Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer.

Single-cell technologies have described heterogeneity across tissues, but the spatial distribution and forces that drive single-cell phenotypes have not been well defined. Combining single-cell RNA and protein analytics in studying the role of stromal cancer-associated fibroblasts (CAFs) in modulating heterogeneity in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) model systems, we have identified significant single-cell population shifts toward invasive epithelial-to-mesenchymal transition (EMT) and proliferative (PRO) phenotypes linked with mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling. Using high-content digital imaging of RNA in situ hybridization in 195 PDAC tumors, we quantified these EMT and PRO subpopulations in 319,626 individual cancer cells that can be classified within the context of distinct tumor gland "units." Tumor gland typing provided an additional layer of intratumoral heterogeneity that was associated with differences in stromal abundance and clinical outcomes. This demonstrates the impact of the stroma in shaping tumor architecture by altering inherent patterns of tumor glands in human PDAC.

Revisiting the performance of cyst fluid carcinoembryonic antigen as a diagnostic marker for pancreatic mucinous cysts: a comprehensive 20-year institutional review.

OBJECTIVE: Elevated pancreatic cyst fluid carcinoembryonic antigen (CEA) has been routinely used to classify mucinous cysts. This study incorporates original data that established the CEA ≥192 ng/mL threshold with over 20 years of additional data and reassesses the diagnostic performance of CEA for differentiating mucinous from non-mucinous cysts. DESIGN: 1169 pancreatic cysts (1999-2021) with CEA results were identified. 394 cases had histological confirmation as the diagnostic standard. Additionally, 237 cysts without histological confirmation demonstrated KRAS, GNAS, or RNF43 mutations by molecular testing and were combined with the histologically confirmed cysts for separate analysis on a total cohort of 631 cysts. RESULTS: Median CEA was significantly higher in mucinous cysts (323.9 ng/mL, n=314) versus non-mucinous cysts (204.6 ng/mL, n=80) (p<0.001). Receiver operating characteristic curve analysis demonstrated an optimal CEA cut-off of 20 ng/mL (area under the curve: 80%), though the specificity was lower than desired (sensitivity 89%, specificity 64%). At the previously established threshold of 192 ng/mL, sensitivity and specificity were 56% and 78%, respectively. To achieve a specificity of 85% as originally reported, a CEA threshold of 250 ng/mL was needed; the 13 false positive cases at this threshold included 4 benign simple cysts, 2 squamoid cysts, 1 serous cystadenoma, 1 lymphoepithelial cyst and 5 more uncommon entities. All results remained similar within the total cohort after including additional cases with KRAS/GNAS/RNF43 mutations only. CONCLUSION: Cyst fluid CEA continues to be a useful test in the diagnosis of mucinous pancreatic cysts but does not appear as specific as previously reported. Raising the CEA threshold to 250 ng/mL to maintain specificity for differentiating mucinous from non-mucinous cysts may be considered.

Absence of a pancreatic microbiome in intraductal papillary mucinous neoplasm.

OBJECTIVE: This study aims to validate the existence of a microbiome within intraductal papillary mucinous neoplasm (IPMN) that can be differentiated from the taxonomically diverse DNA background of next-generation sequencing procedures. DESIGN: We generated 16S rRNA amplicon sequencing data to analyse 338 cyst fluid samples from 190 patients and 19 negative controls, the latter collected directly from sterile syringes in the operating room. A subset of samples (n=20) and blanks (n=5) were spiked with known concentrations of bacterial cells alien to the human microbiome to infer absolute abundances of microbial traces. All cyst fluid samples were obtained intraoperatively and included IPMNs with various degrees of dysplasia as well as other cystic neoplasms. Follow-up culturing experiments were conducted to assess bacterial growth for microbiologically significant signals. RESULTS: Microbiome signatures of cyst fluid samples were inseparable from those of negative controls, with no difference in taxonomic diversity, and microbial community composition. In a patient subgroup that had recently undergone invasive procedures, a bacterial signal was evident. This outlier signal was not characterised by higher taxonomic diversity but by an increased dominance index of a gut-associated microbe, leading to lower taxonomic evenness compared with the background signal. CONCLUSION: The 'microbiome' of IPMNs and other pancreatic cystic neoplasms does not deviate from the background signature of negative controls, supporting the concept of a sterile environment. Outlier signals may appear in a small fraction of patients following recent invasive endoscopic procedures. No associations between microbial patterns and clinical or cyst parameters were apparent.

