The Financial Implications of Pancreatic Surgery: The Hospital Is the Big Winner, Not the Surgeon!

Background: High-volume pancreatic surgery centers require a significant investment in expertise, time, and resources to achieve optimal patient outcomes. A detailed understanding of the economics of major pancreatic surgery is limited among many clinicians and hospital administrators. A greater consideration of these financial aspects may in fact have implications for enhancing clinical care and for a broader sustainability of high-volume pancreatic surgery programs. Methods: In this retrospective observational study, patients who underwent pancreaticoduodenectomy (PD), total pancreatectomy, or distal pancreatectomy at one academic medical center during the fiscal year 2021 were evaluated. Detailed hospital charges and professional fees were obtained for patients using the Qlik perioperative database. Clinical data for the study cohort were gathered from a prospectively maintained, IRB-approved pancreatic surgery database. Charges for the 91-day perioperative period were included. A P < 0.05 was considered significant. Results: During the study period, 159 evaluable patients underwent 1 of 3 designated pancreatic resections included in the analysis. Ninety-seven patients (61%) were diagnosed with adenocarcinoma and 70% (n = 110) underwent PD. The total charges (combined professional and hospital charges) for the cohort encompassing the entire perioperative period were $20,661,759. The median charge per patient was $130,306 (interquartile range [IQR], $34,534). The median direct cost of care was $23,219 (IQR, $6321) and the median contribution margin per case was $10,092 (IQR, $22,949). The median surgeon professional fee charges were $7700 per patient (IQR, $1296) as compared to $3453 (IQR, $1,144) for professional fee receipts (45% of the surgeon charge). The differences between the professional fee charges and receipts per patient were also considerable for other health care professionals such as anesthesiologists ($4945 charges vs $1406 receipts [28%]) and pathologists ($3035 charges vs $680 receipts [22%]). The surgeon professional fees were only 6% of the total charges, while the professional fees for anesthesiology and pathology were 4% and 2% of the total charges, respectively. Supply charges were 3% of the total charges. Longer operative time was correlated with increased hospital and anesthesia charges, without a significant increase in surgeon charges (P < 0.001, P < 0.001, and P = 0.2, respectively). Male sex, diabetes, and low serum albumin correlated with greater total hospital charges (P = 0.01, P = 0.01, and P = 0.03, respectively). Conclusions: The role of the surgeon in the perioperative clinical care of major pancreatic resection patients is crucial and important and is by no means limited to the operative day. Nevertheless, in the context of the current US health care system, the reimbursement to the surgeon in the form of professional fees is a relatively small fraction of the total health care receipts for these patients. This imbalance necessitates a substantial financial partnership between hospitals and their pancreatic surgery units to ensure the long-term viability of these programs.

Major Pancreatic Resection Increases Bone Mineral Density Loss, Osteoporosis, and Fractures.

OBJECTIVE: To assess whether long-term survivors of pancreatic surgery show increased risk to develop impaired bone mineral density, osteoporosis, and vitamin D deficiency. BACKGROUND: Pancreatic resection poses a risk for malabsorption of fat-soluble vitamins and other micronutrients essential for bone mineralization. Here, we evaluated the long-term effects of pancreatic resection on bone mineral density (BMD) and its clinical sequelae. METHODS: This was a two-pronged analysis of post-pancreatectomy patients with a follow-up period greater than 3 years comprising (1) a large, propensity score-matched, cohort study based on a multinational federated research network (FRN) and (2) a retrospective single institution review of clinical and radiographic patient data. In the FRN analysis, an initial cohort of 8,423 post-pancreatectomy patients were identified and propensity score-matched with normal controls. The primary endpoint was the 10-year risk of developing osteoporotic pathological fractures and secondary endpoints included diagnosis of osteoporosis, vitamin-D deficiency, and related therapies. The single institution retrospective analysis identified 224 patients who underwent pancreatic resection between 2005 and 2019. BMD was quantified in CT images acquired before and after surgery. BMD trends and related factors were assessed in a time-series mixed effect linear regression model. RESULTS: A total of 8,080 propensity score-matched pairs were included in the FRN analysis. The analysis revealed a 2.4-fold increase in pathological fractures (P<0.0001) and 1.4-1.5 fold increase in osteoporosis/osteomalacia (P<0.0001) and vitamin-D deficiency (P<0.0001) in post-pancreatectomy patients. Vitamin-D supplements were more common in the pancreatectomy group (OR 1.4, 95% CI 1.28-1.53, P<0.0001), as were specific osteoporosis/osteomalacia treatments such as calcitonin, denosumab, romosozumab, abaloparatide, and teriparatide (OR 2.24, 95%CI 1.69-2.95, P<0.0001). Retrospective analysis of CT imaging revealed that BMD declined more rapidly following pancreatic resection compared to normal historical controls (P=0.015). Older age, pancreatic cancer, and pancreaticoduodenectomy were associated with increased rates of BMD loss (P<0.05, each). CONCLUSIONS: After pancreatic resection, patients are at higher risk for BMD loss and subsequent fractures. As the cohort of pancreatic resection survivorship grows, attention will need to be paid to focused prevention efforts to reduce BMD loss, osteoporosis, and fractures in these vulnerable patients, with specific attention to the pancreatic cancer population.

