Neoadjuvant and Adjuvant Therapy in Resectable Pancreatic Adenocarcinoma.

While pancreatic adenocarcinoma requires surgical resection definitive cure, treatment paradigms are shifting toward a neoadjuvant approach to systemic therapy. Rationale is twofold: micro-metastatic disease is likely present in a majority of patients, reinforcing the importance of systemic therapy regardless of resectability; moreover, systemic therapy is well-tolerated and improves surgical outcomes when delivered preoperatively. Second, a neoadjuvant approach allows for selection of biology and patients most likely to benefit from potentially morbid surgery. This review examines the increasing body of evidence in support of empiric neoadjuvant therapy in pancreatic adenocarcinoma.

National Landscape of Neoadjuvant Therapy in Potentially Resectable Colon Cancer.

INTRODUCTION: Surgery followed by pathology-guided adjuvant therapy is standard treatment for colon cancer. Data from the FOxTROT clinical trial showed potential benefit of a 6-wk neoadjuvant chemotherapy (NACT) in T3/T4 patients. The present study evaluated real-world outcomes of neoadjuvant therapy in a national cohort of patients with resectable colon cancer. METHODS: 169,120 patients with clinical stage I, II, or III colon cancer from the National Cancer Database registry were included. Patients were categorized as having received neoadjuvant therapy followed by surgery (NACT), surgery then adjuvant chemotherapy (AC), or surgery alone. Factors associated with treatment sequencing and outcomes were assessed. RESULTS: Of identified patients, 1.4% received NACT including 0.5% of stage I, 1.8% of stage II, and 3.0% of stage III. For stage I, 5-y overall survival (OS) was 74.7% after AC, 62.2% after NACT, and 76.4% after SA. For stage II, 5-y OS was 73.2% after AC, 66.8% after NACT, and 64.3% after SA. For stage III, 5-y OS was 67.3% after AC, 67.7% after NACT, and 42.4% after SA. Cox proportional-hazards model suggested NACT had worse outcomes versus AC in clinical stages I (hazard ratio [HR] = 1.59, 95% confidence interval [CI] 1.39-1.85, P < 0.01) and II (HR = 1.37, 95% CI 1.23-1.52, P < 0.01). In stage III, there was no difference in OS between NACT and AC (HR = 1.1, 95% CI 0.99-1.22, P = 0.05). CONCLUSIONS: In a real-world national cohort of patients with resectable colon cancer, NACT had no OS benefit over AC. Future studies should examine which subset of patients might benefit from neoadjuvant approaches.

Lymph node metrics following neoadjuvant therapy to refine patient selection for adjuvant chemotherapy in resected pancreatic cancer: A multi-institutional analysis.

BACKGROUND: In patients with localized pancreatic ductal adenocarcinoma (PDAC) undergoing neoadjuvant therapy (NAT) and resection, selection of adjuvant chemotherapy (AC) is typically guided by high-risk features on histopathologic examination. We evaluated the interaction between post-NAT lymph node metrics and AC receipt on survival. METHODS: Patients who received NAT followed by pancreatectomy (2010-2020) at seven centers were reviewed. Overall survival (OS) in patients receiving AC or not was stratified by lymph node positivity (LNP) or lymph node ratio (LNR) dichotomized at 0.1. Cox models evaluated the independent association between these nodal metrics, AC receipt, and OS. RESULTS: Of 464 patients undergoing NAT and resection, 264 (57%) received AC. Patients selected for AC were younger (median 63 vs. 67 years; p < 0.001), received shorter duration of NAT (2.8 vs. 3.2 months; p = 0.01), had fewer postoperative complications (Clavien-Dindo grade > 3: 1.2% vs. 11.7%; p < 0.001), and lower rates of pathologic complete response (4% vs. 11%; p = 0.01). The median number of nodes evaluated was similar between cohorts (n = 20 in both; p = 0.9). Post-NAT LNP rates were not different, and median LNR was 0.1, in AC and non-AC cohorts. Both LNP (hazard ratio [HR]: 2.1, p < 0.001) and LNR (0 < LNR ≤ 0.1: HR: 1.98, p = 0.002; LNR > 0.1: HR 2.46, p < 0.001) were independently associated with OS on Cox modeling, although receipt of AC was not associated with improved OS (median 30.6 vs. 29.4 months; p = 0.2). In patients with LNR > 0.1, receipt of AC was associated with significantly longer OS compared to non-AC (24 vs. 20 months, respectively; p = 0.04). CONCLUSIONS: LNR following NAT, not simply nodal positivity, may be useful to refine selection of AC in resected PDAC.

