Transcriptomic-Based Microenvironment Classification Reveals Precision Medicine Strategies for Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS: The complex tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) has hindered the development of reliable predictive biomarkers for targeted therapy and immunomodulatory strategies. A comprehensive characterization of the TME is necessary to advance precision therapeutics in PDAC. METHODS: A transcriptomic profiling platform for TME classification based on functional gene signatures was applied to 14 publicly available PDAC datasets (n = 1657) and validated in a clinically annotated independent cohort of patients with PDAC (n = 79). Four distinct subtypes were identified using unsupervised clustering and assessed to evaluate predictive and prognostic utility. RESULTS: TME classification using transcriptomic profiling identified 4 biologically distinct subtypes based on their TME immune composition: immune enriched (IE); immune enriched, fibrotic (IE/F); fibrotic (F); and immune depleted (D). The IE and IE/F subtypes demonstrated a more favorable prognosis and potential for response to immunotherapy compared with the F and D subtypes. Most lung metastases and liver metastases were subtypes IE and D, respectively, indicating the role of clonal phenotype and immune milieu in developing personalized therapeutic strategies. In addition, distinct TMEs with potential therapeutic implications were identified in treatment-naive primary tumors compared with tumors that underwent neoadjuvant therapy. CONCLUSIONS: This novel approach defines a distinct subgroup of PADC patients that may benefit from immunotherapeutic strategies based on their TME subtype and provides a framework to select patients for prospective clinical trials investigating precision immunotherapy in PDAC. Further, the predictive utility and real-world clinical applicability espoused by this transcriptomic-based TME classification approach will accelerate the advancement of precision medicine in PDAC.

Postoperative Outcomes Among Patients Undergoing Cancer Surgery: United States versus International Medical Graduates.

OBJECTIVE: We sought to characterize postoperative outcomes among patients who underwent an oncologic operation relative to whether the treating surgeon was an international medical graduate (IMG) versus a United States medical graduate (USMG). SUMMARY BACKGROUND DATA: IMGs comprise approximately one-quarter of the physician workforce in the United States. METHODS: The 100% Medicare Standard Analytic Files were utilized to extract data on patients with breast, lung, hepato-pancreato-biliary (HPB), and colorectal cancer who underwent surgical resection between 2014 and 2020. Entropy balancing (EB) and multivariable regression analysis were performed to evaluate the association between postoperative outcomes among USMG and IMG surgeons. RESULTS: Among 285,930 beneficiaries, 242,914 (85.0%) and 43,016 (15.0%) underwent surgery by a USMG and IMG surgeon, respectively. Overall, 129,576 (45.3%) individuals were male, and 168,848 (59.1%) patients had a Charlson Comorbidity Index score >2. Notably, IMG surgeons were more likely to care for racial/ethnic minority patients (14.7% vs. 12.5%) and those with a high social vulnerability index (33.3% vs. 32.1%) (all P<0.001). On multivariable analysis after EB, patients treated by an IMG surgeon were less likely to experience adverse postoperative outcomes including 90-day readmission (OR 0.89, 95%CI 0.80-0.99) and index complications (OR 0.84, 95%CI 0.74-0.95) versus USMG surgeons (all P<0.05). Patients treated by IMG versus USMG surgeons had no difference in likelihood to achieve a textbook outcome (OR 1.10, 95%CI 0.99-1.21; P=0.077). CONCLUSIONS: Postoperative outcomes among patients treated by IMG surgeons were roughly equivalent to those of USMG surgeons. In addition, IMG surgeons were more likely to care for patients with multiple comorbidities and individuals from vulnerable communities.

Association of Hospital Market Competition with Outcomes of Complex Cancer Surgery.

