Intraductal papillary neoplasms of the bile ducts: a comparative study of a rare disease in Europe and Nagoya, Japan.

BACKGROUND: Intraductal papillary neoplasm of the bile ducts (IPNB) is a rare disease in Western countries. The aim of this study was to compare tumor characteristics, management strategies, and outcomes between Western and Eastern patients who underwent surgical resection for IPNB. METHODS: A multi-institutional retrospective series of patients with IPNB undergoing surgery between January 2010 and December 2020 was gathered under the auspices of the European-African Hepato-Pancreato-Biliary Association (E-AHPBA), and at Nagoya University Hospital, Japan. RESULTS: A total of 85 patients (51% male; median age 66 years) from 28 E-AHPBA centers were compared to 91 patients (64% male; median age 71 years) from Nagoya. Patients in Europe had more multiple lesions (23% vs 2%, P < .001), less invasive carcinoma (42% vs 85%, P < .001), and more intrahepatic tumors (52% vs 24%, P < .001) than in Nagoya. Patients in Europe experienced less 90-day grade >3 Clavien-Dindo complications (33% vs 68%, P < .001), but higher 90-day mortality rate (7.0% vs 0%, P = .03). R0 resections (81% vs 82%) were similar. Overall survival, excluding 90-day postoperative deaths, was similar in both regions. DISCUSSION: Despite performing more extensive resections, the low perioperative mortality rate observed in Nagoya was probably influenced by a combination of patient-, tumor-, and surgery-related factors.

A systematic review of present and future pharmaco-structural therapies for hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a common contemporary, treatable, genetic disorder that can be compatible with normal longevity. While current medical therapies are ubiquitous, they are limited by a lack of solid evidence, are often inadequate, poorly tolerated, and do not alter the natural disease course. As such, there has long been a need for effective, evidence-based, and targeted disease-modifying therapies for HCM. In this review, we redefine HCM as a treatable condition, evaluate current strategies for therapeutic intervention, and discuss novel myosin inhibitors. The majority of patients with HCM have elevated left ventricular outflow tract gradients, which predicts worse symptoms and adverse outcomes. Conventional pharmacological therapies for symptomatic HCM can help improve symptoms but are often inadequate and poorly tolerated. Septal reduction therapies (surgical myectomy and alcohol septal ablation) can safely and effectively reduce refractory symptoms and improve outcomes in patients with obstructive HCM. However, they require expertise that is not universally available and are not without risks. Currently, available therapies do not alter the disease course or the progressive cardiac remodeling that ensues, nor subsequent heart failure and arrhythmias. This has been regarded as an unmet need in the care of HCM patients. Novel targeted pharmacotherapies, namely cardiac myosin inhibitors, have emerged to reverse key pathophysiological changes and alter disease course. Their favorable outcomes led to the early Food and Drug Administration approval of mavacamten, a first-in-class myosin modulator, changing the paradigm for the pharmacological treatment of HCM.

Gallbladder cancer mimicking perihilar cholangiocarcinoma-considerable rate of postoperative reclassification with implications for prognosis.

BACKGROUND: For some patients undergoing resection under the suspicion of a perihilar cholangiocarcinoma (pCCA), postoperative diagnosis may differ from the preoperative diagnosis. While a postoperative finding of benign bile duct stricture is known to affect 3-15% of patients, less has been described about the consequences of finding other biliary tract cancers postoperatively. This study compared pre- and postoperative diagnoses, risk characteristics, and outcomes after surgery for suspected pCCA. METHODS: Retrospective single-center study, Karolinska University Hospital, Stockholm, Sweden (January 2009-May 2017). The primary postoperative outcome was overall survival. Secondary outcomes were disease-free survival and postoperative complications. Survival analysis was performed by the Kaplan-Meier method. RESULTS: Seventy-one patients underwent resection for suspected pCCA. pCCA was confirmed in 48 patients (68%). Ten patients had benign lesions (14%), 2 (3%) were diagnosed with other types of cholangiocarcinoma (CCA, distal n = 1, intrahepatic n = 1), while 11 (15%) were diagnosed with gallbladder cancer (GBC). GBC patients were older than patients with pCCA (median age 71 versus 58 years, p = 0.015), with a large proportion of patients with a high tumor extension stage (≥ T3, 91%). Median overall survival was 20 months (95% CI 15-25 months) for patients with pCCA and 17 months (95% CI 11-23 months) for patients with GBC (p = 0.135). Patients with GBC had significantly shorter median disease-free survival (DFS), 10 months (95% CI 3-17 months) compared 17 months (95% CI 15-19 months) for patients with pCCA (p = 0.010). CONCLUSIONS: At a large tertiary referral center, 15% of patients resected for suspected pCCA were postoperatively diagnosed with GBC. Compared to patients with pCCA, GBC patients were older, with advanced tumors and shorter DFS. The considerable rate of re-classification stresses the need for improved preoperative staging, as these prognostic differences could have implications for treatment strategies.

