Clinical utility of intraductal carcinoma of the prostate in treatment selection for metastatic hormone-sensitive prostate cancer.

BACKGROUND: In recent years, the usefulness of androgen receptor axis-targeted agents (ARATs) such as abiraterone, enzalutamide, and apalutamide for the upfront treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has been demonstrated. However, it remains unclear which patients would truly benefit from these treatments. Furthermore, intraductal carcinoma of the prostate (IDC-P) is a known poor prognostic factor in patients with prostate cancer. We investigated the association between the presence of IDC-P and response to therapy in patients with mHSPC. METHODS: This retrospective analysis included 318 patients with mHSPC who received treatment at Nagoya University and its 12 affiliated institutions between 2014 and 2021. Their biopsy specimens were evaluated for the presence of IDC-P. The patients were classified according to their first-line treatment into the ARAT (n = 100, receiving a combination of androgen-deprivation therapy [ADT] and ARAT) or conventional therapy (n = 218, receiving ADT with or without standard antiandrogen agents) group. We compared the overall survival (OS) and second progression-free survival (PFS2) between the ARAT and conventional groups according to the presence of IDC-P to evaluate whether presence of IDC-P predicts the response to each treatment. PFS2 was defined as the period from mHSPC diagnosis to disease progression on second-line treatment or death. Propensity score matching with one-to-one nearest-neighbor matching was used to minimize the potential effects of selection bias and confounding factors. The clinicopathological variables of the patients were well-balanced after propensity score matching. RESULTS: Most patients in the ARAT (79%) and conventional therapy (71%) groups were ICD-P positive. In the propensity score-matched cohort, the OS and PFS2 of IDC-P-positive patients were significantly longer in the ARAT group than in the conventional group (OS: hazard ratio [HR], 0.36; p = 0.047; PFS2: HR, 0.30; p < 0.001). In contrast, no difference in OS and PFS2 was observed between the ARAT and conventional groups in IDC-P-negative patients (OS: HR, 1.09; p = 0.920; PFS2: HR, 0.40; p = 0.264). CONCLUSIONS: The findings highlight a high prevalence of IDC-P among patients with mHSPC and suggest that IDC-P positivity may be a reliable indicator that ARAT should be implemented as first-line treatment.

Percutaneous transhepatic sclerotherapy for recurrent bleeding ileal varices diagnosed by capsule endoscopy and computed tomography during percutaneous transhepatic venography.

We report a case of acute uncontrolled gastrointestinal bleeding in a patient with liver cirrhosis. A 64-year-old man was admitted to our hospital for further investigation of blood in stools. Preliminary examination by computed tomography (CT) as well as upper and lower endoscopy could not detect the bleeding source. Exploratory laparotomy was considered difficult due to potential easy bleeding and adhesions caused by past abdominal surgery. The hemoglobin level was normalized by blood transfusion. Capsule endoscopy (CE) identified ileal varices. The top of these ileal varices was red, prompting their identification as the source of bleeding. Percutaneous transhepatic venography (PTV) confirmed the presence of many varices in the branch of the superior mesenteric vein, although the bleeding source could not be identified. CT during PTV identified varices protruding into the ileal lumen, which were managed subsequently by percutaneous transhepatic sclerotherapy (PTS). The procedure stopped the bleeding completely. CE proved less invasive and effective in detecting obscure gastrointestinal bleeding. CT during PTV followed by PTS is suitable for diagnosis and treatment of bleeding varices in patients with portal hypertension.

Achievement of sustained viral response after switching treatment from pegylated interferon α-2b to α-2a and ribavirin in patients with recurrence of hepatitis C virus genotype 1 infection after liver transplantation: a case report.