BACKGROUND: The association of hospital market competition, financial costs, and quality of oncologic care has not been well-defined. This study sought to evaluate variations in patient outcomes and financial expenditures after complex cancer surgery across high- and low-competition markets. METHODS: Medicare 100% Standard Analytic Files were used to identify patients with lung, esophageal, gastric, hepatopancreaticobiliary, or colorectal cancer who underwent surgical resection between 2018 and 2021. Data were merged with the annual hospital survey database, and the hospital market Herfindahl-Hirschman index was used to categorize hospitals into low- and high-concentration markets. Multi-level, multivariable regression models adjusting for patient characteristics (i.e., age, sex, comorbidities, and social vulnerability), year of procedure, and hospital factors (i.e., case volume, nurse-bed ratio, and teaching status) were used to assess the association between hospital market competition and outcomes. RESULTS: Among 117,641 beneficiaries who underwent complex oncologic surgery, the mean age was 73.8 ± 6.1 years, and approximately one-half of the cohort was male (n = 56,243, 47.8%). Overall, 63.8% (n = 75,041) of the patients underwent care within a high-competition market. Notably, there was marked geographic variation relative to market competition. High versus low market-competition hospitals were more likely to be in high social vulnerability areas (35.1 vs 27.5%; p < 0.001), as well as care for racial/ethnic minority individuals (13.8 vs 7.7%; p < 0.001), and patients with more comorbidities (≥ 2 Elixhauser comorbidities: 63.1 vs 61.1%; p < 0.001). In the multivariable analysis, treatment at hospitals in high- versus low-competition markets was associated with lower odds of achieving a textbook outcome (odds ratio, 0.95; 95% confidence interval, 0.91-0.99; p = 0.009). Patients at high-competition hospitals had greater mean index hospitalization costs ($19,462.2 [16211.9] vs $18,844.7 [14994.7]) and 90-day post-discharge costs ($7807.8 [15431.3] vs $7332.8 [14038.2]) (both p < 0.001) than individuals at low-competition hospitals. CONCLUSIONS: Hospital market competition was associated with poor achievement of an optimal postoperative outcome and greater hospitalization costs.

Long-term Health Outcomes of New Persistent Opioid Use After Gastrointestinal Cancer Surgery.

BACKGROUND: New persistent opioid use (NPOU) after surgery has been identified as a common complication. This study sought to assess the long-term health outcomes among patients who experienced NPOU after gastrointestinal (GI) cancer surgery. METHODS: Patients who underwent surgery for hepato-pancreato-biliary and colorectal cancer between 2007 and 2019 were identified using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. Mixed-effect multivariable logistic regression and Cox proportional hazard models were used to estimate the risk of mortality and hospital visits related to falls, respiratory events, or pain symptoms. RESULTS: Among 15,456 patients who underwent GI cancer surgery, 967(6.6%) experienced NPOU. Notably, the patients at risk for the development of NPOU were those with a history of substance abuse (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.14-1.84), moderate social vulnerability (OR, 1.26; 95% CI, 1.06-1.50), an advanced disease stage (OR, 4.42; 95% CI, 3.51-5.82), or perioperative opioid use (OR, 3.07; 95% CI, 2.59-3.63. After control for competing risk factors, patients who experienced NPOU were more likely to visit a hospital for falls, respiratory events, or pain symptoms (OR, 1.45, 95% CI 1.18-1.78). Moreover, patients who experienced NPOU had a greater risk of death at 1 year (hazard ratio [HR], 2.15; 95% CI, 1.74-2.66). CONCLUSION: Approximately 1 in 15 patients experienced NPOU after GI cancer surgery. NPOU was associated with an increased risk of subsequent hospital visits and higher mortality. Targeted interventions for individuals at higher risk for NPOU after surgery should be used to help mitigate the harmful effects of NPOU.

Impact of early primary care physician follow-up on hospital readmission following gastrointestinal cancer surgery.

BACKGROUND: We sought to examine the association between primary care physician (PCP) follow-up on readmission following gastrointestinal (GI) cancer surgery. METHODS: Patients who underwent surgery for GI cancer were identified using the Surveillance, Epidemiology and End Results (SEER) database. Multivariable regression was performed to examine the association between early PCP follow-up and hospital readmission. RESULTS: Among 60 957 patients who underwent GI cancer surgery, 19 661 (32.7%) visited a PCP within 30-days after discharge. Of note, patients who visited PCP were less likely to be readmitted within 90 days (PCP visit: 17.4% vs. no PCP visit: 28.2%; p < 0.001). Median postsurgical expenditures were lower among patients who visited a PCP (PCP visit: $4116 [IQR: $670-$13 860] vs. no PCP visit: $6700 [IQR: $870-$21 301]; p < 0.001). On multivariable analysis, PCP follow-up was associated with lower odds of 90-day readmission (OR: 0.52, 95% CI: 0.50-0.55) (both p < 0.001). Moreover, patients who followed up with a PCP had lower risk of death at 90-days (HR: 0.50, 95% CI: 0.40-0.51; p < 0.001). CONCLUSION: PCP follow-up was associated with a reduced risk of readmission and mortality following GI cancer surgery. Care coordination across in-hospital and community-based health platforms is critical to achieve optimal outcomes for patients.