Intraductal papillary neoplasms of the bile duct: a European retrospective multicenter observational study (EUR-IPNB study).

BACKGROUND/PURPOSE: Intraductal papillary neoplasm of the bile duct (IPNB) is a rare disease in Western countries. The main aim of this study was to characterize current surgical strategies and outcomes in the mainly European participating centers. METHODS: A multi-institutional retrospective series of patients with a diagnosis of IPNB undergoing surgery between 1 January 2010 and 31 December 2020 was gathered under the auspices of the European-African Hepato-Pancreato-Biliary Association. The textbook outcome (TO) was defined as a non-prolonged length of hospital stay plus the absence of any Clavien-Dindo grade at least III complications, readmission, or mortality within 90 postoperative days. RESULTS: A total of 28 centers contributed 85 patients who underwent surgery for IPNB. The median age was 66 years (55-72), 49.4% were women, and 87.1% were Caucasian. Open surgery was performed in 72 patients (84.7%) and laparoscopic in 13 (15.3%). TO was achieved in 54.1% of patients, reaching 63.8% after liver resection and 32.0% after pancreas resection. Median overall survival was 5.72 years, with 5-year overall survival of 63% (95% CI: 50-82). Overall survival was better in patients with Charlson comorbidity score 4 or less versus more than 4 ( P =0.016), intrahepatic versus extrahepatic tumor ( P =0.027), single versus multiple tumors ( P =0.007), those who underwent hepatic versus pancreatic resection ( P =0.017), or achieved versus failed TO ( P =0.029). Multivariable Cox regression analysis showed that not achieving TO (HR: 4.20; 95% CI: 1.11-15.94; P =0.03) was an independent prognostic factor of poor overall survival. CONCLUSIONS: Patients undergoing liver resection for IPNB were more likely to achieve a TO outcome than those requiring a pancreatic resection. Comorbidity, tumor location, and tumor multiplicity influenced overall survival. TO was an independent prognostic factor of overall survival.

Incidence and risk factors for anastomotic bile leakage in hepatic resection with bilioenteric reconstruction - A international multicenter study.

BACKGROUND: Anastomotic leak (AL) after bilioenteric reconstruction (BR) is a feared complication after bile duct resection, especially in combination with liver resection. Literature on surgical outcome is sparse. This study aimed to determine the incidence and risk factors for AL after combined liver and bile duct resection with a focus on operative or endoscopic reinterventions. METHODS: Data from consecutive patients who underwent liver resection and BR between 2004 and 2018 in 11 academic institutions in Europe were collected from prospectively maintained databases. RESULTS: Within 921 patients, AL rate was 5.4% with a 30d mortality of 9.6%. Pringle maneuver (p<0.001),postoperative external biliary (p=0.007) and abdominal drainage (p<0.001) were risk factors for clinically relevant AL. Preoperative biliary drainage (p<0.001) was not associated with a higher rate of AL. AL was more frequent in stented patients (76.5%) compared to PTCD (17.6%) or PTCD+stent (5.9%,p=0.017). AL correlated with increased incidence of postoperative liver failure (p=0.036), cholangitis, hemorrhage and sepsis (all p<0.001). CONCLUSION: This multicenter data provides the largest series to date of LR with BR and could help in the management of these patients which are often challenging and hampering the patients' postoperative course negatively.

Molecular adsorbent recirculating system treatment in patients with post-hepatectomy liver failure: Long-term results of a pilot study.

