Biliary complications after adult-to-adult living-donor liver transplantation: An international multicenter study of 3633 cases.

In living-donor liver transplantation, biliary complications including bile leaks and biliary anastomotic strictures remain significant challenges, with incidences varying across different centers. This multicentric retrospective study (2016-2020) included 3633 adult patients from 18 centers and aimed to identify risk factors for these biliary complications and their impact on patient survival. Incidences of bile leaks and biliary strictures were 11.4% and 20.6%, respectively. Key risk factors for bile leaks included multiple bile duct anastomoses (odds ratio, [OR] 1.8), Roux-en-Y hepaticojejunostomy (OR, 1.4), and a history of major abdominal surgery (OR, 1.4). For biliary anastomotic strictures, risk factors were ABO incompatibility (OR, 1.4), blood loss >1 L (OR, 1.4), and previous abdominal surgery (OR, 1.7). Patients experiencing biliary complications had extended hospital stays, increased incidence of major complications, and higher comprehensive complication index scores. The impact on graft survival became evident after accounting for immortal time bias using time-dependent covariate survival analysis. Bile leaks and biliary anastomotic strictures were associated with adjusted hazard ratios of 1.7 and 1.8 for graft survival, respectively. The study underscores the importance of minimizing these risks through careful donor selection and preoperative planning, as biliary complications significantly affect graft survival, despite the availability of effective treatments.

An Analysis of 10,000 Cases of Living Donor Liver Transplantation in Japan: Special Reference to the Graft-Versus-Recipient Weight Ratio and Donor Age.

OBJECTIVE: To analyze 10,000 cases of living donor liver transplantation (LDLT) recipient data to elucidate outcomes with special reference to the graft-versus-recipient weight ratio (GRWR), based on the Japanese Liver Transplantation Society (JLTS) registry. BACKGROUND: The JLTS registry has been accurate and complete in characterizing and following trends in patient characteristics and survival of all patients with LDLT. METHODS: Between November 1989 and August 2021, 10,000 patients underwent LDLT in Japan. The procedures performed during the study period included pediatric liver transplantation (age <18 years, n = 3572) and adult liver transplantation (age ≥18 years, n=6428). Factors related to patient survival (PS) and graft survival (GS) were also analyzed. RESULTS: The GRWR was <0.7, 0.7 to <0.8, 0.8 to <3, 3 to <5, and ≥5 in 0.2%, 2.0%, 61.8%, 31.8%, and 2.6% of pediatric patients and <0.6, 0.6 to <0.7, 0.7 to <0.8, and ≥0.8 in 8.0%, 12.7%, 17.7%, and 61.5% of adult patients, respectively. Among pediatric recipients, the PS rate up to 5 years was significantly better in cases with a GRWR ≤5 than in those with a GRWR >5. When the GRWR and donor age were combined, among adult recipients 50 to 60 years old, the early PS and GS up to 5 years were significantly better in cases with a GRWR ≥0.7, than in those with a GRWR <0.7. (P = 0.02). In adults, a multivariate analysis showed that GRWR <0.6, transplant era (<2011), donor age (>60 years), recipient age (>60 years), model for end-stage liver disease score (≥20), and center volume (<10) were significant prognostic factors for long-term PS. CONCLUSION: Although a satisfactory long-term PS and GS, especially in the recent era (2011-2021), was achieved in the JLTS series, a GRWR ≥5 in pediatric cases and relatively old donors with a GRWR <0.7 in adult cases should be managed with caution.

Intraductal Papillary Mucinous Neoplasm Surveillance Leads to Early Diagnosis and Better Outcomes of Concomitant Cancer.

OBJECTIVE: To examine whether long-term surveillance of intraductal papillary mucinous neoplasms (IPMNs) leads to early diagnosis and better clinical outcomes of pancreatic ductal adenocarcinomas (PDACs) developing concomitantly with IPMNs. SUMMARY BACKGROUND DATA: Long-term image-based surveillance is recommended for patients with low-risk IPMNs. However, it is unknown whether the surveillance can improve surgical and survival outcomes of patients with concomitant PDACs. METHODS: Using a prospective single-institutional cohort of 4,620 patients with pancreatic cysts including 3,638 IPMN patients, we identified 63 patients who developed concomitant PDAC during long-term surveillance. We compared overall survival (OS) of 46 cases with concomitant PDAC to that of 460 matched cases diagnosed with non-IPMN-associated PDAC at the same institution. Multivariable hazard ratios and 95% confidence intervals (CIs) for overall mortality were computed using the Cox regression model with adjustment for potential confounders. RESULTS: Concomitant PDACs were identified at an earlier cancer stage compared to non-IPMN-associated PDACs with 67% and 38% cases identified at stage 2 or earlier, respectively (P<0.001) and 57% and 21% cases with R0 resection, respectively (P<0.001). Compared to non-IPMN-associated PDACs, concomitant PDACs were associated with longer OS (P=0.034) with a multivariable hazard ratio of 0.61 (95% CI, 0.39-0.96). The 5-year survival rate of patients with concomitant PDAC was higher compared to patients with non-IPMN-associated PDAC (34% vs. 18%, respectively; P=0.018). CONCLUSIONS: The surveillance for patients with IPMNs was associated with early identification of concomitant PDACs and longer survival of patients diagnosed with this malignancy.

