Sex as a predictor of clinical phenotype and determinant of immune response in IgG4-related disease: a retrospective study of patients fulfilling the American College of Rheumatology-European League Against Rheumatism classification criteria.

BACKGROUND: IgG4-related disease is a multiorgan fibroinflammatory disease considered to have an autoimmune origin. Case series describing individual organ involvement have suggested differences in phenotypic expression between males and females. We aimed to characterise differences in IgG4-related disease manifestations between male and female patients in a large single-centre cohort. METHODS: In this retrospective, single-centre cohort study, patients were recruited from the Massachusetts General Hospital Rheumatology Clinic (Boston, MA, USA) and classified according to the American College of Rheumatology-European Alliance of Associations for Rheumatology (ACR-EULAR) classification criteria. Only patients satisfying the ACR-EULAR classification criteria were included in the study. Data on age at diagnosis, organ involvement at baseline, treatment status, and pre-treatment laboratory values were collected. Circulating plasmablasts and B-cell subsets were quantitated by flow cytometry. Active disease was defined by an IgG4-related disease Responder Index score of more than 0. Laboratory values were analysed for patients who were untreated at baseline and had active IgG4-related disease. The main outcomes were assessed in all participants with available data. FINDINGS: Of the 564 participants enrolled in the Massachusetts General Hospital Rheumatology Clinic IgG4-related disease Registry, 328 fulfilled ACR-EULAR classification criteria and were included between January, 2008, and May, 2023. There was a strong male predominance (male:female ratio 2·2:1) with 226 (69%) males and 102 (31%) females, which contrasted markedly with our general rheumatology clinic population (0·4:1; p<0·001). The male predominance increased with each decade of life starting at age 40 years. On average, male patients were 5·5 years older at diagnosis than female patients (63·7 years vs 58·2 years; p=0·0031). We observed male patients to have higher ACR-EULAR classification criteria scores at baseline with a median score of 35·0 (IQR 28·0-46·0), compared with 29·5 (25·0-39·0) for females (p=0·0010). The proportion of male patients with pancreatic and renal involvement was almost double the proportion observed in female patients (50% of the male patients had pancreatic involvement, compared with about 26% of the female patients; p<0·0001). Male patients were more likely to have serological abnormalities at baseline. The distribution of IgG4 values differed significantly between male an female sexes, favouring higher values in males. We found that male patients with IgG4-related disease were more likely to have active B-cell responses in the blood as defined by plasmablast expansions. INTERPRETATION: IgG4-related disease is unusual among autoimmune diseases in that it is more likely to affect males than females and to present with a striking sex-dependent organ distribution and degree of B-cell response. These findings highlight important variation between IgG4-related disease and other conditions generally believed to have an autoimmune basis. Most autoimmune diseases, by contrast to IgG4-related disease, demonstrate pronounced predilections for affecting females more frequently than males. Hypotheses surrounding the cause and pathophysiology of this condition need to consider this unusual sex distribution among patients with IgG4-related disease. FUNDING: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Rheumatology Research Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

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.

Proliferative features of IgG4-related disease.

IgG4-related disease is an immune-mediated disease that can lead to substantial morbidity and organ damage. Capable of affecting nearly any organ system or anatomic site, and showing considerable overlap in clinical presentation with various other diseases, IgG4-related disease often poses a diagnostic challenge for clinicians. Furthermore, there are no diagnostic biomarkers with high specificity for IgG4-related disease, and histopathological examination is nuanced and requires clinical correlation for accurate diagnosis. Therefore, it is crucial for clinicians to recognise the clinical phenotypes of IgG4-related disease. The disease is generally considered to have predominantly fibrotic and proliferative (or inflammatory) manifestations, with distinct clinical, serological and histopathological findings associated with each manifestation. However, the fibrotic and proliferative manifestations of this disease frequently occur together, thereby blurring this dichotomous distinction. In this Series paper, we provide a detailed overview of the clinical manifestations typical of the proliferative features of IgG4-related disease, with an emphasis on the diagnostic evaluation and differential diagnosis of each proliferative disease manifestation. In addition, we summarise the immune mechanisms underlying IgG4-related disease, suggest a framework for how to approach management and monitoring after the diagnosis is established, and highlight current unmet needs for patient care surrounding this disease.

