Sphingosine Prevents Rhinoviral Infections.

Rhinoviral infections cause approximately 50% of upper respiratory tract infections and novel treatment options are urgently required. We tested the effects of 10 µM to 20 µM sphingosine on the infection of cultured and freshly isolated human cells with minor and major group rhinovirus in vitro. We also performed in vivo studies on mice that were treated with an intranasal application of 10 µL of either a 10 µM or a 100 µM sphingosine prior and after infection with rhinovirus strains 1 and 2 and determined the infection of nasal epithelial cells in the presence or absence of sphingosine. Finally, we determined and characterized a direct binding of sphingosine to rhinovirus. Our data show that treating freshly isolated human nasal epithelial cells with sphingosine prevents infections with rhinovirus strains 2 (minor group) and 14 (major group). Nasal infection of mice with rhinovirus 1b and 2 is prevented by the intranasal application of sphingosine before or as long as 8 h after infection with rhinovirus. Nasal application of the same doses of sphingosine exerts no adverse effects on epithelial cells as determined by hemalaun and TUNEL stainings. The solvent, octylglucopyranoside, was without any effect in vitro and in vivo. Mechanistically, we demonstrate that the positively charged lipid sphingosine binds to negatively charged molecules in the virus, which seems to prevent the infection of epithelial cells. These findings indicate that exogenous sphingosine prevents infections with rhinoviruses, a finding that could be therapeutically exploited. In addition, we demonstrated that sphingosine has no obvious adverse effects on the nasal mucosa. Sphingosine prevents rhinoviral infections by a biophysical mode of action, suggesting that sphingosine could serve to prevent many viral infections of airways and epithelial cells in general. Future studies need to determine the molecular mechanisms of how sphingosine prevents rhinoviral infections and whether sphingosine also prevents infections with other viruses inducing respiratory tract infections. Furthermore, our studies do not provide detailed pharmacokinetics that are definitely required before the further development of sphingosine.

Contemporary Outcomes of Grade-C Postoperative Pancreatic Fistula in a Nationwide Database.

INTRODUCTION: Grade-C postoperative pancreatic fistulas (POPFs) are dreaded complications following pancreaticoduodenectomy. The aim of this study was to quantify the incidence and risk factors associated with grade C POPF in a national database. METHODS: The National Surgical Quality Improvement Program targeted user files were queried for patients who underwent elective pancreaticoduodenectomy (2014-2020). Outcomes were compared between clinically relevant (CR) grade B POPF and grade C POPF. RESULTS: Twenty-six thousand five hundred fifty-two patients were included, of which 90.1% (n = 23,714) had No CR POPF, 8.7% (n = 2287) suffered grade B POPF, and 1.2% (n = 327) suffered grade C POPF. There was no change in the rate Grade-C fistula overtime (m = 0.06, P = 0.63), while the rate of Grade-B fistula significantly increased (m = +1.40, P < 0.01). Fistula Risk Scores were similar between grade B and C POPFs (high risk: 34.9% versus 31.2%, P = 0.21). Associated morbidity was increased with grade C POPF, including delayed gastric emptying, organ space infections, wound dehiscence, respiratory complications, renal complications, myocardial infarction, and bleeding. On multivariate logistic regression, diabetes mellitus (odds ratio: 1.41 95% confidence interval: 1.06-1.87, P = 0.02) was associated with grade C POPF. CONCLUSIONS: This study represents the largest contemporary series evaluating grade C POPFs. Of those suffering CR POPF, the presence of diabetes mellitus was associated with grade C POPF. While modern management has led to grade C POPF in 1% of cases, they remain associated with alarmingly high morbidity and mortality, requiring further mitigation strategies to improve outcomes.

Preoperative CA 19-9 Predicts Disease Progression in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: An Analysis from the US HIPEC Collaborative.