The Revised R Status is an Independent Predictor of Postresection Survival in Pancreatic Cancer After Neoadjuvant Treatment.

OBJECTIVE: To investigate the oncological outcomes of patients with pancreatic ductal adenocarcinoma (PDAC) who had an R 0 or R 1 resection based on the revised R status (1 mm) after neoadjuvant therapy (NAT). BACKGROUND: The revised R status is an independent prognostic factor in upfront-resected PDAC; however, the significance of 1 mm margin clearance after NAT remains controversial. METHODS: Patients undergoing pancreatectomy after NAT for PDAC were identified from 2 prospectively maintained databases. Clinicopathological and survival data were analyzed. The primary outcomes were overall survival (OS), recurrence-free survival (RFS), and pattern of recurrence in association with R 0 >1 mm and R 1 ≤1 mm resections. RESULTS: Three hundred fifty-seven patients with PDAC were included after NAT and subsequent pancreatic resection. Two hundred eight patients (58.3%) received FOLFIRINOX, 41 patients (11.5%) received gemcitabine-based regimens, and 299 individuals (83.8%) received additional radiotherapy. R 0 resections were achieved in 272 patients (76.2%) and 85 patients (23.8%) had R 1 resections. Median OS after R 0 was 41.0 months, compared with 20.6 months after R 1 resection ( P = 0.002), and even longer after additional adjuvant chemotherapy ( R 0 44.8 vs R1 20.1 months; P = 0.0032). Median RFS in the R 0 subgroup was 17.5 months versus 9.4 months in the R 1 subgroup ( P < 0.0001). R status was confirmed as an independent predictor for OS ( R 1 hazard ratio: 1.56, 95% CI: 1.07-2.26) and RFS ( R 1 hazard ratio: 1.52; 95% CI: 1.14-2.0). In addition, R 1 resections were significantly associated with local but not distant recurrence ( P < 0.0005). CONCLUSIONS: The revised R status is an independent predictor of postresection survival and local recurrence in PDAC after NAT. Achieving R 0 resection with a margin of at least 1 mm should be a primary goal in the surgical treatment of PDAC after NAT.

Unraveling the Long-term Natural History of Branch Duct Intraductal Papillary Mucinous Neoplasm: Beyond 10 years.

OBJECTIVE: To describe the long-term natural history of Branch duct intraductal papillary mucinous neoplasm (BD-IPMN). BACKGROUND: The BD-IPMN is a known precursor of pancreatic cancer, yet its long-term natural history is largely unknown. METHODS: We retrospectively reviewed patients with BD-IPMN who were followed at the Massachusetts General Hospital for at least ten years without surgical intervention. Patient and cyst characteristics, development of worrisome features (WF), need for surgery, and malignancy were recorded. The risk of pancreatic cancer in this cohort was compared with the general population by determining the Standardized Incidence Ratio (SIR). RESULTS: 316 patients with BD-IPMN who were followed for at least ten years without intervention were identified. The median age was 63 years, and the median follow-up was 13.5 years (range 10 - 28.8 years). Median cyst size at diagnosis was 1.2 cm (IQR 0.8 - 1.7), was 1.8 cm (IQR 1.2-2.6) at ten years, and increased to 2.0 cm (IQR 1.3 - 3.0) by the end of surveillance. At the 10-year mark, 24% of patients had WF, and by the end of surveillance, an additional 20% had developed WF or high-risk stigmata. 8.2% of patients developed pancreatic malignancy (high-grade dysplasia or invasive cancer). The SIR for pancreatic cancer was 9.28 (95%CI of 5.82 - 14.06), with almost two-thirds of invasive cancers occurring within the pancreatic cyst. CONCLUSIONS: After ten years of surveillance for BD-IPMN without intervention, the disease continues to progress and one of every 12 patients will develop malignancy. The risk of pancreatic cancer appears to be nine times higher than in the comparable age-matched population.

Lymph Node Yield is Associated with Improved Overall Survival and Increased Time to Recurrence in Node-Negative Pancreatic Ductal Adenocarcinoma Following Neoadjuvant Therapy.

