Patient metabolic profile defined by liver and muscle 18F-FDG PET avidity is independently associated with overall survival in gastric cancer.

BACKGROUND: PET-CT-based patient metabolic profiling is a novel concept to incorporate patient-specific metabolism into gastric cancer care. METHODS: Staging PET-CTs, demographics, and clinicopathologic variables of gastric cancer patients were obtained from a prospectively maintained institutional database. PET-CT avidity was measured in tumor, liver, spleen, four paired muscles, and two paired fat areas in each patient. The liver to rectus femoris (LRF) ratio was defined as the ratio of SUVmean of liver to the average SUVmean of the bilateral rectus femoris muscles. Kaplan-Meier and Cox-proportional hazards models were used to identify the impact of LRF ratio on OS. RESULTS: Two hundred and one patients with distal gastroesophageal (48%) or gastric (52%) adenocarcinoma were included. Median age was 65 years, and 146 (73%) were male. On univariate analysis, rectus femoris PET-CT avidity and LRF ratio were significantly associated with overall survival (p < 0.05). LRF ratio was significantly higher in males, early-stage cancer, patients with an ECOG 0 or 1 performance status, patients with albumin > 3.5 mg/dL, and those with moderately differentiated tumor histology. In multivariable regression, gastric cancer stage, albumin, and LRF ratio were significant independent predictors of overall survival (LRF ratio HR = 0.73 (0.56-0.96); p = 0.024). Survival curves showed that the prognostic impact of LRF was associated with metastatic gastric cancer (p = 0.009). CONCLUSIONS: Elevated LRF ratio, a patient-specific PET-CT-based metabolic parameter, was independently associated with an improvement in OS in patients with metastatic gastric cancer. With prospective validation, LRF ratio may be a useful, host-specific metabolic parameter for prognostication in gastric cancer.

Multivalent tyrosine kinase inhibition promotes T cell recruitment to immune-desert gastric cancers by restricting epithelial-mesenchymal transition via tumour-intrinsic IFN-γ signalling.

OBJECTIVE: Gastric cancer (GC) ranks fifth in incidence and fourth for mortality worldwide. The response to immune checkpoint blockade (ICB) therapy in GC is heterogeneous due to tumour-intrinsic and acquired immunotherapy resistance. We developed an immunophenotype-based subtyping of human GC based on immune cells infiltration to develop a novel treatment option. DESIGN: A algorithm was developed to reclassify GC into immune inflamed, excluded and desert subtypes. Bioinformatics, human and mouse GC cell lines, syngeneic murine gastric tumour model, and CTLA4 blockade were used to investigate the immunotherapeutic effects by restricting receptor tyrosine kinase (RTK) signalling in immune desert (ICB-resistant) type GC. RESULTS: Our algorithm restratified subtypes of human GC in public databases and showed that immune desert-type and excluded-type tumours are ICB-resistant compared with immune-inflamed GC. Moreover, epithelial-mesenchymal transition (EMT) signalling was highly enriched in immune desert-type GC, and syngeneic murine tumours exhibiting mesenchymal-like, compared with epithelial-like, properties are T cell-excluded and resistant to CTLA4 blockade. Our analysis further identified a panel of RTKs as potential druggable targets in the immune desert-type GC. Dovitinib, an inhibitor of multiple RTKs, strikingly repressed EMT programming in mesenchymal-like immune desert syngeneic GC models. Dovitinib activated the tumour-intrinsic SNAI1/2-IFN-γ signalling axis and impeded the EMT programme, converting immune desert-type tumours to immune inflamed-type tumours, sensitising these mesenchymal-like 'cold' tumours to CTLA4 blockade. CONCLUSION: Our findings identified potential druggable targets relevant to patient groups, especially for refractory immune desert-type/ 'cold' GC. Dovitinib, an RTK inhibitor, sensitised desert-type immune-cold GC to CTLA4 blockade by restricting EMT and recruiting T cells.

Combined MEK and STAT3 Inhibition Uncovers Stromal Plasticity by Enriching for Cancer-Associated Fibroblasts With Mesenchymal Stem Cell-Like Features to Overcome Immunotherapy Resistance in Pancreatic Cancer.