INTRODUCTION: Patients with colorectal peritoneal metastases (CRPM) are increasingly treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Unfortunately, data identifying preoperative risk factors for poor oncologic outcomes after this procedure are limited. We aimed to determine the prognostic value of preoperative CEA, CA 125, and CA 19-9 on disease progression after CRS/HIPEC. METHODS: Patients with CRPM treated with curative intent CRS/HIPEC from 12 participating sites in the United States from 2000 to 2017 were identified. Progression-free survival (PFS), defined as disease progression or recurrence, was the primary outcome. RESULTS: In 279 patients who met inclusion criteria, the rate of disease progression was 63.8%, with a median PFS of 11 months (interquartile range [IQR] 5-20). Elevated CA 19-9 was associated with dismal PFS at 2 years (8.9% elevated vs. 30% not elevated, p < 0.01). In 113 patients who underwent upfront CRS/HIPEC, CA 19-9 emerged as the sole tumor marker independently predictive of worse PFS (hazard ratio [HR] 2.88, p = 0.048). In the subgroup of patients who had received neoadjuvant therapy (NAT), no variable was independently predictive of PFS. CA 19-9 levels over 37 U/ml were highly specific for accelerated disease progression after CRS/HIPEC. Lastly, there was no association between PFS and elevated CEA or CA 125. CONCLUSIONS: Elevated CA 19-9 is associated with decreased PFS in patients with CRPM. While traditionally CEA is the main tumor marker assessed in colon cancer, we found that CA 19-9 may better inform preoperative risk stratification for poor oncologic outcomes in patients with CRPM. However, prospective studies are required to confirm this association.

ASO Practice Guidelines Series: Management of Resectable, Borderline Resectable, and Locally Advanced Pancreas Cancer.

Pancreatic adenocarcinoma is an aggressive disease marked by high rates of both local and distant failure. In the minority of patients with potentially resectable disease, multimodal treatment paradigms have allowed for prolonged survival in an increasingly larger pool of well-selected patients. Therefore, it is critical for surgical oncologists to be abreast of current guideline recommendations for both surgical management and multimodal therapy for pancreas cancer. We discuss these guidelines, as well as the underlying data supporting these positions, to offer surgical oncologists a framework for managing patients with pancreatic adenocarcinoma.

Defining the operative time threshold for safety in patients undergoing robotic pancreaticoduodenectomy.

BACKGROUND: Robotic pancreaticoduodenectomy (RPD) is a safe and efficacious procedure in appropriately selected patients, though frequently with increased operative times compared to open pancreaticoduodenectomy (OPD). METHODS: From 2014 to 2019, patients who underwent elective, low-risk, RPDs and OPDs in the NSQIP database were isolated. The operative time threshold (OTT) for safety in RPD patients was estimated by identifying the operative time at which complication rates for RPD patients exceeded the complication rate of the benchmark OPD control. RESULTS: Of 6270 patients identified, 939 (15%) underwent RPD and 5331 (85%) underwent OPD. The incidence of major morbidity or mortality for the OPD cohort was 35.1%. The OTT was identified as 7.7 h. Patients whose RPDs were above the OTT experienced a higher incidence of major morbidity (42.5% vs. 35.0%, p < 0.01) and 30-day mortality (2.7% vs. 1.2%, p = 0.03) than the OPD cohort. Preoperative obstructive jaundice (OR: 1.47, [95% CI: 1.08-2.01]) and pancreatic duct size <3 mm (OR: 2.44, [95% CI: 1.47-4.06]) and 3-6 mm (OR: 2.15, [95% CI: 1.31-3.52]) were risk factors for prolonged RPDs on multivariable regression. CONCLUSION: The operative time threshold for safety, identified at 7.7 h, should be used to improve patient selection for RPDs and as a competency-based quality benchmark.

Multiomic Characterization Reveals a Distinct Molecular Landscape in Young-Onset Pancreatic Cancer.

PURPOSE: Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between patients with young-onset pancreatic cancer (YOPC; younger than 50 years) and patients with average-onset pancreatic cancer (AOPC; 70 years and older). METHODS: We analyzed matched whole-transcriptome and DNA sequencing data from 2,430 patient samples (YOPC, n = 292; AOPC, n = 2,138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data were obtained from insurance claims (n = 4,928); Kaplan-Meier estimates were calculated for age- and molecularly defined cohorts. Significance was determined as FDR-corrected P values (Q) < .05. RESULTS: Patients with YOPC had higher proportions of mismatch repair-deficient/microsatellite instability-high, BRCA2-mutant, and PALB2-mutant tumors compared with patients with AOPC, but fewer SMAD4-, RNF43-, CDKN2A-, and SF3B1-mutant tumors. Notably, patients with YOPC demonstrated significantly lower incidence of KRAS mutations compared with patients with AOPC (81.3% v 90.9%; Q = .004). In the KRAS wild-type subset (n = 227), YOPC tumors demonstrated fewer TP53 mutations and were more likely driven by NRG1 and MET fusions, whereas BRAF fusions were exclusively observed in patients with AOPC. Immune deconvolution revealed significant enrichment of natural killer cells, CD8+ T cells, monocytes, and M2 macrophages in patients with YOPC relative to patients with AOPC, which corresponded with lower rates of HLA-DPA1 homozygosity. There was an association with improved OS in patients with YOPC compared with patients with AOPC with KRAS wild-type tumors (median, 16.2 [YOPC-KRASWT] v 10.6 [AOPC-KRASWT] months; P = .008) but not KRAS-mutant tumors (P = .084). CONCLUSION: In this large, real-world multiomic characterization of age-stratified molecular differences in pancreatic ductal adenocarcinoma, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.

