Multi-omic profiling of intraductal papillary neoplasms of the pancreas reveals distinct expression patterns and potential markers of progression.

In order to advance our understanding of precancers in the pancreas, 69 pancreatic intraductal papillary neoplasms (IPNs), including 64 intraductal papillary mucinous neoplasms (IPMNs) and 5 intraductal oncocytic papillary neoplasms (IOPNs), 32 pancreatic cyst fluid samples, 104 invasive pancreatic ductal adenocarcinomas (PDACs), 43 normal adjacent tissues (NATs), and 76 macro-dissected normal pancreatic ducts (NDs) were analyzed by mass spectrometry. A total of 10,246 proteins and 22,284 glycopeptides were identified in all tissue samples, and 756 proteins with more than 1.5-fold increase in abundance in IPMNs relative to NDs were identified, 45% of which were also identified in cyst fluids. The over-expression of selected proteins was validated by immunolabeling. Proteins and glycoproteins overexpressed in IPMNs included those involved in glycan biosynthesis and the immune system. In addition, multiomics clustering identified two subtypes of IPMNs. This study provides a foundation for understanding tumor progression and targets for earlier detection and therapies. Significance: This multilevel characterization of intraductal papillary neoplasms of the pancreas provides a foundation for understanding the changes in protein and glycoprotein expression during the progression from normal duct to intraductal papillary neoplasm, and to invasive pancreatic carcinoma, providing a foundation for informed approaches to earlier detection and treatment.

Distinct Indications for Adjuvant Therapy in Resected Invasive Mucinous Cystic Neoplasms of the Pancreas Compared with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Surgical and adjuvant management of mucinous cystic neoplasms (MCNs) lacks formal guidelines and data is limited to institutional studies. Factors associated with receipt of adjuvant therapy and any associated impact on survival remain to be clarified. In the absence of other data, guidelines that recommend adjuvant chemotherapy for invasive pancreatic adenocarcinoma have been extrapolated to MCN. PATIENTS AND METHODS: The National Cancer Database (2004-2019) was utilized to identify all patients that underwent pancreatic resection for invasive MCNs. Patients that received neoadjuvant therapy or did not undergo lymphadenectomy were excluded. Patient, tumor, and treatment factors associated with survival were assessed. RESULTS: For 161 patients with invasive MCN, median overall survival (OS) was 133 months and 45% of patients received adjuvant therapy. Multivariable analysis demonstrated that poorly differentiated tumors [odds ratio (OR) 4.19, 95% confidence interval (CI) 1.47-11.98; p = 0.008] and positive lymph node status (OR 2.67, 95% CI 1.02-6.98; p = 0.042) were independent predictors of receiving adjuvant therapy. Lymph node positivity [hazard ratio (HR) 2.90, 95% CI 1.47-5.73; p = 0.002], positive margins (HR 5.28, 95% CI 2.28-12.27; p < 0.001), and stage III disease (HR 12.46, 95% CI 1.40-111.05; p = 0.024) were associated with worse OS. Receipt of adjuvant systemic therapy was independently associated with decreased risk of mortality in node positive patients (HR 0.23, 95% CI 0.10-0.69; p = 0.002). Survival was not associated with adjuvant therapy in patients with negative lymph nodes or margin negative status. CONCLUSION: In contrast to pancreatic ductal adenocarcinoma (PDAC), where adjuvant therapy improves OS for every tumor stage, surgery alone for invasive MCN is not associated with improved OS compared with surgery plus adjuvant therapy in node-negative patients. Surgery alone is likely sufficient for a subset of invasive MCN.

Long-Duration Neoadjuvant Therapy with FOLFIRINOX Yields Favorable Outcomes for Patients Who Undergo Surgery for Pancreatic Cancer.