BACKGROUND & AIMS: We have shown that reciprocally activated rat sarcoma (RAS)/mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and Janus kinase/signal transducer and activator of transcription 3 (STAT3) pathways mediate therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC), while combined MEK and STAT3 inhibition (MEKi+STAT3i) overcomes such resistance and alters stromal architecture. We now determine whether MEKi+STAT3i reprograms the cancer-associated fibroblast (CAF) and immune microenvironment to overcome resistance to immune checkpoint inhibition in PDAC. METHODS: CAF and immune cell transcriptomes in MEKi (trametinib)+STAT3i (ruxolitinib)-treated vs vehicle-treated Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) tumors were examined via single-cell RNA sequencing (scRNAseq). Clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats associated protein 9 silencing of CAF-restricted Map2k1/Mek1 or Stat3, or both, enabled interrogation of CAF-dependent effects on immunologic remodeling in orthotopic models. Tumor growth, survival, and immune profiling via mass cytometry by time-of-flight were examined in PKT mice treated with vehicle, anti-programmed cell death protein 1 (PD-1) monotherapy, and MEKi+STAT3i combined with anti-PD1. RESULTS: MEKi+STAT3i attenuates Il6/Cxcl1-expressing proinflammatory and Lrrc15-expressing myofibroblastic CAF phenotypes while enriching for Ly6a/Cd34-expressing CAFs exhibiting mesenchymal stem cell-like features via scRNAseq in PKT mice. This CAF plasticity is associated with M2-to-M1 reprogramming of tumor-associated macrophages, and enhanced trafficking of cluster of differentiation 8+ T cells, which exhibit distinct effector transcriptional programs. These MEKi+STAT3i-induced effects appear CAF-dependent, because CAF-restricted Mek1/Stat3 silencing mitigates inflammatory-CAF polarization and myeloid infiltration in vivo. Addition of MEKi+STAT3i to PD-1 blockade not only dramatically improves antitumor responses and survival in PKT mice but also augments recruitment of activated/memory T cells while improving their degranulating and cytotoxic capacity compared with anti-PD-1 monotherapy. Importantly, treatment of a patient who has chemotherapy-refractory metastatic PDAC with MEKi (trametinib), STAT3i (ruxolitinib), and PD-1 inhibitor (nivolumab) yielded clinical benefit. CONCLUSIONS: Combined MEKi+STAT3i mitigates stromal inflammation and enriches for CAF phenotypes with mesenchymal stem cell-like properties to overcome immunotherapy resistance in PDAC.

Racial Disparity in Pathologic Response following Neoadjuvant Chemotherapy in Resected Pancreatic Cancer: A Multi-Institutional Analysis from the Central Pancreatic Consortium.

BACKGROUND: Major pathologic response (MPR) following neoadjuvant therapy (NAT) in pancreatic ductal adenocarcinoma (PDAC) patients undergoing resection is associated with improved survival. We sought to determine whether racial disparities exist in MPR rates following NAT in patients with PDAC undergoing resection. METHODS: Patients with potentially operable PDAC receiving at least 2 cycles of neoadjuvant FOLFIRINOX or gemcitabine/nab-paclitaxel ± radiation followed by pancreatectomy (2010-2019) at 7 high-volume centers were reviewed. Self-reported race was dichotomized as Black and non-Black, and multivariable models evaluated the association between race and MPR (i.e., pathologic complete response [pCR] or near-pCR). Cox regression evaluated the association between race and disease-free (DFS) and overall survival (OS). RESULTS: Results of 486 patients who underwent resection following NAT (mFOLFIRINOX 56%, gemcitabine/nab-paclitaxel 25%, radiation 29%), 67 (13.8%) patients were Black. Black patients had lower CA19-9 at diagnosis (median 67 vs. 204 U/mL; P = 0.003) and were more likely to undergo mild/moderate chemotherapy dose modification (40 vs. 20%; P = 0.005) versus non-Black patients. Black patients had significantly lower rates of MPR compared with non-Black patients (13.4 vs. 25.8%; P = 0.039). Black race was independently associated with worse MPR (OR 0.26, 95% confidence interval [CI] 0.10-0.69) while controlling for NAT duration, CA19-9 dynamics, and chemotherapy modifications. There was no significant difference in DFS or OS between Black and non-Black cohorts. CONCLUSIONS: Black patients undergoing pancreatectomy appear less likely to experience MPR following NAT. The contribution of biologic and nonbiologic factors to reduced chemosensitivity in Black patients warrants further investigation.