Current and future advances in practice: IgG4-related disease.

IgG4-related disease (IgG4-RD) is an increasingly recognized cause of fibroinflammatory lesions in patients of diverse racial and ethnic backgrounds and is associated with an increased risk of death. The aetiology of IgG4-RD is incompletely understood, but evidence to date suggests that B and T cells are important players in pathogenesis, both of which are key targets of ongoing drug development programmes. The diagnosis of IgG4-RD requires clinicopathological correlation because there is no highly specific or sensitive test. Glucocorticoids are highly effective, but their use is limited by toxicity, highlighting the need for studies investigating the efficacy of glucocorticoid-sparing agents. B cell-targeted therapies, particularly rituximab, have demonstrated benefit, but no randomized clinical trials have evaluated their efficacy. If untreated or under-treated, IgG4-RD can cause irreversible organ damage, hence close monitoring and consideration for long-term immunosuppression is warranted in certain cases.

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.

A Clinical Guide to the Management of Intraductal Papillary Mucinous Neoplasms: the Need for a More Graded Approach in Clinical Decision-making.

Intraductal papillary mucinous neoplasms (IPMNs) have become a very common diagnosis and represent a spectrum of disease that ranges from benign to malignant lesions. Presently, clinical and radiographic features are used to predict the presence of high-grade dysplasia and invasive cancer to inform treatment decisions of whether to pursuit surgical resection or continued surveillance. However, the natural history of IPMNs is still not completely understood, with guidelines from different societies providing contradictory recommendations. This underscores the challenge in balancing the risk of missing cancer with long-term surveillance and the morbidity associated with surgical resection. In this review, we aim to reconcile the differences in the guidelines' recommendations and provide a clinical framework to the management of IPMNs with hopes of adding clarity to how treatment decisions should be made. We also highlight recent advances made in the field and future efforts that can minimize rates of missing cancer while also reducing the number of unnecessary operations.

IPMN-LEARN: A linear support vector machine learning model for predicting low-grade intraductal papillary mucinous neoplasms.

Backgrounds/Aims: We aimed to build a machine learning tool to help predict low-grade intraductal papillary mucinous neoplasms (IPMNs) in order to avoid unnecessary surgical resection. IPMNs are precursors to pancreatic cancer. Surgical resection remains the only recognized treatment for IPMNs yet carries some risks of morbidity and potential mortality. Existing clinical guidelines are imperfect in distinguishing low-risk cysts from high-risk cysts that warrant resection. Methods: We built a linear support vector machine (SVM) learning model using a prospectively maintained surgical database of patients with resected IPMNs. Input variables included 18 demographic, clinical, and imaging characteristics. The outcome variable was the presence of low-grade or high-grade IPMN based on post-operative pathology results. Data were divided into a training/validation set and a testing set at a ratio of 4:1. Receiver operating characteristics analysis was used to assess classification performance. Results: A total of 575 patients with resected IPMNs were identified. Of them, 53.4% had low-grade disease on final pathology. After classifier training and testing, a linear SVM-based model (IPMN-LEARN) was applied on the validation set. It achieved an accuracy of 77.4%, with a positive predictive value of 83%, a specificity of 72%, and a sensitivity of 83% in predicting low-grade disease in patients with IPMN. The model predicted low-grade lesions with an area under the curve of 0.82. Conclusions: A linear SVM learning model can identify low-grade IPMNs with good sensitivity and specificity. It may be used as a complement to existing guidelines to identify patients who could avoid unnecessary surgical resection.

Nuclear GSK-3ß and Oncogenic KRas Lead to the Retention of Pancreatic Ductal Progenitor Cells Phenotypically Similar to Those Seen in IPMN.