Hemorrhage Sites and Mitigation Strategies After Pancreaticoduodenectomy.

Importance: Postpancreatectomy hemorrhage is an uncommon but highly morbid complication of pancreaticoduodenectomy. Clinical evidence often draws suspicion to the gastroduodenal artery stump, even without a clear source. Objective: To determine the frequency of gastroduodenal artery bleeding compared to other sites and the results of mitigation strategies. Design, Setting, and Participants: This cohort study involved a retrospective analysis of data for consecutive patients who had pancreaticoduodenectomy from 2011 to 2021 at Memorial Sloan Kettering Cancer Center (MSK) and Thomas Jefferson University Hospital (TJUH). Exposures: Demographic, perioperative, and disease-related variables. Main Outcomes and Measures: The incidence, location, treatment, and outcomes of primary (initial) and secondary (recurrent) hemorrhage requiring invasive intervention were analyzed. Imaging studies were re-reviewed by interventional radiologists to confirm sites. Results: Inclusion criteria were met by 3040 patients (n = 1761 MSK, n = 1279 TJUH). Patients from both institutions were similar in age (median [IQR] age at MSK, 67 [59-74] years, and at TJUH, 68 [60-75] years) and sex (at MSK, 814 female [46.5%] and 947 male [53.8%], and at TJUH, 623 [48.7%] and 623 male [51.3%]). Primary hemorrhage occurred in 90 patients (3.0%), of which the gastroduodenal artery was the source in 15 (16.7%), unidentified sites in 24 (26.7%), and non-gastroduodenal artery sites in 51 (56.7%). Secondary hemorrhage occurred in 23 patients; in 4 (17.4%), the gastroduodenal artery was the source. Of all hemorrhage events (n = 117), the gastroduodenal artery was the source in 19 (16.2%, 0.63% incidence in all pancreaticoduodenectomies). Gastroduodenal artery hemorrhage was more often associated with soft gland texture (14 [93.3%] vs 41 [62.1%]; P = .02) and later presentation (median [IQR], 21 [15-26] vs 10 days [5-18]; P = .002). Twenty-three patients underwent empirical gastroduodenal artery embolization or stent placement, 7 (30.4%) of whom subsequently experienced secondary hemorrhage. Twenty percent of all gastroduodenal artery embolizations/stents (8/40 patients), including 13% (3/13 patients) of empirical treatments, were associated with significant morbidity (7 hepatic infarction, 4 biliary stricture), with a 90-day mortality rate of 38.5% (n = 5) for patients with these complications vs 7.8% without (n = 6; P = .008). Ninety-day mortality was 12.2% (n = 11) for patients with hemorrhage (3 patients [20%] with primary gastroduodenal vs 8 [10.7%] for all others; P = .38) compared with 2% (n = 59) for patients without hemorrhage. Conclusions and Relevance: In this study, postpancreatectomy hemorrhage was uncommon and the spectrum was broad, with the gastroduodenal artery responsible for a minority of bleeding events. Empirical gastroduodenal artery embolization/stent without obvious sequelae of recent hemorrhage was associated with significant morbidity and rebleeding and should not be routine practice. Successful treatment of postpancreatectomy hemorrhage requires careful assessment of all potential sources, even after gastroduodenal artery mitigation.

The Clinical Implications of KRAS Mutations and Variant Allele Frequencies in Pancreatic Ductal Adenocarcinoma.

The KRAS proto-oncogene is a major driver of pancreatic tumorigenesis and is nearly ubiquitously mutated in pancreatic ductal adenocarcinoma (PDAC). KRAS point mutations are detected in over 90% of PDAC cases, and these mutations have been shown to be associated with worse therapy response and overall survival. Pathogenic KRAS mutations are mostly limited to codons 12, 13 and 61, with G12D, G12V, G12R, Q61H, and G13D accounting for approximately 95% of the mutant cases. Emerging data have shown the importance of specific mutant subtypes, as well as KRAS variant allele frequency on clinical prognosis. Furthermore, novel technologies and therapies are being developed to target specific mutant subtypes, with encouraging early results. In this paper, we aim to review the recent studies regarding the relative impact of specific mutant KRAS subtypes on oncologic outcomes, the application of variant allele frequency in next generation sequencing analyses, and the ongoing research into therapies targeting specific mutant KRAS subtypes.