OBJECTIVE: To determine if lymph node yield (LNY) is associated with improved overall survival (OS) and time to recurrence (TTR) in patients with node-negative pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant therapy (NAT). BACKGROUND: Lymph node yield has been associated with survival in solid gastrointestinal cancers, including PDAC. METHODS: Patients with pathological T stage I-III, node-negative (N0), PDAC treated with NAT followed by pancreatoduodenectomy were identified in the Massachusetts General Hospital (MGH) pancreatectomy database and the National Cancer Database (NCDB). A cutoff point of 22 nodes was identified in the NCDB using the point with the optimal (log-rank test) split. Overall survival and TTR were evaluated using univariate and multivariable analyses. RESULTS: In the MGH cohort, 233 node-negative patients following NAT were included. A LNY ≥ 22 was associated with prolonged median OS (59 months vs. 25 months, P<0.001) and prolonged TTR (32 months vs. 14 months, P=0.019). On multivariable analysis, LNY was an independent predictor of survival (HR 0.97, 95% CI 0.95-0.99, P=0.034) per sampled node. In the NCDB, 2,029 node-negative patients following NAT were included. A LNY ≥ 22 was associated with prolonged median OS (49 months vs. 33 months, P<0.001). On multivariable analysis, LNY was an independent predictor of survival (HR 0.99, 95% CI 0.98-0.99, P<0.001) per sampled node. CONCLUSION: Lymph node yield was associated with improved oncologic outcomes in patients treated with NAT followed by pancreatoduodenectomy in two independent datasets. Responsible mechanisms by which LNY impacts the outcomes of node-negative patients following NAT warrant further exploration.

Reappraising the Role of Intraoperative Neck Margin Revision in Post-Neoadjuvant Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma: A Multi-Institutional Analysis.

OBJECTIVE: To investigate whether revision of pancreatic neck margin based on intraoperative frozen section analysis has oncologic value in post-neoadjuvant pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: The role of intraoperative neck margin revision has been controversial, with little information specific to post-neoadjuvant PD. METHODS: Patients who underwent post-neoadjuvant PD (2013-2019) for conventional PDAC with frozen section analysis of neck margin at three academic institutions were included. Overall survival (OS) and recurrence-free survival (RFS) were compared across three groups: complete resection achieved en-bloc (CR-EB), complete resection achieved non-en-bloc (CR-NEB), and incomplete resection (IR). RESULTS: Among the 671 patients included, 524 (78.1%) underwent CR-EB, 119 (17.7%) CR-NEB and 28 (4.2%) IR. Patients undergoing CR-NEB and IR exhibited larger tumors and lower rates of RECIST response, requiring vascular resections more often. Likewise, CR-NEB and IR were associated with a worse pathological profile than CR-EB. The incidence of postoperative complications and access to adjuvant treatment were comparable among groups. A CR-EB was associated with the longest OS duration (34.3 mo). In patients with positive neck margin, obtaining a CR-NEB via re-excision was associated with a comparable OS relative to patients with an IR (26.9 vs. 27.1 mo, P=0.901). Similar results were observed for RFS. At multivariable analysis, neck margin status was not independently associated with survival and recurrence. CONCLUSION: Conversion of an initially positive pancreatic neck margin by additional resection is not associated with oncologic benefits in post-neoadjuvant PD and cannot be routinely recommended.

Complexity and Experience Grading to Guide Patient Selection for Minimally-invasive Pancreatoduodenectomy: An ISGPS Consensus.

OBJECTIVE: The ISGPS aims to develop a universally accepted complexity and experience grading system to guide the safe implementation of robotic and laparoscopic minimally-invasive pancreatoduodenectomy (MIPD). BACKGROUND: Despite the perceived advantages of MIPD, its global adoption has been slow due to the inherent complexity of the procedure and challenges to acquiring surgical experience. Its wider adoption must be undertaken with an emphasis towards appropriate patient selection according to adequate surgeon and center experience. METHODS: The ISGPS developed a complexity and experience grading system to guide patient selection for MIPD based on an evidence-based review and a series of discussions. RESULTS: The ISGPS complexity and experience grading system for MIPD is subclassified into patient-related risk factors and provider experience-related variables. The patient-related risk factors include anatomical (main pancreatic and common bile duct diameters), tumor-specific (vascular contact), and conditional (obesity and previous complicated upper abdominal surgery/disease) factors, all incorporated in an A-B-C classification, graded as no, a single, and multiple risk factors. The surgeon and center experience-related variables include surgeon total MIPD experience (cut-offs 40 and 80) and center annual MIPD volume (cut-offs 10 and 30), all also incorporated in an A-B-C classification. CONCLUSION: This ISGPS complexity and experience grading system for robotic and laparoscopic MIPD may enable surgeons to optimally select patients after duly considering specific risk factors known to influence the complexity of the procedure. This grading system will likely allow for a thoughtful and stepwise implementation of MIPD and facilitate a fair comparison of outcome between centers and countries.

