Therapeutic effects of the combined androgen blockade therapy versus luteinizing hormone-releasing hormone analog monotherapy in patients with hormone naïve metastatic prostate cancer: a multi-institutional comparative analysis

BackgroundThe clinical benefit of the combined androgen blockade (CAB) therapy over luteinizing hormone-releasing hormone analog (LH-RHa) monotherapy for hormone naïve metastatic prostate cancer (mHNPC) is unclear. Therefore, we retrospectively compare the effectiveness of CAB with the LH-RHa monotherapy on the prognosis of Japanese patients with mHNPC.MethodsWe retrospectively evaluated the prognosis of 517 patients diagnosed with mHNPC between August 2001 and May 2017. The patients’ data were obtained from the Michinoku Urological Cancer Research Group database and Hirosaki University-related hospitals. Patients were divided into the CAB and LH-RHa monotherapy groups based on primary androgen deprivation therapy (ADT). Overall survival (OS), cancer-specific survival (CSS), and castrate-resistant prostate cancer-free survival (CRPC-FS) were compared between the two groups using the Kaplan-Meier curve analysis. Inverse probability of treatment weighting (IPTW)-adjusted Cox hazard proportional analyses was performed to investigate the effect of primary ADT on oncological outcomes.ResultsThe median age was 73 years old. The numbers of patients in the CAB and LH-RHa monotherapy groups were 447 and 70, respectively. The Kaplan-Meier curve analysis showed no significant differences in either 5-year OS (56.7% vs. 52.5%, P=0.277), CSS (61.1% vs. 56.4%, P=0.400), and CRPC-FS (33.1% vs. 31.1%, P=0.529) between the groups. IPTW-adjusted multivariate Cox hazard proportional analyses showed no significant differences in OS, CSS, and CRPC-FS between the two groups.ConclusionsNo significant differences in oncological outcomes were observed between the CAB and LH-RHa monotherapy groups in patients with mHNPC.     

Preparation of Asialofetuin-Labeled Liposomes with Encapsulated Human Interferon-γ and Their Uptake by Isolated Rat Hepatocytes

The selective delivery of human recombinant interferon (IFN)- to isolated rat hepatocytes was studied with asialofetuin (AF)-labeled liposomes. AF-liposomes containing buffer solution were initially prepared by the detergent removal method, and IFN- was subsequently encapsulated by the freeze-thawing method without loss of activity. Virtually no free [³²P]IFN- was internalized into isolated rat hepatocytes, whereas AF-liposomes containing [³²P]IFN- were taken up to a significant degree. Liposomal binding to the hepatocytes (estimated at 4°C) was one-fifth of the uptake (estimated at 37°C). Since the uptake was inhibited by the addition of free AF, AF-liposomes may be taken up by the action of galactose-binding protein on the hepatocytic cell surface. The liposome preparation method reported in this paper provides a useful means for the encapsulation of unstable macromolecules into AF-liposomes. AF-liposomes were found effectively to carry IFN- into hepatocytes in vitro.     

Risk factors for hepatocellular carcinoma at baseline and 1 year after initiation of nucleos(t)ide analog therapy for chronic hepatitis B

Nucleos(t)ide analogs (NAs) cannot completely suppress the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to identify the risk factors for HCC development in naïve CHB patients treated with current NA. Patients receiving NA (n = 905) were recruited retrospectively from the 17 hospitals of the Japanese Red Cross Liver Study Group. All treatment-naïve patients had been receiving current NA continuously for more than 1 year until the end of the follow-up. We analyzed the accuracy of predictive risk score using the area under receiver operating characteristic curve. The albumin–bilirubin (ALBI) score was significantly improved by NA therapy (−0.171 ± 0.396; p < 0.001 at Week 48). A total of 72 (8.0%) patients developed HCC over a median follow-up of 6.2 (1.03–15.7) years. An independent predictive factor of HCC development was older age, cirrhosis, lower platelet counts at baseline and ALBI score, and alpha-fetoprotein (AFP) at 1 year after NA therapy according to multivariate analysis. The accuracy was assessed using the PAGE-B, mPAGE-B, aMAP, APA-B, and REAL-B scores that included these factors. Discrimination was generally acceptable for these models. aMAP and REAL-B demonstrated high discrimination with 0.866/0.862 and 0.833/0.859 for 3- and 5-year prediction from the status of 1 year after NA therapy, respectively. Baseline age and platelet count, as well as ALBI and AFP one year after NA, were useful for stratifying carcinogenesis risk. The aMAP and REAL-B scores were validated with high accuracy in Japanese CHB patients.     

Clinicopathological features of hereditary breast cancer

The possible role of germline mutations ofBRCA1 andBRCA2 as causative agents of familial breast cancer was assessed. Their possible involvement in the carcinogenesis of hereditary breast cancer was investigated using 63 clinically suspect families. Twenty-one lineages (33.3%) had mutations in one of the twoBRCA genes. This relatively low incidence suggested that germline mutations in unknown genes are involved in the carcinogenesis of hereditary breast cancer in the Japanese population. However, the clinicopathological features characteristic of hereditary breast cancer, such as early disease onset, a high incidence of bilateral breast cancer, and a high incidence of multiple primary carcinomas in other organs were confirmed in the present study.     

