA.0000000000004155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856053PMC
September 2020

Institutional variation in recovery after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: An opportunity for enhanced recovery pathways.

J Surg Oncol 2020 Oct 5;122(5):980-985. Epub 2020 Jul 5.

Department of Surgery, City of Hope National Medical Center, Duarte, California.

Background: Variations in care have been demonstrated both within and among institutions in many clinical settings. By standardizing perioperative practices, Enhanced Recovery After Surgery (ERAS) pathways reduce variation in perioperative care. We sought to characterize the variation in cytoreductive surgery (CRS)/heated intraperitoneal chemotherapy (HIPEC) perioperative practices among experienced US medical centers.

Methods: Data from the US HIPEC Collaborative represents a retrospective multi-institutional cohort study of CRS and CRS/HIPEC procedures performed from 12 major academic institutions. Patient characteristics and perioperative practices were reported and compared. Institutional variation was analyzed using hierarchical mixed-effects linear (continuous outcomes) or logistic (binary outcomes) regression models.

Results: A total of 2372 operations were included. CRS/HIPEC was performed most commonly for appendiceal histologies (64.2%). The rate of complications (overall 56.3%, range: 31.8-70.9) and readmissions (overall 20.6%, range: 8.9-33.3) varied by institution (P < .001). Institution-level variation in perioperative practice patterns existed among measured ERAS pathway process/outcomes (P < .001). The percentages of variation with each process/outcome measure attributable solely to institutional practices ranged from 0.6% to 66.6%.

Conclusions: Significant variation exists in the perioperative care of patients undergoing CRS/HIPEC at major US academic institutions. These findings provide a strong rationale for the investigation of best practices in CRS/HIPEC patients.
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http://dx.doi.org/10.1002/jso.26099DOI Listing
October 2020

Isolation and Characterization of Patient-derived Pancreatic Ductal Adenocarcinoma Organoid Models.

J Vis Exp 2020 01 14(155). Epub 2020 Jan 14.

Moores Cancer Center, University of California San Diego; Department of Surgery, Division of Surgical Oncology, University of California San Diego;

Pancreatic ductal adenocarcinoma (PDAC) is amongst the most lethal malignancies. Recently, next-generation organoid culture methods enabling the 3-dimensional (3D) modeling of this disease have been described. Patient-derived organoid (PDO) models can be isolated from both surgical specimens as well as small biopsies and form rapidly in culture. Importantly, organoid models preserve the pathogenic genetic alterations detected in the patient's tumor and are predictive of the patient's treatment response, thus enabling translational studies. Here, we provide comprehensive protocols for adapting tissue culture workflow to study 3D, matrix embedded, organoid models. We detail methods and considerations for isolating and propagating primary PDAC organoids. Furthermore, we describe how bespoke organoid media is prepared and quality controlled in the laboratory. Finally, we describe assays for downstream characterization of the organoid models such as isolation of nucleic acids (DNA and RNA), and drug testing. Importantly we provide critical considerations for implementing organoid methodology in a research laboratory.
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http://dx.doi.org/10.3791/60364DOI Listing
January 2020

Results of the NRG Oncology/RTOG 0848 Adjuvant Chemotherapy Question-Erlotinib+Gemcitabine for Resected Cancer of the Pancreatic Head: A Phase II Randomized Clinical Trial.

Am J Clin Oncol 2020 03;43(3):173-179

Memorial Sloan Kettering Cancer, New York.

Purpose: NRG/RTOG 0848 was designed to determine whether adjuvant radiation with fluoropyrimidine sensitization improved survival following gemcitabine-based adjuvant chemotherapy for patients with resected pancreatic head adenocarcinoma. In step 1 of this protocol, patients were randomized to adjuvant gemcitabine versus the combination of gemcitabine and erlotinib. This manuscript reports the final analysis of these step 1 data.

Methods: Eligibility-within 10 weeks of curative intent pancreaticoduodenectomy with postoperative CA19-9<180. Gemcitabine arm-6 cycles of gemcitabine. Gemcitabine+erlotinib arm-gemcitabine and erlotinib 100 mg/d. Two hundred deaths provided 90% power (1-sided α=0.15) to detect the hypothesized OS signal (hazard ratio=0.72) in favor of the arm 2.