Glycogen synthase kinase-3ß (GSK-3ß) is a downstream target of oncogenic KRas and can accumulate in the nucleus in pancreatic ductal adenocarcinoma (PDA). To determine the interplay between oncogenic KRas and nuclear GSK-3ß in PDA development, we generated Lox-STOP-Lox (LSL) nuclear-targeted GSK-3ß animals and crossed them with LSL-KRasG12D mice under the control of the Pdx1-cre transgene-referred to as KNGC. Interestingly, 4-week-old KNGC animals show a profound loss of acinar cells, the expansion of ductal cells, and the rapid development of cystic-like lesions reminiscent of intraductal papillary mucinous neoplasm (IPMN). RNA-sequencing identified the expression of several ductal cell lineage genes including AQP5. Significantly, the Aqp5+ ductal cell pool was proliferative, phenotypically distinct from quiescent pancreatic ductal cells, and deletion of AQP5 limited expansion of the ductal pool. Aqp5 is also highly expressed in human IPMN along with GSK-3ß highlighting the putative role of Aqp5+ ductal cells in human preneoplastic lesion development. Altogether, these data identify nGSK-3ß and KRasG12D as an important signaling node promoting the retention of pancreatic ductal progenitor cells, which could be used to further characterize pancreatic ductal development as well as lineage biomarkers related to IPMN and PDA.

Number of Worrisome Features and Risk of Malignancy in Intraductal Papillary Mucinous Neoplasm.

BACKGROUND: The 2017 revised International Association of Pancreatology guidelines for management of intraductal papillary mucinous neoplasm (IPMN) describe worrisome features (WF) and high-risk stigmata (HRS), recommending resection in the latter and further work-up and close surveillance for patients with WF. The effect of multiple WF on the likelihood of malignancy has not been evaluated. STUDY DESIGN: Eight hundred ten patients who underwent pancreatic resection for IPMN in 2 tertiary referral centers were identified from prospective institutional databases. Patients were retrospectively categorized into subgroups according to the number of WF or HRS and presence of malignancy, defined as high-grade dysplasia (HGD) or invasive cancer on final pathology. RESULTS: Three hundred seventy-nine (47%) patients had HRS, 370 (46%) had 1 or more WF, and 61 patients (7%) had neither. Malignancy was present in 70% (n = 267) of patients with HRS and in 30% (n = 127) of those with WF. Only 3 of 61 patients without WF/HRS had malignancy, and all only in the form of HGD. The risk of malignancy increased in a stepwise fashion with the number of WF, to 22%, 34%, and 59% with 1, 2, and 3 WF, respectively (p = 0.001), and reached 100% in patients with 4 or more WF. Although the relative risks differed for particular WF, the areas under the curve were not statistically different. CONCLUSION: We confirm that presence of HRS in IPMN is associated with a very high likelihood of malignancy. The presence of a single WF has a malignancy risk of 22%, and additional WF increase this risk significantly. When 3 or more WF are present, the risk is similar to that of HRS.

Using A Customized SMS Program to Promote Colonoscopy Adherence and Support Bowel Cleanliness for Spanish-speaking Patients.

INTRODUCTION: Low colorectal cancer (CRC) screening rates among Hispanic and Latino patients result in advanced disease at the time of diagnosis and decreased survival chances. METHODS: We performed a prospective study at an academic endoscopy center in Boston, Massachusetts from May 1, 2019 to January 31, 2020. We identified 887 Spanishspeaking patients as controls and enrolled 412 (59%) Spanish-speaking patients in a short message service (SMS) program for pre-procedure instructions. RESULTS: Intervention and control group participants were similar in age, sex, and indications. Patients receiving SMS messages were less likely to no-show or cancel last minute (OR=1.66, 95%CI=0.44-0.83, p=.002) and had more adequate bowel preparations compared with the control arm (OR=1.55, 95%CI=0.45-0.92, p=.01). Overall, 93% (117/126) of patients stated they would "highly recommend" the program to others. CONCLUSIONS: Our automated SMS reminders for colonoscopy preparation increased appointment adherence, bowel preparation quality, and showed good patient satisfaction among Spanish speakers.

ABO blood group distribution and risk of malignancy in patients undergoing resection for intraductal papillary mucinous neoplasm (IPMN).