We report a case in which sustained viral response was achieved after switching treatment from pegylated interferon (PEG-IFN) α-2b to α-2a and ribavirin (RBV) in patients with recurrence of hepatitis C virus (HCV) infection after living donor liver transplantation. The patient was a 62-year-old man with liver cirrhosis due to HCV genotype 1b infection. The patient had 8 amino acid (aa) substitutions in the interferon sensitivity-determining region, and had substitutions for mutant and wild-type at aa70 and aa91, respectively, in the core region. The patient had minor genotype (GG) IL28B single nucleotide polymorphisms (rs8099917). He had initially received interferon α-2b and RBV for 2 years, and later developed hepatocellular carcinoma (HCC). After surgical resection of HCC, he subsequently received PEG-IFN α-2b and RBV for 1.5 years, without undetectable viremia during the treatment course. Due to recurrence of HCC, the patient received a living donor liver transplantation. Later on, hepatitis C relapsed. For the management of relapse, he received another course of PEG-IFN α-2b and RBV. However, breakthrough viremia occurred. PEG-IFN was thus switched from α-2b to α-2a and RBV for another 17 months. The patient eventually achieved a sustained viral response.

Prediction of response to peginterferon-alfa-2b plus ribavirin therapy in Japanese patients infected with hepatitis C virus genotype 1b.

Variation at the IL-28B locus was recently reported to be a significant predictive factor of viral response to pegylated-interferon plus ribavirin combination therapy against chronic hepatitis C. Predictive factors for the effect of therapy, including IL-28B polymorphism rs8099917 and viral and clinical factors were investigated. A total of 288 patients were enrolled who were chronically infected with hepatitis C virus (HCV) genotype 1b and treated with combination therapy. Among them, 87 patients completed 48 weeks of therapy without dose reduction or discontinuation. In multivariate regression analysis, the rs8099917 TT genotype was the only independent factor significantly associated with sustained viral response (P = 0.016, OR 61.5), whereas substitutions at amino acid 70 (aa 70) of the HCV core protein (P = 0.038, OR 5.9) and non-TT genotypes (P = 0.002, OR 17.2) were associated with nonvirological response. Both factors were also associated with viral dynamics during the initial stage of the therapy. Correlation analysis revealed that rs8099917 genotype was correlated with γ-glutamyl transpeptidase, hyaluronic acid, and HCV core aa 70. In conclusion, host (IL-28B polymorphism) and viral (aa 70) factors independently affect response to combination therapy.

A first case of hepatic angiosarcoma treated with recombinant interleukin-2.

A 60 year-old woman was admitted to our hospital because of management of multiple liver tumors. According to image findings and liver biopsy, she was diagnosed as having epithelioid hemangioendothelioma of the liver accompanied by metastases in the spleen, lungs and bones. Based on the spread of the liver tumors and the extensive systemic metastases, she was considered inoperable. Instead, she received hepatic arterial infusion therapy using recombinant interleukin-2. However, she died due to liver failure about two months after admission. Autopsy revealed that the liver tumor was angiosarcoma. It is difficult to differentiate angiosarcoma from epithelioid hemangioendothelioma based on the image findings and pathological findings of percutaneous liver biopsy. Many cases are diagnosed as angiosarcoma at autopsy. There is no established effective treatment for hepatic angiosarcoma, because the tumor stage at the time of diagnosis is often progressive. To date, immunotherapy with recombinant interleukin-2 has been reported to be effective clinically for cutaneous angiosarcoma, such as of the scalp and facial skin. To our knowledge, there have been no reported cases of hepatic angiosarcoma treated with recombinant interleukin-2. Our case is important should recombinant interleukin-2 be considered effective for hepatic angiosarcoma in the future.

[Significant regression of a cavernous hepatic hemangioma to a sclerosed hemangioma over 12 years: a case study].