Results: From November 17, 2009 to February 28, 2014, 163 patients were randomized and evaluable for arm 1 and 159 for arm 2. Median age was 63 (39 to 86) years. CA19-9 ≤90 in 93%. Arm 1: 32 patients (20%) grade 4 and 2 (1%) grade 5 adverse events; arm 2, 27 (17%) grade 4 and 3 (2%) grade 5. GI adverse events, arm 1: 22% grade ≥3 and arm 2: 28%, (P=0.22). The median follow-up (surviving patients) was 42.5 months (min-max: <1 to 75). With 203 deaths, the median and 3-year OS (95% confidence interval) are 29.9 months (21.7, 33.4) and 39% (30, 45) for arm 1 and 28.1 months (20.7, 30.9) and 39% (31, 47) for arm 2 (log-rank P=0.62). Hazard ratio (95% confidence interval) comparing OS of arm 2 to arm 1 is 1.04 (0.79, 1.38).

Conclusions: The addition of adjuvant erlotinib to gemcitabine did not provide a signal for increased OS in this trial.
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http://dx.doi.org/10.1097/COC.0000000000000633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280743PMC
March 2020

Sexual dimorphism and the role of estrogen in the immune microenvironment of liver metastases.

Nat Commun 2019 12 17;10(1):5745. Epub 2019 Dec 17.

Department of Medicine, McGill University, Montreal, QC, Canada.

Liver metastases (LM) remain a major cause of cancer-associated death and a clinical challenge. Here we explore a sexual dimorphism observed in the regulation of the tumor immune microenvironment (TIME) of LM, wherein the accumulation of myeloid-derived suppressor cells (MDSC) and regulatory T cells in colon and lung carcinoma LM is TNFR2-dependent in female, but not in male mice. In ovariectomized mice, a marked reduction is observed in colorectal, lung and pancreatic carcinoma LM that is reversible by estradiol reconstitution. This is associated with reduced liver MDSC accumulation, increased interferon-gamma (IFN-γ) and granzyme B production in CD8 T cells and reduced TNFR2, IDO2, TDO and Serpin B9 expression levels. Treatment with tamoxifen increases liver cytotoxic T cell accumulation and reduces colon cancer LM. The results identify estrogen as a regulator of a pro-metastatic immune microenvironment in the liver and a potential target in the management of liver metastatic disease.
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http://dx.doi.org/10.1038/s41467-019-13571-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917725PMC
December 2019

Adherence with operative standards in the treatment of gastric cancer in the United States.

Gastric Cancer 2020 05 19;23(3):550-560. Epub 2019 Nov 19.

Department of Surgery, University of California, San Diego, Moores Cancer Center, 3855 Health Sciences Drive, Mail Code 0987, La Jolla, CA, 92024, USA.

Background: Despite multiple clinical trials and practice guidelines for the treatment of gastric cancer, oncologic outcomes have not improved in the United States. One potential reason could be differences in the quality of surgery as performed in a controlled trial versus in practice.

Methods: Using the National Cancer Database, rates of adherence with operative standards for gastrectomy for cancer were analyzed. Of the numerous evidence-based operative standards outlined in the manual, two were reliably measured in the NCDB: (1) achieving and R0 resection, and (2) having > 16 lymph nodes examined. Univariable and multivariable Cox proportional hazard modeling and logistic regression were performed.

Results: A total of 28,705 patients with gastric adenocarcinoma who underwent curative-intent gastrectomy during 2004-2014 were identified. Only 36.5% of stage 0/I patients, and 41.8% of stage II/III patients, met minimum standards. Predictors for meeting standards included age < 65, fewer comorbidities, Asian/Pacific Islander race, and treatment at academic and high-volume centers. Patients who met standards had longer OS (stage 0/I: 104.9 versus 66.6 months; stage II/III: 40.6 versus 26.0 months; p < 0.001 for both). Meeting standards was a significant predictor for improved OS for both stage 0/I and II/III patients (HR = 0.665 and HR = 0.747, respectively, p < 0.001 for both).