BACKGROUND: In 2023 alone, it's estimated that over 64,000 patients will be diagnosed with PDAC and more than 50,000 patients will die of the disease. Current guidelines recommend neoadjuvant therapy for patients with borderline resectable and locally advanced PDAC, and data is emerging on its role in resectable disease. Neoadjuvant chemotherapy may increase the number of patients able to receive complete chemotherapy regimens, increase the rate of microscopically tumor-free resection (R0) margin, and aide in identifying unfavorable tumor biology. To date, this is the largest study to examine surgical outcomes after long-duration neoadjuvant chemotherapy for PDAC. METHODS: Retrospective analysis of single-institution data. RESULTS: The routine use of long-duration therapy in our study (median cycles: FOLFIRINOX = 10; gemcitabine-based = 7) is unique. The majority (85%) of patients received FOLFIRINOX without radiation therapy; the R0 resection rate was 76%. Median OS was 41 months and did not differ significantly among patients with resectable, borderline-resectable, or locally advanced disease. CONCLUSIONS: This study demonstrates that in patients who undergo surgical resection after receipt of long-duration neoadjuvant FOLFIRINOX therapy alone, survival outcomes are similar regardless of pretreatment resectability status and that favorable surgical outcomes can be attained.

Improved survival of patients receiving immunotherapy and chemotherapy following curative-intent resection of colorectal liver metastases.

BACKGROUND: Despite significant advancements in the treatment of patients with colorectal liver metastases (CRLMs), only a minority will experience long-term survival. This study aimed to determine the effect of chemotherapy (CT) and immunotherapy (IT) compared with that of CT alone on patient survival after surgical resection. METHODS: Patients undergoing curative-intent liver resection followed by adjuvant systemic therapy for stage IV colon cancer were identified using the National Cancer Database. Patients were stratified into type of therapy (CT alone vs CT + IT) and microsatellite status. Propensity score-weighted analysis was performed through 1:1 matching based on the nearest neighbor method. RESULTS: Of 9943 patients who underwent resection of CRLMs, 7971 (80%) received systemic adjuvant therapy. Of 7971 patients, 1432 (18%) received a combination of CT and IT. Microsatellite status was not associated with overall survival (OS). Adjuvant CT + IT was associated with increased 3-year OS compared with that of CT alone in both the unmatched cohort (55% vs 48%, respectively; P < .001) and matched cohort (52% vs 48%, respectively; P = .050). On multivariate analysis, older age, positive resection margins, and KRAS mutation were independent predictors of poor survival, whereas the administration of adjuvant CT + IT was an independent predictor of improved survival. CONCLUSION: IT combined with CT was associated with improved survival compared with that of CT alone after curative-intent resection of CRLMs, regardless of microsatellite instability status. Clinical trials to determine optimal patient selection, IT regimen, and long-term efficacy to improve outcomes of patients with CRLMs are warranted.

Metastatic melanoma to small bowel: metastasectomy is supported in the era of immunotherapy and checkpoint inhibitors.

BACKGROUND: Metastatic melanoma to the small bowel is an aggressive disease often accompanied by obstruction, abdominal pain, and gastrointestinal bleeding. With advancements in melanoma treatment, the role for metastasectomy continues to evolve. Inclusion of novel immunotherapeutic agents, such as checkpoint inhibitors, into standard treatment regimens presents potential survival benefits for patients receiving metastasectomy. CASE PRESENTATION: We report an institutional experience of 15 patients (12 male, 3 female) between 2014-2022 that underwent small bowel metastasectomy for metastatic melanoma and received perioperative systemic treatment. Median age of patients was 64 years (range: 35-83 years). No patients died within 30 days of their surgery, and the median hospital length of stay was 5 days. Median overall survival in these patients was 30.1 months (range: 2-115 months). Five patients died from disease (67 days, 252 days, 426 days, 572 days, 692 days postoperatively), one patient died of non-disease related causes (1312 days postoperatively), six patients are alive with disease, and three remain disease free. CONCLUSIONS: This case series presents an updated perspective of the utility of metastasectomy for small bowel metastasis in the age of novel immunotherapeutic agents as standard systemic treatment. Small bowel metastasectomy for advanced melanoma performed in conjunction with perioperative systemic therapy is safe and appears to promote long-term survival and enhanced quality of life.