BACKGROUND: The ABO blood type has been associated with risk of development of several malignancies, including pancreatic cancer. Data regarding IPMN is equivocal. To investigate this further, we analyzed the association between the ABO blood group and the presence of malignancy in a large cohort of resected IPMN and its influence in survival. METHODS: 819 patients who underwent pancreatic resection for IPMN in the Massachusetts General Hospital (MGH) and Cambridge University Hospitals NHS Foundation Trust (CUH) from January 1993 to December 2020 were identified from prospective institutional databases. Pathological characteristics and blood type were correlated. RESULTS: The distribution of blood types A, B, AB and O was 384 (47%), 92 (11%), 44 (5%) and 299 (37%), respectively. This blood type distribution was different than the reference population of the MGH and the CUH, which is 55% non-O blood group, and 45% type O. There was a significant predominance of non-O blood types when compared with O-blood type in patients with malignant IPMN (i.e. patients with high-grade dysplasia and invasive cancer) (67% vs 33%, OR 1.31 95%CI: 0.98-1.75, p = 0.069). The association was stronger for IPMN with invasive cancer (OR 1.43 95%CI: 1.01-2.02, p = 0.039). Blood group did not influence survival. CONCLUSION: Non-O blood type is associated with need for resection in IPMN and with presence of invasive carcinoma.

Outcomes of EUS-guided transluminal gallbladder drainage in patients without cholecystitis.

BACKGROUND AND OBJECTIVES: Cholecystectomy is the gold standard for most gallbladder-related disease. However, many patients with gallbladder disease are poor surgical candidates. Current nonsurgical gallbladder drainage (GBD) methods include percutaneous cholecystostomy and endoscopic ultrasound-guided transluminal GBD (EUS-GBD). Outcomes for EUS-GBD for the treatment of noncholecystitis (NC) gallbladder disease have not been defined. MATERIALS AND METHODS: Cases were identified using procedural data from a quaternary academic hospital for endoscopic procedures from 2015 to 2020. Patients who underwent EUS-GBD for acute cholecystitis, biliary colic, gallstone pancreatitis, and secondary prevention of gallstone disease were included. RESULTS: Fifty-five cases of EUS-GBD were identified over the 5-year study period. Forty-one cases were performed for acute cholecystitis, and 15 were performed for other NC indications. Indications for NC drainage included primary treatment of symptomatic biliary colic and secondary prevention of gallstone pancreatitis and choledocholithiasis. There was no statistically significant difference in complications, mortality, or reintervention requirements. There was a 13.3% rate of immediate complications in the NC group, which were all medically managed. CONCLUSIONS: EUS-GBD appears to be a safe and effective way to manage gallstone disease in nonsurgical candidates with NC gallbladder-related disease. Overall complications and readmissions were infrequent. Complication rates were similar to those published in patients who underwent EUS-GBD for acute cholecystitis.

Pancreatic acinar cell carcinoma: A multi-center series on clinical characteristics and treatment outcomes.

BACKGROUND: Acinar cell carcinoma (ACC) is a very rare tumor of the exocrine pancreas, representing less than 1% of all pancreatic malignancies. The majority of data regarding ACC are limited to small case series. METHODS: This is a retrospective study conducted at a large healthcare system from 1996 to 2019. Patients with pathologically confirmed ACC were included, and demographic data, tumor characteristics, and treatment outcomes were abstracted by chart review. Survival curves were obtained by using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Sixty-six patients with ACC were identified. The median patient age at diagnosis was 64, and 42% presented with metastatic disease. The majority presented with abdominal pain or pancreatitis (69%), and laboratory parameters did not correlate with tumor size, metastatic disease, or survival. Several somatic abnormalities were noted in tumors (BRCA2, TP53, and mismatch-repair genes). In patients with localized disease that underwent resection, the median time to develop metastatic lesions was 13 months. The median overall survival (OS) was 24.7 months from diagnosis, with a survival difference based on metastatic disease at diagnosis (median 15 vs 38 mos). Surgery was associated with improved survival in non-metastatic cases (p = 0.006) but not metastatic cases (p = 0.22), and chemotherapy showed OS benefit in metastatic disease (p < 0.01). Patients with metastatic ACC treated after 2010 utilized more platinum-based agents, and there was a OS benefit to FOLFOX or FOLFIRINOX chemotherapy compared to gemcitabine or capecitabine-based regimens (p = 0.006). CONCLUSION: Pancreatic ACC patients often present with advanced disease. Surgery was associated with survival benefit among patients presenting with localized disease. The use of FOLFOX or FOLFIRINOX chemotherapy regimens was associated with improved OS in metastatic patients. These data add to our knowledge in this rare malignancy, and improves understanding about the genomic underpinnings, prognosis and treatment for acinar cancers.