The Top Ten Annals of Surgical Oncology Original Articles on Twitter/X: 2020-2023.

Social media has become omnipresent in society, especially given that it enables the rapid and widespread communication of news, events, and information. Social media platforms have become increasingly used by numerous surgical societies to promote meetings and surgical journals to increase the visibility of published content. In September 2020, Annals of Surgical Oncology (ASO) established its Social Media Committee (SMC), which has worked to steadily increase the visibility of published content on social media platforms, namely X (formerly known as Twitter). The purpose of this review is to highlight the 10 ASO original articles with the most engagement on X, based on total number of mentions, since the founding of the SMC. These articles encompass a wide variety of topics from various oncologic disciplines including hepatopancreatobiliary, breast, and gynecologic surgery.

Postoperative Adverse Events Following Neoadjuvant Therapy and Surgery for Borderline Resectable Pancreatic Cancer in a Phase 2 Clinical Trial (Alliance A021501).

BACKGROUND: Postoperative adverse events (AEs) in patients with borderline resectable pancreatic ductal adenocarcinoma (BR-PC) treated with neoadjuvant therapy and pancreatectomy in the national cooperative group setting have not been previously characterized. We conducted a preplanned secondary analysis of patients enrolled on the Alliance A021501 clinical trial to quantify perioperative AE rates. METHODS: The A021501 phase 2 trial randomized patients with BR-PC to receive 8 doses of mFOLFIRINOX (Arm 1) or 7 doses of mFOLFIRINOX and hypofractionated radiotherapy (Arm 2), followed by pancreatectomy (December 31, 2016 to May 31, 2019). Adverse events were assessed 90 days after pancreatectomy. RESULTS: Of 126 enrolled patients, 51 (40%) underwent pancreatectomy (n = 32, Arm 1; n = 19, Arm 2) at 28 institutions. Five (10%) patients required reoperation within 90 days; 56% of patients (n = 27/48) experienced at least one grade 3 or higher AE (50% vs. 67%, p = 0.37). Ninety-day mortality was 2.0%. Readmission was less frequent in Arm 1 (16% vs. 42%, p = 0.05), but there were no differences between study arms in rates of reoperation (13% vs. 5%), pancreatic fistula or intra-abdominal abscess requiring drainage (9% vs. 16%), or wound infection (6% vs. 16%). Pancreatic fistula or intra-abdominal abscess requiring drainage was associated with receipt of adjuvant therapy (p = 0.012). No difference in overall survival was observed based on occurrence of postoperative AEs (hazard ratio = 1.1; 95% confidence interval 0.5-2.6). CONCLUSIONS: In this multicenter study, rates of postoperative AEs were consistent with those previously reported. Multimodality trials of preoperative therapy for BR-PC may be performed in the cooperative group setting with careful quality assurance and safety monitoring. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02839343.

Rituximab in Childhood and Juvenile Pemphigus Vulgaris: A Systematic Review.

Pemphigus vulgaris (PV) is a chronic autoimmune blistering disorder characterized by the loss of intraepithelial adhesion, affecting the skin and mucous membranes. Both males and females are affected, although it predominantly affects females in their fifth and sixth decades of life. Approximately 1.4 to 3.7% of PV cases occur in the pediatric population (≤18 years of age), and may be classified into childhood/pediatric PV, which affects individuals under 12 years old, and juvenile/adolescent PV, affecting those between 12 and 18 years old. Due to its rare occurrence in children and adolescents, there is often a delay in diagnosis and treatment in this age group. A systematic literature search was conducted on MEDLINE/PubMed, Web of Science, EMBASE, SCOPUS, and Cochrane Library databases to evaluate the efficacy of rituximab (RTX) in childhood and juvenile PV patients. The Joanna Briggs Institute (JBI) Critical Appraisal Checklist was employed to assess the risk of bias in case reports and series, while the Cochrane ROBINS-I tool was utilized for evaluating observational studies or non-randomized intervention studies. A total of 18 studies encompassing 46 juvenile or childhood PV patients in the pediatric and adolescent age groups were included for qualitative synthesis. The studies included nine case reports, two case series, five retrospective studies, one prospective study, and one open-label pilot study. Almost all cases of childhood and juvenile PV achieved either complete or partial remission after undergoing RTX treatment during the final follow-up periods. Furthermore, most cases reported no relapse, and only minor adverse events were noted in the RTX treatment group. Despite its potential benefits, the utilization of RTX in pediatric patients raises concerns due to the scarcity of evidence and the absence of controlled studies specific to this age group. Further exploration is necessary to establish a standardized treatment regimen for RTX in pediatric PV, which involves identifying the optimal dosage, frequency, treatment cycle duration, and maintenance therapy duration.