Propensity Score-matched Analysis Comparing Robotic Versus Laparoscopic Minor Liver Resections of the Anterolateral Segments: an International Multi-center Study of 10,517 Cases.

OBJECTIVE: To compare the outcomes of robotic minor liver resections (RMLR) versus laparoscopic (L) MLR of the anterolateral segments. BACKGROUND: Robotic liver surgery has been gaining prominence over the years with increasing usage for a myriad of hepatic resections. Robotic liver resections(RLR) has demonstrated non-inferiority to laparoscopic(L)LR while illustrating advantages over conventional laparoscopy especially for technically difficult and major LR. However, the advantage of RMLR for the anterolateral(AL) (segments II, III, IVb, V and VI) segments, has not been clearly demonstrated. METHODS: Between 2008 to 2022, 15,356 of 29,861 patients from 68 international centres underwent robotic(R) or laparoscopic minor liver resections (LMLR) for the AL segments Propensity score matching (PSM) analysis was performed for matched analysis. RESULTS: 10,517 patients met the study criteria of which 1,481 underwent RMLR and 9,036 underwent LMLR. A PSM cohort of 1,401 patients in each group were identified for analysis. Compared to the LMLR cohort, the RMLR cohort demonstrated significantly lower median blood loss (75ml vs. 100ml, P<0.001), decreased blood transfusion (3.1% vs. 5.4%, P=0.003), lower incidence of major morbidity (2.5% vs. 4.6%, P=0.004), lower proportion of open conversion (1.2% vs. 4.5%, P<0.001), shorter post operative stay (4 days vs. 5 days, P<0.001), but higher rate of 30-day readmission (3.5% vs. 2.1%, P=0.042). These results were then validated by a 1:2 PSM analysis. In the subset analysis for 3,614 patients with cirrhosis, RMLR showed lower median blood loss, decreased blood transfusion, lower open conversion and shorter post operative stay than LMLR. CONCLUSION: RMLR demonstrated statistically significant advantages over LMLR even for resections in the AL segments although most of the observed clinical differences were minimal.

The Revised Kyoto Criteria and Risk of Malignancy Among Patients With Intraductal Papillary Mucinous Neoplasms.

BACKGROUND & AIMS: The revised Kyoto guidelines have a new catalog of high-risk stigmata and worrisome features for the risk stratification of intraductal papillary mucinous neoplasms (IPMNs). We aimed to validate the stratification system in terms of short- and long-term risks of pancreatic carcinoma. METHODS: We included 3336 patients diagnosed with IPMNs in 2000-2021 and examined short-term (≤6 months) and long-term risks of pancreatic carcinoma diagnosis. We used the multivariable competing-risks proportional hazards regression model to calculate subdistribution hazard ratios for long-term incidence of pancreatic carcinoma with adjustment for potential confounders. RESULTS: In short-term analyses, pancreatic carcinomas were prevalent predominantly in IPMNs with high-risk stigmata (49% vs 1.3% and 0.05% in IPMNs with worrisome features and no risk factors, respectively). In long-term analyses of worrisome features, the main pancreatic duct diameter of 5-9.9 mm, acute pancreatitis, and IPMN growth rate of 2.5 mm/y were associated with a high incidence with multivariable subdistribution hazard ratios of 3.46 (95% confidence interval [CI], 2.04-5.89), 5.65 (95% CI, 1.86-17.2), and 3.83 (95% CI, 2.14-6.86), respectively. An increasing number of worrisome features at baseline was associated with a higher prevalence and incidence of pancreatic carcinoma (Ptrend < .001). Patients with 1, 2, and 3-4 worrisome features had multivariable subdistribution hazard ratios for pancreatic cancer incidence of 1.43 (95% CI, 0.93-2.19), 2.17 (95% CI, 1.17-4.05), and 10.1 (95% CI, 4.20-24.5), respectively (vs no positive feature). CONCLUSIONS: The revised Kyoto criteria stratify IPMN patients well in terms of the short- and long-term risks of pancreatic carcinoma diagnosis, potentially informing personalized patient management.