Accuracy of models to prognosticate survival after surgery for pancreatic cancer in the era of neoadjuvant therapy.

BACKGROUND: Outcomes for pancreatic adenocarcinoma (PDAC) remain difficult to prognosticate. Multiple models attempt to predict survival following the resection of PDAC, but their utility in the neoadjuvant population is unknown. We aimed to assess their accuracy among patients that received neoadjuvant chemotherapy (NAC). METHODS: We performed a multi-institutional retrospective analysis of patients who received NAC and underwent resection of PDAC. Two prognostic systems were evaluated: the Memorial Sloan Kettering Cancer Center Pancreatic Adenocarcinoma Nomogram (MSKCCPAN) and the American Joint Committee on Cancer (AJCC) staging system. Discrimination between predicted and actual disease-specific survival was assessed using the Uno C-statistic and Kaplan-Meier method. Calibration of the MSKCCPAN was assessed using the Brier score. RESULTS: A total of 448 patients were included. There were 232 (51.8%) females, and the mean age was 64.1 years (±9.5). Most had AJCC Stage I or II disease (77.7%). For the MSKCCPAN, the Uno C-statistic at 12-, 24-, and 36-month time points was 0.62, 0.63, and 0.62, respectively. The AJCC system demonstrated similarly mediocre discrimination. The Brier score for the MSKCCPAN was 0.15 at 12 months, 0.26 at 24 months, and 0.30 at 36 months, demonstrating modest calibration. CONCLUSIONS: Current survival prediction models and staging systems for patients with PDAC undergoing resection after NAC have limited accuracy.

Urolithin A attenuates severity of chronic pancreatitis associated with continued alcohol intake by inhibiting PI3K/AKT/mTOR signaling.

Heavy alcohol consumption is the dominant risk factor for chronic pancreatitis (CP); however, treatment and prevention strategies for alcoholic chronic pancreatitis (ACP) remains limited. The present study demonstrates that ACP induction in C57BL/6 mice causes significant acinar cell injury, pancreatic stellate cell (PSC) activation, exocrine function insufficiency, and an increased fibroinflammatory response when compared with alcohol or CP alone. Although the withdrawal of alcohol during ACP recovery led to reversion of pancreatic damage, continued alcohol consumption with established ACP perpetuated pancreatic injury. In addition, phosphokinase array and Western blot analysis of ACP-induced mice pancreata revealed activation of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and cyclic AMP response element binding protein (CREB) signaling pathways possibly orchestrating the fibroinflammatory program of ACP pathogenesis. Mice treated with urolithin A (Uro A, a gut-derived microbial metabolite) in the setting of ACP with continued alcohol intake (during the recovery period) showed suppression of AKT and P70S6K activation, and acinar damage was significantly reduced with a parallel reduction in pancreas-infiltrating macrophages and proinflammatory cytokine accumulation. These results collectively provide mechanistic insight into the impact of Uro A on attenuation of ACP severity through suppression of PI3K/AKT/mTOR signaling pathways and can be a useful therapeutic approach in patients with ACP with continuous alcohol intake.NEW & NOTEWORTHY Our novel findings presented here demonstrate the utility of Uro A as an effective therapeutic agent in attenuating alcoholic chronic pancreatitis (ACP) severity with alcohol continuation after established disease, through suppression of the PI3K/AKT/mTOR signaling pathway.

Distinct Genomic Profiles are Associated With Conversion to Resection and Survival in Patients With Initially Unresectable Colorectal Liver Metastases Treated With Systemic and Hepatic Artery Chemotherapy.