A sixties woman was found to have diagnosed by abdominal ultrasonography with a tumor in the left lobe of the liver and was referred to our institution in 1998. Abdominal magnetic resonance imaging (MRI) showed a typical, 70×45 mm cavernous hemangioma, which was followed up by annual MRI. In 2006, 8 years after the initial diagnosis, the MRI showed that the tumor had reduced to 30×15 mm. Although atypical of hemangioma, review of the annual observations indicated a diagnosis of regressive hemangioma, which also accorded with clinical observations. In 2009, a liver biopsy was performed by laparotomy during gastrectomy for gastric cancer. Pathological examination of the biopsy revealed sclerosed hemangioma tissue, confirming the diagnosis of regression of a cavernous hemangioma to a sclerosed hemangioma over 12 years.

Clinical and virological effects of long-term (over 5 years) lamivudine therapy.

Ideally, long-term lamivudine therapy should not induce tyrosine-methionine-aspartate-aspartate (YMDD) mutants (reverse transcription [rt]; rt M204I/V) in patients with chronic hepatitis B. There is little or no information on the clinical features of patients who do not develop such mutants. We analyzed 368 patients who received lamivudine therapy for more than 6 months between 1995 and 2003. Among them, 98 patients were negative for YMDD mutants during 5-year lamivudine therapy. Multivariate analysis identified hepatitis B e antigen (HBeAg) negativity, lack of cirrhosis, and high gamma glutamyltranspeptidase (GGTP) level as independent factors associated with lack of emergence of YMDD mutants during 5-year treatment. In these 98 patients, 21 patients developed YMDD mutants in the 5-year posttreatment follow-up. Old age was identified as the only factor associated with the emergence of YMDD mutants during that period. For all patients, 53 showed no elevation of alanine aminotransferase (ALT) or viral load after emergence of YMDD mutants during 5 years. Short latency to emergence of YMDD mutants, mixed (tyrosine-isoleucine-aspartate-aspartate (YIDD) [rtM204I] + tyrosine-valine-aspartate-aspartate (YVDD) [rtM204V]) type, and low ALT level were identified as independent factors associated with elevation ALT or viral load. HBeAg negativity, lack of cirrhosis, and high GGTP level were associated with lack of emergence of YMDD mutants during 5-year period. Young age protected against emergence of YMDD mutants over the 5-year period. Moreover, after the emergence of YMDD mutants, short latency to the emergence of YMDD mutant, mixed type mutants, and low baseline ALT level were associated with elevation of ALT or viral load.

Prolongation of interferon therapy for recurrent hepatitis C after living donor liver transplantation: analysis of predictive factors of sustained virological response, including amino acid sequence of the core and NS5A regions of hepatitis C virus.

OBJECTIVE: The aim of the present retrospective study was to evaluate the therapeutic efficacy and predictive factors of prolongation of treatment with peginterferon (PEGIFN) combined with ribavirin (RBV) for recurrent hepatitis C after living donor liver transplantation (LDLT). METHODS: Fifty-three patients underwent LDLT due to HCV-related end-stage liver disease. Sixteen patients were removed from the study as a result of early death (n=14), no recurrence of HCV (n=1) and refusal of antiviral therapy (n=1). Therapy is ongoing in another 10 patients. The remaining 27 patients were available to establish the efficacy of IFN therapy. HCV genotype was 1b in 24 patients. All patients with genotype 1b were treated with IFN therapy for at least 48 weeks after HCV RNA levels had become undetectable. Amino acid substitutions in the HCV core region and NS5A region were analyzed by direct sequencing before LDLT. RESULTS: The rate of sustained virological response (SVR) was 37.0% (10/27). SVR rate in patients with genotype 1 was 29.2% (7/24) and 100% (3/3) in patients with genotype 2. Most patients with genotype 1b whose HCV RNA reached undetectable levels achieved SVR (87.5%; 7/8). However, mutation of the HCV core region and number of ISDR mutations were not associated with SVR rate in LDLT in our study. CONCLUSIONS: Prolonged IFN therapy for more than 48 weeks after HCV RNA reached undetectable levels might prevent virological relapse of HCV.

Pilot study of systemic combination therapy with S-1, an oral fluoropyrimidine, and cisplatin for hepatocellular carcinoma with extrahepatic metastases.