Older Age as a Worrisome Feature in Patients With Intraductal Papillary Mucinous Neoplasms: A Long-Term Surveillance Study.

INTRODUCTION: Aging has been implicated in the development of various cancer types. No study has specifically investigated age at intraductal papillary mucinous neoplasm (IPMN) diagnosis in relation to the long-term risk of pancreatic carcinogenesis. METHODS: Within a prospective cohort of 4,104 patients diagnosed with pancreatic cysts, we identified 3,142 patients with IPMNs and examined an association of age at IPMN diagnosis with the incidence of pancreatic carcinoma. Using the multivariable competing-risks proportional hazards regression model, we estimated subdistribution hazard ratios (SHRs) and 95% confidence intervals (CIs) for pancreatic carcinoma incidence according to age at IPMN diagnosis. RESULTS: During 22,187 person-years of follow-up, we documented 130 patients diagnosed with pancreatic carcinoma (64 with IPMN-derived carcinoma and 66 with concomitant ductal adenocarcinoma). Older age at IPMN diagnosis was associated with a higher risk of pancreatic cancer incidence ( Ptrend = 0.002). Compared with patients younger than 55 years, patients aged 55-64, 65-74, and ≥ 75 years had adjusted SHRs of 1.80 (95% CI, 0.75-4.32), 2.56 (95% CI, 1.10-5.98), and 3.31 (95% CI, 1.40-7.83), respectively. Patients aged 70 years and older had a numerically similar adjusted SHR compared with patients younger than 70 years with worrisome features defined by the international consensus guidelines (1.73 [95% CI, 1.01-2.97] and 1.66 [95% CI, 0.89-3.10], respectively). DISCUSSION: Older patients with IPMNs were at a higher risk of developing pancreatic carcinoma during surveillance. Surgically fit elderly patients may be good candidates for periodic surveillance aimed at a reduction of pancreatic cancer-related deaths.

Is Repeat Resection for Recurrent Intrahepatic Cholangiocarcinoma Warranted? Outcomes of an International Analysis.

BACKGROUND: Recurrence of intrahepatic cholangiocarcinoma (ICC) after liver resection (LR) remains high, and optimal therapy for recurrent ICC is challenging. Herein, we assess the outcomes of patients undergoing repeat resection for recurrent ICC in a large, international multicenter cohort. PATIENTS AND METHODS: Outcomes of adults from six large hepatobiliary centers in North America, Europe, and Asia with recurrent ICC following primary LR between 2001 and 2015 were analyzed. Cox models determined predictors of post-recurrence survival. RESULTS: Of patients undergoing LR for ICC, 499 developed recurrence. The median time to recurrence was 10 months, and 47% were intrahepatic. Overall 3-year post-recurrence survival rate was 28.6%. In total, 121 patients (25%) underwent repeat resection, including 74 (61%) repeat LRs. Surgically treated patients were more likely to have solitary intrahepatic recurrences and significantly prolonged survival compared with those receiving locoregional or systemic therapy alone with a 3-year post-recurrence survival rate of 47%. Independent predictors of post-recurrence death included time to recurrence < 1 year [HR 1.66 (1.32-2.10), p < 0.001], site of recurrence [HR 1.74 (1.28-2.38), p < 0.001], macrovascular invasion [HR 1.43 (1.05-1.95), p = 0.024], and size of recurrence > 3 cm [HR 1.68 (1.24-2.29), p = 0.001]. Repeat resection was independently associated with decreased post-recurrence death [HR 0.58 0.43-0.78), p < 0.001]. CONCLUSIONS: Repeat resection for recurrent ICC in select patients can result in extended survival. Thus, challenging the paradigm of offering these patients locoregional or chemo/palliative therapy alone as the mainstay of treatment.

Outcomes after distal pancreatectomy with or without splenectomy for intraductal papillary mucinous neoplasm: international multicentre cohort study.