OBJECTIVE: To examine genomic correlates of conversion to resection (CTR and overall survival (OS) in patients with initially unresectable colorectal liver metastasis (IU-CRLM) treated with combination systemic and hepatic artery infusion (HAI) chemotherapy. BACKGROUND: In patients presenting with IU-CRLM, combination systemic and HAI chemotherapy enables CTR with associated long-term OS in a subset of patients. Genomic correlates of CTR and OS in IU-CRLM have not been previously explored. METHODS: Specimens from IU-CRLM patients receiving systemic/HAI chemotherapy (2003-2017) were submitted for next-generation sequencing. Fisher Exact test assessed associations with CTR, and Kaplan-Meier/Cox methods assessed associations with OS from HAI initiation. RESULTS: Of 128 IU-CRLM patients, 51 (40%) underwent CTR at median 6 months (range: 3-35) from HAI initiation. CTR and persistently unresectable cohorts differed significantly in preoperative systemic chemotherapy exposure, node-positive primary status, and size of largest liver metastasis. Median and 5-year OS was 66 months and 51%. CTR was associated with prolonged survival (time-dependent HR 0.23,95% CI: 0.12-0.46, P < 0.001). The most frequently altered genes were APC (81%), TP53 (77%), and KRAS (37%). Oncogenic mutations in SOX9 and BRAF were associated with CTR. BRAF mutations, any RAS pathway alterations, and co-altered RAS/RAF-TP53 mutations wereassociated with worse survival. Classification and regression tree analysis defined prognostically relevant clusters of genomic risk to reveal co-altered RAS/RAF-TP53 as the highest risk subgroup. Co-altered RAS/RAF-TP53 remained independently associated with worse survival (HR 2.52, 95% CI: 1.37-4.64, P = 0.003) after controlling for CTR, number of liver metastases, and preoperative extrahepatic disease. CONCLUSIONS: Distinct genomic profiles are associated with CTR and survival in patients with IU-CRLM treated with HAI/systemic chemotherapy. Presence of SOX9, BRAF , and co-altered RAS/RAF- TP53 mutations are promising biomarkers that, when validated in larger datasets, may impact treatment of IU-CRLM patients.

Landmark Series: Importance of Pancreatic Resection Margins.

An important goal of cancer surgery is to achieve negative surgical margins and remove all disease completely. For pancreatic neoplasms, microscopic margins may remain positive despite gross removal of the palpable mass, and surgeons must then consider extending resection, even to the point of completion pancreatectomy, an option that renders the patient with significant adverse effects related to exocrine and endocrine insufficiency. Counterintuitively, extending resection to ensure clear margins may not improve patient outcome. Furthermore, the goal of improving survival by extending the resection may not be achieved, as an initial positive margin may indicate more aggressive underlying tumor biology. There is a growing body of literature on this topic, and this landmark series review will examine the key publications that guide our management for resection of pancreatic ductal adenocarcinoma, intraductal papillary mucinous neoplasms, and pancreatic neuroendocrine tumors.

Intraoperative Pancreatic Neck Margin Assessment During Pancreaticoduodenectomy for Pancreatic Adenocarcinoma in the Era of Neoadjuvant Therapy: A Multi-institutional Analysis from the Central Pancreatic Consortium.

BACKGROUND: Data regarding the survival impact of converting frozen-section (FS):R1 pancreatic neck margins to permanent section (PS):R0 by additional resection (i.e., converted-R0) during upfront pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC) are conflicting. The impact of neoadjuvant therapy on this practice and its relationship with overall survival (OS) is incompletely understood. METHODS: We reviewed PDAC patients (80% borderline resectable/locally advanced [BR/LA]) undergoing pancreaticoduodenectomy after neoadjuvant therapy at seven, academic, high-volume centers (2010-2018). Multivariable models examined the association of PS:R0, PS:R1, and converted-R0 margins with OS. RESULTS: Of 272 patients receiving at least 2 (median 4) cycles of neoadjuvant chemotherapy (71% mFOLFIRINOX or gemcitabine/nab-paclitaxel) and undergoing pancreaticoduodenectomy with intraoperative frozen-section assessment of the transected pancreatic neck margin, PS:R0 (n = 220, 80.9%) was observed in a majority of patients; 18 patients (6.6%) had converted-R0 margins following additional resection, whereas 34 patients (12.5%) had persistently positive PS:R1 margins. At a median follow-up of 42 months, PS:R0 resection was associated with improved OS compared with either converted-R0 or PS:R1 resection (median 25 vs. 14 vs. 16 months, respectively; p = 0.023), with no survival difference between the converted-R0 and PS:R1 groups (p = 0.9). On Cox regression, SMA margin positivity (hazard ratio 2.2, p = 0.012), but not neck margin positivity (hazard ratio 1.2, p = 0.65), was associated with worse OS. CONCLUSIONS: In this multi-institutional cohort of predominantly BR/LA PDAC patients undergoing pancreaticoduodenectomy following modern neoadjuvant therapy, pursuing a negative neck margin intraoperatively if the initial margin is positive does not appear to be associated with improved survival.