BACKGROUND/AIMS: The aim of this pilot study was to elucidate the efficacy and safety of systemic combination therapy with S-1 and cisplatin (CDDP) for hepatocellular carcinoma (HCC) patients with extrahepatic metastases. METHODOLOGY: Sixteen patients were enrolled in this pilot study. Two weeks of combination therapy represented one cycle, followed by two-to-four weeks rest. In each cycle, S-1 was administrated orally at 80-120 mg (depending on body surface area) every day and cisplatin was administrated intravenously at 60 mg/m2 on day 8. Response, overall survival and adverse effects were assessed. RESULT. No patient had intrahepatic HCC and all patients had a class A Child-Pugh score. Regarding overall response, 2 (13%), 0 (0%), 5 (31%), and 9 (56%) patients showed complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), respectively, giving an overall response rate of 13% (2/16). The overall survival rate at 12 months was 77%. With regard to NCI-CTC grade-3 adverse reactions, 2 (13%), 2 (13%), and 6 (38%) patients developed nausea, anorexia, and neutropenia, respectively. No grade-4 adverse reaction or toxicity-related death occurred. CONCLUSION; S-1/CDDP is a potentially safe and effective combination therapy for HCC patients with extrahepatic metastases.

[A case of endocrine cell carcinoma of the ileum: sonographic findings and clinical outcome].

A 56-year-old man, who had been complaining of diarrhea for several months, was admitted for further examination of a hepatic tumor. A needle biopsy of the hepatic tumor suggested metastatic carcinoid tumor. The primary tumor was found in the ileum by extracorporeal sonographic examination and a barium meal study. We performed a partial excision of the ileum, lymph node resection, wedge biopsy of the liver, and catheterization from the right iliac artery to the hepatic artery for intraarterial chemotherapy. The pathological diagnosis was endocrine cell carcinoma of the ileum and local lymph nodes and hepatic metastasis. After surgery, the patient has been treated with continuous intraarterial infusion of CDDP and 5FU. The liver tumors almost disappeared. As of 20 months after the surgery, the patient is well and is being followed in the outpatient clinic.

[A case of mucosal Schwann cell hamartoma].

A 40-year-old man was referred to our hospital because of a positive fecal occult blood test. Colonoscopy revealed many small whitish nodules in the mucosa of the sigmoid colon. Specimens endoscopically resected from the lesions revealed spindle cell proliferation in the lamina propria. Immunohistochemical study revealed strong and diffuse positivity for S-100 protein. Results of staining for neurofilament protein and epithelial membrane antigen were negative. The neurogenic tumors were diagnosed as mucosal Schwann cell hamartoma. No clinical features of multiple endocrine neoplasia type 2B or neurofibromatosis type 1 were found in the present case.

Multicentric hepatocarcinogenesis at 6 and 13 years after sustained viral response to hepatitis C virus.

A 68-year-old Japanese woman with chronic hepatitis C infection who achieved sustained viral response (SVR) was followed up regularly. Six years after SVR, alpha fetoprotein (AFP) was increased. Hepatocellular carcinoma (HCC) was diagnosed by computed tomography and was excised by hepatic resection. Thirteen years after SVR, AFP increased again, and HCC recurrence was detected, which was excised by hepatic resection. Each HCC was <2 cm in diameter, with no vascular invasion. The primary HCC was moderately differentiated, while the secondary was well-to-moderately differentiated. Based on the clinicopathological features, the hepatocarcinogenesis was considered multicentric. Our case illustrates the importance of long-term follow-up of patients who achieve SVR.

Clinical features and prognosis in patients with hepatocellular carcinoma that developed after hepatitis C virus eradication with interferon therapy.