BACKGROUND: International guidelines on intraductal papillary mucinous neoplasm (IPMN) recommend a formal oncological resection including splenectomy when distal pancreatectomy is indicated. This study aimed to compare oncological and surgical outcomes after distal pancreatectomy with or without splenectomy in patients with presumed IPMN. METHODS: An international, retrospective cohort study was undertaken in 14 high-volume centres from 7 countries including consecutive patients after distal pancreatectomy for IPMN (2005-2019). Patients were divided into spleen-preserving distal pancreatectomy (SPDP) and distal pancreatectomy with splenectomy (DPS). The primary outcome was lymph node metastasis (LNM). Secondary outcomes were overall survival, duration of operation, blood loss, and secondary splenectomy. RESULTS: Overall, 700 patients were included after distal pancreatectomy for IPMN; 123 underwent SPDP (17.6%) and 577 DPS (82.4%). The rate of malignancy was 29.6% (137 patients) and the overall rate of LNM 6.7% (47 patients). Patients with preoperative suspicion of malignancy had a LNM rate of 17.2% (23 of 134) versus 4.3% (23 of 539) among patients without suspected malignancy (P < 0.001). Overall, SPDP was associated with a shorter operating time (median 180 versus 226 min; P = 0.001), less blood loss (100 versus 336 ml; P = 0.001), and shorter hospital stay (5 versus 8 days; P < 0.001). No significant difference in overall survival was observed between SPDP and DPS for IPMN after correction for prognostic factors (HR 0.50, 95% c.i. 0.22 to 1.18; P = 0.504). CONCLUSION: This international cohort study found LNM in 6.7% of patients undergoing distal pancreatectomy for IPMN. In patients without preoperative suspicion of malignancy, SPDP seemed oncologically safe and was associated with improved short-term outcomes compared with DPS.

Evaluation of pancreatic chymotrypsin activity for on-site prediction of clinically relevant postoperative pancreatic fistula.

OBJECTIVES: Although the risk of complications due to postoperative pancreatic fistula (POPF) have been evaluated based on the amylase level in drained ascitic fluid, this method has much room for improvement regarding diagnostic accuracy and facility of the measurement. This study aimed to investigate the clinical value of measuring pancreatic chymotrypsin activity for rapid and accurate prediction of POPF after pancreaticoduodenectomy. METHODS: In 52 consecutive patients undergoing pancreaticoduodenectomy, the chymotrypsin activity in pancreatic juice was measured by calculating the increase in fluorescence intensity during the first 5 min after activation with an enzyme-activatable fluorophore. The predictive value for clinically relevant POPF (CR-POPF) was compared between this technique and the conventional method based on the amylase level. RESULTS: According to receiver operating characteristic analyses, pancreatic chymotrypsin activity on postoperative day (POD) 3 measured with a multiplate reader had the highest predictive value for CR-POPF (area under the curve [AUC], 0.752; P < 0.001), yielding 77.8 % sensitivity and 68.8 % specificity. The AUC and sensitivity/specificity of the amylase level in ascitic fluid on POD 3 were 0.695 (P = 0.053) and 77.8 %/41.2 %, respectively. Multivariable analysis identified high pancreatic chymotrypsin activity on POD 3 as an independent risk factor for CR-POPF. Measurement of pancreatic chymotrypsin activity with a prototype portable fluorescence photometer could significantly predict CR-POPF (AUC, 0.731; P = 0.010). CONCLUSION: Measurement of pancreatic chymotrypsin activity enabled accurate and rapid prediction of CR-POPF after pancreaticoduodenectomy. This can help surgeons to implement appropriate drain management at the patient's bedside without delay.

Genetic alteration of SLCO1B3 defines constitutional indocyanine green excretory defect in patients who underwent hepatectomy.

AIM: Constitutional indocyanine green (ICG) excretory defects must be distinguished when assessing liver function. The absence of OATP1B3 expression due to homogenous alterations in the SLCO1B3 gene has been recently reported to induce ICG excretory defects; however, its association with the clinical examinations and the clinical implications of heterogeneous SLCO1B3 gene alteration remain unclear. METHODS: OATP1B3 expression was evaluated in 49 patients who underwent hepatectomy after evaluation of the ICG retention rate at 15 min (ICGR15) and technetium-99 m-galactosyl serum albumin (99mTc-GSA) hepatic scintigraphy. Additionally, alterations in SLCO1B3 were analyzed in patients without OATP1B3 expression. Subsequently, 59 patients who underwent hepatectomy for colorectal liver metastasis (CRLM) were analyzed. RESULTS: Of 49 patients, 6 (12%) had absent OATP1B3 expression. They had significantly higher ICGR15 value (74.7% vs. 23.5%; p < 0.0001), better modified albumin-bilirubin (ALBI) grade (≤grade 2A, 100% vs. 42%; p = 0.010), more normal 99mTc-GSA hepatic scintigraphy (100% vs. 28%; p = 0.0003), and better pathological liver fibrosis (F0-1, 100% vs. 49%; p = 0.027) compared to those with OATP1B3 expression. Three available frozen blocks of cases without OATP1B3 expression showed homozygous alterations in SLCO1B3. Of 59 patients with CRLM in normal liver background, five (8.5%) had heterozygous insertion in SLCO1B3, however they had no difference in ICGR15 values or other clinical findings compared to the other patients. CONCLUSIONS: Constitutional ICG excretory defects may be defined by the complete absence of OATP1B3 expression. The modified ALBI grade and 99mTc-GSA hepatic scintigraphy were useful for detecting constitutional ICG excretory defects.

c-Met inhibitor upregulates E-cadherin, which is lost in portal vein tumor thrombus of hepatocellular carcinoma.