BACKGROUND: Post-hepatectomy liver failure (PHLF) is the leading cause of postoperative mortality following major liver resection. Between December 2012 and May 2015, 10 consecutive patients with PHLF (according to the Balzan criteria) following major/extended hepatectomy were included in a prospective treatment study with the molecular adsorbent recirculating system (MARS). Sixty- and 90-day mortality rates were 0% and 10%, respectively. Of the nine survivors, four still had liver dysfunction at 90 days postoperatively. One-year overall survival (OS) of the MARS-PHLF cohort was 50%. The present study aims to assess long-term outcome of this cohort compared to a historical control cohort. METHODS: To compare long-term outcome of the MARS-PHLF treatment cohort with PHLF patients not treated with MARS, the present study includes all 655 patients who underwent major hepatectomy at Karolinska University Hospital between 2010 and 2018. Patients with PHLF were identified according to the Balzan criteria. RESULTS: The cohort was split into three time periods: pre-MARS period (n = 192), MARS study period (n = 207), and post-MARS period (n = 256). The 90-day mortality of patients with PHLF was 55% (6/11) in the pre-MARS period, 14% during the MARS study period (2/14), and 50% (3/6) in the post-MARS period (p = 0.084). Median OS (95% confidence interval (CI)) was 37.8 months (29.3-51.7) in the pre-MARS cohort, 57 months (40.7-75.6) in the MARS cohort, and 38.8 months (31.4-51.2) in the post-MARS cohort. The 5-year OS of 10 patients included in the MARS study was 40% and the median survival 11.6 months (95% CI: 3 to not releasable). In contrast, for the remaining 21 patients fulfilling the Balzan criteria during the study period but not treated with MARS, the 5-year OS and median survival were 9.5% and 7.3 months (95% CI, 0.5-25.9), respectively (p = 0.138)). CONCLUSIONS: MARS treatment may contribute to improved outcome of patients with PHLF. Further studies are needed.The initial pilot study was registered at ClinicalTrials.gov (NCT03011424).

Surgical Outcomes and Trends for Chronic Pancreatitis: An Observational Cohort Study from a High-Volume Centre.

Surgery for chronic pancreatitis (CP) is considered as a last resort treatment. The present study aims to determine the short- and medium-term outcomes of surgical treatment for CP with a comparison between duodenum-preserving pancreatic head resection (DPPHR) and pancreatoduodenectomy (PD). The trends in surgical procedures were also examined. This was a retrospective cohort study of patients who underwent surgery for CP between 2000 and 2019 at the Karolinska University Hospital. One hundred and sixty-two patients were included. Surgery performed included drainage procedures (n = 2), DPPHR (n = 35), resections (n = 114, of these PD in n = 65) and other procedures (n = 11). Morbidity occurred in 17%, and the 90-day mortality was 1%. Complete or partial pain relief was achieved in 65% of patients. No significant difference in morbidity was observed between the DPPHR and PD groups: 17% vs. 20% (p = 0.728). Pain relief did not differ between the groups (62% for DPPHR vs. 73% for PD, p = 0.142). The frequency of performed DPPHR decreased, whereas the rate of PD remained unaltered. Surgical treatment for CP is safe and effective. DPPHR and PD are comparable regarding post-operative morbidity and are equally effective in achieving pain relief. Trends over time revealed PD as more commonly performed compared to DPPHR.

Redefining resection margins and dissection planes in perihilar cholangiocarcinoma-radical resection is a rare event.

Radical tumor resection (pR0) is prognostic for disease-free and overall survival after resection of perihilar cholangiocarcinoma (pCCA). However, no universal agreement exists on the definition of radical resection and histopathological reporting. The aim of this study was to provide a standardized protocol for histopathological assessment and reporting of the surgical specimen obtained after resection for pCCA. All consecutive patients operated for pCCA with curative intent at the Karolinska University Hospital, Stockholm, Sweden between 2012 and 2021 were included. A standardized protocol for histopathological assessment and reporting of the surgical specimen after liver resection for pCCA is presented. A detailed mapping of the transection margins and dissection planes was performed. The results of applying different existing pR0 definitions were compared. Sixty-eight patients with pCCA were included. Five transection margins and two dissection planes were defined. By defining pR0 as cancer-free margins and planes tolerating distances <1mm, the pR0 rate was 66%. However, when pR0 was set as >1mm from invasive cancer to all resection margins and dissection planes, the pR0 rate fell to 16%. This study supports the use of thorough and standardized pathological handling, assessment and reporting of resection margins and dissection planes of surgical specimens of pCCA.