Surveillance for Presumed BD-IPMN of the Pancreas: Stability, Size, and Age Identify Targets for Discontinuation.

BACKGROUND & AIMS: Currently, most patients with branch duct intraductal papillary mucinous neoplasms (BD-IPMN) are offered indefinite surveillance, resulting in health care costs with questionable benefits regarding cancer prevention. This study sought to identify patients in whom the risk of cancer is equivalent to an age-matched population, thereby justifying discontinuation of surveillance. METHODS: International multicenter study involving presumed BD-IPMN without worrisome features (WFs) or high-risk stigmata (HRS) at diagnosis who underwent surveillance. Clusters of individuals at risk for cancer development were defined according to cyst size and stability for at least 5 years, and age-matched controls were used for comparison using standardized incidence ratios (SIRs) for pancreatic cancer. RESULTS: Of 3844 patients with presumed BD-IPMN, 775 (20.2%) developed WFs and 68 (1.8%) HRS after a median surveillance of 53 (interquartile range 53) months. Some 164 patients (4.3%) underwent surgery. Of the overall cohort, 1617 patients (42%) remained stable without developing WFs or HRS for at least 5 years. In patients 75 years or older, the SIR was 1.12 (95% CI, 0.23-3.39), and in patients 65 years or older with stable lesions smaller than 15 mm in diameter after 5 years, the SIR was 0.95 (95% CI, 0.11-3.42). The all-cause mortality for patients who did not develop WFs or HRS for at least 5 years was 4.9% (n = 79), and the disease-specific mortality was 0.3% (n = 5). CONCLUSIONS: The risk of developing pancreatic malignancy in presumed BD-IPMN without WFs or HRS after 5 years of surveillance is comparable to that of the general population depending on cyst size and patient age. Surveillance discontinuation could be justified after 5 years of stability in patients older than 75 years with cysts <30 mm, and in patients 65 years or older who have cysts ≤15 mm.

Prognostic performance of microscopic size measurements in small invasive carcinomas arising in intraductal papillary mucinous neoplasms of the pancreas.

AIMS: Small invasive carcinomas arising in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas can present as multiple, small foci. In such cases, there is no clear optimal measurement method for determining the invasive size for tumour staging and prognostication. METHODS: In all, 117 small invasive IPMNs (size of largest invasive component ≤2 cm) from seven institutions (2000-2016) were reviewed, and all individual foci of invasive carcinoma were measured. T stages (AJCC 8th edition) based on the largest single focus size (LS), average size of all foci (AS), and total sum of all foci (TS) were examined in association with clinicopathologic parameters and patient outcomes. RESULTS: The cohort comprised IPMNs with invasive tubular-type (n = 82, 70%) and colloid-type (n = 35, 30%) carcinomas. The mean LS, AS, and TS were 0.86, 0.71, and 1.32 cm, respectively. Based on the LS, AS, and TS, respectively, 48, 65, and 39 cases were classified as pT1a; 22, 18, and 11 cases as pT1b; and 47, 34, and 50 cases as pT1c. Higher pT stages based on all measurements were significantly associated with small vessel, large vessel, and perineural invasion (P < 0.05). LS-, AS-, and TS-based pT stages were not significantly associated with recurrence-free survival (RFS) or overall survival (OS) by univariate or multivariate analyses. However, among tubular-type carcinomas, higher LS-, AS-, and TS-based pT stages trended with lower RFS (based on 1-, 3-, and 5-year survival rates). All microscopic measurement methods were most predictive of RFS and OS using a 1.5-cm cutoff, with LS significantly associated with both RFS and OS by univariate and multivariate analysis. CONCLUSIONS: For invasive tubular-type carcinomas arising in IPMN, microscopic size-based AJCC pT stages were not significant predictors of patient outcomes. However, for LS, a size threshold of 1.5 cm was optimal for stratifying both RFS and OS. The AJCC 8th ed. may not be applicable for stratifying small invasive IPMNs with colloid-type histology that generally portend a more favourable prognosis.