Surgical outcomes and healthcare expenditures among patients with dementia undergoing major surgery.

BACKGROUND: We sought to define surgical outcomes among elderly patients with Alzheimer's disease and related dementias (ADRD) following major thoracic and gastrointestinal surgery. METHODS: A retrospective cohort study was used to identify patients who underwent coronary artery bypass grafting (CABG), abdominal aortic aneurysm (AAA) repair, pneumonectomy, pancreatectomy, and colectomy. Individuals were identified from the Medicare Standard Analytic Files and multivariable regression was utilized to assess the association of ADRD with textbook outcome (TO), expenditures, and discharge disposition. RESULTS: Among 1,175,010 Medicare beneficiaries, 19,406 (1.7%) patients had a preoperative diagnosis of ADRD (CABG: n = 1,643, 8.5%; AAA repair: n = 5,926, 30.5%; pneumonectomy: n = 590, 3.0%; pancreatectomy: n = 181, 0.9%; and colectomy: n = 11,066, 57.0%). After propensity score matching, patients with ADRD were less likely to achieve a TO (ADRD: 31.2% vs. no ADRD: 40.1%) or be discharged to home (ADRD: 26.7% vs. no ADRD: 46.2%) versus patients who did not have ADRD (both p < 0.001). Median index surgery expenditures were higher among patients with ADRD (ADRD: $28,815 [IQR $14,333-$39,273] vs. no ADRD: $27,101 [IQR $13,433-$38,578]; p < 0.001) (p < 0.001). On multivariable analysis, patients with ADRD had higher odds of postoperative complications (OR 1.32, 95% CI 1.25-1.40), extended length-of-stay (OR 1.26, 95% CI 1.21-1.32), 90-day readmission (OR 1.37, 95% CI 1.31-1.43), and 90-day mortality (OR 1.76, 95% CI 1.66-1.86) (all p < 0.001). CONCLUSION: Preoperative diagnosis of ADRD was an independent risk factor for poor postoperative outcomes, discharge to non-home settings, as well as higher healthcare expenditures. These data should serve to inform discussions and decision-making about surgery among the growing number of older patients with cognitive deficits.

Textbook oncologic outcomes among patients undergoing laparoscopic, robotic and open surgery for intrahepatic and perihilar cholangiocarcinoma.

BACKGROUND: Textbook oncologic outcome (TOO) serves as a composite, oncologic metric for surgical quality of care. We sought to evaluate variations in TOO among patients undergoing laparoscopic, robotic, and open surgery for intrahepatic (iCCA) and perihilar (pCCA) cholangiocarcinoma. METHODS: Patients who underwent liver resection for iCCA and pCCA between 2010 and 2018 were identified from the National Cancer Database. Entropy balancing was performed for covariate balancing and multivariable regression was used to evaluate the association between surgical approach and TOO. RESULTS: Among 5434 patients who underwent hepatic resection between 2010 and 2018, 3888 (71.6%) had iCCA, and 1546 (28.4%) had pCCA. TOO was achieved in 11.7% (n = 454), and 18.8% (n = 291) of patients with iCCA and pCCA, respectively. There was a difference in achievement of TOO relative to operative approach among patients with iCCA (robotic: 6.2% vs. laparoscopic: 8.1% vs. open: 12.5%; p = 0.002). After entropy balancing, patients with iCCA undergoing laparoscopic surgery had 32% reduced odds of achieving TOO (Ref: open surgery; laparoscopic, OR 0.68, 95%CI 0.49-0.93; p = 0.016; robotic, OR 0.69, 95%CI 0.34-1.39; p = 0.298). CONCLUSIONS: Usage of composite oncologic measures such as TOO may allow for a holistic assessment of different approaches to hepatic resection among patients with CCA.

Biliary Adverse Events During Neoadjuvant Therapy for Pancreatic Cancer.