Vascular Regenerative Capacity and the Obesity Paradox in Coronary Artery Disease.

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Functional coronary angiography in symptomatic patients with no obstructive coronary artery disease.

BACKGROUND: Patients without obstructive coronary artery disease (CAD) may have epicardial or microvascular dysfunction. The purpose of this study was to characterize patterns of epicardial and microvascular dysfunction in men and women with stable and unstable angina undergoing functional coronary angiography to inform medical therapy. METHODS: 163 symptomatic patients with ≤50% diameter stenosis and fractional flow reserve (FFR) > 0.8 underwent endothelium-dependent epicardial and microvascular function after intracoronary acetylcholine (10-4  M, 81 mcg over 3 minutes). Endothelium-independent function was assessed using coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) after intravenous adenosine (140 ug/kg/min). Coronary microvascular dysfunction (CMD) was defined as CFR < 2.5, HMR ≥2, or ≤50% change in coronary blood flow with acetylcholine (CBFACH ). RESULTS: Seventy-two percent had endothelial-dependent epicardial dysfunction (response to ACH: % ∆ in coronary artery diameter and ∆%CBFACH ) and 92% had CMD. Among CMD patients, 65% had CFR < 2.5, 35% had HMR ≥2, and 60% had CBFACH change ≤50%. CFR modestly correlated with HMR (r = -0.38, p < .0001). Among patients with normal CFR, 26% had abnormal epicardial and 20% had abnormal microvascular endothelial dysfunction. Women had a lower CFR (p = .02), higher FFR (p = .03) compared to men. There were no differences in epicardial and microvascular function between patients with stable and unstable angina. CONCLUSION: In patients with no obstructive CAD: CMD is prevalent, abnormal CFR does not correlate with epicardial or microvascular endothelial dysfunction, women have lower CFR, higher FFR but similar endothelial function compared to men.

Intrahepatic Microdialysis for Monitoring of Metabolic Markers to Detect Rejection Early After Liver Transplantation.

OBJECTIVES: The clinical and biochemical manifestations of acute rejection after liver transplantation are nonspecific, and a liver biopsy is often needed to verify the diagnosis. This may delay treatment. The aim of this study was to evaluate whether monitoring of intrahepatic glucose, lactate, pyruvate, and glycerol by microdialysis can be used to predict rejection early after liver transplantation. METHODS: Seventy-one patients undergoing liver transplantation were included in the study. The patients were monitored using microdialysis for up to 6 days postoperatively. Patients who developed acute rejection within 1 month were identified according to standard protocol. Area under the curve (AUC) was calculated for 12-hour intervals for glucose, lactate, pyruvate, glycerol, and lactate/pyruvate ratio. Patients with and without rejection were compared with respect to these parameters, as well as standard liver blood investigations and time-zero biopsies. RESULTS: The lactate/pyruvate ratio was higher at 0 to 12 hours in the group with rejection as compared to the group without rejection. Glucose was lower in the group with rejection at 24 to 48 hours. Also, the intrahepatic lactate levels at 48 to 72 hours and pyruvate levels at 60 to 72 hours after liver transplantation, were higher in the rejection group. The lactate/pyruvate ratio at 0 to 12 hours and lactate at 60 to 72 hours were two independent risk factors for rejection within the first month after liver transplantation. No significant differences in glycerol levels could be detected between the two patient groups. CONCLUSIONS: Microdialysis monitoring following liver transplantation may be useful in the detection of the metabolic events that precede rejection. The metabolic patterns detected by microdialysis early after transplantation indicate a possible relation between primary ischemia-reperfusion injury and the development of rejection. Identifying these patterns may help to identify patients at risk for the development of acute rejection and may help select those who may benefit from higher dose of immunosuppression early after liver transplantation.

Posttraumatic Subacute Effusive-Constrictive Pericarditis After a Motor Vehicle Accident.