Impact of preoperative endoscopic procedures on adverse event rates after surgical resection for main-duct and mixed-type intraductal papillary mucinous neoplasms (IPMNs).

BACKGROUND: Main-duct (MD-) and mixed-type (MT-) IPMNs harbor an increased risk of pancreatic cancer and warrant surgical resection. Preoperative endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) are important in the diagnosis of IPMNs. The aim of this study was to investigate whether endoscopic procedures manipulating the MD impact postoperative adverse events in patients with MD- and MT-IPMNs. METHODS: We performed a retrospective study of 369 patients who underwent resections for MD- or MT-IPMN at two tertiary centers (2000-2019). Multivariable logistic regression analyses were performed for postoperative adverse events to compare the risks between intervention (ERCP, EUS-FNA with branch duct (BD) aspirated, EUS-FNA with MD aspirated from the duct directly or cyst/mass arising from MD) versus no-intervention group. RESULTS: 33.1 % of patients had a preoperative ERCP and 69.4 % had EUS-FNA. Postoperative adverse events included: 30-day readmission (12.7 %), delayed gastric emptying (13.8 %), pancreatic fistula (10.3 %), abdominal abscess (5.7 %), cardiopulmonary adverse events (11.4 %), and mortality (1.4 %). The model was adjusted for potential confounders. There were no significant differences between the ERCP and no-ERCP groups for specific adverse events. Compared to no-EUS-FNA groups, groups of EUS-FNA with BD aspiration and EUS-FNA with MD aspiration from the main pancreatic duct directly or cyst/mass arising from MD did not show a significant increase in specific adverse events. CONCLUSIONS: Postoperative adverse events were not significantly increased among patients who had ERCP or EUS-FNA before surgical resection for MD- or MT-IPMNs. Endoscopic procedures directly sampling the MD can be safely pursued for diagnostic purposes in selected cases.

International evidence-based Kyoto guidelines for the management of intraductal papillary mucinous neoplasm of the pancreas.

This study group aimed to revise the 2017 international consensus guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, and mainly focused on five topics; the revision of high-risk stigmata (HRS) and worrisome features (WF), surveillance of non-resected IPMN, surveillance after resection of IPMN, revision of pathological aspects, and investigation of molecular markers in cyst fluid. A new development from the prior guidelines is that systematic reviews were performed for each one of these topics, and published separately to provide evidence-based recommendations. One of the highlights of these new "evidence-based guidelines" is to propose a new management algorithm, and one major revision is to include into the assessment of HRS and WF the imaging findings from endoscopic ultrasound (EUS) and the results of cytological analysis from EUS-guided fine needle aspiration technique, when this is performed. Another key element of the current guidelines is to clarify whether lifetime surveillance for small IPMNs is required, and recommends two options, "stop surveillance" or "continue surveillance for possible development of concomitant pancreatic ductal adenocarcinoma", for small unchanged BD-IPMN after 5 years surveillance. Several other points are also discussed, including identifying high-risk features for recurrence in patients who underwent resection of non-invasive IPMN with negative surgical margin, summaries of the recent observations in the pathology of IPMN. In addition, the emerging role of cyst fluid markers that can aid in distinguishing IPMN from other pancreatic cysts and identify those IPMNs that harbor high-grade dysplasia or invasive carcinoma is discussed.

The multidisciplinary pancreatic cyst clinic: A collaborative approach to streamlined management.