Sphingosine is involved in PAPTP-induced death of pancreas cancer cells by interfering with mitochondrial functions.

Pancreas ductal adenocarcinoma belongs to the most common cancers, but also to the tumors with the poorest prognosis. Here, we pharmacologically targeted a mitochondrial potassium channel, namely mitochondrial Kv1.3, and investigated the role of sphingolipids and mutated Kirsten Rat Sarcoma Virus (KRAS) in Kv1.3-mediated cell death. We demonstrate that inhibition of Kv1.3 using the Kv1.3-inhibitor PAPTP results in an increase of sphingosine and superoxide in membranes and/or membranes associated with mitochondria, which is enhanced by KRAS mutation. The effect of PAPTP on sphingosine and mitochondrial superoxide formation as well as cell death is prevented by sh-RNA-mediated downregulation of Kv1.3. Induction of sphingosine in human pancreas cancer cells by PAPTP is mediated by activation of sphingosine-1-phosphate phosphatase and prevented by an inhibitor of sphingosine-1-phosphate phosphatase. A rapid depolarization of isolated mitochondria is triggered by binding of sphingosine to cardiolipin, which is neutralized by addition of exogenous cardiolipin. The significance of these findings is indicated by treatment of mutated KRAS-harboring metastasized pancreas cancer with PAPTP in combination with ABC294640, a blocker of sphingosine kinases. This treatment results in increased formation of sphingosine and death of pancreas cancer cells in vitro and, most importantly, prolongs in vivo survival of mice challenged with metastatic pancreas cancer. KEY MESSAGES: Pancreatic ductal adenocarcinoma (PDAC) is a common tumor with poor prognosis. The mitochondrial Kv1.3 ion channel blocker induced mitochondrial sphingosine. Sphingosine binds to cardiolipin thereby mediating mitochondrial depolarization. Sphingosine is formed by a PAPTP-mediated activation of S1P-Phosphatase. Inhibition of sphingosine-consumption amplifies PAPTP effects on PDAC in vivo.

Evaluation of KRAS inhibitor-directed therapies for pancreatic cancer treatment.

Despite significant advancements in the treatment of other cancers, pancreatic ductal adenocarcinoma (PDAC) remains one of the world's deadliest cancers. More than 90% of PDAC patients harbor a Kirsten rat sarcoma (KRAS) gene mutation. Although the clinical potential of anti-KRAS therapies has long been realized, all initial efforts to target KRAS were unsuccessful. However, with the recent development of a new generation of KRAS-targeting drugs, multiple KRAS-targeted treatment options for patients with PDAC have entered clinical trials. In this review, we provide an overview of current standard of care treatment, describe RAS signaling and the relevance of KRAS mutations, and discuss RAS isoform- and mutation-specific differences. We also evaluate the clinical efficacy and safety of mutation-selective and multi-selective inhibitors, in the context of PDAC. We then provide a comparison of clinically relevant KRAS inhibitors to second-line PDAC treatment options. Finally, we discuss putative resistance mechanisms that may limit the clinical effectiveness of KRAS-targeted therapies and provide a brief overview of promising therapeutic approaches in development that are focused on mitigating these resistance mechanisms.

Body composition measurements and clinical outcomes in patients with resectable pancreatic adenocarcinoma - analysis from SWOG S1505.