Effusive-constrictive pericarditis is typically caused by tuberculosis or other severe inflammatory conditions that affect the pericardium. We report a case of effusive-constrictive pericarditis consequent to a motor vehicle accident. A 32-year-old man with gastroesophageal reflux disease presented with severe substernal chest pain of a month's duration and dyspnea on exertion for one week. Echocardiograms revealed a moderate pericardial effusion, and the diagnosis was subacute effusive-constrictive pericarditis. After thorough tests revealed nothing definitive, we learned that the patient had been in a motor vehicle accident weeks before symptom onset, which made blunt trauma the most likely cause of pericardial injury and effusion. Medical management resolved the effusion and improved his symptoms. To our knowledge, this is the first report of effusion from posttraumatic constrictive pericarditis associated with a motor vehicle accident. We encourage providers to consider recent trauma as a possible cause of otherwise idiopathic pericarditis.

Racial Differences in Diuretic Efficiency, Plasma Renin, and Rehospitalization in Subjects With Acute Heart Failure.

BACKGROUND: Black patients have higher rates of hospitalization for acute heart failure than other race/ethnic groups. We sought to determine whether diuretic efficiency is associated with racial differences in risk for rehospitalization after acute heart failure. METHODS: A post hoc analysis was performed on 721 subjects (age, 68±13 years; 22% black) enrolled in 3 acute heart failure clinical trials: ROSE-AHF (Renal Optimization Strategies Evaluation in Acute Heart Failure), DOSE-AHF (Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure), and CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Repeated-measures ANOVA was used to test for a race×time effect on measures of decongestion. Diuretic efficiency was calculated as net fluid balance per total furosemide equivalents. In a subset of subjects, Cox regression was used to examine the association between race and rehospitalization according to plasma renin activity (PRA). RESULTS: Compared with nonblack patients, black patients were younger and more likely to have nonischemic heart failure. During the first 72 to 96 hours, there was greater fluid loss (P=0.001), decrease in NT-proBNP (N-terminal pro-B-type natriuretic peptide; P=0.002), and lower levels of PRA (P<0.0001) in black patients. Diuretic efficiency was higher in black than in nonblack patients (403 [interquartile range, 221-795] versus 325 [interquartile range, 154-698]; P=0.014). However, adjustment for baseline PRA attenuated the association between black race and diuretic efficiency. Over a median follow-up of 68 (interquartile range, 56-177) days, there was an increased risk of all-cause and heart failure-specific rehospitalization in nonblack patients with increasing levels of PRA, while the risk of rehospitalization was relatively constant across levels of PRA in black patients. CONCLUSIONS: Higher diuretic efficiency in black patients with acute heart failure may be related to racial differences in activity of the renin-angiotensin-aldosterone system.

From Fad to Fact: Evaluating the Impact of Emerging Diets on the Prevention of Cardiovascular Disease.

Cardiovascular disease remains one of the most prevalent and preventable chronic conditions worldwide. Diet modification is the foundation of cardiovascular disease prevention. Several dietary approaches have emerged to promote better cardiovascular health. The rapid dissemination of anecdotal and observational data through the internet and social media has caused confusion amongst providers and patients. The aim of this comprehensive review is to present objective insights into 2 of today's most popular fad diets: ketogenic diet and intermittent fasting. We will evaluate the performance of these diets based on their impact on cardiovascular risk factors.

Hepatopancreatoduodenectomy -a controversial treatment for bile duct and gallbladder cancer from a European perspective.

BACKGROUND: Hepatopancreatoduodenectomy (HPD) is an aggressive operation for treatment of advanced bile duct and gallbladder cancer associated with high perioperative morbidity and mortality, and uncertain oncological benefit in terms of survival. Few reports on HPD from Western centers exist. The purpose of this study was to evaluate safety and efficacy for HPD in European centers. METHOD: Members of the European-African HepatoPancreatoBiliary Association were invited to report all consecutive patients operated with HPD for bile duct or gallbladder cancer between January 2003 and January 2018. The patient and tumor characteristics, perioperative and survival outcomes were analyzed. RESULTS: In total, 66 patients from 19 European centers were included in the analysis. 90-day mortality rate was 17% and 13% for bile duct and gallbladder cancer respectively. All factors predictive of perioperative mortality were patient and disease-specific. The three-year overall survival excluding 90-day mortality was 80% for bile duct and 30% for gallbladder cancer (P = 0.013). In multivariable analysis R0-resection had a significant impact on overall survival. CONCLUSION: HPD, although being associated with substantial perioperative mortality, can offer a survival benefit in patient subgroups with bile duct cancer and gallbladder cancer. To achieve negative resection margins is paramount for an improved survival outcome.