BACKGROUND: Pancreatic cysts are often incidentally detected on routine imaging studies. Of these, mucinous cysts have a malignant potential. Several guidelines propose different management strategies, and implementation in patient care is inconsistent in the absence of dedicated infrastructure. METHODS: To address the challenges of pancreatic cyst diagnosis and management, we established a multidisciplinary pancreas cyst clinic (PCC) within our health system. This clinic encompasses both tertiary care academic centers and community hospitals, with leadership from surgical oncology, gastroenterology, and radiology. Our PCC's primary goal is to provide accurate diagnosis and tailored management recommendations for all patients with pancreatic cysts. Additionally, we maintain a prospective database to study the disease's natural history and the outcomes of various treatment strategies. CLINIC INFRASTRUCTURE: The clinic meets once per week for 45 min virtually via Zoom in the mornings. Patients are referred via electronic medical record (EMR) order, telephone call, or email from patient or referring provider. A dedicated advanced practice provider reviews referrals several times per day, calls patients to gather clinical data, ensures imaging is uploaded, and coordinates logistical aspects of the meeting during the dedicated time. Conferences are attended by representatives from surgery, radiology, medical pancreatology, and interventional gastroenterology. Each patient case is reviewed in detail and recommendations are submitted to referring providers and patients via an EMR message and letter. For patients requiring imaging surveillance, patients are followed longitudinally by the referring provider, gastroenterology team, or surgical team. For patients requiring endoscopic ultrasound (EUS) or surgical consultation, expedited referral to these services is made with prompt subsequent evaluation. RESULTS: A total of 1052 patients from our health system were evaluated between 2020 and 2021. Of these, 196 (18.6 %) underwent EUS, 41 (3.9 %) underwent upfront surgical resection, and the remainder were referred to gastroenterology (141-13.4 %), surgery (314-29.8 %), or back to their referring provider (597-56.7 %) for ongoing surveillance in collaboration with their primary care provider (PCP). Of cysts under surveillance, 61.3 % remained stable, 13.2 % increased in size, and 2 % decreased in size. A total of 2.3 % of patients were recommended to discontinue surveillance. CONCLUSIONS: The PCC provides infrastructure that has served to provide multidisciplinary review and consensus recommendations to patients with pancreatic cysts. This has served to improve the application of guidelines while providing individualized recommendations to each patient, while aiding non-expert referring providers throughout the region.

A Genome-wide Association Study Reveals a Novel Susceptibility Locus for Pancreas Divisum at 3q29.

INTRODUCTION: Pancreas divisum (PD) is a common congenital anomaly of the pancreas, but its genetic basis remains unknown. The purpose of this genome-wide association study was to identify genetic loci associated with PD. METHODS: Using the Mass General Brigham Biobank, patients diagnosed with PD were identified. Quality control and imputation were performed using standard approaches. Single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥ 5% were tested for association with PD using mixed linear model-based association analysis. The significance threshold was set at 5 × 10-8. RESULTS: A total of 13,940 subjects were included, of which 251 (1.8%) were diagnosed with PD. A genetic locus in chromosome 3q29 was found to be associated with PD (lead SNP rs3850646, MAFPD = 34.6% vs. MAFcontrols = 26.4%, beta = 0.0106, P = 1.47 × 10-8). The identified locus is located in the phosphatidylinositol glycan anchor biosynthesis class Xand p21 activated kinase 2genes. The heritability of PD was estimated at 27.5%. (Expression quantitative trait loci) and chromatin interaction analysis found 12 genes whose expression may be regulated by SNPs in this genomic locus. CONCLUSIONS: The results of this study suggest that a genetic locus at 3q29 is associated with PD. This locus is in the phosphatidylinositol glycan anchor biosynthesis class X and p21 activated kinase 2 genes. Twelve candidate genes were identified whose expression may be regulated by this locus. These findings may help us understand both normal and aberrant pancreatic development and may aid in clinical evaluation and genetic counseling of patients with PD and associated diseases, such as acute pancreatitis.

Altered exocrine function can drive adipose wasting in early pancreatic cancer.

Malignancy is accompanied by changes in the metabolism of both cells and the organism1,2. Pancreatic ductal adenocarcinoma (PDAC) is associated with wasting of peripheral tissues, a metabolic syndrome that lowers quality of life and has been proposed to decrease survival of patients with cancer3,4. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic5,6. Here we show that loss of both adipose and muscle tissue occurs early in the development of pancreatic cancer. Using mouse models of PDAC, we show that tumour growth in the pancreas but not in other sites leads to adipose tissue wasting, suggesting that tumour growth within the pancreatic environment contributes to this wasting phenotype. We find that decreased exocrine pancreatic function is a driver of adipose tissue loss and that replacement of pancreatic enzymes attenuates PDAC-associated wasting of peripheral tissues. Paradoxically, reversal of adipose tissue loss impairs survival in mice with PDAC. When analysing patients with PDAC, we find that depletion of adipose and skeletal muscle tissues at the time of diagnosis is common, but is not associated with worse survival. Taken together, these results provide an explanation for wasting of adipose tissue in early PDAC and suggest that early loss of peripheral tissue associated with pancreatic cancer may not impair survival.