Role of Tyrosine Nitrosylation in Stress-Induced Major Depressive Disorder: Mechanisms and Implications.

Major depressive disorder (MDD) has a lifetime prevalence of approximately 10% and is one of the most common diseases worldwide. Although many pathogenetic mechanisms of MDD have been proposed, molecular details and a unifying hypothesis of the pathogenesis of MDD remain to be defined. Here, we investigated whether tyrosine nitrosylation, which is caused by reaction of the C-atom 3 of the tyrosine phenol ring with peroxynitrate (ONOO-), plays a role in experimental MDD, because tyrosine nitrosylation may affect many cell functions altered in MDD. To this end, we induced stress through glucocorticoid application or chronic environmental unpredictable stress and determined tyrosine nitrosylation in the hippocampus through immuno-staining and ELISA. The role of catalases and peroxidases for tyrosine nitrosylation was measured using enzyme assays. We show that glucocorticoid- and chronic unpredictable environmental stress induced tyrosine nitrosylation in the hippocampus. Long-term treatment of stressed mice with the classical antidepressants amitriptyline or fluoxetine prevented tyrosine nitrosylation. Tyrosine nitrosylation was also prevented through i.v. application of anti-ceramide antibodies or recombinant ceramidase to neutralize or degrade, respectively, blood plasma ceramide that has been recently shown to induce experimental MDD. Finally, the application of phosphatidic acid, previously shown to be reduced in the hippocampus upon stress, also reverted stress-induced tyrosine nitrosylation. The inhibition of tyrosine nitrosylation by interfering with the formation of NO radicals at least partly restored normal behavior in stressed mice. These data suggest that tyrosine nitrosylation might contribute to the pathogenesis of MDD and targeting this process might contribute to the treatment of MDD.

Potential involvement of the bone marrow in experimental Graves' disease and thyroid eye disease.

Introduction: Graves' disease is an autoimmune disorder caused by auto-antibodies against the thyroid stimulating hormone receptor (TSHR). Overstimulation of the TSHR induces hyperthyroidism and thyroid eye disease (TED) as the most common extra thyroidal manifestation of Graves' disease. In TED, the TSHR cross talks with the insulin-like growth factor 1 receptor (IGF-1R) in orbital fibroblasts leading to inflammation, deposition of hyaluronan and adipogenesis. The bone marrow may play an important role in autoimmune diseases, but its role in Graves' disease and TED is unknown. Here, we investigated whether induction of experimental Graves' disease and accompanying TED involves bone marrow activation and whether interference with IGF-1R signaling prevents this activation. Results: Immunization of mice with TSHR resulted in an increase the numbers of CD4-positive T-lymphocytes (p ≤0.0001), which was normalized by linsitinib (p = 0.0029), an increase of CD19-positive B-lymphocytes (p= 0.0018), which was unaffected by linsitinib and a decrease of GR1-positive cells (p= 0.0038), which was prevented by linsitinib (p= 0.0027). In addition, we observed an increase of Sca-1 positive hematopietic stem cells (p= 0.0007) and of stromal cell-derived factor 1 (SDF-1) (p ≤0.0001) after immunization with TSHR which was prevented by linsitinib (Sca-1: p= 0.0008, SDF-1: p ≤0.0001). TSHR-immunization also resulted in upregulation of CCL-5, IL-6 and osteopontin (all p ≤0.0001) and a concomitant decrease of the immune-inhibitory cytokines IL-10 (p= 0.0064) and PGE2 (p ≤0.0001) in the bone marrow (all p≤ 0.0001). Treatment with the IGF-1R antagonist linsitinib blocked these events (all p ≤0.0001). We further demonstrate a down-regulation of arginase-1 expression (p= 0.0005) in the bone marrow in TSHR immunized mice, with a concomitant increase of local arginine (p ≤0.0001). Linsitinib induces an upregulation of arginase-1 resulting in low arginase levels in the bone marrow. Reconstitution of arginine in bone marrow cells in vitro prevented immune-inhibition by linsitinib. Conclusion: Collectively, these data indicate that the bone marrow is activated in experimental Graves' disease and TED, which is prevented by linsitinib. Linsitinib-mediated immune-inhibition is mediated, at least in part, by arginase-1 up-regulation, consumption of arginine and thereby immune inhibition.