Genomic Predictors of Recurrence Patterns After Complete Resection of Colorectal Liver Metastases and Adjuvant Hepatic Artery Infusion Chemotherapy.

BACKGROUND: Despite curative hepatectomy, most colorectal liver metastasis (CRLM) patients relapse locally within 2 years. Genomic predictors for hepatic recurrence are poorly understood. This study was designed to identify genomic signatures for recurrence in resected CRLM patients treated with adjuvant hepatic artery infusion (HAI) and/or systemic (SYS) chemotherapy. METHODS: Patients undergoing curative hepatectomy and adjuvant HAI+SYS or SYS between January 2000 and October 2017 with next-generation sequencing data were catalogued. Gene and signaling-level alterations were checked for association with time to any (AR), liver (LR), and extrahepatic recurrence (ER) by using Kaplan-Meier analysis. RESULTS: Of 172 receiving HAI+SYS, 100 patients recurred, with 69 LR and 83 ER. Five- and ten-year LR-free rates were 57% (95% confidence interval [CI] 48-65%) and 51% (95% CI 41-60%), respectively. Five- and 10-year ER-free, rates were 51% (95% CI 43-58%) and 45% (95% CI 36-54%), respectively. More ER was observed with tumors harboring altered KRAS (38% [95% CI 25-50%] vs. 63% [95% CI 53-71%], p-adj = 0.003) and RAS/RAF (36% [95% CI 25-48%] vs. 66% [95% CI 56-74%], p-adj < 0.001) than wild-type. Co-altered RAS/RAF-TP53 was associated with worse AR (26% [95% CI 14-40%] vs. 48% [95% CI 39-57%], p-unadj < 0.001), ER (30% [95% CI 17-45%] vs. 62% [95% CI 53-70%], p-unadj < 0.001), and LR rate (40% [95% CI 24-57%] vs. 70% [95% CI 60-77%], p-unadj = 0.002). On multivariable analysis, controlling for clinical risk score, ablation, margin status, and primary T-stage, co-altered RAS/RAF-TP53 was associated with increased risk for AR (HR = 2.14, 95% CI 1.38-3.31, p-unadj < 0.001), LR (HR = 1.79, 95% CI 1.06-3.02, p-unadj = 0.029), and ER (HR = 2.81, 95% CI 1.78-4.44, p-unadj < 0.001). CONCLUSIONS: Altered KRAS, RAS/RAF, and RAS/RAF-TP53 associated with earlier local and distant recurrence in resected CRLM patients receiving adjuvant HAI+SYS. Co-altered RAS/RAF-TP53 was a novel predictor of LR warranting investigation of whether genomic cooperativity is associated with this relapsing phenotype. Systemic therapies tailored to high-risk tumor biology are needed to reduce distant relapse after hepatectomy.

Diagnostic laparoscopy is underutilized in the staging of gastric adenocarcinoma regardless of hospital type: An US safety net collaborative analysis.