Peripancreatic fluid collections following distal pancreatectomy and splenectomy-when is intervention warranted?

BACKGROUND: Peripancreatic fluid collections after distal pancreatectomy and splenectomy are commonly identified on postoperative cross-sectional imaging. This study aimed to determine the incidence, natural history, and indications for intervention. METHODS: We conducted a retrospective review of patients with peripancreatic fluid collections after distal pancreatectomy with or without splenectomy between 2013 and 2018, approved by our institutional review board. The chi-square test was used for categorical variables, the Mann-Whitney U test for continuous variables, and Fisher's exact test was used for values in which the sample size was less than 5 to compare data. RESULTS: During the study period, 235 patients underwent distal pancreatectomy with or without splenectomy, and 182 patients with postoperative imaging were included. In the cohort of patients with postoperative imaging, 83 (46%) had peripancreatic fluid collections, of which 46 (55%) were symptomatic fluid collections (SFCs) and 37 (45%) were asymptomatic fluid collections (AFCs). Those with SFC had a higher incidence of postoperative morbidity (46% vs 8%; P = .0002), most commonly postoperative pancreatic fistula (90%). Of patients with SFC, 34 (74%) underwent treatment via percutaneous drainage (n = 26), endoscopic drainage (n = 7), or antibiotics alone (n = 1). AFCs (n = 37) were observed. Collections that were intervened upon resolved significantly faster than those observed, 3.5 months vs 13.2 months (P < .0001), respectively. CONCLUSION: Asymptomatic patients may be observed with or without serial imaging and the AFC will typically resolve spontaneously with time. Patients who develop symptoms should generally be intervened upon with drainage if deemed feasible, given that this reduces the time to resolution.

Impact of antecolic vs transmesocolic reconstruction on delayed gastric emptying following pancreaticoduodenectomy.

BACKGROUND: Delayed gastric emptying (DGE) is a common complication after pancreaticoduodenectomy. There remains an active debate over the effect of gastrointestinal (GI) reconstruction techniques, such as antecolic (AC) or transmesocolic (TMC) reconstruction, on DGE rates. This study compared the rates of DGE between AC reconstruction and TMC reconstruction after pylorus-preserving pancreaticoduodenectomy (PPPD) and classic pancreaticoduodenectomy (PD). METHODS: This was a retrospective analysis of a prospectively maintained pancreatic surgery database in a single, high-volume center. Demographic, perioperative, and surgical outcome data were recorded from patients who underwent a PD or PPPD between 2013 and 2021. DGE grades were classified using the International Study Group of Pancreatic Surgeons (ISGPS) criteria. Postoperatively, all patients were managed using an accelerated Whipple recovery protocol. RESULTS: A total of 824 patients were assessed, with 303 patients undergoing AC reconstruction and 521 patients undergoing TMC reconstruction. The risk of DGE was significantly greater in patients who received an AC reconstruction than in patients who received a TMC reconstruction (odds ratio [OR], 1.51; 95% CI, 1.07-2.15; P < .05). In addition, AC reconstruction was shown to have a greater incidence of severe DGE (ISGPS grades B or C) than TMC reconstruction, with approximately a 2-fold increase in severe DGE (OR, 1.94; 95% CI, 1.10-3.45; P < .05). Logistic regression and propensity score matching have found increased DGE incidence with AC reconstruction (OR: 1.69 and 1.73, respectively; P < .05). CONCLUSIONS: Although the correlation between GI reconstruction methods and DGE remains a subject of ongoing debate, our study indicated that TMC reconstruction may be superior to AC reconstruction in minimizing the development and severity of DGE for patients after PD.

Association of Mutant KRAS Alleles With Morphology and Clinical Outcomes in Pancreatic Ductal Adenocarcinoma.