OBJECTIVE: To describe a high-volume experience with biliary drainage before neoadjuvant therapy (NAT) for patients with operable pancreatic cancer (PC) and characterize the association between biliary adverse events (BAEs) and patient outcome. BACKGROUND: Patients with PC presenting with biliary obstruction require durable decompression before NAT. METHODS: Patients with operable PC and tumor-associated biliary obstruction were examined and grouped by the presence or absence of a BAE during NAT. The incidence, timing, and management of BAEs are described, and outcomes, including the completion of all treatment and overall survival (OS), were compared. RESULTS: Of 426 patients who received pretreatment biliary decompression, 92 (22%) experienced at least 1 BAE during NAT, and 56 (13%) required repeat intervention on their biliary stent. The median duration of NAT was 161 days for all patients and was not different in the group that experienced BAEs. The median time from initial stent placement to BAE was 64 days. An interruption in the delivery of NAT (median 7 days) occurred in 25 (6%) of 426 patients. Among 426 patients, 290 (68%) completed all NAT, including surgery: 60 (65%) of 92 patients with BAE and 230 (69%) of 334 patients without BAE ( P =0.51). Among 290 patients who completed NAT and surgery, the median OS was 39 months, 26 months for the 60 patients with BAE, and 43 months for the 230 patients without BAE ( P =0.02). CONCLUSIONS: During extended multimodal NAT for PC, 22% of patients experienced a BAE. Although BAEs were not associated with a significant interruption of treatment, patients who experienced a BAE had worse OS.

An Exosome-based Transcriptomic Signature for Noninvasive, Early Detection of Patients With Pancreatic Ductal Adenocarcinoma: A Multicenter Cohort Study.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and most patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lacks adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly micro RNAs (miRNAs), offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC. METHODS: Small RNA sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 nondisease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs were prioritized that discriminated patients with PDAC from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n = 191) using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. RESULTS: The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf- and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (area under the curve [AUC] = 0.98 training cohort; AUC = 0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages I and II; AUC = 0.93). Furthermore, this transcriptomic signature successfully identified CA19-9 negative cases (<37 U/mL; AUC = 0.96), when analyzed in combination with CA19-9 levels, significantly improved the overall diagnostic accuracy (AUC = 0.99 vs AUC = 0.86 for CA19-9 alone). CONCLUSIONS: In this study, an exosome-based liquid biopsy signature for the noninvasive and robust detection of patients with PDAC was developed.

CA19-9 Response to First-Line Neoadjuvant FOLFIRINOX and Second-Line Gemcitabine/Nab-Paclitaxel for Patients with Operable Pancreatic Cancer.

BACKGROUND: Response to second-line (2L) neoadjuvant therapy for operable pancreatic cancer (PC) is understudied. This study examined carbohydrate antigen 19-9 (CA19-9) response to first-line (1L) and 2L chemotherapy. METHODS: The study identified patients with operable PC and elevated CA19-9 (≥ 35 U/mL with total bilirubin < 2 mg/dL) who received 1L FOLFIRINOX (FFX). The patients were restaged after 2 months and based on response, received additional FFX or gemcitabine/nab-paclitaxel (GnP) as part of total neoadjuvant therapy. Response was defined as a decrease in tumor size on computed tomography (CT) imaging or a decline in CA19-9 of 50% or more and preserved performance status. RESULTS: For operable PC with an elevated CA19-9, 108 patients received 1L FFX. After 2 months of chemotherapy, the decision was made to continue FFX (FFX ≥ FFX) for 76 (70%) of the 108 patients and switch to GnP (FFX ≥ GnP)) for 32 (30%) of the patients. Of the 32 FFX ≥ GnP patients, 27 had no evidence of radiographic or biochemical (CA19-9) response to 1L FFX. Of these 27 patients, 26 (96%) demonstrated a response to 2L GnP. After 4 months of chemotherapy, 62 (82%) of the 76 FFX ≥ FFX patients had a CA19-9 response compared with 31 (97%) of the 32 FFX ≥ GnP patients (p = 0.04). CONCLUSIONS: Lack of biochemical response to 2 months of 1L FFX may identify a subgroup of patients with a very high rate of response to 2L GnP, emphasizing the importance of assessing treatment response at 2-month intervals.

