Machine learning for individualized prediction of hepatocellular carcinoma development after the eradication of hepatitis C virus with antivirals.

BACKGROUND AND AIMS: Accurate risk stratification for hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) is necessary for optimal surveillance. We aimed to develop and validate a machine learning (ML) model to predict the risk of HCC after achieving an SVR in individual patients. METHODS: In this multicenter cohort study, 1742 patients with chronic hepatitis C who achieved an SVR were enrolled. Five ML models were developed including DeepSurv, gradient boosting survival analysis, random survival forest (RSF), survival support vector machine, and a conventional Cox proportional hazard model. Model performance was evaluated using Harrel' c-index and was externally validated in an independent cohort (977 patients). RESULTS: During the mean observation period of 5.4 years, 122 patients developed HCC (83 in the derivation cohort and 39 in the external validation cohort). The RSF model showed the best discrimination ability using seven parameters at the achievement of an SVR with a c-index of 0.839 in the external validation cohort and a high discriminative ability when the patients were categorized into three risk groups (P <0.001). Furthermore, this RSF model enabled the generation of an individualized predictive curve for HCC occurrence for each patient with an app available online. CONCLUSIONS: We developed and externally validated an RSF model with good predictive performance for the risk of HCC after an SVR. The application of this novel model is available on the website. This model could provide the data to consider an effective surveillance method. Further studies are needed to make recommendations for surveillance policies tailored to the medical situation in each country. IMPACT AND IMPLICATIONS: A novel prediction model for HCC occurrence in patients after hepatitis C virus eradication was developed using machine learning algorithms. This model, using seven commonly measured parameters, has been shown to have a good predictive ability for HCC development and could provide a personalized surveillance system.

[A case of advanced pancreatic cancer with spontaneous tumor lysis syndrome].

A 74-year-old male with pancreatic cancer and multiple huge liver metastases received palliative care due to the cancer progression after chemotherapy. The patient was admitted to our hospital for increased abdominal pain and dehydration. Tumor lysis syndrome was diagnosed on the fifth hospital day owing to the advancement of renal impairment, hyperuricemia, hyperkalemia, and hyperphosphatemia. The patient's condition rapidly deteriorated despite increased intravenous infusion and the provision of antihyperuricemia medicine and demised on the seventh hospital day. Autopsy results revealed generalized necrosis of the tumor, consistent with tumor lysis syndrome.

Impact of Obesity and Heavy Alcohol Consumption on Hepatocellular Carcinoma Development after HCV Eradication with Antivirals.

BACKGROUND AND AIMS: It remains unclear whether obesity increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C who achieved a sustained virological response (SVR) with antiviral therapy. METHODS: In this multicenter cohort study, we enrolled patients with chronic hepatitis C who achieved SVR with interferon (IFN)-based therapy (IFN group) or direct-acting antiviral (DAA) therapy (DAA group) between January 1, 1990, and December 31, 2018. The patients underwent regular surveillance for HCC. Cumulative incidence of and the risk factors for HCC development after SVR were assessed using the Kaplan-Meier method and Cox proportional hazard regression analysis, respectively. RESULTS: Among 2,055 patients (840 in the IFN group and 1,215 in the DAA group), 75 developed HCC (41 in the IFN group and 34 in the DAA group) during the mean observation period of 4.1 years. The incidence rates of HCC at 1, 2, and 3 years were 1.2, 1.9, and 3.0%, respectively. Multivariate analysis revealed that in addition to older age, lower albumin level, lower platelet count, higher alpha-fetoprotein level, and absence of dyslipidemia, obesity (body mass index ≥25 kg/m2) and heavy alcohol consumption (≥60 g/day) were independent risk factors for HCC development, with adjusted hazard ratio (HR) of 2.53 (95% confidence interval [CI]: 1.51-4.25) and 2.56 (95% CI: 1.14-5.75), respectively. The adjusted HR was not significant between the 2 groups (DAA vs. IFN; HR 1.19, 95% CI: 0.61-2.33). CONCLUSIONS: Obesity and heavy alcohol consumption increased the risk of HCC development after SVR.

IgG4-related retroperitoneal fibrosis and sclerosing cholangitis independent of autoimmune pancreatitis. A recurrent case after a 5-year history of spontaneous remission.