BACKGROUND: Diagnostic laparoscopy (DL) is a key component of staging for locally advanced gastric adenocarcinoma (GA). We hypothesized that utilization of DL varied between safety net (SNH) and affiliated tertiary referral centers (TRCs). METHODS: Patients diagnosed with primary GA eligible for DL were identified from the US Safety Net Collaborative database (2012-2014). Clinicopathologic factors were analyzed for association with use of DL and findings on DL. Overall survival (OS) was analyzed by Kaplan-Meier method. RESULTS: Among 233 eligible patients, 69 (30%) received DL, of which 24 (35%) were positive for metastatic disease. Forty percent of eligible SNH patients underwent DL compared to 21.5% at TRCs. Lack of insurance was significantly associated with decreased use of DL (OR 0.48, p < 0.01), while African American (OR 6.87, p = 0.02) and Asian race (OR 3.12, p ≤ 0.01), signet ring cells on biopsy (OR 3.14, p < 0.01), and distal tumors (OR 1.62, p < 0.01) were associated with increased use. Median OS of patients with a negative DL was better than those without DL or a positive DL (not reached vs. 32 vs. 12 months, p < 0.005, Figure 1). CONCLUSIONS: Results from DL are a strong predictor of OS in GA; however, the procedure is underutilized. Patients from racial minority groups were more likely to undergo DL, which likely accounts for higher DL rates among SNH patients.

Prescription patterns of pancreatic enzyme replacement therapy for patients with pancreatic cancer in the United States.

BACKGROUND: Exocrine pancreatic insufficiency (EPI) is frequently seen in patients with pancreatic cancer (PDAC) and is thought to contribute to nutritional complications. While EPI can be pharmacologically temporized with pancreatic enzyme replacement therapy (PERT), there is lack of clear evidence informing its use in PDAC. Here we aim to survey pancreatic surgeons regarding their utilization of PERT in the management of EPI for PDAC. METHODS: An online survey was distributed to the members of The Americas Hepato-Pancreato-Biliary Association (AHPBA) and The Pancreas Club. RESULTS: 86.5% (180/208) of surgeons prescribe PERT for at least some resectable/borderline resectable PDAC cases. Only a minority of surgeons order investigations to confirm EPI before starting PERT (28.1%) or test for adequacy of therapy (28.3%). Few surgeons believe that PERT has an effect on overall survival (19.7%) or disease-free survival (6.25%) in PDAC. CONCLUSION: PERT is widely prescribed in patients with resectable/borderline resectable PDAC, but investigations establishing EPI and assessing PERT adequacy are underutilized. A substantial proportion of surgeons are unclear as to the effect of PERT on survival outcomes in PDAC. These data call for prospective studies to establish guidelines for optimal use of PERT and its effects on survival outcomes in PDAC.

National Institutes of Health Career Development (K) Awards to Young Surgeons: An Academic Milestone or One-hit Wonder?

OBJECTIVE: To assess contemporary trends in the National Institutes of Health (NIH) Career Development (K) Awards within the Departments of Surgery and its impact on the likelihood of achieving independent R01 grants. BACKGROUND: The NIH provides K-type Career Development Awards to nurture young clinicians toward a productive academic career, thereby maintaining a pipeline of physician-scientists. However, the impact of K awards on career trajectory of surgeons remains unclear. METHODS: The NIH grant data was queried for all new K08/K23 grants awarded to Departments of Surgery (1999-2019). Principal Investigators' data and grant-related information was obtained. RESULTS: The NIH awarded 298 K08/23 surgical grants ($41,893,170) over the last 2 decades. Median budget increased from $116,370 to $167,508 (P<0.001). Of grantees, 83.2% were MDs, 15.1% MD/PhD, and 1.7% PhDs, with 25.2% being women. Principal Investigators' were mostly practicing surgeons (91.1%) with fellowship training (82.4%) and young in their careers {4 [interquartile ranges (IQR) 4] years of experience}. Vascular surgery (15.9%), Complex General Surgical Oncology (15.1%), and Trauma/Critical Care (14.6%) were the most frequent specialties. Awards were associated with 3,336 publications [median 8/project (IQR 13)]. The majority of K grantees (77.2%) currently hold an academic faculty position. Only 32.2% of awardees received independent R01 grant funding, at a median of 5.5 years (IQR 5) after their K awards. Sex (P = 0.71), previous fellowship training (P = 0.63), type of surgical specialty (P = 0.72), or MD/PhD degree (P = 0.75) were not associated with increased likelihood of achieving a subsequent R01 award. CONCLUSION: Although the majority of K awardees maintain an academic career, only a limited number of grantees progress to obtain NIH R01 funding. Increased mentorship, financial support, and infrastructure are needed to facilitate career development awardees opportunities to enhance their ability to achieve independent funding.