Becoming a Sustainable Academic Surgeon.

INTRODUCTION: Health care facilities represent a significant source of pollution, contributing to the growing problems associated with global warming. The resulting climate change impacts our health through worsening air and water quality, diminished access to nutritious food, and safe shelter. METHODS: We outline here the not only the role of the surgeon in contributing to climate change, but also ways in which to minimize one's carbon footprint. RESULTS: Surgeons are leaders within healthcare systems. Adopting environmentally conscious practices can reduce solid waste, energy usage, and carbon emissions. Practices outside of the clinical setting can also incorporate sustainability, including the use of virtual recruitment and educational programs, as well as thoughtful and conscientious travel practices. CONCLUSIONS: Academic surgery combines clinical practice with an element of leadership, at all levels. Our recognition and action to reduce wasteful practices can help leave a better earth for generations to come.

Neoadjuvant chemotherapy for pancreatic cancer: Quality over quantity.

BACKGROUND AND OBJECTIVES: The ideal duration of neoadjuvant chemotherapy (NACT) in patients with localized pancreatic adenocarcinoma (PDAC) treated with curative intent is unclear. We sought to determine the prognostic significance of both duration of NACT and Carbohydrate Antigen 19-9 (CA19-9) normalization to NACT. METHODS: We examined patients with resectable and borderline resectable PDAC treated with NACT and chemoradiation. Patients were compared by NACT duration (2 vs. 4 months) and by CA19-9 normalization after NACT. RESULTS: Among 171 patients, 83 (49%) received 2 months of NACT, and 88 (51%) received 4 months. After NACT completion, 115 (67%) patients had persistently elevated CA19-9, and 56 (33%) had normalized. Of the 125 patients who had successful surgery, 73 (58%) had normalized CA19-9 postoperatively. Duration of NACT was not associated with overall survival (OS) while CA19-9 normalization after NACT (regardless of duration) was associated with improved OS (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35-0.89, p = 0.02). Adjuvant chemotherapy was associated with improved OS among patients without CA19-9 normalization after NACT (HR 0.42, CI 0.20-0.86, p = 0.02) but not among those that normalized, independent of duration. CONCLUSIONS: CA19-9 normalization after NACT is a clinically significant endpoint of treatment; patients without CA19-9 normalization may benefit from additional therapy.

Outcomes of plastic surgical reconstruction in extremity and truncal soft tissue sarcoma: Results from the US Sarcoma Collaborative.

BACKGROUND: This study aimed to define how utilization of plastic surgical reconstruction (PSR) affects perioperative outcomes, locoregional recurrence-free survival (LRRFS), and overall survival (OS) after radical resection of extremity and truncal soft tissue sarcoma (ETSTS). The secondary aim was to determine factors associated with PSR. METHODS: Patients who underwent resection of ETSTS between 2000 and 2016 were identified from a multi-institutional database. PSR was defined as complex primary closure requiring a plastic surgeon, skin graft, or tissue-flap reconstruction. Outcomes included PSR utilization, postoperative complications, LRRFS, and OS. RESULTS: Of 2750 distinct operations, 1060 (38.55%) involved PSR. Tissue-flaps (854, 80.57%) were most commonly utilized. PSR was associated with a higher proportion of R0 resections (83.38% vs. 74.42%, p < 0.001). Tissue-flap PSR was associated with local wound complications (odds ratio: 1.81, confidence interval: 1.21-2.72, p = 0.004). Neither PSR nor postoperative complications were independently associated with LRRFS or OS. High-grade tumors (1.60, 1.13-2.26, p = 0.008) and neoadjuvant radiation (1.66, 1.20-2.30, p = 0.002) were associated with the need for PSR. CONCLUSION: Patients with ETSTS undergoing resection with PSR experienced acceptable rates of complications and a higher rate of negative margins, which were associated with improved LRRFS and OS. High tumor grade and neoadjuvant radiation were associated with requirement of PSR.

Attitudes and Beliefs about Hysterectomy in Patients with Uterine Fibroids.