BACKGROUND: We evaluated the clinical features and the prognostic factors of hepatocellular carcinoma (HCC) developed after hepatitis C virus (HCV) eradication with interferon (IFN) therapy. METHODS: Forty-one consecutive patients who developed HCC after HCV eradication with IFN therapy were enrolled. Clinical features were reviewed, and overall survival and associated factors were analyzed. The recurrence rate in 26 patients receiving radical therapy was also analyzed. RESULTS: Twenty patients developed HCC within 5 years after the end of IFN therapy, 9 patients developed the disease from 5 to 10 years after the end of the therapy, 9 patients developed the disease from 10 to 15 years after the end of the therapy, and 3 patients developed the disease from 15 years after the end of the therapy. Multivariate analysis of independent variables for the development of HCC within 5 years identified age >55 years at HCV eradication (P = 0.007) and heavy alcohol intake (P = 0.009). The 5-year survival rate was 64%. On multivariate analysis of overall survival for the 41 patients, the only risk factor with prognostic influence was radical therapy (P = 0.010), which was associated with a cumulative 5-year survival rate of 91%. The only independent factor for the receipt of radical therapy was regular surveillance for HCC (P = 0.004). Among patients receiving radical therapy, the 3- and 5-year recurrence rates were 18 and 18%, respectively. CONCLUSION: We found that, despite HCV eradication, patients with the risk factors of high age at HCV eradication and heavy alcohol intake might be at heightened risk for the development of HCC within 5 years after HCV eradication. In contrast, risk factors for the development of HCC more than 10 years after HCV eradication were uncertain. These findings indicate the need for long-term surveillance for HCC after HCV eradication.

Clinical outcome of esophageal varices after hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with major portal vein tumor thrombus.

AIM: To analyze the clinical outcome of esophageal varices (EV) after hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) and major portal vein tumor thrombus (Vp3/4). METHODS: The study subjects were 45 consecutive patients who received HAIC for HCC with Vp3/4 between January 2005 and December 2009. HAIC comprised the combination therapy of intra-arterial 5-FU with interferon-α (5-FU/IFN) in 23 patients and low-dose cisplatin plus 5-FU (FP) in 22. Radiotherapy (RT) was also provided in 19 patients for portal vein tumor thrombosis. Aggravation rate for EV and overall survival rate were analyzed. RESULTS: The aggravation rates for EV were 47% and 64% at 12 and 24 months, respectively. The survival rates were 47% and 33% at 12 and 24 months, respectively. The response rates to 5-FU/IFN and FP were 35% and 41%, while the disease control rates in these two groups were 57% and 50%, respectively. There were no significant differences in the objective response and disease control between 5-FU/IFN and FP. Multivariate analysis identified size of EV (F2/F3) (HR = 7.554, P = 0.006) and HCC disease control (HR = 5.948, P = 0.015) as significant and independent determinants of aggravation of EV, and HCC disease control (HR = 12.233, P < 0.001), metastasis from HCC (HR = 11.469, P = 0.001), ascites (HR = 8.825, P = 0.003) and low serum albumin (HR = 4.953, P = 0.026) as determinants of overall survival. RT for portal vein tumor thrombosis tended to reduce the aggravation rate for EV in patients with these risk factors. CONCLUSIONS: Hepatocellular carcinoma disease control was the most significant and independent factor for aggravation of EV and overall survival in HCC patients with major portal vein tumor thrombosis treated with HAIC.

Eradication of hepatitis C virus genotype 1 after liver transplantation by interferon therapy before surgery: Report of three patients with analysis of interleukin-28 polymorphism, hepatitis C virus core region and interferon-sensitivity determining region.