Feeding Jejunostomy Tube in Patients Undergoing Esophagectomy: Utilization and Outcomes in a Nationwide Cohort.

BACKGROUND: Feeding jejunostomy (JT) tubes are often utilized as an adjunct to optimize nutrition for successful esophagectomy; however, their utility has come into question. The aim of this study was to evaluate utilization and outcomes associated with JTs in a nationwide cohort of patients undergoing esophagectomy. METHODS: The NSQIP database was queried for patients who underwent elective esophagectomy. JT utilization was assessed between 2010 and 2019. Post-operative outcomes were compared between those with and without a JT on patients with esophagectomy-specific outcomes (2016-2019), with results validated using a propensity score-matched (PSM) analysis based on key clinicopathologic factors, including tumor stage. RESULTS: Of the 10,117 patients who underwent elective esophagectomy over the past decade, 53.0% had a JT placed concurrently and 47.0% did not. Utilization of JTs decreased over time, accounting for 60.0% of cases in 2010 compared to 41.7% in 2019 (m = - 2.14 95%CI: [- 1.49]-[- 2.80], p < 0.01). Patients who underwent JT had more composite wound complications (17.0% vs. 14.1%, p = 0.02) and a higher rate of all-cause morbidity (40.4% vs. 35.5%, p = 0.01). Following PSM, 1007 pairs were identified. Analysis of perioperative outcomes demonstrated a higher rate of superficial skin infections (6.1% vs. 3.5%, p = 0.01) in the JT group. However, length of stay, reoperation, readmission, anastomotic leak, composite wound complications, all-cause morbidity, and mortality rates were similar between groups. CONCLUSIONS: Among patients undergoing elective esophagectomy, feeding jejunostomy tubes were utilized less frequently over the past decade. Similar perioperative outcomes among matched patients support the safety of esophagectomy without an adjunct feeding jejunostomy tube.

Neighborhood-Level Socioeconomic Disadvantage Predicts Outcomes in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Malignancy.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) improves survival in select patients with peritoneal metastases (PM), but the impact of social determinants of health on CRS/HIPEC outcomes remains unclear. PATIENTS AND METHODS: A retrospective review was conducted of a multi-institutional database of patients with PM who underwent CRS/HIPEC in the USA between 2000 and 2017. The area deprivation index (ADI) was linked to the patient's residential address. Patients were categorized as living in low (1-49) or high (50-100) ADI residences, with increasing scores indicating higher socioeconomic disadvantage. The primary outcome was overall survival (OS). Secondary outcomes included perioperative complications, hospital/intensive care unit (ICU) length of stay (LOS), and disease-free survival (DFS). RESULTS: Among 1675 patients 1061 (63.3%) resided in low ADI areas and 614 (36.7%) high ADI areas. Appendiceal tumors (n = 1102, 65.8%) and colon cancer (n = 322, 19.2%) were the most common histologies. On multivariate analysis, high ADI was not associated with increased perioperative complications, hospital/ICU LOS, or DFS. High ADI was associated with worse OS (median not reached versus 49 months; 5 year OS 61.0% versus 28.2%, P < 0.0001). On multivariate Cox-regression analysis, high ADI (HR, 2.26; 95% CI 1.13-4.50; P < 0.001), cancer recurrence (HR, 2.26; 95% CI 1.61-3.20; P < 0.0001), increases in peritoneal carcinomatosis index (HR, 1.03; 95% CI 1.01-1.05; P < 0.001), and incomplete cytoreduction (HR, 4.48; 95% CI 3.01-6.53; P < 0.0001) were associated with worse OS. CONCLUSIONS: Even after controlling for cancer-specific variables, adverse outcomes persisted in association with neighborhood-level socioeconomic disadvantage. The individual and structural-level factors leading to these cancer disparities warrant further investigation to improve outcomes for all patients with peritoneal malignancies.