Impact of safety-net hospital burden on achievement of textbook oncologic outcomes following resection in for stage I-IV colorectal cancer.

BACKGROUND AND OBJECTIVES: Textbook oncologic outcome (TOO) is a benchmark for high-quality surgical cancer care but has not been studied at safety-net hospitals (SNH). The study sought to understand how SNH burden affects TOO achievement in colorectal cancer. METHODS: The National Cancer Database was queried for colorectal cancer patients who underwent resection for stage I-III plus stage IV with liver-only metastases (2010-2019). TOO was defined as R0 resection, AJCC-compliant lymphadenectomy (>12 nodes), no prolonged LOS, no 30-day mortality/readmission, and receipt of stage-appropriate adjuvant chemotherapy. RESULTS: Of 487,195 patients, 66.7% achieved TOO. Lower achievement was explained by adequate lymphadenectomy (87.3%), non-prolonged LOS (76.3%), and receipt of adjuvant chemotherapy in stage III (60.3%) and IV (54.1%). Treatment at high burden hospitals (HBH, >10% Medicaid/uninsured) was a predictor of non-TOO (Stage I/II: OR 0.83, III: OR 0.86, IV: OR 0.83; all p < 0.001). Achieving TOO was associated with decreased mortality (Stage I/II: HR 0.49, III: HR 0.48, IV: HR 0.57; all p < 0.001), and HBH treatment was a predictor of mortality (Stage I/II: HR 1.09, III: HR 1.05, IV: HR 1.07; all p < 0.05). CONCLUSIONS: Treatment at higher SNH burden hospitals was associated with less frequent TOO achievement and increased mortality. Quality improvement targets include receipt of adjuvant chemotherapy and avoidance of prolonged LOS.

Surgical Cancer Care in Safety-Net Hospitals: a Systematic Review.

BACKGROUND: Tertiary medical centers in the USA provide specialized, high-volume surgical cancer care, contributing standards for quality and outcomes. For the most vulnerable populations, safety-net hospitals (SNHs) remain the predominant provider of both complex and routine healthcare needs. The objective of this study was to evaluate access to and quality of surgical oncology care within SNHs. METHODS: A comprehensive and systematic review of the literature was conducted using PubMed, EMBASE, and Cochrane Library databases to identify all studies (January 2000-October 2021) reporting the delivery of surgical cancer care at SNHs in the USA (PROSPERO #CRD42021290092). These studies describe the process and/or outcomes of surgical care for gastrointestinal, hepatopancreatobiliary, or breast cancer patients seeking treatment at SNHs. RESULTS: Of 3753 records, 37 studies met the inclusion criteria. Surgical care for breast cancer (43%) was the most represented, followed by colorectal (30%) and hepatopancreatobiliary (16%) cancers. Financial constraints, cultural and language barriers, and limitations to insurance coverage were cited as common reasons for disparities in care within SNHs. Advanced disease at presentation was common among cancer patients seeking care at SNHs (range, 24-61% of patients). Though reports comparing cancer survival between SNHs and non-SNHs were few, results were mixed, underscoring the variability in care seen across SNHs. CONCLUSIONS: These findings highlight barriers in care facing many cancer patients. Continued efforts should address improving both access and quality of care for SNH patients. Future models include a transition away from a two-tiered system of resourced and under-resourced hospitals toward an integrated cancer system.

A Machine Learning Approach to Predict Postoperative Pancreatic Fistula After Pancreaticoduodenectomy Using Only Preoperatively Known Data.