AIM: Portal vein tumor thrombus (PVTT) in hepatocellular carcinoma (HCC) is an essential therapeutic and prognostic factor. E-cadherin plays a crucial role in adhesive properties and intercellular interaction in various cancer tissues, including HCC, but the expression profile and functional contribution of E-cadherin in PVTT remain unknown. This study aimed to analyze the expression of E-cadherin in the main tumor tissue and PVTT tissue of HCC, and evaluate the functional roles of E-cadherin in PVTT formation. METHODS: A retrospective analysis was performed using the medical records of patients who underwent liver resection for HCC with PVTT, analyzing tissue specimens from 1995 to 2016. E-cadherin expression is evaluated using immunohistochemistry and western blot. The study also uses a c-Met inhibitor to explore its impact on E-cadherin expression in vitro and in vivo using cell lines and a tumor xenograft mouse model. RESULTS: The results revealed a reduced E-cadherin expression in PVTT tissue than in the main tumor tissue. The inhibition of c-Met activation, frequently detected in HCC, upregulated E-cadherin expression in HCC cell lines. Furthermore, treatment with c-Met inhibitors induced changes in epithelial morphology, and inhibited migration and invasion of HCC cell lines. CONCLUSIONS: This study demonstrates the downregulation of E-cadherin in PVTT, and underscores the potential of c-Met inhibition in upregulating E-cadherin and inhibiting metastatic behavior. Understanding the significance of E-cadherin and c-Met in HCC progression provides a foundation for future clinical investigations into the therapeutic effects of c-Met inhibitors on PVTT in HCC patients.

Fatal Hyperacute Liver Failure due to Varicella Zoster Virus Immediately After Living-Donor Liver Transplantation: A Case Report and Review of the Literature.

BACKGROUND: Although acute hepatitis caused by varicella zoster virus mostly develops in immunocompromised patients, hyperacute liver failure is very rare. To our knowledge, there are no previous reports on liver transplant patients. METHODS: We report the first case of fatal hyperacute liver failure due to varicella zoster virus immediately after living-donor liver transplantation without cutaneous lesions and review the literature. RESULT: The present case exhibited rapid development and progression of acute liver failure from postoperative days 11-13, despite being seropositive for varicella zoster virus but unvaccinated and on immunosuppression before transplantation. Especially in solid organ transplantation, only six cases of severe acute liver failure that included hepatic encephalopathy and/or impaired consciousness and sudden extremely high (> 4000 U/L) serum aspartate aminotransferase levels have been reported in heart, lung, and kidney transplant patients. CONCLUSIONS: Early diagnosis of hyperacute liver failure due to varicella zoster virus is challenging because the disease progresses rapidly and skin lesions are absent.

Liver Resection for Hepatocellular Carcinoma With Tumor Thrombus in the Inferior Vena Cava or Right Atrium: A Large-scale Multicenter Survey Conducted in Japan.

OBJECTIVE: To clarify the short and long-term postoperative outcomes and surgical indications for patients accompanied by hepatocellular carcinoma with tumor thrombus (TT) in the inferior vena cava (IVC) or right atrium (RA). BACKGROUND: These patients are known to have an extremely poor prognosis; however, the postoperative outcomes have not been fully verified because of the rarity of this disease. METHODS: We contacted 211 specialized centers in Japan and collected data on liver resection for hepatocellular carcinoma with TT in the IVC or RA from centers with experience performing surgery for such patients. The patient characteristics, operative procedures, and surgical outcomes were then analyzed. RESULTS: A total of 119 patients from 23 institutions were enrolled; 49 patients had TT in the IVC below the diaphragm (type I), 42 had TT in the IVC above the diaphragm (type II), and 28 had TT entering the RA (type III). The severity and frequency of postoperative complications did not differ among the 3 groups. There was one surgery-related death in the type III group. The median survival times were 2.47 years in the type I group, 1.77 years in the type II group, and 1.02 years in the type III group. Multivariate analysis identified an indocyanine green retention rate at 15 minutes >15% and ≥3 tumors as prognostic factors affecting survival, whereas the use of cardiopulmonary bypass and ≥3 tumors were risk factors for recurrence. CONCLUSIONS: As the postoperative prognosis of patients with type I or type II disease and of patients with no risk factors is relatively good, surgery should be considered for these patient populations.