BACKGROUND: Sarcopenic obesity and muscle attenuation have been associated with survival in patients with borderline resectable and advanced pancreatic ductal adenocarcinoma (PDA); however, these relationships are unknown for patients with resectable PDA. This study examined the associations between skeletal muscle and adipose tissue as measured on baseline computed tomography (CT) and the overall survival (OS) of participants with resectable PDA in a secondary analysis of the Southwest Oncology Group S1505 clinical trial (identifier: NCT02562716). METHODS: The S1505 phase II clinical trial enrolled patients with resectable PDA who were randomized to receive modified FOLFIRINOX or gemcitabine and nab-paclitaxel as perioperative chemotherapy, followed by surgical resection. Baseline axial CT images at the L3 level were analyzed with externally validated software, and measurements were recorded for skeletal muscle area and skeletal muscle density, visceral adipose tissue area (VATA) and density, and subcutaneous adipose tissue area and density. The relationships between CT metrics and OS were analyzed using Cox regression models, with adjustment for baseline participant characteristics. RESULTS: Of 98 eligible participants with available baseline abdominal CT, 8 were excluded because of imaging quality (eg, orthopedic hardware), resulting in 90 evaluable cases: 51 men (57.0%; mean age, 63.2 years [SD, 8.5]; mean body mass index [BMI], 29.3 kg/m2 [SD, 6.4]), 80 White (89.0%), 6 Black (7.0%), and 4 unknown race (4.0%). Sarcopenia was present in 32 participants (35.9%), and sarcopenic obesity was present in 10 participants (11.2%). Univariable analyses for the 6 variables of interest indicated that the standardized mean difference (hazard ratio [HR], 0.75; 95% CI, 0.57-0.98; P = .04) was statistically significantly associated with OS. In models adjusted for sex, race, age, BMI, performance score, contrast use, sarcopenia, and sarcopenic obesity, VATA was statistically significantly associated with OS (HR, 1.58; 95% CI, 1.00-2.51; P = .05). No difference was observed in OS between participants according to sarcopenic obesity or sarcopenia categories. The median OS estimates were 25.1 months for participants without sarcopenic obesity, 18.6 months for participants with sarcopenic obesity, 23.6 months for participants without sarcopenia, and 27.9 months for participants with sarcopenia. CONCLUSION: This was the first study to systematically evaluate body composition parameters in a prospective multicenter trial of patients with resectable PDA who received perioperative chemotherapy. Visceral adipose tissue was associated with survival; however, there was no association between OS and sarcopenia or sarcopenic obesity. Further studies should evaluate these findings in more detail.

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.

Basal Cell Adenoma of the Upper Lip: Report of a Rare Case With Literature Review.

Basal cell adenoma (BCA) is a rare, benign tumor originating from the epithelial cells of the salivary glands. It was earlier categorized as a subtype of monomorphic adenoma with distinctive histopathological features. BCA usually manifests as asymptomatic, slow-growing masses that exhibit a site and age predilection, commonly affecting the major salivary glands of elderly female patients. Histologically, solid, trabecular, tubular, and membranous patterns are recognized. It is imperative to establish a precise distinction between BCA, pleomorphic adenoma, and malignant salivary gland tumors before initiating treatment to ensure effective management. The standard treatment approach is surgical resection of the tumor. Recurrence and malignant transformation rarely occur, except for the membranous subtype. This article aims to report an unusual case of BCA arising from a minor salivary gland in the upper lip. The post-operative course was unremarkable, with complete healing of the surgical site. No recurrence was observed during a one-year follow-up. BCA arising from a minor salivary gland in the upper lip is an extremely uncommon entity. A comprehensive review of BCA in the upper lip, reported from 1991 to December 2023, revealed only 14 cases.

Long-Term Neuropsychiatric, Neurocognitive, and Functional Outcomes of Patients Receiving ECMO: A Systematic Review and Meta-Analysis

BACKGROUND AND OBJECTIVES: Despite the common occurrence of neurologic complications during extracorporeal membrane oxygenation (ECMO) support, data on long-term neuropsychiatric, neurocognitive, and functional outcomes are sparse. We aimed to determine the prevalence of long-term neuropsychiatric symptoms, neurocognitive and functional impairment, and favorable neurologic outcomes in adult patients who receive ECMO. METHODS: PubMed, Embase, Cochrane, Web of Science, and Scopus were searched for text related to ECMO and neuropsychiatric, neurocognitive, and functional outcomes from inception to May 3, 2023. Our primary outcome was the prevalence of neuropsychiatric symptoms (pain/discomfort, anxiety, depression, posttraumatic stress disorder [PTSD], and sleep disturbance) at long-term (≥6 months) follow-up. Our secondary outcomes were the prevalence of neurocognitive impairment (memory, attention, and reasoning), functional impairment (daily activities, physical activity/mobility, and personal/self-care), and favorable neurologic outcomes (Cerebral Performance Category ≤2, modified Rankin scale ≤3, or Glasgow Outcome Scale ≥4). This study was registered in PROSPERO (CRD42023420565). RESULTS: We included 59 studies with 3,280 patients (median age 54 years, 69% male). The cohort consisted of 86% venoarterial (VA)-ECMO (n = 2,819) and 14% venovenous (VV)-ECMO (n = 461) patients. More than 10 tools were used to assess neuropsychiatric and neurocognitive outcomes, indicating a lack of standardization in assessment methodologies. The overall prevalence of neuropsychiatric symptoms was 41% (95% CI 33%-49%): pain/discomfort (52%, 95% CI 42%-63%), sleep disturbance (37%, 95% CI 0%-98%), anxiety (36%, 95% CI 27%-46%), depression (31%, 95% CI 22%-40%), and PTSD (18%, 95% CI 9%-29%). The prevalence of neurocognitive impairment was 38% (95% CI 13%-65%). The prevalence of functional impairment was 52% (95% CI 40%-64%): daily activities (54%, 95% CI 41%-66%), mobility (41%, 95% CI 28%-54%), and self-care (21%, 95% CI 13%-31%). The prevalence of neuropsychiatric symptoms in VV-ECMO patients was higher than that in VA-ECMO patients (55% [95% CI 34%-75%] vs 32% [95% CI 23%-41%], p = 0.01), though the prevalence of neurocognitive and functional impairment was not different between the groups. The prevalence of favorable neurologic outcomes was not different at various follow-ups: 3 months (23%, 95% CI 12%-36%), 6 months (25%, 95% CI 16%-35%), and ≥1 year (28%, 95% CI 21%-36%, p = 0.68). DISCUSSION: A substantial proportion of ECMO patients seemed to experience neuropsychiatric symptoms and neurocognitive and functional impairments at long-term follow-up. Considerable heterogeneity in methodology for gauging these outcomes exists, warranting the need for standardization. Multicenter prospective observational studies are indicated to further investigate risk factors for these outcomes in ECMO-supported patients.