BACKGROUND: Clinically-relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD) is a major postoperative complication and the primary determinant of surgical outcomes. However, the majority of current risk calculators utilize intraoperative and postoperative variables, limiting their utility in the preoperative setting. Therefore, we aimed to develop a user-friendly risk calculator to predict CR-POPF following PD using state-of-the-art machine learning (ML) algorithms and only preoperatively known variables. METHODS: Adult patients undergoing elective PD for non-metastatic pancreatic cancer were identified from the ACS-NSQIP targeted pancreatectomy dataset (2014-2019). The primary endpoint was development of CR-POPF (grade B or C). Secondary endpoints included discharge to facility, 30-day mortality, and a composite of overall and significant complications. Four models (logistic regression, neural network, random forest, and XGBoost) were trained, validated and a user-friendly risk calculator was then developed. RESULTS: Of the 8666 patients who underwent elective PD, 13% (n = 1160) developed CR-POPF. XGBoost was the best performing model (AUC = 0.72), and the top five preoperative variables associated with CR-POPF were non-adenocarcinoma histology, lack of neoadjuvant chemotherapy, pancreatic duct size less than 3 mm, higher BMI, and higher preoperative serum creatinine. Model performance for 30-day mortality, discharge to a facility, and overall and significant complications ranged from AUC 0.62-0.78. CONCLUSIONS: In this study, we developed and validated an ML model using only preoperatively known variables to predict CR-POPF following PD. The risk calculator can be used in the preoperative setting to inform clinical decision-making and patient counseling.

Non-Canonical Activin A Signaling Stimulates Context-Dependent and Cellular-Specific Outcomes in CRC to Promote Tumor Cell Migration and Immune Tolerance.

We have shown that activin A (activin), a TGF-ß superfamily member, has pro-metastatic effects in colorectal cancer (CRC). In lung cancer, activin activates pro-metastatic pathways to enhance tumor cell survival and migration while augmenting CD4+ to CD8+ communications to promote cytotoxicity. Here, we hypothesized that activin exerts cell-specific effects in the tumor microenvironment (TME) of CRC to promote anti-tumoral activity of immune cells and the pro-metastatic behavior of tumor cells in a cell-specific and context-dependent manner. We generated an Smad4 epithelial cell specific knockout (Smad4-/-) which was crossed with TS4-Cre mice to identify SMAD-specific changes in CRC. We also performed IHC and digital spatial profiling (DSP) of tissue microarrays (TMAs) obtained from 1055 stage II and III CRC patients in the QUASAR 2 clinical trial. We transfected the CRC cells to reduce their activin production and injected them into mice with intermittent tumor measurements to determine how cancer-derived activin alters tumor growth in vivo. In vivo, Smad4-/- mice displayed elevated colonic activin and pAKT expression and increased mortality. IHC analysis of the TMA samples revealed increased activin was required for TGF-ß-associated improved outcomes in CRC. DSP analysis identified that activin co-localization in the stroma was coupled with increases in T-cell exhaustion markers, activation markers of antigen presenting cells (APCs), and effectors of the PI3K/AKT pathway. Activin-stimulated PI3K-dependent CRC transwell migration, and the in vivo loss of activin lead to smaller CRC tumors. Taken together, activin is a targetable, highly context-dependent molecule with effects on CRC growth, migration, and TME immune plasticity.

National Practice Patterns in Malignant Peritoneal Mesothelioma: Updates in Management and Survival.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare malignancy with a historically poor prognosis. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as an effective therapy for patients with peritoneal malignancies. A contemporary analysis of trends in management of and survival from MPM is warranted. METHODS: Patients with MPM were identified from the National Cancer Database (2004-2018). Patients were categorized by treatment (CRS-HIPEC, CRS-chemotherapy, CRS only, chemotherapy only, no treatment), and joinpoint regression was employed to compute the annual percent change (APC) in treatment over time. Multivariable Cox proportional hazards models were used to analyze factors associated with survival. RESULTS: Of 2683 patients with MPM, 19.1% underwent CRS-HIPEC, and 21.1% received no treatment. Joinpoint regression revealed a statistically significant increase in the proportion of patients undergoing CRS-HIPEC over time (APC 3.21, p = 0.01), and a concurrent decrease in the proportion of patients who underwent no treatment (APC - 2.21, p = 0.02). Median overall survival was 19.5 months. Factors independently associated with survival included CRS-HIPEC, CRS, histology, sex, age, race, Charlson Comorbidity Index, insurance, and hospital type. Although there was a strong association between year of diagnosis and survival on univariate analysis (2016-2018 HR 0.67, p < 0.001), this association was attenuated after adjustment for treatment. CONCLUSIONS: CRS-HIPEC is increasingly employed as a treatment for MPM. In parallel, there has been a decrease in patients receiving no treatment with an increase in overall survival. These findings suggest that patients with MPM may be receiving more appropriate therapy; however, a substantial proportion of patients may remain undertreated.