Does Major Pancreatic Surgery Have Utility in Nonagenarians with Pancreas Cancer?

OBJECTIVE: This study aims to define the role of surgery and assess different therapies for nonagenarians with localized, nonmetastatic pancreatic adenocarcinoma (PDAC). METHODS: The National Cancer Database (NCDB) was queried for patients ≥ 90 years of age with nonmetastatic, localized PDAC from 2004-2016. Postoperative mortality was assessed at 30 and 90 days in patients receiving pancreatoduodenectomy or total pancreatectomy. Overall survival (OS) was compared between three treatment groups: surgery alone, chemotherapy alone, and chemoradiation (chemoRT) alone. RESULTS: Of 380,524 patients with PDAC, 98 patients ≥ 90 years of age underwent curative-intent resection; 55% were female and 75% had a Charlson-Deyo comorbidity score of 0. A total of 17% received postoperative chemotherapy, 51.1% had poorly differentiated tumors with a median tumor size of 3 cm, 55.1% had positive lymph nodes, and 19.4% had positive resection margins. Postoperative median length of stay was 11 days. Postoperative 30- and 90-day mortality was 10.0% and 18.9%, respectively. Median OS for the surgery alone group was 11.6 months compared with 20.4 months in those receiving adjuvant therapy (p = 0.01). Among nonoperative PDAC patients, median OS in patients receiving chemotherapy only (n = 207) was 7.2 months, while chemoRT only (n = 100) was similar to surgery only (11 versus 11.6 months, p = 0.97). CONCLUSIONS: Even in well-selected nonagenarians, pancreatoduodenectomy or total pancreatectomy carries a high mortality rate. While adjuvant therapy after resection provides the best survival, it is seldom achieved, and chemoRT alone affords identical survival statistics as surgery alone. These data suggest it is reasonable to consider chemoRT as initial therapy, then reassess candidacy for resection if performance status allows.

Clinical Presentation Patterns and Survival Outcomes of Hispanic Patients With Gastric Cancer.

BACKGROUND: Hispanic patients have a higher incidence of gastric cancer when compared to non-Hispanics. Outlining clinicodemographic characteristics and assessing the impact of ethnicity on stage-specific survival may identify opportunities to improve gastric cancer care for this population. METHODS: Patients with gastric cancer in the US Safety Net Collaborative (2012-2014) were retrospectively reviewed. Demographics, clinicopathologic characteristics, operative details, and outcomes were compared between Hispanic and non-Hispanic patients. Early onset gastric cancer was defined as age <50 years. Kaplan-Meier and Cox proportional-hazards models were used to identify the impact of ethnicity on disease-specific survival (DSS). RESULTS: Seven hundred and ninety-seven patients were included, of which 219 (28%) were Hispanic. Hispanic patients were more likely to seek care at safety-net hospitals (66 vs 39%) and be uninsured (36 vs 17%), and less likely to have a primary care provider (PCP) (46 vs 75%; all P<0.05). Hispanic patients were twice as likely to present with early onset gastric cancer (28 vs 15%) and were more frequently diagnosed in the emergency room (54 vs 37%) with both abdominal pain and weight loss (44 vs 31%; all P <0.05). Treatment paradigms, operative outcomes, and DSS were similar between Hispanic and non-Hispanic patients when accounting for cancer stage. Cancer stage, pathologically positive nodes, and negative surgical margins were independently associated with DSS. CONCLUSIONS: A diagnosis of gastric cancer must be considered in previously healthy Hispanic patients who present to the emergency room with both abdominal pain and weight loss. Fewer than 50% of Hispanic patients have a PCP, indicating poor outpatient support. Efforts to improve outpatient support and screening may improve gastric cancer outcomes in this vulnerable population.

Surgical management of hepatocellular carcinoma patients with portal vein thrombosis: The United States Safety Net and Academic Center Collaborative Analysis.