STUDY OBJECTIVE: To investigate the attitudes toward and beliefs about hysterectomy that influence the decision of women with symptomatic uterine fibroids regarding hysterectomy. DESIGN: A prospective survey study. SETTING: An outpatient clinic. PATIENTS: Patients in an urban, academic complex gynecology outpatient clinic at the age of 35 years or older with uterine fibroids and without previous hysterectomy were invited to participate. A total of 67 participants were surveyed between December 2020 and February 2022. INTERVENTIONS: Data were collected on demographics, Uterine Fibroid Symptom Health-Related Quality of Life (UFS-QOL) Questionnaire scores, and beliefs regarding hysterectomy via a web-based survey. Participants were posed with clinical scenarios and asked to indicate a preference for hysterectomy or myomectomy and stratified into groups by acceptability of hysterectomy as a treatment option for fibroids. MEASUREMENTS AND MAIN RESULTS: Data were analyzed using chi-square or Fisher exact tests, t tests, or Wilcoxon tests as appropriate. The mean age of participants was 46.2 (SD 7.5) years, and 57% of participants self-identified as White/Caucasian. The mean UFS-QOL symptoms score was 50 (SD 26) and the mean overall health-related quality of life score was 52 (SD 28). Notably, 34% of participants preferred hysterectomy whereas 54% preferred myomectomy assuming equivalent efficacy; 44% of those who preferred myomectomy did not desire future fertility. There were no differences observed in UFS-QOL scores. Participants opting for a hysterectomy believed that it would improve their mood/emptions, relationship with partner, general quality of life, sense of femininity, feeling whole, identity/body image, sexuality, and relationships. Those who opted for a myomectomy believed all those factors would worsen with a hysterectomy, and in addition, it would worsen their vaginal moisture and their partner's experience. CONCLUSION: Many factors affect a patient's decisions regarding hysterectomy for uterine fibroids beyond those related to fertility, including factors related to body image, sexuality, and relationships. Physicians should consider these factors when counseling patients and recognize their importance to facilitate improved shared decision making.

Pancreaticogastrostomy as a fistula mitigating strategy for a high-risk pancreatic anastomosis following pancreaticoduodenectomy.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD) has been associated with soft gland texture and/or small pancreatic duct. We hypothesized that selective use of pancreaticogastrostomy (PG) over pancreaticojejunostomy (PJ) in those scenarios would decrease the rate of CR-POPF. METHODS: Review of prospective database of all PD's performed at a single institution between 2009 and 2019 was performed. The pancreatic remnant was deemed "high risk" if soft gland and/or small duct were present. RESULTS: PJ was performed in 199 (147 "low-risk" and 52 "high-risk") cases, and 110 patients (all "high-risk") had a PG. Overall CR-POPF rate was 11.9% with no difference between the groups. Risk-stratified analysis within PJ group showed CR-POPF rate of 5.4% versus 36% in "low-risk" versus "high risk" scenarios, respectively; the use of PG significantly decreased CR-POPF rate (9.1%, p < 0.0001). Gastrointestinal bleeding was more likely to occur following PG than PJ. Soft gland texture and gastrointestinal bleeding were the strongest predictors of CR-POPF in PJ and PG groups, respectively. CONCLUSION: Selective use of PG after PD in "high-risk" scenarios mitigates the risk of CR-POPF. Increased rate of gastrointestinal bleeding calls for further refinement of the technique and heightened postoperative vigilance.

Updates and new directions in the use of radiation therapy for the treatment of pancreatic adenocarcinoma: dose, sensitization, and novel technology.

Panc reatic ductal adenocarcinoma (PDAC) is a devastating malignancy. There have been few advances that have substantially improved overall survival in the past several years. On its current trajectory, the deaths from PDAC are expected to cross that from all gastrointestinal cancers combined by 2030. Radiation therapy is a technically very complex modality that bridges multiple different treatment strategies. It represents a hybrid among advanced diagnostic imaging, local (often ablative) intervention, and heterogeneous biological mechanisms contributing to normal and oncologic cell kill. In this article, we bring an overview of the several promising strategies that are currently being investigated to improve outcomes using radiation therapy for patients with PDAC.