CONTEXT: A new clinicopathological concept of IgG4-related sclerosing disease affecting various organs has recently been proposed in relation to autoimmune pancreatitis. This report describes the case of IgG4-related retroperitoneal fibrosis and sclerosing cholangitis independent of autoimmune pancreatitis, which recurred after a long period of spontaneous remission. CASE REPORT: An 80-year-old Japanese man presented with obstructive jaundice owing to a hepatic hilum bile duct stricture. Coincidentally, a soft tissue mass surrounding the abdominal aorta, suggesting retroperitoneal fibrosis, was identified. Unexpectedly, spontaneous regression of obstructive jaundice together with retroperitoneal fibrosis occurred. The presence of high serum IgG4 concentrations measured later led us to consider a possible association with autoimmune pancreatitis; however, there were no clinical features confirming autoimmune pancreatitis. After a 5-year history of spontaneous clinical remission, there was an elevation of serum IgG4 levels and renal dysfunction owing to bilateral hydronephrosis caused by a reemergence of the retroperitoneal mass. Evaluation by endoscopic retrograde cholangiopancreatography revealed a biliary stricture, suggesting sclerosing cholangitis which was observed without the presence of any pancreatic duct abnormality. The subsequent excellent results obtained using steroid therapy, namely the decrease in serum IgG4 levels and the regression of the retroperitoneal mass, strongly suggested that the present case was an IgG4-related sclerosing disease. Aside from high serum IgG4 concentrations, markedly elevated levels of serum IgE was found retrospectively, although the clinical significance remains unknown. CONCLUSION: When we encounter fibrotic diseases of unknown etiology, we should measure serum IgG4 concentrations and monitor the disease activity over long periods even after achieving clinical remission.

Hall magnetohydrodynamic turbulence with a magnetic Prandtl number larger than unity.

Turbulence structures with the magnetic Prandtl number larger than unity are studied by means of direct numerical simulations of homogeneous, isotropic, and incompressible Hall magnetohydrodynamic (MHD) turbulence driven by a random force. Spectral and spatial structures on the scales smaller than the ion skin depth are focused upon in this numerical paper. The numerical simulations reveal the emergence of a new power law in the velocity field whereas it is not observed in MHD turbulence simulation without the Hall term. An order estimate of the energy budget in the spectral space shows that this new power law appears in association with the Hall effect and that a balance between the Lorentz force and the viscous dissipation is crucial for formation of the power law. A resemblance to an elastic turbulence is found in the power-law-formation mechanism. Frequent eruptions of strong current ribbons accompanying strong palinstrophy density are observed, showing generation of the palinstrophy density by the Lorentz force at the scales below the ion skin depth. These properties in spectral and spatial structures characterize a high magnetic Prandtl number Hall MHD turbulence at the scales smaller than the ion skin depth.

An autopsy case of autoimmune pancreatitis after a 6-year history of steroid therapy accompanied by malignant dissemination of unknown origin.

Little is known about the long-term outcome of autoimmune pancreatitis (AIP), and whether AIP possesses malignant potential. We report herein a 68-year-old Japanese AIP patient who rapidly developed systemic malignant dissemination of unknown origin, resulting in death. The patient was diagnosed histopathologically as having AIP in 1999. After a 6-year history of 5 mg/day of prednisolone therapy, a sudden onset of abdominal pain and convulsive seizure occurred, and the patient died on the tenth hospital day owing to diffuse peritoneal disseminations and metastases in the bilateral lungs and brain. Autopsy disclosed that the primary site was renal cell carcinoma, detectable only by autopsy, originating in the left kidney. On microscopy, metastatic cells obtained from the brain, lung, and peritoneum were composed of pleomorphic malignant cells identical to those from the renal cell carcinoma. Unexpectedly, abundant IgG4-positive plasma cell infiltration, suggesting high activity of AIP in pancreatic parenchyma and around dilated bile ducts, was still observed.

Rat Bite Fever Caused by Streptobacillus moniliformis in a Cirrhotic Patient Initially Presenting with Various Systemic Features Resembling Henoch-Schönlein Purpura.

We herein report the case of a 61-year-old Japanese cirrhotic patient who developed rat bite fever (RBF) and whose first presentation was serious clinical features mimicking those of Henoch-Schönlein purpura (HSP). In addition to the critical clinical conditions, since the histopathology from purpuric skin eruptions was not inconsistent with that of HSP, therapy with prednisolone was promptly started in order to prevent his death. However, initial blood culture on admission yielded a small and slow-growing bacterial growth, which was gradually revealed by further subculture to be a peculiar bacterium, Streptobacillus moniliformis, leading to a definitive diagnosis of RBF. After the immediate cessation of prednisolone, the patient was treated with a more appropriate antibiotic and consequently made a full recovery. An immunocompromised condition with seriously decompensated liver cirrhosis together with moderately severe chronic kidney disease (CKD) in this patient probably exacerbated the severity of the disease.