Evaluation of Intrahepatic Lactate/Pyruvate Ratio As a Marker for Ischemic Complications Early After Liver Transplantation-A Clinical Study.

BACKGROUND: Lactate/pyruvate ratio has been introduced as a sensitive marker for ischemia in the transplanted liver. In the present study, we aimed to evaluate lactate/pyruvate ratio measured in the liver by microdialysis as a marker for ischemic complications early after liver transplantation. METHODS: Forty-five patients undergoing liver transplantation were included in the study. A microdialysis catheter was placed in the liver graft directly following liver transplantation and the metabolites lactate and pyruvate measured for up to 6 days and the lactate/pyruvate ratio calculated. The association between increased intrahepatic lactate/pyruvate ratio and ischemic complications was studied. RESULTS: One of 45 patients developed hepatic arterial thrombosis. Forty-four events with increased lactate/pyruvate ratio were identified in 24 patients. In none of the 24 patients that had a raised lactate/pyruvate ratio could we detect occurrence of any ischemic complication. In the patient that did have hepatic arterial thrombosis, the lactate/pyruvate ratio did not show a significant prolonged rise. CONCLUSIONS: An increase in the intrahepatic lactate/pyruvate ratio is not necessarily indicative of ischemic complications and is thus not a reliable marker for monitoring of clinically significant ischemia in the liver early after transplantation.

Viral Hepatitis and Acute Liver Failure: Still a Problem.

Although the overall prevalence is on the decline, viral hepatitis still plays a major role in the development of acute liver failure (ALF) worldwide. Hepatitis A, B, D, and E contribute to most fulminant viral courses. These viruses have not gained much attention in recent years yet remain relevant from a clinical perspective as the incidence in certain populations is on the increase. Other viral therapies and immunotherapies are currently being examined as treatments for hepatitis D and hepatitis E. Clinicians should still maintain a high index of suspicion for viral causes in approaching patients with ALF.

A Case of Anterior Spinal Artery Syndrome Caused by Streptococcus mitis Endocarditis.

BACKGROUND: Infectious endocarditis (IE) typically occurs in the setting of intravenous drug use, prosthetic heart valves, or rheumatic heart disease. However, there are a few reports of IE occurring in the setting of immunosuppression secondary to cancer and/or chemotherapy. Here, we present a case of a cancer patient who developed anterior spinal artery (ASA) syndrome secondary to a septic embolus from IE. CASE PRESENTATION: A 78-year-old male with a history of gastroesophageal cancer treated with chemotherapy and radiation presented to the hospital after a fall at home. He reported experiencing dyspnea and orthopnea for two weeks prior to presentation. In the ED, his vital signs were stable, and his examination was significant for a flaccid paralysis of the right lower extremity. Diagnosis of septic emboli secondary to IE was made after the echocardiogram showed the presence of vegetations on the aortic valve, blood cultures were positive for Streptococcus mitis, and thoracic spine MRI was indicative of an infarction at T10. DISCUSSION: This case highlights the presence of IE in the setting of cancer and chemotherapy. Although cancer is a rare cause of IE, clinicians must maintain a high index of suspicion in order to minimize the sequelae of IE.

Vanishing Bile Duct Syndrome in a Patient with Uterine Cancer and Paraneoplastic Systemic Sclerosis.

Vanishing bile duct syndrome (VBDS) is a rare entity of acquired disorders resulting in cholestasis secondary to progressive destruction of intrahepatic bile ducts. The syndrome has been described in the setting of autoimmune disorders, medication toxicities, genetic disorders, infectious etiologies, and in rare cases, neoplastic processes. There are no known case reports of VBDS in the setting of uterine malignancy. We present a case of VBDS in a patient with underlying uterine cancer complicated by paraneoplastic systemic sclerosis.