Does intensity-modulated radiation therapy by helical tomotherapy for prostate cancer increase the subsequent risk of bladder cancer? A propensity score-matched analysis.

OBJECTIVES: This study aimed to evaluate the risk of bladder cancer after intensity-modulated radiation therapy (IMRT) using helical tomotherapy for prostate cancer in comparison to the risk post-radical prostatectomy (RP) using propensity score-matched analysis and to assess the risk factors for bladder cancer. METHODS: This retrospective study included 2067 patients with non-metastatic prostate cancer treated at our institution between June 2007 and December 2016. Of these, 1547 patients were treated with IMRT and 520 underwent RP. The propensity scores were calculated using age, National Comprehensive Cancer Network risk classification, prostate volume, Brinkman index, and follow-up time as matched covariates. A propensity score-matched patient cohort (n = 718; IMRT: 359, RP: 359) was created, and the risk of bladder cancer after treatment was compared. RESULTS: In total, bladder cancer was detected in 33 patients. Five patients in the IMRT group and one in the RP group died of bladder cancer. In the propensity score-matched analysis, the 5-year bladder cancer-free survival rate was significantly lower in the IMRT group than in the RP group (91.7% and 96.2%, respectively; p < 0.001). Multivariate analysis revealed that IMRT and the Brinkman index were the risk factors for bladder cancer in this cohort (odds ratio = 5.085, 95% confidence interval = 1.436-18.008, p = 0.012 and odds ratio = 1.001, 95% confidence interval = 1.000-1.001, p = 0.010, respectively). CONCLUSIONS: IMRT for prostate cancer using helical tomotherapy increases the subsequent risk of bladder cancer compared with RP and is an independent risk factor for bladder cancer similar to smoking.

Robotic-assisted laparoscopic radical prostatectomy for treatment of a newly identified lesion revealed no viable cells in the previously treated area with microwave focal therapy.

Introduction: Histological outcome of the targeted focal therapy is in principle confirmed by targeted needle biopsy from the treated area in clinical trial. Herein, we report a rare case in which the MFT was followed by RARP. Case presentation: A 68-year-old man with PSA 9.6 ng/mL and PI-RADS 4 lesion in the right transition zone on multi-parametric MRI underwent MR/ultrasound fusion-guided targeted biopsy, which revealed grade-group 1 cancer. Targeted focal therapy with microwave ablation was performed, resulting in disappearance of the PI-RADS 4 lesion at post-operative 4 months. However, PSA rose to 11.5 ng/mL, and a new PI-RADS 4 lesion, was identified in the left peripheral zone. RARP was performed to reveal new grade-group 3 cancer, and no viable cells in the previously treated area with MFT. Conclusion: RARP was safely performed even after MFT and proved the pathological complete response of microwave ablation.

Preoperative prediction of malignant involvement of resected ureters in patients undergoing radical cystectomy for bladder cancer.

OBJECTIVE: To investigate preoperative predictors of ureteral involvement of bladder malignancy and to develop a novel preoperative model for the prediction of ureteral involvement in bladder cancer patients undergoing radical cystectomy. METHODS: This study included 197 consecutive bladder cancer patients treated with radical cystectomy. The correlations of preoperative factors with ureteral involvement were analyzed by univariate analysis with Pearson's χ(2-) test and multivariate logistic regression analysis with a stepwise selection procedure. RESULTS: Positive ureteral involvement was observed in 38 (19.3%) patients. Tumor location (involvement of the vesical trigone), clinical T stage (≥ cT3) and the number of tumors (≥ 3), but not sex, tumor grade and histological features determined by transurethral resection of bladder tumor, tumor size, shape of tumor, concomitant presence of carcinoma in situ, preoperative intravesical therapy, number of transurethral resection of bladder tumor procedures or the presence of hydronephrosis were significantly associated with ureteral involvement in the univariate analysis. Multivariate logistic regression analysis confirmed that the aforementioned three significant factors identified in the univariate analysis were significant independent predictors of ureteral involvement. The probability of ureteral involvement estimated by a combination of these three parameters was well correlated with the real incidence (R = 0.904, P = 0.0021). CONCLUSIONS: Tumor location (involvement of vesical trigone), clinical T stage (≥ cT3) and the number of tumors (≥ 3) are significant independent preoperative predictors of ureteral involvement of malignancy in bladder cancer patients undergoing radical cystectomy. Our predictive model might be useful for preoperative prediction of ureteral tumor involvement.

Antibody responses after BNT162b2 vaccination in Japanese geriatric intermediate care facilities.

Background: To evaluate antibody responses against the primary series of vaccination of severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2] vaccines in the staff and residents of Japanese geriatric intermediate care facilities. Methods: All subjects (159 staff and 96 residents) received two doses of the BNT162b2 mRNA vaccine 3 weeks apart. Baseline data of subject were collected using a structured form. Serum samples were collected three times: before vaccination, 3 weeks after the first dose, and 4 weeks after the second dose, and anti-receptor binding domain of the spike protein of SARS-CoV-2 [anti-RBD] IgG was measured using two immunoassays. Results: After the second dose, geometric mean titers [GMT] of anti-RBD with both the Abbott and Roche assay were significantly lower in residents than staff (2282 AU/mL vs. 8505 AU/mL, and 258 U/mL vs. 948 U/mL, respectively). Multivariate analysis of characteristics affecting antibody responses (≥1280 AU/mL for Abbott and > 210 U/mL for Roche) showed lower odds ratios [ORs] for older age (adjusted OR per 10 year increase [aOR] = 0.62, 95 % confidence interval [95 %CI]; 0.38-1.02), steroid usage (aOR = 0.09, 95 %CI; 0.01-0.60) and regular nonsteroidal anti-inflammatory drugs [NSAIDs] usage (aOR = 0.16, 95 %CI; 0.03-0.88). Conclusions: Elderly people and steroid and NSAID users had lower antibody responses following the second vaccine dose.