Novel Benchmark for Adult-to-Adult Living-donor Liver Transplantation: Integrating Eastern and Western Experiences.

OBJECTIVE: To define benchmark values for adult-to-adult living-donor liver transplantation (LDLT). BACKGROUND: LDLT utilizes living-donor hemiliver grafts to expand the donor pool and reduce waitlist mortality. Although references have been established for donor hepatectomy, no such information exists for recipients to enable conclusive quality and comparative assessments. METHODS: Patients undergoing LDLT were analyzed in 15 high-volume centers (≥10 cases/year) from 3 continents over 5 years (2016-2020), with a minimum follow-up of 1 year. Benchmark criteria included a Model for End-stage Liver Disease ≤20, no portal vein thrombosis, no previous major abdominal surgery, no renal replacement therapy, no acute liver failure, and no intensive care unit admission. Benchmark cutoffs were derived from the 75th percentile of all centers' medians. RESULTS: Of 3636 patients, 1864 (51%) qualified as benchmark cases. Benchmark cutoffs, including posttransplant dialysis (≤4%), primary nonfunction (≤0.9%), nonanastomotic strictures (≤0.2%), graft loss (≤7.7%), and redo-liver transplantation (LT) (≤3.6%), at 1-year were below the deceased donor LT benchmarks. Bile leak (≤12.4%), hepatic artery thrombosis (≤5.1%), and Comprehensive Complication Index (CCI ® ) (≤56) were above the deceased donor LT benchmarks, whereas mortality (≤9.1%) was comparable. The right hemiliver graft, compared with the left, was associated with a lower CCI ® score (34 vs 21, P < 0.001). Preservation of the middle hepatic vein with the right hemiliver graft had no impact neither on the recipient nor on the donor outcome. Asian centers outperformed other centers with CCI ® score (21 vs 47, P < 0.001), graft loss (3.0% vs 6.5%, P = 0.002), and redo-LT rates (1.0% vs 2.5%, P = 0.029). In contrast, non-benchmark low-volume centers displayed inferior outcomes, such as bile leak (15.2%), hepatic artery thrombosis (15.2%), or redo-LT (6.5%). CONCLUSIONS: Benchmark LDLT offers a valuable alternative to reduce waitlist mortality. Exchange of expertise, public awareness, and centralization policy are, however, mandatory to achieve benchmark outcomes worldwide.

Clinical Outcomes of Intraductal Papillary Mucinous Neoplasms With Dilatation of the Main Pancreatic Duct.

BACKGROUND & AIMS: Dilatation of the main pancreatic duct (MPD) has been a surgical indication for intraductal papillary mucinous neoplasms (IPMNs). Few studies have investigated long-term outcomes of IPMNs with MPD dilatation. METHODS: Among 3610 patients diagnosed with pancreatic cysts between 1994 and 2021, we identified 2829 IPMN patients, including 282 patients with MPD ≥5 mm, and examined short-term (≤6 months) and long-term risks of pancreatic carcinoma. Utilizing competing risks proportional hazards models, we estimated subdistribution hazard ratios for incidence of pancreatic carcinoma with adjustment for potential confounders. RESULTS: In analyses of short-term outcomes of the 282 patients with MPD dilatation, 72 (26%) patients were diagnosed with pancreatic carcinoma based on surgical or nonsurgical exploration. During long-term follow-up of 168 patients, we documented 24 (14%) patients diagnosed with pancreatic carcinoma (18 with IPMN-derived carcinoma and 6 with concomitant ductal adenocarcinoma). The patients with the MPD = 5-9.9 mm had cumulative incidence rates of pancreatic carcinoma diagnosis of 8.1% (95% confidence interval [CI], 4.3%-13.5%) and 10.0% (95% CI, 5.5%-15.9%) at 2 and 5 years, respectively; and the patients with the MPD ≥10 mm had the corresponding rates of 16.0% (95% CI, 3.6-36.5%) and 33.3% (95% CI, 10.3%-58.8%). The multivariable subdistribution hazard ratios were 2.78 (95% CI, 1.57-4.90) and 7.00 (95% CI, 2.58-19.0) for the MPD = 5-9.9 mm and ≥10 mm (vs <5 mm), respectively. CONCLUSIONS: IPMNs with MPD dilatation at baseline were associated with higher prevalence and incidence of pancreatic carcinoma compared with IPMNs with no MPD dilatation.

MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages.