Conclusions: For standards that are measurable in the NCDB, adherence is poor. Improved adherence with operative standards may improve survival for gastric cancer patients in the U.S. There is a need for better measuring of, and adherence with, operative standards in gastrectomy for cancer.
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http://dx.doi.org/10.1007/s10120-019-01028-5DOI Listing
May 2020

Detection and Quantification of GPCR mRNA: An Assessment and Implications of Data from High-Content Methods.

ACS Omega 2019 Oct 30;4(16):17048-17059. Epub 2019 Sep 30.

Department of Pharmacology, Department of Surgery, Moores Cancer Center, and Department of Medicine, University of California, San Diego, La Jolla, California 92093-0636, United States.

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and targets for approved drugs. The analysis of GPCR expression is, thus, important for drug discovery and typically involves messenger RNA (mRNA)-based methods. We compared transcriptomic complementary DNA (cDNA) (Affymetrix) microarrays, RNA sequencing (RNA-seq), and quantitative polymerase chain reaction (qPCR)-based TaqMan arrays for their ability to detect and quantify expression of endoGPCRs (nonchemosensory GPCRs with endogenous agonists). In human pancreatic cancer-associated fibroblasts, RNA-seq and TaqMan arrays yielded closely correlated values for GPCR number (∼100) and expression levels, as validated by independent qPCR. By contrast, the microarrays failed to identify ∼30 such GPCRs and generated data poorly correlated with results from those methods. RNA-seq and TaqMan arrays also yielded comparable results for GPCRs in human cardiac fibroblasts, pancreatic stellate cells, cancer cell lines, and pulmonary arterial smooth muscle cells. The magnitude of mRNA expression for several Gq/11-coupled GPCRs predicted cytosolic calcium increase and cell migration by cognate agonists. RNA-seq also revealed splice variants for endoGPCRs. Thus, RNA-seq and qPCR-based arrays are much better suited than transcriptomic cDNA microarrays for assessing GPCR expression and can yield results predictive of functional responses, findings that have implications for GPCR biology and drug discovery.
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http://dx.doi.org/10.1021/acsomega.9b02811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796235PMC
October 2019

Precision Chemoradiotherapy for HER2 Tumors Using Antibody Conjugates of an Auristatin Derivative with Reduced Cell Permeability.

Mol Cancer Ther 2020 01 9;19(1):157-167. Epub 2019 Oct 9.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California.

The most successful therapeutic strategies for locally advanced cancers continue to combine decades-old classical radiosensitizing chemotherapies with radiotherapy. Molecular targeted radiosensitizers offer the potential to improve the therapeutic ratio by increasing tumor-specific kill while minimizing drug delivery and toxicity to surrounding normal tissue. Auristatins are a potent class of anti-tubulins that sensitize cells to ionizing radiation damage and are chemically amenable to antibody conjugation. To achieve tumor-selective radiosensitization, we synthesized and tested anti-HER2 antibody-drug conjugates of two auristatin derivatives with ionizing radiation. Monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) were attached to the anti-HER2 antibodies trastuzumab and pertuzumab through a cleavable linker. While MMAE is cell permeable, MMAF has limited cell permeability as free drug resulting in diminished cytotoxicity and radiosensitization. However, when attached to trastuzumab or pertuzumab, MMAF was as efficacious as MMAE in blocking HER2-expressing tumor cells in G-M. Moreover, MMAF anti-HER2 conjugates selectively killed and radiosensitized HER2-rich tumor cells. Importantly, when conjugated to targeting antibody, MMAF had the advantage of decreased bystander and off-target effects compared with MMAE. In murine xenograft models, MMAF anti-HER2 antibody conjugates had less drug accumulated in the normal tissue surrounding tumors compared with MMAE. Therapeutically, systemically injected MMAF anti-HER2 conjugates combined with focal ionizing radiation increased tumor control and improved survival of mice with HER2-rich tumor xenografts. In summary, our results demonstrate the potential of cell-impermeable radiosensitizing warheads to improve the therapeutic ratio of radiotherapy by leveraging antibody-drug conjugate technology.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-1302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946877PMC
January 2020

Association of an acute pain service with postoperative outcomes following pancreaticoduodenectomy.