Lack of microsatellite instability in human prostate-cancer

DNA replication errors are especially frequent in repetitive DNA sequences, including microsatellites. Thus, microsatellites are sensitive indicators of the genetic instability observed in many types of human cancers, particularly colorectal cancer. We tested prostate carcinomas for the presence of microsatellite alleles not present in normal tissue from the same individuals. Analysis of 7 microsatellites in each of 30 patients revealed instability at only one microsatellite in one tumor. This level of microsatellite instability, considerably lower than that reported previously, may reflect differences in patient pools. We discuss the implications of the genetic stability of prostate cancers relative to other cancers.     

Unilateral Multicentric Breast Carcinoma Studied by Whole Mammary Gland Serial Sectioning

The incidence and clinicopathologic features of unilateral multicentric breast cancer (UMBC) were studied by mammary gland serial sectioning in 116 cases of clinically defined monocentric breast cancer (MONBC) examined histopathologically at the Nagano Cancer Detection Center. UMBC was defined as: 1) histopathologically discontinuous tumors each with an intraductal spread, 2) at least one tumor-free section separating two tumors, and 3) a large primary tumor and other small secondary tumors. UMBC was detected in 23 of 116 cases (19.8%), all with one secondary tumor. Primary and secondary tumors were located in the same quadrant in 34.8% and in different ones in 65.2%. The secondary tumors were <5 mm in size in 56.5%. Secondary tumors, averaging 8.3 mm in size and 25.5 mm in distance from the primary tumor, were almost exclusively noninvasive carcinomas, including 15 (65.4%) noninvasive ductal carcinomas and several special types. The primary and secondary tumors were of the same histologic type in 3 of 23 cases. UMBC patients averaged 6 years younger than MONBC patients, and the incidence of UMBC tended to be higher in younger patients (p<0.1). UMBC tended to occur more frequently in quadrant with an average histologie tumor size significantly smaller than that in MONBC (p<0.01). The histologie types of the primary tumor in UMBC and MONBC were similar, with common types predominant. Lymph node metastases tended to be slightly more frequent in MONBC. This high incidence of UMBC calls for careful attention when considering breast conserving therapy.     

Studies on the tumor-promoting activities of additives in biomaterials: inhibition of metabolic cooperation by additives such as pigments and phenolic antioxidants

The inhibitory activities on the intercellular gap-junctional communication were investigated using the V79 metabolic cooperation (MC) assay for the detection of tumor-promoting activities of additives such as pigments and phenolic antioxidants. Among six pigments, four chemicals showed inhibitory activities. The inhibitory potencies were ranked in the following order: sudan I > purple 201 > blue 204 > green 202. Sudan I and purple 201 showed stronger inhibitory activities than lithocholic acid, which is known to be a tumor promotor. However, quinizarine and red 225 did not inhibit at any concentration. Relating to eight phenolic antioxidants, four chemicals also showed inhibitory activities. Combining the present findings with previous ones, there are many factors that have tumor-promoting activities via inhibitory action on gap-junctional intercellular communication in biomaterials.     

Non-suture end-to-end anastomoses between polytetrafluoroethylene graft and vessels for blood access

BACKGROUND: Non-suture end-to-end anastomoses between polytetrafluoroethylene grafts and blood vessels were achieved using absorbable cuff material in experimental and clinical studies. The cuff was made of a synthetic biodegradable material, a lactic-glycolic acid copolymer, similar in composition to conventional absorbable surgical sutures. METHODS: In the experimental study, vascular anastomoses for prosthetic interposition of the infrarenal aorta in rabbits were created using the cuff method. Six months after surgery, the cuff anastomoses sites were examined angiographically and microscopically and found to be patent and smooth without neointimal hyperplasia. RESULTS: The cuff layer had been completely absorbed. The clinical application used a similar technique and involved the creation of forearm bridge graft fistula in twelve patients for hemodialysis. In eight patients, Doppler fistula flow rate ranged from 167 ml/min to 392 ml/min. Ten of the twelve patients continued dialysis uneventfully. The one-year patency rate was 78% (7/9). The longest patency period was 920 days and the graft access continued to maintain sufficient blood flow for hemodialysis. CONCLUSIONS: This absorbable cuff material is therefore well suited for the construction of prosthetic vascular end-to-end anastomoses.     

A technique for reconstruction of the medial patellofemoral ligament

Additional medial patellofemoral ligament reconstruction was performed successfully on six consecutive patients with recurrent dislocation of the patella because of residual patellar instability after medial transfer of the tibial tubercle. A technique for medial patellofemoral ligament reconstruction is described, and complications and postoperative management are discussed. The reconstruction was performed using a double strand hamstring tendon graft in five patients and iliotibial allograft in one. Good stabilization of the patella was achieved in all six patients, resulting in improved confidence in higher levels of activity. The satisfactory outcome of additional medial patellofemoral ligament reconstruction suggests the possibility that the procedure may be part of the optional procedure in proximal realignment for recurrent dislocation of the patella.