CONTEXT.­: Mutant KRAS is the main oncogenic driver in pancreatic ductal adenocarcinomas (PDACs). However, the clinical and phenotypic implications of harboring different mutant KRAS alleles remain poorly understood. OBJECTIVE.­: To characterize the potential morphologic and clinical outcome differences in PDACs harboring distinct mutant KRAS alleles. DESIGN.­: Cohort 1 consisted of 127 primary conventional PDACs with no neoadjuvant therapy, excluding colloid/mucinous, adenosquamous, undifferentiated, and intraductal papillary mucinous neoplasm-associated carcinomas, for which an in-house 42-gene mutational panel had been performed. A morphologic classification system was devised wherein each tumor was assigned as conventional, papillary/large duct (P+LD, defined as neoplastic glands with papillary structure and/or with length ≥0.5 mm), or poorly differentiated (when the aforementioned component was 60% or more of the tumor). Cohort 2 was a cohort of 88 PDACs in The Cancer Genome Atlas, which were similarly analyzed. RESULTS.­: In both cohorts, there was significant enrichment of P+LD morphology in PDACs with KRAS G12V and G12R compared with G12D. In the entire combined cohort, Kaplan-Meier analyses showed longer overall survival (OS) with KRAS G12R as compared with G12D (median OS of 1255 versus 682 days, P = .03) and in patients whose PDACs displayed P+LD morphology as compared with conventional morphology (median OS of 1175 versus 684 days, P = .04). In the adjuvant-only subset, KRAS G12R had the longest OS compared with G12D, G12V, and other alleles (median OS unreached/undefined versus 1009, 1129, and 1222 days, respectively). CONCLUSIONS.­: PDACs with different mutant KRAS alleles are associated with distinct morphologies and clinical outcomes, with KRAS G12R allele associated with P+LD morphology and longer OS when compared with G12D using Kaplan-Meier studies.

Contemporary report of surgical outcomes after single-stage total pancreatectomy: A 10-year experience.

BACKGROUND: Surgeons rarely perform elective total pancreatectomy (TP). Our study seeks to report surgical outcomes in a contemporary series of single-stage (SS) TP patients. METHODS: Between the years 2013 to 2023 we conducted a retrospective review of 60 consecutive patients who underwent SSTP. Demographics, pathology, treatment-related variables, and survival were recorded and analyzed. RESULTS: SSTP consisted of 3% (60/1859) of elective pancreas resections conducted. Patient median age was 68 years. Ninety percent of these patients (n = 54) underwent SSTP for pancreatic ductal adenocarcinoma (PDAC). Conversion from a planned partial pancreatectomy to TP occurred intraoperatively in 31 (52%) patients. Fifty-nine patients (98%) underwent an R0 resection. Median length of hospital stay was 6 days. The majority of morbidities were minor, with 27% patients (n = 16) developing severe complications (Clavien-Dindo ≥3). Thirty and ninety-day mortality rates were 1.67% (one patient) and 5% (three patients), respectively. Median survival for the entire cohort was 24.4 months; 22.7 months for PDAC patients, with 1-, 3-, and 5-year survival of 68%, 43%, and 16%, respectively. No mortality occurred in non-PDAC patients (n = 6). CONCLUSION: Elective single-stage total pancreatectomy can be a safe and appropriate treatment option. SSTP should be in the armamentarium of surgeons performing pancreatic resection.

International Expert Consensus on Defining Textbook Oncologic Outcomes in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastasis.

BACKGROUND: Textbook oncologic outcome (TOO) is a composite metric shown to correlate with improved survival after curative intent oncologic procedures. Despite increasing use among disciplines in surgical oncology, no consensus exists for its definition in cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). STUDY DESIGN: An international consensus-based study employed a Delphi methodology to achieve agreement. Fifty-four senior surgeons from the peritoneal surface malignancies field received a questionnaire comprising TOO parameters divided into 3 surgical domains: operative, short-term, and long-term postoperative outcomes. Two online meetings with participants defined the new criteria. Consensus was achieved when 75% of agreement rate was reached. Clinical data of patients who underwent CRS and HIPEC for colorectal peritoneal metastasis between 2010 and 2022 from 1 designated center (Sheba Medical Center) were collected, the consensus definition applied and outcomes analyzed. RESULTS: Thirty-eight surgeons (70%) participated. Expert consensus TOO parameters for colorectal peritoneal metastasis CRS and HIPEC included the absence of unplanned reoperations during 30 days postoperation, absence of severe postoperative complications (Clavien-Dindo ≥III), absence of unplanned readmissions during 30 days postoperation, 90-day postoperative mortality, and absence of contraindications for chemotherapy within 12 weeks from operation, and included the achievement of complete cytoreduction (CC0). The study cohort consisted of 251 patients, and 151 (60%) met TOO criteria. Patients who achieved TOO had significantly better overall survival (median 67.5 months, 95% CI) vs patients who did not achieve TOO (median 44.6 months, 95% CI, p < 0.001) and significantly improved disease-free survival (median, 12 months, 95% CI, vs 9 months, 95% CI, p = 0.01). CONCLUSIONS: Achievement of TOO as defined by consensus statement is associated with improved survival.