The achievement of sustained viral response (SVR) with interferon (IFN) therapy before liver transplantation (LT) is difficult due to liver dysfunction, pancytopenia and frequent side-effects. Here, we report eradication of hepatitis C virus (HCV) genotype 1 after LT in three patients by IFN therapy before surgery. All three patients achieved virological response (VR), namely, fall in serum HCV RNA titer below the detection limit of real-time polymerase chain reaction (PCR) during IFN administration. However, HCV RNA rebound after cessation of treatment in all three patients; namely, they could not achieve SVR despite treatment with pegylated (PEG) IFN plus ribavirin. All three patients had wild-type amino acids (a.a.) at either aa70 or aa91 in the core region. Genotyping of IL-28 single nucleotide polymorphisms (rs8099917) showed TT genotype in two patients and TG genotype in one. All three patients developed multiple hepatocellular carcinomas during the clinical course, and requested living donor LT using liver grafts from their relatives. The patients were treated with IFN to immediately before LT, at which time they remained negative for HCV RNA in serum by real-time PCR. The three patients were followed-up for 14-15 months after LT, during which they remained negative for HCV RNA despite no further IFN therapy. In conclusion, it is possible to eradicate HCV after LT by inducing VR with continuous IFN therapy to before LT in spite of viral and host evidences reflecting low susceptibility to IFN treatment.

Zoledronic acid delays disease progression of bone metastases from hepatocellular carcinoma.

AIM: We conducted a retrospective cohort study to investigate the efficacy of combination therapy with radiotherapy (RT) and zoledronic acid for bone metastases from hepatocellular carcinoma (HCC). Additionally, we investigated the efficacy of zoledronic acid for non-irradiated bone metastases. METHODS: This study consisted of 31 patients who had received RT for bone metastases. Twelve of these patients with 23 sites of bone metastases were also treated with zoledronic acid (Z group). In the Z group, 14 sites received RT and nine sites did not. Nineteen patients with 38 sites of bone metastases were not treated with zoledronic acid (non-Z group). In the non-Z group, 22 sites received RT and 16 did not. We compared survival, pain response, time to pain progression, radiographic response, time to radiographic progression, and safety between groups. RESULTS: While pain response rates were similar between the two groups, time to pain progression rates of irradiated and non-irradiated bone metastases was significantly lower in the Z (0% and 20% at 6 months, respectively) than in the non-Z group (34% and 66% at 6 months, respectively) (P = 0.045 and P = 0.005). Further, while radiographic response rates were similar between the two groups, time to radiographic progression rate of non-irradiated bone metastases was significantly lower in the Z (29% at 3 months) than in the non-Z group (91% at 3 months) (P = 0.009). No significant side-effects were documented. CONCLUSION: Zoledronic acid delayed the pain progression of both irradiated and non-irradiated bone metastases and the radiographic progression of non-irradiated bone metastases from HCC.

Transcatheter chemoembolization for unresectable hepatocellular carcinoma and comparison of five staging systems.

AIM: We compared the ability of five staging system to predict survival in patients with hepatocellular carcinoma (HCC) treated with chemoembolization. METHODS: The study subjects were 214 patients with HCC treated with repeated chemoembolization alone using cisplatin and lipiodol. Predictors of survival were assessed by multivariate analysis. Before chemoembolization was carried out, the modified Japan Integrated Staging (m-JIS), Japan Integrated Staging (JIS score), Barcelona (BCLC) stage, Liver Cancer Study Group of Japan/Tumor-Node-Metastasis (LCSGJ/TNM) and Italian score (CLIP score) were checked. To validate the prognostic value of these staging systems, the survival curve was obtained and analyzed by the Kaplan-Meier method. Discriminatory ability and predictive power were compared using Akaike's information criterion (AIC) score and the likelihood ratio (LR) χ(2) . RESULTS: Overall survival was 1 year in 82.9%, 3 years in 39.9% and 5 years in 15.1%. Multivariate analysis identified more than 90% lipiodol accumulation (grade I) after the first chemoembolization (P = 0.001), absence of portal vein tumor thrombosis (PVTT) (P < 0.001) and liver damage A (P = 0.012) as independent determinants of survival. AIC score and the LR χ(2) showed superior predictive power of the m-JIS system in 95 patients with grade I accumulation of lipiodol after first chemoembolization. CONCLUSION: The discriminate ability of the m-JIS score is substantially better than those of other staging systems and has better prognostic predictive power in patients with grade I accumulation of lipiodol after first chemoembolization.