Preoperative cholangitis is an independent risk factor for mortality in patients after pancreatoduodenectomy for pancreatic cancer.

OBJECTIVES: Preoperative biliary stenting is required for patients with obstructive jaundice from pancreatic adenocarcinoma who are receiving neoadjuvant chemotherapy. While in most patients this approach results in durable biliary drainage, some patients develop cholangitis during neoadjuvant treatment. Further, several studies have shown that preoperative cholangitis in patients with hepatobiliary malignancies can result in substantially unfavorable outcomes. The aim of this study was to evaluate the impact of preoperative cholangitis in patients who underwent pancreaticoduodenectomy after completing neoadjuvant chemotherapy. METHODS: Participants: all adult patients (n = 449) diagnosed with pancreatic adenocarcinoma from January 1st, 2013 to March 31st, 2018 who pursued treatment at the Massachusetts General Hospital were screened. Of these 449 patients, 97 met final inclusion criteria of receiving neoadjuvant chemotherapy with intent to pursue curative surgery. Data were collected via retrospective chart review including baseline characteristics, survival, episodes of preoperative cholangitis, and surgical complications. RESULTS: In patients completing successful pancreaticoduodenectomy surgery, preoperative cholangitis is associated with increased mortality (HR 2.67, 95% CI:1.16-6.13). This finding is independent of postoperative outcomes or tumor recurrence rate. The presence of cholangitis did not impact completion of neoadjuvant chemotherapy (92% vs 85%, p = 0.5) or ability to proceed to surgery (76% vs 75%, p = 1.0). Preoperative cholangitis was not associated with postoperative morbidity (42.1% vs 45.1%, p = 1.0). CONCLUSIONS: One episode of cholangitis during neoadjuvant chemotherapy is associated with increased mortality following successful pancreaticoduodenectomy, independent of immediate postoperative outcomes or tumor recurrence. Preoperative cholangitis does not affect ability to pursue neoadjuvant chemotherapy or complete successful surgery. Patients who develop cholangitis during the neoadjuvant chemotherapy treatment phase may reflect a distinct phenotype of patients with PDAC with a complex and more challenging clinical course.

Evaluating triage protocols for endoscopic ultrasound-guided fine needle biopsies of the pancreas.

INTRODUCTION: Pancreatic endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) acquires both direct smear and small core biopsy specimens. The triage protocols for pancreatic FNBs to cytopathology (CP) or gastrointestinal surgical pathology (GIP) are controversial and vary by institution. MATERIAL AND METHODS: Pancreatic EUS-FNBs obtained with the SharkCore FNB were reviewed from January 2014 to June 2019. The specimen characteristics and pathology data, including tissue triage, were obtained from the electronic medical records. We assessed the diagnostic yield, defined as malignant, specific neoplastic, or benign, and the operating characteristics at the time of rapid on-site evaluation (ROSE) and final diagnosis. RESULTS: We reviewed 324 pancreatic FNBs from 313 patients. Of the 324 FNBs, 260 (80%) obtained concurrent direct smear and core biopsy specimens, 30 (12%) of which were divided between CP and GIP. Of the 51 core-only specimens, 47 (92%) were reviewed by CP and 4 (8%) by GIP. ROSE improved the overall diagnostic yield by 10% and accuracy by 9%. When core specimens were reviewed independently, the diagnostic accuracy was 93% for CP (n = 248) and 100% for GIP (n = 33). All false-negative results of the CP-reviewed cores were due to sampling error. Concurrent smear review improved EUS-FNB performance, increasing the negative predictive value by 10% and accuracy by 3% compared with core review alone. CONCLUSIONS: CP and GIP can accurately interpret pancreatic EUS-FNB specimens. However, triage of concurrent EUS-FNB-acquired smear and core specimens to CP may be most efficient as CPs are trained to assess adequacy at the time of ROSE, as well as interpret all parts of the biopsy, minimizing the risk of discordant pathology reports.