Clinical Intricacies and Advances in Neuroendocrine Tumors: An Organ-Based Multidisciplinary Approach.

ABSTRACT: Neuroendocrine neoplasms (NENs) are rare neoplasms originating from neuroendocrine cells, with increasing incidence due to enhanced detection methods. These tumors display considerable heterogeneity, necessitating diverse management strategies based on factors like organ of origin and tumor size. This article provides a comprehensive overview of therapeutic approaches for NENs, emphasizing the role of imaging in treatment decisions. It categorizes tumors based on their locations: gastric, duodenal, pancreatic, small bowel, colonic, rectal, appendiceal, gallbladder, prostate, lung, gynecological, and others. The piece also elucidates the challenges in managing metastatic disease and controversies surrounding MEN1-neuroendocrine tumor management. The article underscores the significance of individualized treatment plans, underscoring the need for a multidisciplinary approach to ensure optimal patient outcomes.

Uncinate Duct Dilatation Predicts Additional Risk for High-Grade Dysplasia or Invasive Carcinoma Among Fukuoka-Positive Intraductal Papillary Mucinous Neoplasms.

OBJECTIVE: To determine whether uncinate duct dilatation (UDD) increases the risk of high-grade dysplasia or invasive carcinoma (HGD/IC) in Fukuoka-positive intraductal papillary mucinous neoplasms (IPMNs). BACKGROUND: Though classified as a branch duct, the uncinate duct is the primary duct of the pancreatic ventral anlage. We hypothesized that UDD, like main duct dilatation, confers additional risk for HGD/IC. METHODS: A total of 467 patients met inclusion criteria in a retrospective cohort study of surgically resected IPMNs at the Massachusetts General Hospital. We used multivariable logistic regression to analyze the association between UDD (defined as ≥4 mm) and HGD/IC, controlling for Fukuoka risk criteria. In a secondary analysis, the modeling was repeated in the 194 patients with dorsal branch duct IPMNs (BD-IPMNs) in the pancreatic neck, body, or tail. RESULTS: Mean age at surgery was 70, and 229 (49%) patients were female. In total, 267 (57%) patients had only worrisome features and 200 (43%) had at least 1 high-risk feature. UDD was present in 164 (35%) patients, of whom 118 (73%) had HGD/IC. On multivariable analysis, UDD increased the odds of HGD/IC by 2.8-fold, even while controlling for Fukuoka risk factors (95% CI: 1.8-4.4, P <0.001). Prevalence of HGD/IC in all patients with UDD was 73%, compared with 74% in patients with high-risk stigmata and 73% in patients with main duct IPMNs. In the secondary analysis, UDD increased the odds of HGD/IC by 3.2-fold in patients with dorsal BD-IPMNs (95% CI: 1.3-7.7, P =0.010). CONCLUSIONS: UDD confers additional risk for HGD/IC unaccounted for by current Fukuoka criteria. Further research can extend this study to Fukuoka-negative patients, including unresected patients.

Underlying Bias in the Treatment of Pancreatic Cancer: Minorities Treated at the Same Facilities are Less Likely to Receive Neoadjuvant Therapy.

OBJECTIVE: To identify disparities in access to NAT for PDAC at the prehospital and intrahospital phases of care. SUMMARY OF BACKGROUND DATA: Delivery of NAT in PDAC is susceptible to disparities in access. There are limited data that accurately locate the etiology of disparities at the prehospital and intrahospital phases of care. METHODS: Retrospective cohort of patients ≥18 years old with clinical stage I-II PDAC from the 2010-2016 National Cancer Database. Multiple logistic regression was used to assess 2 sequential outcomes: (1) access to an NAT facility (prehospital phase) and (2) receipt of NAT at an NAT facility (intrahospital phase). RESULTS: A total of 36,208 patients were included for analysis in the prehospital phase of care. Higher education, longer travel distances, being treated at academic/research or integrated network cancer programs, and more recent year of diagnosis were independently associated with receipt of treatment at an NAT facility. All patients treated at NAT facilities (31,099) were included for the second analysis. Higher education level and receiving care at an academic/research facility were independently associated with increased receipt of NAT. NonBlack racial minorities (including American Indian, Asian, Pacific Islanders), being Hispanic, being uninsured, and having Medicaid insurance were associated with decreased receipt of NAT at NAT facilities. CONCLUSIONS: Non-Black racial minorities and Hispanic patients were less likely to receive NAT at NAT facilities compared to White and non-Hispanic patients, respectively. Discrepancies in administration of NAT while being treated at NAT facilities exist and warrant urgent further investigation.