J Perioper Pract 2019 10 16;30(10):309-314. Epub 2019 Sep 16.

Department of Anesthesiology, Division of Regional Anesthesia and Acute Pain, University of California, San Diego, USA.

The aim of this retrospective study was to evaluate the effect of implementing the combination of thoracic epidural analgesia and multimodal analgesia by a dedicated acute pain service on opioid consumption and postoperative outcomes in patients undergoing pancreaticoduodenectomy. Opioid consumption during postoperative days 0-3 was compared in the acute pain service versus non-acute pain service cohort. Between matched cohorts, the median (quartiles) total opioid consumption during postoperative days 0-3 was 114mg morphine equivalents (54.7, 212.4mg morphine equivalents) in the non-acute pain service cohort and 47.4mg morphine equivalents (38.1, 100.8mg morphine equivalents) in the acute pain service cohort; the median difference was 44.8mg morphine equivalents (95% CI 14.2-90.2mg morphine equivalents, p = 0.002). The median difference in hospital length of stay was 2.0 days (95% confidence interval 0.8-4.0, p = 0.01), favouring the acute pain service cohort. A dedicated acute pain service implementing thoracic epidural analgesia in conjunction with multimodal analgesia was associated with decreased opioid consumption and hospital length of stay.
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http://dx.doi.org/10.1177/1750458919874616DOI Listing
October 2019

Optimal Surveillance Frequency After CRS/HIPEC for Appendiceal and Colorectal Neoplasms: A Multi-institutional Analysis of the US HIPEC Collaborative.

Ann Surg Oncol 2020 Jan 26;27(1):134-146. Epub 2019 Jun 26.

Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.

Background: No guidelines exist for surveillance following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for appendiceal and colorectal cancer. The primary objective was to define the optimal surveillance frequency after CRS/HIPEC.

Methods: The U.S. HIPEC Collaborative database (2000-2017) was reviewed for patients who underwent a CCR0/1 CRS/HIPEC for appendiceal or colorectal cancer. Radiologic surveillance frequency was divided into two categories: low-frequency surveillance (LFS) at q6-12mos or high-frequency surveillance (HFS) at q2-4mos. Primary outcome was overall survival (OS).

Results: Among 975 patients, the median age was 55 year, 41% were male: 31% had non-invasive appendiceal (n = 301), 45% invasive appendiceal (n = 435), and 24% colorectal cancer (CRC; n = 239). With a median follow-up time of 25 mos, the median time to recurrence was 12 mos. Despite less surveillance, LFS patients had no decrease in median OS (non-invasive appendiceal: 106 vs. 65 mos, p < 0.01; invasive appendiceal: 120 vs. 73 mos, p = 0.02; colorectal cancer [CRC]: 35 vs. 30 mos, p = 0.8). LFS patients had lower median PCI scores compared with HFS (non-invasive appendiceal: 10 vs. 19; invasive appendiceal: 10 vs. 14; CRC: 8 vs. 11; all p < 0.01). However, on multivariable analysis, accounting for PCI score, LFS was still not associated with decreased OS for any histologic type (non-invasive appendiceal: hazard ratio [HR]: 0.28, p = 0.1; invasive appendiceal: HR: 0.73, p = 0.42; CRC: HR: 1.14, p = 0.59). When estimating annual incident cases of CRS/HIPEC at 375 for non-invasive appendiceal, 375 invasive appendiceal and 4410 colorectal, LFS compared with HFS for the initial two post-operative years would potentially save $13-19 M/year to the U.S. healthcare system.

Conclusions: Low-frequency surveillance after CRS/HIPEC for appendiceal or colorectal cancer is not associated with decreased survival, and when considering decreased costs, may optimize resource utilization.
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http://dx.doi.org/10.1245/s10434-019-07526-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925634PMC
January 2020

Obstruction-Free Survival Following Operative Intervention for Malignant Bowel Obstruction in Appendiceal Cancer.

Ann Surg Oncol 2019 Oct 12;26(11):3611-3617. Epub 2019 Jun 12.

Department of Surgery, University of California, San Diego Moores Cancer Center, La Jolla, CA, USA.