Acute onset of nephrotic syndrome during interferon-alpha retreatment for chronic active hepatitis C.

A 57-year-old woman was scheduled to receive recombinant interferon-alpha retreatment for chronic active hepatitis C. During the course of therapy, the patient showed rapid onset of oliguria, dizziness, edema, and a pre-shock state. She was subsequently admitted to hospital and was diagnosed as having nephrotic syndrome. After admission, albumin-dominant proteinuria persisted despite the discontinuation of interferon therapy. Light microscopy of a renal needle biopsy specimen showed interstitial lymphoid cell infiltration, but no marked changes of the glomeruli and no staining for immunoglobulin or complement. Electron microscopy showed diffuse effacement of the glomerular epithelial foot processes, leading to a diagnosis of minimal change nephrotic syndrome with interstitial nephritis. Proteinuria resolved after the initiation of oral prednisolone therapy (1 mg/kg per day). The number of patients with chronic hepatitis C requiring interferon retreatment is increasing rapidly. We herein report this rare case of acute onset of nephrotic syndrome during interferon-alpha retreatment.

Thrombopoietin-producing hepatocellular carcinoma.

A 66-year-old man with hepatocellular carcinoma (HCC) showed marked thrombocytosis (110.7 x 10(4)/microl). Bone marrow (BM) aspirates demonstrated an increase of mature megakaryocytes (MgK). The serum thrombopoietin (TPO) level was increased to about 100-fold that of the normal level in the terminal stage. However, the platelet count gradually decreased to 13.5 x 10(4)/microl. The autopsy specimen revealed normoplastic BM with decreased MgK, mainly consisting of the immature type, and it was negative for tumor cells. Liver specimen showed markedly fatty metamorphosis. Immunohistochemical staining of TPO demonstrated that hepatocytes were weakly stained and HCC cells strongly stained, suggesting TPO-producing HCC.

A rapidly progressive and fatal case of nonalcoholic steatohepatitis following pancreaticoduodenectomy.

Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) usually occurs in patients with metabolic syndrome. However, it can develop in relation with pancreaticoduodenectomy (PD) independent of insulin resistance. NAFLD/NASH potentially progresses to liver cirrhosis and subsequent end-stage liver disease, but in general the disease progression is very slow. We here report the case of a 57-year-old Japanese woman who underwent PD for pancreatic head cancer, subsequent to which she developed rapidly progressive NASH without prior liver diseases, resulting in death due to hepatic failure 5 months after PD. Marked body weight loss was a distinguishing clinical feature. Severe malnutrition induced by pancreatic exocrine insufficiency, postoperative eating disorder and exacerbation of diabetes mellitus were thought to be etiologically associated with the rapid progression of her disease. This case suggests the necessity of close hepatic surveillance as well as nutritional evaluation followed by prophylactic pancreatic enzyme replacement and nutritional supply after PD.

Fulminant hepatic failure accompanied by fatal rhabdomyolysis following exertional heatstroke.

We present a previously healthy 38-year-old Japanese man who developed exertional heatstroke (EHS) following a long-distance run and presented with fulminant hepatic failure (FHF) accompanied by a life-threatening flare-up of rhabdomyolysis. Intensive life-supporting medical procedures, including plasma exchange, hemodiafiltration, steroid pulse therapy, and anticoagulant treatment enabled the patient to survive FHF. Initially, his general condition was thought to be improving; however, smoldering rhabdomyolysis suddenly flared up with a marked increase in creatine kinase levels when the dose of steroids was reduced, subsequent to which his condition deteriorated rapidly, eventually resulting in death. The serum levels of interleukin-6 measured retrospectively were found to be markedly elevated and to have fluctuated synchronously with the disease activity. This case report demonstrates that EHS can cause FHF and severe rhabdomyolysis, the outcome of which was tragic even though FHF was substantially well managed; however, the clinical evidence suggests the possible therapeutic efficacy of steroid therapy for refractory rhabdomyolysis occurring in EHS.

A case of syphilis presenting with initial syphilitic hepatitis and serological recurrence with cerebrospinal abnormality.

We present the case of an immunocompetent 50-year-old Japanese man with a cerebrospinal fluid (CSF) abnormality relevant to syphilis; his original presentation was liver dysfunction, the etiology of which was uncertain until positive serology for syphilis was identified. Liver dysfunction was promptly resolved after oral penicillin therapy; however, serological recurrence developed. CSF abnormality associated with syphilis was confirmed by subsequent lumbar puncture. Syphilis should be included in the differential diagnosis of patients with liver dysfunction of unknown etiology, and possible neurosyphilis should be considered when the treatment becomes refractory, even when there is no evidence of neurological manifestations.