The Role of Adjuvant Therapy in Duodenal Adenocarcinoma and Intestinal Subtype Ampullary Carcinoma after Curative Resection.

OBJECTIVE: Defining the role of adjuvant therapy in duodenal adenocarcinoma (DAC) and intestinal subtype ampullary carcinoma (iAC). SUMMARY BACKGROUND DATA: DAC and iAC share a similar histological differentiation but the benefit of adjuvant therapy remains unclear. METHODS: Patients undergoing curative-intent surgical resection for DAC and iAC between 2010 and 2021 at five high-volume centers were included. Patient baseline, perioperative and long-term oncological outcomes were evaluated. Statistical testing was performed with SPSS 25 (IBM). RESULTS: A total of 136 patients with DAC and 171 with iAC were identified. Patients with DAC had more advanced tumors than those with iAC. Median overall survival (OS) in DAC patients was 101 months versus 155 months for iAC patients (P=0.098). DAC had a higher rate of local (14.1% vs. 1.2%, P<0.001) and systemic recurrence (30.4% vs. 3.5%, P<0.001). Adjuvant therapy failed to improve overall survival in all patients with DAC and iAC. For DAC, patients with perineural invasion, but not other negative prognostic factors had improved OS rates with adjuvant therapy (72 m vs. 44 m, P=0.044). IAC patients with N+ (190 m vs. 57 m, P=0.003), T3-4 (177 m vs. 59 m, P=0.050) and perineural invasion (150 m vs. 59 m, P=0.019) had improved OS rates with adjuvant therapy. CONCLUSION: While adjuvant therapy fails to improve OS in all patients with DAC and iAC in the current study, it improved overall survival in DAC patients with perineural invasion and in iAC patients with T3-4 tumors, positive lymph nodes, and perineural invasion.

"Evolving Trends in Pancreatic Cystic Tumors: A 3-Decade Single-Center Experience With 1290 Resections".

OBJECTIVE: The aim of this study was to describe our institutional experience with resected cystic tumors of the pancreas with emphasis on changes in clinical presentation and accuracy of preoperative diagnosis. SUMMARY BACKGROUND DATA: Incidental discovery of pancreatic cystic lesions has increased and has led to a rise in pancreatic resections. It is important to analyze surgical outcomes from these procedures, and the prevalence of malignancy, pre-malignancy and resections for purely benign lesions, some of which may be unintended. METHODS: Retrospective review of a prospective database spanning 3 decades. Presence of symptoms, incidental discovery, diagnostic studies, type of surgery, postoperative outcomes, and concordance between presumptive diagnosis and final histopathology were recorded. RESULTS: A total of 1290 patients were identified, 62% female with mean age of 60 years. Fifty-seven percent of tumors were incidentally discovered. Ninety-day operative mortality was 0.9% and major morbidity 14.4%. There were 23 different diagnosis, but IPMN, MCN, and serous cystadenoma comprised 80% of cases. Concordance between preoperative and final histopathological diagnosis increased by decade from 45%, to 68%, and is presently 80%, rising in parallel with the use of endoscopic ultrasound, cytology, and molecular analysis. The addition of molecular analysis improved accuracy to 91%. Of misdiagnosed cases, half were purely benign and taken to surgery with the presumption of malignancy or premalignancy. The majority of these were serous cystadenomas. CONCLUSIONS: Indications and diagnostic work-up of cystic tumors of the pancreas have changed over time. Surgical resection can be performed with very low mortality and acceptable morbidity and diagnostic accuracy is presently 80%. About 10% of patients are still undergoing surgery for purely benign lesions that were presumed to be malignant or premalignant. Further refinements in diagnostic tests are required to improve accuracy.