Repurposing the FDA-approved anthelmintic pyrvinium pamoate for pancreatic cancer treatment: study protocol for a phase I clinical trial in early-stage pancreatic ductal adenocarcinoma.

BACKGROUND: Recent reports of the utilisation of pyrvinium pamoate (PP), an FDA-approved anti-helminth, have shown that it inhibits pancreatic ductal adenocarcinoma (PDAC) cell growth and proliferation in-vitro and in-vivo in preclinical models. Here, we report about an ongoing phase I open-label, single-arm, dose escalation clinical trial to determine the safety and tolerability of PP in PDAC surgical candidates. METHODS AND ANALYSIS: In a 3+3 dose design, PP is initiated 3 days prior to surgery. The first three patients will be treated with the initial dose of PP at 5 mg/kg orally for 3 days prior to surgery. Dose doubling will be continued to a reach a maximum of 20 mg/kg orally for 3 days, if the previous two dosages (5 mg/kg and 10 mg/kg) were tolerated. Dose-limiting toxicity grade≥3 is used as the primary endpoint. The pharmacokinetic and pharmacodynamic (PK/PD) profile of PP and bioavailability in humans will be used as the secondary objective. Each participant will be monitored weekly for a total of 30 days from the final dose of PP for any side effects. The purpose of this clinical trial is to examine whether PP is safe and tolerable in patients with pancreatic cancer, as well as assess the drug's PK/PD profile in plasma and fatty tissue. Potential implications include the utilisation of PP in a synergistic manner with chemotherapeutics for the treatment of pancreatic cancer. ETHICS AND DISSEMINATION: This study was approved by the Thomas Jefferson Institutional Review Board. The protocol number for this study is 20F.041 (Version 3.1 as of 27 October 2021). The data collected and analysed from this study will be used to present at local and national conferences, as well as, written into peer-reviewed manuscript publications. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05055323.

Association of Smoking and Respiratory Disease History with Pancreatic Pathologies Requiring Surgical Resection.

BACKGROUND: The purpose of this study was to examine the relationship between various respiratory conditions, including hypercapnic respiratory disease, and a multitude of resected pancreatic lesions. METHODS: This retrospective case-control study queried a prospectively maintained database of patients who underwent pancreaticoduodenectomy between January 2015 and October 2021. Patient data, including smoking history, medical history, and pathology reports, were recorded. Patients with no smoking history and no concomitant respiratory conditions were designated as the control group. RESULTS: A total of 723 patients with complete clinical and pathological data were identified. Male current smokers showed increased rates of PDAC (OR 2.33, 95% CI 1.07-5.08, p = 0.039). Male patients with COPD had a markedly increased association with IPMN (OR 3.02, CI 1.08-8.41, p = 0.039), while females with obstructive sleep apnea had a four-fold increase in risk of IPMN compared to women in the control group (OR 3.89, CI 1.46-10.37, p = 0.009). Surprisingly, female patients with asthma had a decreased incidence of pancreatic and periampullary adenocarcinoma (OR 0.36, 95% CI 0.18-0.71. p < 0.01). CONCLUSION: This large cohort study reveals possible links between respiratory pathologies and various pancreatic mass-forming lesions.

Chronic Obstructive Pulmonary Disease Is Associated with Worse Oncologic Outcomes in Early-Stage Resected Pancreatic and Periampullary Cancers.

Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer mortality in the United States. Hypoxic and hypercapnic tumor microenvironments have been suggested to promote tumor aggressiveness. The objective of this study was to evaluate the association between chronic obstructive pulmonary disease (COPD) and oncologic survival outcomes in patients with early-stage PDAC and periampullary cancers. In this case-control study, patients who underwent a pancreaticoduodenectomy during 2014-2021 were assessed. Demographic, perioperative, histologic, and oncologic data were collected. A total of 503 PDAC and periampullary adenocarcinoma patients were identified, 257 males and 246 females, with a mean age of 68.1 (±9.8) years and a mean pre-operative BMI of 26.6 (±4.7) kg/m2. Fifty-two percent of patients (N = 262) reported a history of smoking. A total of 42 patients (8.3%) had COPD. The average resected tumor size was 2.9 ± 1.4 cm and 65% of the specimens (N = 329) were positive for lymph-node involvement. Kaplan-Meier analysis showed that COPD was associated with worse overall and disease-specific survival (p < 0.05). Cox regression analysis showed COPD to be an independent prognostic factor (HR = 1.5, 95% CI 1.0-2.3, p = 0.039) along with margin status, lymphovascular invasion, and perineural invasion (p < 0.05 each). A 1:3 nearest neighbor propensity score matching was also employed and revealed COPD to be an independent risk factor for overall and disease-specific survival (OR 1.8 and OR 1.6, respectively; p < 0.05 each). These findings may support the rationale posed by in vitro laboratory studies, suggesting an important impact of hypoxic and hypercapnic tumor respiratory microenvironments in promoting therapy resistance in cancer.