Background: Patients with peritoneal metastases from appendiceal cancer are at high risk of malignant bowel obstruction (MBO), which is associated with significant morbidity and mortality. There are no definitive treatment guidelines regarding operative intervention for MBO. We sought to evaluate the efficacy and safety of operative intervention in this population.

Methods: We identified patients with peritoneal metastases from appendiceal cancer who underwent surgery for MBO at our institution between 2011 and 2018. Baseline characteristics, postoperative complications, and follow-up data were collected. The primary endpoint was obstruction-free survival (OFS). Other endpoints were postoperative recovery of bowel function, 60-day Clavien-Dindo (CD) morbidity, and overall survival (OS).

Results: Twenty-six patients underwent operative treatment for MBO, of whom 14 had high-grade (HG) histology and 12 had low-grade (LG) histology. Seven (25.9%) patients had severe (CD grade 3 or higher) 60-day complications, including one (3.8%) postoperative death. All remaining patients had return of bowel function and resumed oral intake during hospitalization. Six (23.1%) patients had repeat admissions for MBO after surgery. Median OFS was 17.0 months (95% confidence interval [CI] 2.3-31.8), and median OS was 18.5 months (95% CI 3.6-33.3) following surgery.

Conclusion: In this carefully selected group of patients with peritoneal metastases from appendiceal cancer, surgery for MBO provided durable palliation with acceptable morbidity.
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http://dx.doi.org/10.1245/s10434-019-07507-4DOI Listing
October 2019

Incidence, Risk Factors, and Prevention Strategies for Venous Thromboembolism after Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

Ann Surg Oncol 2019 Jul 7;26(7):2276-2284. Epub 2019 May 7.

Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, USA.

Background: The risk factors and incidence of venous thromboembolism (VTE) are not well defined in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). We sought to characterize the incidence, risk factors, and pharmacothromboprophylaxis strategies for VTE after CRS/HIPEC.

Patients And Methods: We performed a retrospective study of CRS/HIPEC procedures at our institution from 8/2007 to 11/2017, examining the 60-day VTE incidence. Baseline, potential risk factor, and prevention strategy data were collected. Univariate and multivariate regression analysis was used to determine risk factors associated with 60-day VTEs.

Results: We identified 25 60-day VTEs among 447 CRS/HIPEC procedures (5.6%). VTEs were discovered on median postoperative day 20 (range 2-59); pulmonary emboli (68%) were the most common type of VTE. The 60-day VTE rate was 10.2% before versus 4.9% after initiation of a policy to discharge patients on pharmacothromboprophylaxis (p = 0.10). Patients with 60-day VTEs had longer average length of stay (14 vs. 11 days, p = 0.01) and higher 60-day mortality rate (4% vs. 0.2%, p = 0.02) than those without VTEs. Caprini score (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.10-2.15, p = 0.01), preoperative serum albumin level (OR 0.40, 95% CI 0.16-1.00, p = 0.05), and 60-day non-VTE serious morbidity (OR 3.45, 95% CI 1.25-9.51, p = 0.02) were risk factors associated with 60-day VTEs on multivariate analysis.

Conclusions: VTEs are relatively common after CRS/HIPEC and are associated with high Caprini scores, low serum albumin levels, and additional inpatient comorbidities. They result in longer length of stay and higher mortality rate. Compliance with current guidelines for extended postoperative thromboprophylaxis was likely associated with reduced VTE rate.
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http://dx.doi.org/10.1245/s10434-019-07414-8DOI Listing
July 2019

Primary Tumor Sidedness is Predictive of Survival in Colon Cancer Patients Treated with Cytoreductive Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy: A US HIPEC Collaborative Study.

Ann Surg Oncol 2019 Jul 23;26(7):2234-2240. Epub 2019 Apr 23.

Department of Surgery, University of California, San Diego, San Diego, CA, USA.

Introduction: The clinical relevance of primary tumor sidedness is not fully understood in colon cancer patients with peritoneal metastasis treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

Methods: This was a retrospective cohort study of a multi-institutional database of patients with peritoneal surface malignancy at 12 participating high-volume academic centers from the US HIPEC Collaborative.