Intratumoral Cell Neighborhoods Coordinate Outcomes in Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease characterized by a spatially heterogeneous tumor microenvironment. Within the PDA microenvironment, cells organize into communities where cell fate is influenced by neighboring cells of diverse ontogeny and function. However, it remains unclear how cell neighborhoods in the tumor microenvironment evolve with treatment and impact clinical outcomes. METHODS: Here, using automated chromogenic multiplex immunohistochemistry and unsupervised computational image analysis of human PDA tumors, we investigated cell neighborhoods in surgically resected tumors from patients with chemotherapy-naïve PDA (n = 59) and neoadjuvant chemotherapy-treated PDA (n = 57). Single cells were defined by lineage markers (CD3, CD8, Foxp3, CD68, CK19), proliferation (Ki67), and neighboring cells. RESULTS: Distinct intratumoral immune and tumor cell subsets were defined by neighboring cells. Higher content of stromal-associated macrophages was seen in chemotherapy-naïve tumors from long-term survivors (overall survival >3 years) compared with short-term survivors (overall survival <1 year), whereas immune-excluded tumor cells were higher in short-term survivors. Chemotherapy-treated vs -naïve tumors showed lower content of tumor-associated T cells and macrophages but similar densities of stromal-associated immune cells. However, proliferating tumor cell subsets with immune-rich neighborhoods were higher in chemotherapy-treated tumors. In a blinded analysis of tumors from patients treated with neoadjuvant chemotherapy, a composite index comprising lower quantities of immune-excluded tumor cells and higher spatially distinct immune cell subsets was associated with prolonged survival. CONCLUSIONS: Together, these data provide new insights into discrete cell communities in PDA and show their clinical relevance.

Breast infections: A review of current literature.

Breast infections are common, affect women of all ages, and are associated with significant morbidity. Despite overall prevalence, treatment varies significantly based on provider or institution and no central treatment guidelines exist to direct the management of breast infections. This article provides a summary of the current trends in management of breast infections. The etiology, epidemiology, risk factors, presentation, diagnosis, and treatment of mastitis and breast abscesses (and their relative subdivisions) are explored based on the current literature. Trends in microbiology are reviewed and an approach to antibiotic coverage is proposed. Overall, there is a lack of randomized-controlled trials focused on the treatment of breast infections. This has resulted in an absence of clinical practice guidelines for the management of breast abscesses and variable practice patterns. The development of best-care protocols or pathways could provide more uniformity in care of breast infections.

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.

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.

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.

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.

Social media and academic surgical research dissemination.

Academic research dissemination has evolved tremendously throughout the 20th and early 21st centuries. With the advent of new technology and remote communication, the fast and efficient sharing of ideas has spread worldwide and has been appropriately embraced by academic surgical researchers. The use of social media by surgeons has expanded our ability to share hypotheses and published works that lead to higher degrees of collaboration than previously possible. The strengths of social media use for research dissemination in surgery include immediate collaboration on a global scale, faster dissemination of results previously hindered by the publishing process, open peer review from a wider audience, and enhancing the experience of academic meetings. However, social media use for research dissemination is not perfect and is hindered by lack of author verification, public misinterpretation, and lack of standardized enforceable professional guidelines. To combat these potential pitfalls, surgical societies should prioritize specific and intervenable guidelines for surgeons regarding the appropriate use of social media for research dissemination.