Neutrophil to Lymphocyte Ratio in Patients Who Received Neoadjuvant Treatment before Gastrectomy.

BACKGROUND: The neutrophil to lymphocyte ratio (NLR) has demonstrated prognostic value in various malignant conditions, including gastric adenocarcinoma. However, chemotherapy may affect NLR. OBJECTIVES: To evaluate the prognostic value of NLR as an accessory decision-making tool in terms of operating patients after neoadjuvant chemotherapy in patients with resectable gastric cancer. METHODS: We collected oncologic, perioperative, and survival data of patients with gastric adenocarcinoma who underwent curative intent gastrectomy and D2 lymphadenectomy between 2009 and 2016. The NLR was calculated from preoperative laboratory tests and classified as high (> 4) and low (≤ 4). The t-test, chi-square, Kaplan-Meier analysis, and Cox multivariate regression models were used to assess associations of clinical, histologic, and hematological variables with survival. RESULTS: For 124 patients the median follow-up was 23 months (range 1-88). High NLR was associated with greater rate of local complication (r=0.268, P < 0.01). The rate of major complications (Clavien-Dindo ≥ 3) was higher in the high NLR group (28% vs. 9%, P = 0.022). Among the 53 patients who received neoadjuvant chemotherapy, those with low NLR had significantly improved disease-free survival (DFS) (49.7 vs. 27.7 months, P = 0.025). Low NLR was not significantly associated with overall survival (mean survival, 51.2 vs. 42.3 months, P = 0.19). Multivariate regression identified NLR group (P = 0.013), male gender (P = 0.04), and body mass index (P = 0.026) as independently associated with DFS. CONCLUSIONS: Among gastric cancer patients planned for curative intent surgery who underwent neoadjuvant chemotherapy, NLR may have prognostic value, particularly regarding DFS and postoperative complications.

Salvage endoscopic ultrasound-guided gastrojejunostomy as a bridge to definitive surgical therapy for duodenal adenocarcinoma presenting with duodenal stent obstruction.

The utilization of endoscopic ultrasound-guided gastrojejunostomy (EUS-GJ) in the setting of an obstructed (ingrown) duodenal stent as a bridge to pancreaticoduodenectomy (PD) remains undescribed. Herein, we report a case study of a 51-year-old patient who underwent EUS-GJ using lumen apposing metal stent (LAMS) for an obstructed duodenal stent during neoadjuvant treatment for duodenal adenocarcinoma. The patient ultimately underwent surgical resection by a classic PD 14 weeks after LAMS placement. EUS-GJ using LAMS represents a potential option as a salvage bridge to surgery for duodenal obstruction in the setting of an obstructed duodenal stent.

Implementation of an opioid reduction toolkit in pancreatectomy patients significantly increases patient awareness of safe practice and decreases amount prescribed and consumed.

BACKGROUND: Postoperative opioid abuse following surgery is a major concern. This study sought to create an opioid reduction toolkit to reduce the number of narcotics prescribed and consumed while increasing awareness of safe disposal in pancreatectomy patients. METHODS: Prescription, consumption, and refill request data for postoperative opioids were collected from patients receiving an open pancreatectomy before and after the implementation of an opioid reduction toolkit. Outcomes included safe disposal practice awareness for unused medication. RESULTS: 159 patients were included in the study: 24 in the pre-intervention and 135 in the post-intervention group. No significant demographic or clinical differences existed between groups. Median morphine milliequivalents (MMEs) prescribed were significantly reduced from 225 (225-310) to 75 (75-113) in the post-intervention group (p < 0.0001). Median MMEs consumed were significantly reduced from 109 (111-207) to 15 (0-75), p < 0.0001), as well. Refill request rates remained equivalent during the study (Pre: 17% v Post: 13%, p = 0.9) while patient awareness of safe disposal increased (Pre: 25% v Post: 62%, p < 0.0001). DISCUSSION: An opioid reduction toolkit significantly reduced the number of postoperative opioids prescribed and consumed after open pancreatectomy, while refill request rates remained the same and patients' awareness of safe disposal increased.

A Novel 3DNA® Nanocarrier effectively delivers payloads to pancreatic tumors.