Results: Overall, 336 patients with colon primary tumors who underwent curative-intent CRS with or without HIPEC were identified; 179 (53.3%) patients had right-sided primary tumors and 157 (46.7%) had left-sided primary tumors. Patients with right-sided tumors were more likely to be older, male, have higher Peritoneal Cancer Index (PCI), and have a perforated primary tumor, but were less likely to have extraperitoneal disease. Patients with complete cytoreduction (CC-0/1) had a median disease-free survival (DFS) of 11.5 months (95% confidence interval [CI] 7.6-15.3) versus 13.1 months (95% CI 9.5-16.8) [p = 0.158] and median overall survival (OS) of 30 months (95% CI 23.5-36.6) versus 45.4 months (95% CI 35.9-54.8) [p = 0.028] for right- and left-sided tumors; respectively. Multivariate analysis revealed that right-sided primary tumor was an independent predictor of worse DFS (hazard ratio [HR] 1.75, 95% CI 1.19-2.56; p =0.004) and OS (HR 1.72, 95% CI 1.09-2.73; p = 0.020).

Conclusion: Right-sided primary tumor was an independent predictor of worse DFS and OS. Relevant clinicopathologic criteria, such as tumor sidedness and PCI, should be considered in patient selection for CRS with or without HIPEC, and guide stratification for clinical trials.
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http://dx.doi.org/10.1245/s10434-019-07373-0DOI Listing
July 2019

Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.

Nature 2019 05 17;569(7754):131-135. Epub 2019 Apr 17.

Department of Surgery, Division of Surgical Oncology, University of California San Diego School of Medicine, La Jolla, CA, USA.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance. Furthermore, PSC activation occurs very early during PDAC tumorigenesis, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.
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http://dx.doi.org/10.1038/s41586-019-1130-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565370PMC
May 2019

MST1R kinase accelerates pancreatic cancer progression via effects on both epithelial cells and macrophages.

Oncogene 2019 07 9;38(28):5599-5611. Epub 2019 Apr 9.

Division of Surgical Oncology, Department of Surgery, University of California, San Diego, La Jolla, CA, 92093, USA.

The MST1R (RON) kinase is overexpressed in >80% of human pancreatic cancers, but its role in pancreatic carcinogenesis is unknown. In this study, we examined the relevance of Mst1r kinase to Kras driven pancreatic carcinogenesis using genetically engineered mouse models. In the setting of mutant Kras, Mst1r overexpression increased acinar-ductal metaplasia (ADM), accelerated the progression of pancreatic intraepithelial neoplasia (PanIN), and resulted in the accumulation of (mannose receptor C type 1) MRC1+, (arginase 1) Arg+ macrophages in the tumor microenvironment. Conversely, absence of a functional Mst1r kinase slowed PanIN initiation, resulted in smaller tumors, prolonged survival and a reduced tumor-associated macrophage content. Mst1r expression was associated with increased production of its ligand Mst1, and in orthotopic models, suppression of Mst1 expression resulted in reduced tumor size, changes in macrophage polarization and enhanced T cell infiltration. This study demonstrates the functional significance of Mst1r during pancreatic cancer initiation and progression. Further, it provides proof of concept that targeting Mst1r can modulate pancreatic cancer growth and the microenvironment. This study provides further rationale for targeting Mst1r as a therapeutic strategy.
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http://dx.doi.org/10.1038/s41388-019-0811-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625868PMC
July 2019

A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma.

Cell 2019 04 4;177(3):572-586.e22. Epub 2019 Apr 4.

Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progression. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. In particular, the nuclear hormone receptor retinoic-acid-receptor-related orphan receptor gamma (RORγ), known to drive inflammation and T cell differentiation, was upregulated during pancreatic cancer progression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Further, a large-scale retrospective analysis in patients revealed that RORγ expression may predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. Collectively, these data identify an orthogonal co-option of immuno-regulatory signals by pancreatic cancer stem cells, suggesting that autoimmune drugs should be evaluated as novel treatment strategies for pancreatic cancer patients.
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http://dx.doi.org/10.1016/j.cell.2019.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711371PMC
April 2019