A variant form of autoimmune pancreatitis successfully treated by steroid therapy, accompanied by von Meyenburg complex.

Diagnostic criteria for autoimmune pancreatitis (AIP) have been proposed and used clinically because, despite its unique clinicopathological features, AIP does not have disease-specific serological tests for confirmation. However, diagnosis of a patient with pancreatic lesions mimicking cancer who deviates from these diagnostic criteria is still difficult. We present herein a patient with a variant form of AIP successfully diagnosed by fine-needle biopsy, whose response to steroid therapy was excellent. A 55-year-old Japanese man was admitted to hospital because of jaundice and pancreatic head mass. AIP was considered as one of the differential diagnoses; however, as the patient showed neither pancreatic duct narrowing nor immunological abnormalities, he did not meet the Japanese diagnostic criteria for AIP. Histopathology of the pancreatic mass demonstrated abundant infiltration by lymphocytes and interstitial fibrosis, which suggested AIP. Immunoreaction to IgG4, which is supposed to be specific to AIP, was not observed; however, response to subsequent prednisolone therapy was good, with dramatic pancreatic head mass regression. Aside from the pancreatic head mass, diffusely spreading small lesions were observed throughout the liver. The likelihood of a potential association with extrapancreatic lesions of AIP was considered and led us to carry out a liver biopsy, which revealed biliary hamartoma, also called von Meyenburg complex (VMC). As IgG4-positive plasma cell infiltration was not demonstrated in the hamartomatous regions, the hepatic condition was thought to have occurred incidentally; however, to the best of our knowledge, this is the first report in which the association between AIP and VMC was investigated and discussed.

Hepatocellular carcinoma and Crohn's disease: a case report and review.

Hepatocellular carcinoma (HCC) is usually known to develop in patients with underlying high-risk liver diseases such as viral hepatitis, cirrhosis and alcohol abuse, whereas reports dealing with HCC in Crohn's disease (CD) are limited. We present a case of HCC, which developed sequentially within a short period in a 52-year-old Japanese man with a 36-year history of CD without risky conditions for HCC. He also had not taken immunosuppressants such as azathioprine. Although the definitive etiological factors contributing to hepatocarcinogenesis in the present case could not be elucidated, further close surveillance is required.

Drug-induced hypersensitivity syndrome associated with reactivation of human herpesvirus 6 presenting with severe hepatic injury.

Little is known about the pathophysiology of liver complication seen in drug-induced hypersensitivity syndrome (DIHS). We describe herein a 32-year-old Japanese man with DIHS due to salazosulfapyridine (SASP) associated with reactivation of human herpesvirus 6 (HHV-6) presenting with severe acute hepatic injury. The patient, with a 1-year history of ulcerative colitis (UC), presented with high fever and abnormally elevated liver enzymes. Six weeks prior to his symptoms, prednisolone (PSL) and SASP had been started because of UC aggravation. Besides fever and liver dysfunction, the appearance of atypical lymphocytes together with eosinophils and generalized erythematous maculopapular skin rash developed sequentially, and a diagnosis of DIHS was established. Despite cessation of SASP and increased dose of PSL, his initial abnormalities continued, and biphasic second alanine aminotransferase (ALT) flare with deep jaundice worsened. Based on the significant increase in the titer of HHV-6 IgG antibodies at the second peak of ALT level without HHV-6 IgM antibody elevation, strongly suggesting reactivation of the virus, HHV-6 was first considered to directly contribute to the deterioration of liver function. However, extensive histological analysis of the liver led to the realization that the cause of the DIHS liver injury was essentially drug-related hepatotoxicity induced by SASP, causing wide-ranging damage to both the hepatocytes and cholangiocytes.

Hepatocellular carcinoma with direct invasion to the stomach causing gastrointestinal hemorrhage.

A 54-year-old man had undergone transcatheter arterial embolization (TAE) three times to treat hepatitis B virus-related hepatocellular carcinoma (HCC), but recurrence was found in June 2005. A large tumor in the left lateral portion of the liver showed extrahepatic growth and was attached to the gastric wall. TAE was performed a forth time. In September 2005, the patient was admitted with worsening anemia. Computed tomography and upper gastrointestinal endoscopy revealed that the HCC had directly invaded the stomach and caused gastrointestinal hemorrhage. Endoscopic hemostasis was effective, but the patient died because of worsening hepatic failure.