INTRODUCTION: Standard-of-care systemic chemotherapies for pancreatic ductal adenocarcinoma (PDAC) currently have limited clinical benefits, in addition to causing adverse side effects in many patients. One factor known to contribute to the poor chemotherapy response is the poor drug diffusion into PDAC tumors. Novel treatment methods are therefore drastically needed to improve targeted delivery of treatments. Here, we evaluated the efficacy of the 3DNA® Nanocarrier (3DNA) platform to direct delivery of therapeutics to PDAC tumors in vivo. MATERIALS AND METHODS: A panel of PDAC cell lines and a patient tissue microarray were screened for established tumor-specific proteins to identify targeting moieties for active targeting of the 3DNA. NRG mice with or without orthotopic MIA PaCa-2-luciferase PDAC tumors were treated intraperitoneally with 100 µl of fluorescently labeled 3DNA. RESULTS: Folic acid and transferrin receptors were significantly elevated in PDAC compared to normal pancreas. Accordingly, both folic acid- and transferrin-conjugated 3DNA treatments significantly increased delivery of 3DNA specifically to tumors in comparison to unconjugated 3DNA treatment. In the absence of tumors, there was an increased clearance of both folic acid-conjugated 3DNA and unconjugated 3DNA, compared to the clearance rate in tumor-bearing mice. Lastly, delivery of siLuciferase by folic acid-conjugated 3DNA in an orthotopic model of luciferase-expressing PDAC showed significant and prolonged suppression of luciferase protein expression and activity. CONCLUSION: Our study progresses the 3DNA technology as a reliable and effective treatment delivery platform for targeted therapeutic approaches in PDAC.

A rare metastatic mesenteric malignant PEComa with TSC2 mutation treated with palliative surgical resection and nab-sirolimus: a case report.

BACKGROUND: Malignant perivascular epithelioid cell tumors (PEComas) are exceedingly rare malignant mesenchymal neoplasms with characteristic morphological and immunohistochemical (IHC) patterns. However, some malignant PEComas are poorly differentiated with atypical histopathological features, making a definitive diagnosis difficult. PEComas are most commonly found in females and often show either TSC1 or TSC2 alterations, which result in the activation of the mTOR pathway, or TFE3 fusions. Given these molecular characteristics, mTOR inhibitors have recently been approved by the FDA in the treatment of malignant PEComas, particularly in those with TSC1/2 alterations. Therefore, molecular analyses may be helpful for both the diagnostic workup of and predicting response to mTOR inhibitors in cases of malignant PEComas. CASE PRESENTATION: Here, we report a case of an aggressive, 23 cm mesenteric malignant PEComa with multiple peritoneal metastases in a young male patient. Pathological examination of the initial biopsy showed a malignant epithelioid neoplasm with high-grade morphology and atypical immunoprofile, which precluded a definitive diagnosis. Because of the patient's excessive transfusion requirements due to intra-tumoral hemorrhage, a palliative R2 resection was performed. Histopathological examination of the tumor revealed focal immunoreactivity for Melan-A, HMB-45, desmin, and CD117. Although a diagnosis of malignant PEComa was favored, other entities such as epithelioid gastrointestinal stromal tumor (GIST) or melanoma could not be definitively ruled out. Given the favored diagnosis, the patient was started on sirolimus, an mTOR inhibitor, rather than chemotherapy. Molecular analyses were performed and the tumor was found to harbor mutations in TP53 and TSC2, supporting a definitive diagnosis of malignant PEComa. The patient was then switched to nab-sirolimus, with initial stabilization of the disease. CONCLUSIONS: This report details a multidisciplinary approach for the diagnosis and management of a highly aggressive, metastatic malignant PEComa in a young male patient. The basis for the treatment of malignant PEComas with the recently FDA-approved mTOR inhibitor, nab-sirolimus, is also reviewed. In summary, this case highlights the importance of molecular analysis, particularly TSC1/2 alterations, for both the definitive diagnosis of malignant PEComas and predicting their response to nab-sirolimus.