Identification of Serum miRNA Signature and Establishment of a Nomogram for Risk Stratification in Patients With Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: The aim of the study was to perform mRNA-miRNA regulatory network analyses to identify a miRNA panel for molecular subtype identification and stratification of high-risk patients with pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Recent transcriptional profiling effort in PDAC has led to the identification of molecular subtypes that associate with poor survival; however, their clinical significance for risk stratification in patients with PDAC has been challenging. METHODS: By performing a systematic analysis in The Cancer Genome Atlas and International Cancer Genome Consortium cohorts, we discovered a panel of miRNAs that associated with squamous and other poor molecular subtypes in PDAC. Subsequently, we used logistic regression analysis to develop models for risk stratification and Cox proportional hazard analysis to determine survival prediction probability of this signature in multiple cohorts of 433 patients with PDAC, including a tissue cohort (n = 199) and a preoperative serum cohort (n = 51). RESULTS: We identified a panel of 9 miRNAs that were significantly upregulated (miR-205-5p and -934) or downregulated (miR-192-5p, 194-5p, 194-3p, 215-5p, 375-3p, 552-3p, and 1251-5p) in PDAC molecular subtypes with poor survival [squamous, area under the receiver operating characteristic curve (AUC) = 0.90; basal, AUC = 0.89; and quasimesenchymal, AUC = 0.83]. The validation of this miRNA panel in a tissue clinical cohort was a significant predictor of overall survival (hazard ratio = 2.48, P < 0.0001), and this predictive accuracy improved further in a risk nomogram which included key clinicopathological factors. Finally, we were able to successfully translate this miRNA predictive signature into a liquid biopsy-based assay in preoperative serum specimens from PDAC patients (hazard ratio: 2.85, P = 0.02). CONCLUSION: We report a novel miRNA risk-stratification signature that can be used as a noninvasive assay for the identification of high-risk patients and potential disease monitoring in patients with PDAC.

Pancreatobiliary Maljunction-associated Gallbladder Cancer Is as Common in the West, Shows Distinct Clinicopathologic Characteristics and Offers an Invaluable Model for Anatomy-induced Reflux-associated Physio-chemical Carcinogenesis.

OBJECTIVE: To determine the associations of pancreatobiliary maljunction (PBM) in the West. BACKGROUND: PBM (anomalous union of common bile duct and pancreatic duct) is mostly regarded as an Asian-only disorder, with 200X risk of gallbladder cancer (GBc), attributed to reflux of pancreatic enzymes. Methods: Radiologic images of 840 patients in the US who underwent pancreatobiliary resections were reviewed for PBM and contrasted with 171 GBC cases from Japan. RESULTS: Eight % of the US GBCs (24/300) had PBM (similar to Japan; 15/ 171, 8.8%), in addition to 1/42 bile duct carcinomas and 5/33 choledochal cysts. None of the 30 PBM cases from the US had been diagnosed as PBM in the original work-up. PBM was not found in other pancreatobiliary disorders. Clinicopathologic features of the 39 PBM-associated GBCs (US:24, Japan:15) were similar; however, comparison with non-PBM GBCs revealed that they occurred predominantly in females (F/M = 3); at younger (<50-year-old) age (21% vs 6.5% in non-PBM GBCs; P = 0.01); were uncommonly associated with gallstones (14% vs 58%; P < 0.001); had higher rate of tumor-infiltrating lymphocytes (69% vs 44%; P = 0.04); arose more often through adenoma-carcinoma sequence (31% vs 12%; P = 0.02); and had a higher proportion of nonconventional carcinomas (21% vs 7%; P = 0.03). Conclusions: PBM accounts for 8% of GBCs also in the West but is typically undiagnosed. PBM-GBCs tend to manifest in younger age and often through adenoma-carcinoma sequence, leading to unusual carcinoma types. If PBM is encountered, cholecystectomy and surveillance of bile ducts is warranted. PBM-associated GBCs offer an invaluable model for variant anatomy-induced chemical (reflux-related) carcinogenesis.