BACKGROUND & AIMS: Chromatin architecture governs cell lineages by regulating the specific gene expression; however, its role in the diversity of cancer development remains unknown. Among pancreatic cancers, pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMN) with an associated invasive carcinoma (IPMNinv) arise from 2 distinct precursors, and their fundamental differences remain obscure. Here, we aimed to assess the difference of chromatin architecture regulating the transcriptional signatures or biological features in pancreatic cancers. METHODS: We established 28 human organoids from distinct subtypes of pancreatic tumors, including IPMN, IPMNinv, and PDAC. We performed exome sequencing (seq), RNA-seq, assay for transposase-accessible chromatin-seq, chromatin immunoprecipitation-seq, high-throughput chromosome conformation capture, and phenotypic analyses with short hairpin RNA or clustered regularly interspaced short palindromic repeats interference. RESULTS: Established organoids successfully reproduced the histology of primary tumors. IPMN and IPMNinv organoids harbored GNAS, RNF43, or KLF4 mutations and showed the distinct expression profiles compared with PDAC. Chromatin accessibility profiles revealed the gain of stomach-specific open regions in IPMN and the pattern of diverse gastrointestinal tissues in IPMNinv. In contrast, PDAC presented an impressive loss of accessible regions compared with normal pancreatic ducts. Transcription factor footprint analysis and functional assays identified that MNX1 and HNF1B were biologically indispensable for IPMN lineages. The upregulation of MNX1 was specifically marked in the human IPMN lineage tissues. The MNX1-HNF1B axis governed a set of genes, including MYC, SOX9, and OLFM4, which are known to be essential for gastrointestinal stem cells. High-throughput chromosome conformation capture analysis suggested the HNF1B target genes to be 3-dimensionally connected in the genome of IPMNinv. CONCLUSIONS: Our organoid analyses identified the MNX1-HNF1B axis to be biologically significant in IPMN lineages.

New Diagnostic Modality Combining Mass Spectrometry and Machine Learning for the Discrimination of Malignant Intraductal Papillary Mucinous Neoplasms.

BACKGROUND: An intraductal papillary mucinous neoplasm (IPMN) is a pancreatic tumor with malignant potential. Although we anticipate a sensitive method to diagnose the malignant conversion of IPMN, an effective strategy has not yet been established. The combination of probe electrospray ionization-mass spectrometry (PESI-MS) and machine learning provides a promising solution for this purpose. METHODS: We prospectively analyzed 42 serum samples obtained from IPMN patients who underwent pancreatic resection between 2020 and 2021. Based on the postoperative pathological diagnosis, patients were classified into two groups: IPMN-low grade dysplasia (n = 17) and advanced-IPMN (n = 25). Serum samples were analyzed by PESI-MS, and the obtained mass spectral data were converted into continuous variables. These variables were used to discriminate advanced-IPMN from IPMN-low grade dysplasia by partial least square regression or support vector machine analysis. The areas under receiver operating characteristics curves were obtained to visualize the difference between the two groups. RESULTS: Partial least square regression successfully discriminated the two disease classes. From another standpoint, we selected 130 parameters from the entire dataset by PESI-MS, which were fed into the support vector machine. The diagnostic accuracy was 88.1%, and the area under the receiver operating characteristics curve was 0.924 by this method. Approximately 10 min were required to perform each method. CONCLUSION: PESI-MS combined with machine learning is an easy-to-use tool with the advantage of rapid on-site analysis. Here, we show the great potential of our system to diagnose the malignant conversion of IPMN, which would be a promising diagnostic tool in clinical settings.

Long-term survival from progressive multifocal leukoencephalopathy in living-donor liver transplant recipient with preformed donor-specific antibody.

Intensive immunosuppression has enabled liver transplantation even in recipients with preformed donor-specific antibodies (DSA), an independent risk factor for graft rejection. However, these recipients may also be at high risk of progressive multifocal encephalopathy (PML) due to the comorbid immunosuppressed status. A 58-year-old woman presented with self-limited focal-to-bilateral tonic-clonic seizures 9 months after liver transplantation. She was desensitized using rituximab and plasma exchange before transplantation and was subsequently treated with steroids, tacrolimus, and everolimus after transplantation for her preformed DSA. Neurological examination revealed mild acalculia and agraphia. Cranial MRI showed asymmetric, cortex-sparing white matter lesions that increased over a week in the left frontal, left parietal, and right parieto-occipital lobes. Polymerase chain reaction (PCR) of the cerebrospinal fluid for the JC supported the diagnosis of PML. Immune reconstitution by reducing the immunosuppressant dose stopped lesion expansion, and PCR of the cerebrospinal fluid for the JC virus became negative. Graft rejection occurred 2 months after immune reconstitution, requiring readjustment of immunosuppressants. Forty-eight months after PML onset, the patient lived at home without disabling deficits. Intensive immunosuppression may predispose recipients to PML after liver transplantation with preformed DSA. Early immune reconstitution and careful monitoring of graft rejection may help improve outcomes.