It is not necessary to resect all mucinous cystic neoplasms of the pancreas: current guidelines do not reflect the actual risk of malignancy.

BACKGROUND: Mucinous Cystic Neoplasms (MCN) of the pancreas are premalignant cysts for which current guidelines support pancreatic resection. The primary aim of this systematic review and meta-analysis is to define the pooled rate of malignancy for MCN. METHODS: A systematic review of eligible studies published between 2000 and 2021 was performed on PubMed and Embase. Primary outcome was rate of malignancy. Data regarding high-risk features, including cyst size and mural nodules, were collected and analyzed. RESULTS: A total of 40 studies and 3292 patients with resected MCN were included in the final analysis. The pooled rate of malignancy was 16.1% (95%CI 13.1-19.0). The rate of malignant MCN in studies published before 2012 was significantly higher than that of studies published after recent guidelines were published (21.0% vs 14.9%, p < 0.001). Malignant MCN were larger than benign (mean difference 25.9 mm 95%CI 14.50-37.43, p < 0.001) with a direct correlation between size and presence of malignant MCN (R2 = 0.28, p = 0.020). A SROC identified a threshold of 65 mm to be associated with the diagnosis of malignant MCN. Presence of mural nodules was associated with the diagnosis of a malignant MCN (OR = 4.34, 95%CI 3.00-6.29, p < 0.001). CONCLUSION: Whereas guidelines recommend resection of all MCN, the rate of malignancy in resected MCN is 16%, implying that surveillance has a role in most cases, and that surgical selection criteria are warranted. Size and presence of mural nodules are significantly associated with an increased risk of malignant degeneration, small MCN and without mural nodules can be considered for surveillance.

Drain Placement After Pancreatic Resection: Friend or Foe For Surgical Site Infections?

BACKGROUND: Despite multiple studies and randomized trials, there remains controversy over whether drains should be placed, and if so for how long, after pancreas resection. The aim was to determine if post-pancreatectomy drain placement and timing of drain removal were associated with differences in infectious outcomes and, if so, which specific procedures and infectious sites were most at risk. METHODS: The ACS-NSQIP targeted pancreatectomy database was utilized to identify patients who underwent pancreatectomies between 2015 and 2020 with postoperative drain placement for retrospective cohort analysis. A propensity score matching analyses was conducted to determine associations between drain placement and surgical site infections (SSI). RESULTS: Of 39,057 pancreatic resections, 66.4% were proximal pancreatectomies, and 33.6% were distal pancreatectomies. After propensity score matching, drain placement was not associated with significantly lower rates of superficial SSI (7% vs 9%, p = 0.755) or organ/space SSI (17% vs 16%, p = 0.647) after proximal pancreatectomy. After distal pancreatectomy, drain placement was associated with higher rates of organ/space SSI (12% vs 9%, p = 0.010). Drain removal on or after postoperative day 3 was significantly associated with higher rates of SSI in both proximal and distal pancreatectomy. CONCLUSIONS: Drain placement is associated with an increased rate of organ/space SSI after distal pancreatectomy and not after pancreaticoduodenectomy. When drains are utilized, early removal is associated with a reduction of SSI after all types of pancreatectomy. In surgical units where post-pancreatectomy SSI is a concern, selective drain placement for high-risk glands or after distal pancreatectomy, combined with early drain removal, may be considered.