Transcriptomic Profiling Identifies an Exosomal microRNA Signature for Predicting Recurrence Following Surgery in Patients With Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: We performed genome-wide expression profiling to develop an exosomal miRNA panel for predicting recurrence following surgery in patients with PDAC. SUMMARY OF BACKGROUND DATA: Pretreatment risk stratification is essential for offering individualized treatments to patients with PDAC, but predicting recurrence following surgery remains clinically challenging. METHODS: We analyzed 210 plasma and serum specimens from 4 cohorts of PDAC patients. Using a discovery cohort (n = 25), we performed genome-wide sequencing to identify candidate exosomal miRNAs (exo-miRNAs). Subsequently, we trained and validated the predictive performance of the exo-miRNAs in two clinical cohorts (training cohort: n = 82, validation cohort: n = 57) without neoadjuvant therapy (NAT), followed by a post-NAT clinical cohort (n = 46) as additional validation. RESULTS: We performed exo-miRNA expression profiling in plasma specimens obtained before any treatment in a discovery cohort. Subsequently we optimized and trained a 6-exo-miRNA risk-prediction model, which robustly discriminated patients with recurrence [area under the curve (AUC): 0.81, 95% confidence interval (CI): 0.70-0.89] and relapse-free survival (RFS, P < 0.01) in the training cohort. The identified exo-miRNA panel was successfully validated in an independent validation cohort (AUC: 0.78, 95% CI: 0.65- 0.88, RFS: P < 0.01), where it exhibited comparable performance in the post-NAT cohort (AUC: 0.72, 95% CI: 0.57-0.85, RFS: P < 0.01) and emerged as an independent predictor for RFS (hazard ratio: 2.84, 95% CI: 1.30-6.20). CONCLUSIONS: We identified a novel, noninvasive exo-miRNA signature that robustly predicts recurrence following surgery in patients with PDAC; highlighting its potential clinical impact for optimized patient selection and improved individualized treatment strategies.

Pancreatic ductal adenocarcinomas associated with intraductal papillary mucinous neoplasms (IPMNs) versus pseudo-IPMNs: relative frequency, clinicopathologic characteristics and differential diagnosis.

The literature is highly conflicted on what percentage of pancreatic ductal adenocarcinomas (PDACs) arise in association with intraductal papillary mucinous neoplasms (IPMNs). Some studies have claimed that even small (Sendai-negative) IPMNs frequently lead to PDAC. Recently, more refined pathologic definitions for mucin-lined cysts were provided in consensus manuscripts, but so far there is no systematic analysis regarding the frequency and clinicopathologic characteristics of IPMN-mimickers, i.e., pseudo-IPMNs. In this study, as the first step in establishing frequency, we performed a systematic review of the pathologic findings in 501 consecutive ordinary PDACs, which disclosed that 10% of PDACs had associated cysts ≥1 cm. While 31 (6.2%) of these were IPMN or mucinous cystic neoplasm (MCN), 19 (3.8%) were other cyst types that mimicked IPMN (pseudo-IPMNs) per recent WHO/consensus criteria. As the second step of the study, we performed a comparative clinicopathologic analysis by also including our entire surgical pathology/consultation databases that was comprised of 60 IPMN-associated PDACs, 30 MCN-associated PDACs and 40 pseudo-IPMN-associated PDACs. We found that 84% of true IPMNs were pre-operatively recognized, whereas IPMN was considered in differential diagnosis of 33% of pseudo-IPMNs. Of the 40 pseudo-IPMNs, there were 15 secondary duct ectasias; 6 large-duct-type PDACs; 5 pseudocysts; 5 cystic tumor necrosis; 4 simple mucinous cysts; 3 groove pancreatitis-associated paraduodenal wall cysts; and 2 congenital cysts. Microscopically, pseudo-IPMNs had at least partial mucinous-lining mimicking IPMN but had smaller cystic (mean = 1.9 cm) and larger PDAC (mean = 3.8 cm) components compared to true IPMNs (cyst = 5.7 cm; PDAC = 2.0 cm). In summary, in this pathologically verified analysis that utilized refined criteria, 10% of PDACs were discovered to have cysts ≥1 cm, about two-thirds of which were IPMN/MCN but about one-third were pseudo-IPMNs. True IPMNs underlying the PDACs are often large and are already diagnosed pre-operatively as having an IPMN component, whereas only a third of the pseudo-IPMNs receive IPMN diagnosis by imaging and their cysts are smaller. At the histopathologic level, pseudo-IPMNs are highly prone to misdiagnosis as IPMN, which presumably accounts for much higher association of IPMNs with PDAC as reported in some studies. The subtle but salient characteristics of pseudo-IPMNs elucidated in this study should be combined with careful radiological/clinical correlation in order to exclude pseudo-IPMNs.