Validation of the AJCC 8th Edition Staging System for Disseminated Appendiceal Cancer Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Multi-institutional Analysis.

BACKGROUND: The AJCC 8th edition stratifies stage IV disseminated appendiceal cancer (dAC) patients based on grade and pathology. This study was designed to externally validate the staging system and to identify predictors of long-term survival. METHODS: A 12-institution cohort of dAC patients treated with CRS ± HIPEC was retrospectively analyzed. Overall survival (OS) and recurrence-free survival (RFS) were analyzed by using Kaplan-Meier and log-rank tests. Univariate and multivariate cox-regression was performed to assess factors associated with OS and RFS. RESULTS: Among 1009 patients, 708 had stage IVA and 301 had stage IVB disease. Median OS (120.4 mo vs. 47.2 mo) and RFS (79.3 mo vs. 19.8 mo) was significantly higher in stage IVA compared with IVB patients (p < 0.0001). RFS was greater among IVA-M1a (acellular mucin only) than IV M1b/G1 (well-differentiated cellular dissemination) patients (NR vs. 64 mo, p = 0.0004). Survival significantly differed between mucinous and nonmucinous tumors (OS 106.1 mo vs. 41.0 mo; RFS 46.7 mo vs. 21.2 mo, p < 0.05), and OS differed between well, moderate, and poorly differentiated (120.4 mo vs. 56.3 mo vs. 32.9 mo, p < 0.05). Both stage and grade were independent predictors of OS and RFS on multivariate analysis. Acellular mucin and mucinous histology were associated with better OS and RFS on univariate analysis only. CONCLUSIONS: AJCC 8th edition performed well in predicting outcomes in this large cohort of dAC patients treated with CRS ± HIPEC. Separation of stage IVA patients based on the presence of acellular mucin improved prognostication, which may inform treatment and long-term, follow-up strategies.

Acid sphingomyelinase expression is associated with survival in resectable pancreatic ductal adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) is one of the most common cancers worldwide. Unfortunately, the prognosis of PDAC is rather poor, and for instance, in the USA, over 47,000 people die because of pancreatic cancer annually. Here, we demonstrate that high expression of acid sphingomyelinase in PDAC strongly correlates with long-term survival of patients, as revealed by the analysis of two independent data sources. The positive effects of acid sphingomyelinase expression on long-term survival of PDAC patients were independent of patient demographics as well as tumor grade, lymph node involvement, perineural invasion, tumor stage, lymphovascular invasion, and adjuvant therapy. We also demonstrate that genetic deficiency or pharmacological inhibition of the acid sphingomyelinase promotes tumor growth in an orthotopic mouse model of PDAC. This is mirrored by a poorer pathologic response, as defined by the College of American Pathologists (CAP) score for pancreatic cancer, to neoadjuvant therapy of patients co-treated with functional inhibitors of the acid sphingomyelinase, in particular tricyclic antidepressants and selective serotonin reuptake inhibitors, in a retrospective analysis. Our data indicate expression of the acid sphingomyelinase in PDAC as a prognostic marker for tumor progression. They further suggest that the use of functional inhibitors of the acid sphingomyelinase, at least of tricyclic antidepressants and selective serotonin reuptake inhibitors in patients with PDAC, is contra-indicated. Finally, our data also suggest a potential novel treatment of PDAC patients with recombinant acid sphingomyelinase. KEY MESSAGES: Pancreatic ductal adenocarcinoma (PDAC) is a common tumor with poor prognosis. Expression of acid sphingomyelinase (ASM) determines outcome of PDAC. Genetic deficiency or pharmacologic inhibition of ASM promotes tumor growth in a mouse model. Inhibition of ASM during neoadjuvant treatment for PDAC correlates with worse pathology. ASM expression is a prognostic marker and potential target in PDAC.

FOLFIRINOX or Gemcitabine-based Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Cancer: A Multi-institutional, Patient-Level, Meta-analysis and Systematic Review.