Hypercapnic Tissue Gene Expression and Survival in Early-Stage Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer. Hypercapnic tumor microenvironments were previously shown to promote cancer chemoresistance. In this study, we aimed to investigate the impact of tissue hypercapnia on PDAC prognosis. STUDY DESIGN: PDAC cancer-cell lines were cultured in normocapnic (5% CO 2 ) and hypercapnic conditions (10% CO 2 ). RNA was extracted, and whole-exome transcriptome was sequenced. Differentially expressed genes were identified and used to construct a "hypercapnic gene set." PDAC transcriptomic patient data from the Tumor Cancer Genome Atlas was used to calculate single-sample gene set enrichment scores based on each patient's tissue expression of the hypercapnic gene set. Tissue hypercapnic scores (HSs) in PDAC patients (TMN stages Ia-IIb) were determined and correlated with clinicopathological parameters and overall survival. RESULTS: A cohort of 135 resected stage I-II PDAC patients were assessed in this study. The average age was 65 ± 11.0 years, and the male:female ratio was 74:61. Median overall survival was 19.5 ± 1.4 months. High HSs were associated with increased tumor stage (p < 0.05) and higher lymph-node ratio (p < 0.05). In active smokers, high HS also correlated with smoking pack-years (p < 0.05). Cox regression analysis revealed high HS to be an independent prognostic factor for overall survival (hazard ratio [HR] 2.66, p = 0.004), along with lymph-node ratio (HR 4.2, p = 0.002) and age at diagnosis (HR 2.63, p = 0.01). CONCLUSIONS: The pancreatic tumor microenvironment plays an integral role in tumor aggressiveness, and our previous in vitro data suggest that hypercapnia promotes an aggressive, more resistant phenotype. Herein, we show that in early-stage pancreatic cancer, hypercapnic tissue signatures corresponded with a worse overall survival.

Distress, Depression, and the Effect of ZIP Code in Pancreaticobiliary Cancer Patients and Their Significant Others.

BACKGROUND: Distress screening of cancer patients is mandated by the American College of Surgeons Commission on Cancer. Clinical implementation remains limited, particularly in surgical oncology settings in individuals with pancreaticobiliary cancers. STUDY DESIGN: This study evaluated differences in mean distress scores based on the National Comprehensive Cancer Network Distress Thermometer & Problem List for patients with pancreaticobiliary cancers, benign pancreatic conditions, and for their significant others (SOs). The distress screening was conducted at the first office visit and postoperatively in a subset of those who had surgery. Distress Thermometer (DT) scores were dichotomized at ≤5 vs >5 and at ≥7 and correlated with Problem List items. The US ZIP Code database was used to correlate income range, percent poverty, and unemployment in the patient's self-identified ZIP code. Regression models were fitted to identify independent predictors of distress. RESULTS: A total of 547 patients and 184 SOs were evaluated. Thirty percent of patients had DT scores >5, with pancreatic adenocarcinoma patients reporting the highest levels of distress. SOs of pancreatic adenocarcinoma patients reported even greater distress than the patients themselves. As the number of pre-existing medical problems increased; so did DT scores. Distress correlated with physical and emotional problems and worry about insurance coverage and transportation. Higher income level predicted higher DT scores, although poverty predicted lower DT scores. Depression was present in 12% of the patients. Distress improved in those undergoing surgery. CONCLUSIONS: Distress and depression in pancreaticobiliary cancer patients and SOs are prevalent. The findings of this study have multiple actionable implications and require diagnosis, treatment, and referral to supportive care resources.

The Imperative of Assessing Quality of Life in Patients Presenting to a Pancreaticobiliary Surgery Clinic.

OBJECTIVE: The objective of this study was to determine baseline health-related quality of life (QoL) in patients with pancreatic adenocarcinoma, periampullary cancers, and benign pancreaticobiliary (PB) conditions at the time of the first visit to a PB surgery clinic, and to explore the relationship between QoL, demographics, clinical parameters, complications, and survival. SUMMARY BACKGROUND DATA: Few studies have examined baseline QoL measures, the impact of comorbidities, age, sex, and smoking on subsequent postoperative complications and survival in patients with pancreatic adenocarcinoma, related PB cancers, and with benign PB conditions. METHODS: Data were collected from scheduled patients at a PB surgery clinic between 2013 and 2018. The Brief Pain Inventory, Fact-Hepatobiliary Scale, and Facit-Fatigue questionnaires were administered. QoL parameters were compared between PB cancer patients and those with benign disease. RESULTS: A total of 462 individuals with PB cancers and benign diseases exhibited baseline physical well-being, functional well-being, fatigue, and overall QoL at or below the 75th percentile of wellness at the time of the first office visit. Younger age, smoking, and mental health comorbidities contributed significantly to decreased QoL. PA patients were 7 times more likely to die in the follow-up period than the benign disease group. Black patients had higher pain scores and were 3 times more likely to have a postsurgery complication. Sex differences were identified regarding fatigue, pain, and overall QoL. CONCLUSIONS: This large cohort of PB cancer and benign disease patients exhibited significantly impaired baseline QoL. GI problems, weight loss, smoking, cardiovascular, pulmonary disease, and history of anxiety and depression contributed significantly to reduced QoL. The study sheds a cautionary light on the burden of PB disease at the time of surgical evaluation and its relationship to diminished QoL.