BACKGROUND: Although consensus guidelines generally discourage any surgical management (ASM; i.e., resection and/or transplantation) in patients with hepatocellular carcinoma (HCC) and portal vein thrombosis (PVT), recent series from Asia have challenged this paradigm. METHODS: Patients from the US Safety Net Collaborative database (2012-2014) with localized HCC and radiographically confirmed PVT were propensity-score matched based on demographic and clinicopathologic factors associated with receipt of ASM and overall survival (OS). OS was compared between patients undergoing ASM and those not selected for surgery. RESULTS: Of 1910 HCC patients, 207 (14.5%) had localized disease and PVT. The majority received either liver-directed therapies (LDTs; 34%) and/or targeted systemic therapies (36%). Twenty-one patients (10.1%) underwent ASM (resection [n = 11], transplantation [n = 10]); a third experienced any complication with no 30-day mortalities. Independent predictors of undergoing ASM were younger age, recent hepatology consultation, and lower model of end-stage liver disease (MELD) score. After matching for age, comorbidities, MELD, tumor size, receipt of LDT, or systemic therapy, OS was significantly longer for patients selected for ASM versus non-ASM patients (median not reached vs. 5.8 months, p < .001). CONCLUSION: In a large North American multi-institutional cohort, a minority of HCC patients with PVT were selected for ASM. Resection or transplantation was associated with improved survival and may have a role in the multimodality management in selected patients.

Is there a difference in utilization of a perioperative treatment approach for gastric cancer between safety net hospitals and tertiary referral centers?

BACKGROUND AND OBJECTIVES: Perioperative therapy is a favored treatment strategy for gastric cancer. We sought to assess utilization of this approach at safety net hospitals (SNH) and tertiary referral centers (TRC). MATERIALS AND METHODS: Patients in the US Safety Net Collaborative (2012-2014) with resectable gastric cancer across five SNH and their sister TRC were included. Primary outcomes were receipt of neoadjuvant chemotherapy (NAC) and perioperative therapy. RESULTS: Of 284 patients, 36% and 64% received care at SNH and TRC. The distribution of Stage II/III resectable disease was similar across facilities. Receipt of NAC at SNH and TRC was similar (56% vs. 46%, p = 0.27). Compared with overall clinical stage, 38% and 36% were pathologically downstaged at SNH and TRC, respectively. Among patients who received NAC, those who also received adjuvant chemotherapy at SNH and TRC were similar (66% vs. 60%, p = 0.50). Asian race and higher clinical stage were associated with receipt of perioperative therapy (both p < 0.05) while treatment facility type was not. CONCLUSIONS: There was no difference in utilization of a perioperative treatment strategy between facility types for patients with gastric cancer. Pathologic downstaging from NAC was similar across treatment facilities, suggesting similar quality and duration of therapy. Treatment at an SNH is not a barrier to receiving standard-of-care perioperative therapy for gastric cancer.

Attrition during neoadjuvant chemotherapy for gastric adenocarcinoma is associated with decreased survival: A United States Safety-Net Collaborative analysis.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is standard management for localized gastric cancer (GC). Attrition during NAC due to treatment-related toxicity or functional decline is considered a surrogate for worse biologic outcomes; however, data supporting this paradigm are lacking. We investigated factors predicting attrition and its association with overall survival (OS) in GC. METHODS: Patients with nonmetastatic GC initiating NAC were identified from the US Safety-Net Collaborative (2012-2014). Patient/treatment-related characteristics were compared between attrition/nonattrition cohorts. Cox models determined factors associated with OS. RESULTS: Of 116 patients initiating NAC, attrition during prescribed NAC occurred in 24%. No differences were observed in performance status, comorbidities, treatment at safety-net hospital, or clinicopathologic factors between cohorts. Despite absence of distinguishing factors, attrition was associated with worse OS (median: 11 vs. 37 months; p = 0.01) and was an independent predictor of mortality (hazard ratio [HR]: 4.7, 95% confidence interval [CI]: 1.5-15.2; p = 0.02). Fewer patients with attrition underwent curative-intent surgery (39% vs. 89%; p < 0.001). Even in patients undergoing surgical exploration (n = 89), NAC attrition remained an independent predictor of worse OS (HR: 50.8, 95% CI: 3.6-717.8; p = 0.004) despite similar receipt of adjuvant chemotherapy. CONCLUSION: Attrition during NAC for nonmetastatic GC is independently associated with worse OS, even in patients undergoing surgery. Attrition during NAC may reflect unfavorable tumor biology not captured by conventional staging metrics.