BACKGROUND: Pancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is currently unclear what chemotherapy should be preferred for patients with BRPC or LAPC. METHODS: We performed a systematic review and multi-institutional meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC. Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based. RESULTS: A total of 23 studies comprising 2930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment. OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) (p < 0.0001). In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p < 0.0001). This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens. The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO. In patients with LAPC, resection rates were 0.19 with Gemcitabine and 0.28 with FIO. In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083). A similar trend was observed in resected patients converted from LAPC. CONCLUSIONS: In patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with Gemcitabine-based chemotherapy appears to provide a survival benefit for patients that are ultimately unresectable. For patients that undergo surgical resection, outcomes are similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting.

Multi-omic characterization reveals a distinct molecular landscape in young-onset pancreatic cancer.

Purpose: Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between young-onset pancreatic cancer (YOPC; <50-yrs.) and average-onset pancreatic cancer (AOPC; ≥70-yrs.) patients. Methods: We analyzed matched whole-transcriptome and DNA sequencing data from 2430 patient samples (YOPC, n=292; AOPC, n=2138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data was obtained from insurance claims (n=4928); Kaplan-Meier estimates were calculated for age-and molecularly-defined cohorts. Significance was determined as FDR-corrected P -values ( Q )<0.05. Results: YOPC patients had higher proportions of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H), BRCA2 -mutant, and PALB2 -mutant tumors compared with AOPC patients, but fewer SMAD4-, RNF43-, CDKN2A- , and SF3B1- mutant tumors. Notably, YOPC patients demonstrated significantly lower incidence of KRAS mutations compared with AOPC patients (81.3% vs. 90.9%; Q =0.004). In the KRAS- wildtype subset (n=227), YOPC tumors demonstrated fewer TP53 mutations and were more likely driven by NRG1 and MET fusions, while BRAF fusions were exclusively observed in AOPC patients. Immune deconvolution revealed significant enrichment of natural killer (NK) cells, CD8 + T cells, monocytes, and M2 macrophages in YOPC patients relative to AOPC patients, which corresponded with lower rates of HLA-DPA1 homozygosity. There was an association with improved OS in YOPC patients compared with AOPC patients with KRAS -wildtype tumors (median 16.2 [YOPC- KRAS WT ] vs. 10.6 [AOPC- KRAS WT ] months; P =0.008) but not KRAS -mutant tumors ( P =0.084). Conclusion: In this large, real-world multi-omic characterization of age-stratified molecular differences in PDAC, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.

Long-Term Survival Outcomes after Operative Management of Chronic Pancreatitis: Two Decades of Experience.

BACKGROUND: Chronic pancreatitis is a debilitating, life-altering disease; however, the long-term outcomes after operative intervention have not been established. STUDY DESIGN: Patients who underwent operative intervention at a single institution between 2000 and 2020 for chronic pancreatitis were included, and survival was assessed using the National Death Index. RESULTS: A total of 493 patients who underwent 555 operative interventions for chronic pancreatitis during 2 decades were included. Of these patients, 48.5% underwent total pancreatectomy ± islet autotransplantation, 21.7% underwent a duodenal preserving pancreatic head resection and/or drainage procedure, 16.2% underwent a pancreaticoduodenectomy, and 12.8% underwent a distal pancreatectomy. The most common etiology of chronic pancreatitis was idiopathic (41.8%), followed by alcohol (28.0%) and known genetic polymorphisms (9.9%). With a median follow-up of 83.9 months, median overall survival was 202.7 months, with a 5- and 10-year overall survival of 81.3% and 63.5%. One hundred sixty-five patients were deceased, and the most common causes of death included infections (16.4%, n=27), cardiovascular disease (12.7%, n=21), and diabetes-related causes (10.9%, n=18). On long-term follow-up, 73.1% (n=331) of patients remained opioid free, but 58.7% (n=266) had insulin-dependent diabetes. On multivariate Cox proportional hazards modeling, only persistent opioid use (hazard ratio 3.91 [95% CI 2.45 to 6.24], p < 0.01) was associated with worse overall survival. CONCLUSIONS: Our results represent the largest series to date evaluating long-term survival outcomes in patients with chronic pancreatitis after operative intervention. Our data give insight into the cause of death and allow for the development of mitigation strategies and long-term monitoring of comorbid conditions.