Correlation between recurrence-free survival and overall survival after upfront surgery for resected colorectal liver metastases.

BACKGROUND: The role of recurrence-free survival (RFS) as a valid surrogate endpoint for overall survival (OS) in patients who underwent upfront surgery for colorectal liver metastases remains uncertain. The aim of the study was to compare the two survival measures in a nationwide cohort of upfront resected colorectal liver metastasis. METHODS: Data from patients with colorectal liver metastases without extrahepatic metastases who underwent curative surgery for liver metastases were retrieved from the Japanese nationwide database (data collection 2005-2007 and 2013-2014). RFS, OS, and survival after recurrence were estimated using the Kaplan-Meier method. The correlation (ρ) between RFS and OS was assessed using the rank correlation method combined with iterative multiple imputation, to account for censoring. As a secondary analysis, the correlation was evaluated according to adjuvant chemotherapy regimen. In sensitivity analysis, the pairwise correlation between RFS and OS was calculated. RESULTS: A total of 2385 patients with colorectal liver metastases were included. In the primary analysis, there was a moderately strong correlation between RFS and OS (ρ = 0.73, 95 per cent c.i. 0.70 to 0.76). The strength of the correlation was similar regardless of the adjuvant treatment regimen (oxaliplatin plus 5-fluorouracil: ρ = 0.72, 0.67 to 0.77; 5-fluorouracil alone: ρ = 0.72, 0.66 to 0.76; observation: ρ = 0.74, 0.69 to 0.78). The mean(s.d.) pairwise correlation coefficient between 3-year RFS and 5-year OS was 0.87(0.06). CONCLUSION: In surgically treated patients with colorectal liver metastases, there was a moderately strong correlation between RFS and OS, which was unaffected by the treatment regimen. Further validation using a trial-level analysis is required.

Protocol of the RACB study: a multicenter, single-arm, prospective study to evaluate the efficacy of resection of initially unresectable hepatocellular carcinoma with atezolizumab combined with bevacizumab.

BACKGROUND: Although the standard therapy for advanced-stage hepatocellular carcinoma (HCC) is systemic chemotherapy, the combination of atezolizumab and bevacizumab (atezo + bev) with a high objective response rate may lead to conversion to resection in patients with initially unresectable HCC. This study aims to evaluate the efficacy of atezo + bev in achieving conversion surgery and prolonged progression-free survival (PFS) for initially unresectable HCC. METHODS: The RACB study is a prospective, single-arm, multicenter, phase II trial evaluating the efficacy of combination therapy with atezo + bev for conversion surgery in patients with technically and/or oncologically unresectable HCC. The main eligibility criteria are as follows: (1) unresectable HCC without a history of systemic chemotherapy, (2) at least one target lesion based on RECIST ver. 1.1, and (3) a Child‒Pugh score of 5-6. The definition of unresectable tumors in this study includes macroscopic vascular invasion and/or extrahepatic metastasis and massive distribution of intrahepatic tumors. Patients will be treated with atezolizumab (1200 mg/body weight) and bevacizumab (15 mg/kg) every 3 weeks. If the patient is considered resectable on radiological assessment 12 weeks after initial chemotherapy, the patient will be treated with atezolizumab monotherapy 3 weeks after combination chemotherapy followed by surgery 3 weeks after atezolizumab monotherapy. If the patient is considered unresectable, the patient will continue with atezo + bev and undergo a radiological assessment every 9 weeks until resectable or until disease progression. The primary endpoint is PFS, and the secondary endpoints are the overall response rate, overall survival, resection rate, curative resection rate, on-protocol resection rate, and ICG retention rate at 15 min after atezo + bev therapy. The assessments of safety and quality of life during the treatment course will also be evaluated. The number of patients has been set at 50 based on the threshold and the expected PFS rate at 6 months after enrollment of 40% and 60%, respectively, with a one-sided alpha error of 0.05 and power of 0.80. The enrollment and follow-up periods will be 2 and 1.5 years, respectively. DISCUSSION: This study will elucidate the efficacy of conversion surgery with atezo + bev for initially unresectable HCC. In addition, the conversion rate, safety and quality of life during the treatment course will also be demonstrated. TRIAL REGISTRATION: This study is registered in the Japan Registry of Clinical Trials (jRCTs051210148, January 7, 2022).