The Long-Term Effect of Intensity Modulated Radiation Therapy for Prostate Cancer on Testosterone Levels.

Purpose: Concern about a long-term effect of the delivery of intensity modulated radiation therapy (IMRT) for prostate cancer on serum testosterone levels remains unelucidated. We evaluated how IMRT for localized prostate cancer affects serum testosterone levels during a follow-up period of up to 10 years. Methods and Materials: We retrospectively evaluated data from 182 patients with localized prostate cancer who underwent definitive IMRT alone between 2007 and 2014. Serum total testosterone (TT) levels were measured by blood draws between 6 AM and 11 AM before treatment and at every posttreatment follow-up for 10 years. Pretreatment values and each posttreatment testosterone value were compared using a Wilcoxon signed rank test. The data set was stratified into 4 groups based on the pretreatment testosterone (pre-TT) values using quartiles. Results: The median absolute or relative changes in TT levels from pretreatment were -0.42 ng/mL or -12.0% at 3 months after radiation therapy (P < .0001). Subsequently, TT levels gradually recovered to nearly the pretreatment levels 24 to 36 months after IMRT. When analyzed according to the pre-TT quartile, median TT levels initially decreased at the 3- to 12-month period in all the quartiles; however, median TT levels increased from the 18-month period in the first and second quartile groups, whereas they were maintained at less than the pretreatment levels in the third and the fourth quartile groups throughout the entire decade after radiation therapy. The proportion of patients with hypogonadal status, defined as TT levels <3.00 ng/mL, did not increase over time. Conclusions: A transient and modest decrease of TT levels after IMRT spontaneously recovered to the pretreatment levels at the 24- to 36-month period except in patients in the higher quartile of pre-TT. This might have been partly owing to a variable sensitivity of individual testicular function to scattered radiation. Patients with lower pre-TT did not demonstrate a progressive overall rate of hypogonadism until 10 years after radiation therapy.

Safety and efficacy of docetaxel, estramustine phosphate and hydrocortisone in hormone-refractory prostate cancer patients.

OBJECTIVE: To assess the combination of docetaxel (DTX), estramustine phosphate (EMP) and hydrocortisone for patients with hormone-refractory prostate cancer (HRPC). METHODS: A total of 63 patients with HRPC were treated with a chemotherapeutic regimen including DTX, EMP, and hydrocortisone. Clinical and pathological features were correlated to serum prostate-specific antigen (PSA) recurrence and survival rates. Incidence and degree of toxicities were also retrospectively reviewed. RESULTS: A median of 11 courses of chemotherapy was administered per patient. PSA levels decreased by >50% in 32 (51%) patients and >90% in 18 (29%) patients. Median time to PSA progression was 6 months (range from 1 to 41 months) and median time of overall survival was 14 months (range from 1 to 56 months). In a univariate analysis to predict overall survival, PSA, hemoglobin, alkaliphosphatase, and performance status prior to the chemotherapy were significant factors. Despite grade 3-4 neutropenia in 87% of patients, grade 5 interstitial pneumonia in one patient and grade 4-5 myocardial infarction in two patients were recognized, the regimen seemed to be relatively safe. CONCLUSIONS: Combination chemotherapy with DTX, EMP and hydrocortisone provides survival benefits for patients with HRPC with an acceptable toxicity profile. We need to further evaluate who might benefit most from this regimen.

Effects of CXCR4 antagonist CTCE-9908 on prostate tumor growth.

BACKGROUND: Recent reports have linked the survival-promoting effect of CXCR4 to the up regulation of Bcl-2 protein expression. MATERIALS AND METHODS: To further elucidate the relationship between Bcl-2 and CXCR4, tumorigenicity was evaluated in in vitro and in vivo models following treatment with CTCE-9908, a CXCR4 antagonist peptide. RESULTS: In vitro, CTCE-9908 inhibited cellular proliferation in PC-3-Bcl-2 and PC-3-Neo cell lines Furthermore in our xenograft model, CTCE-9908 delivered via daily intraperitoneal injections resulted in a statistically significant reduction in tumor size compared to control (396 + 205 mm(3) vs. 1,010 + 215 mm(3) respectively, p < 0.05) in the Bcl-2 expressing tumors. This reduction was associated with knockdown of VEGF, inhibition of angiogenesis and lymphangiogenesis, and induction of apoptosis. CTCE-9908 therapy was also associated with a marked reduction in intra-tumoral host cells expressing VEGFR1 and CD11b myeloid-derived suppressor cells (MDSC). CONCLUSION: These data show that CXCR4 antagonists represent a valuable addition to the cancer therapeutic arsenal. Such agents may have beneficial synergistic dual-effects in reducing tumor cell proliferation directly, and indirectly through perturbation of the tumor microenvironment. Further studies of the novel CTCE-9908 compound in prostate and other solid tumor inhibition are warranted. Prostate 69: 1460-1469, 2009. (c) 2009 Wiley-Liss, Inc.

Interspecific and intersexual learning rate differences in four butterfly species.

Learning plays an important role in food acquisition for a wide range of insects and has been demonstrated to be essential during flower foraging in taxa such as bees, parasitoid wasps, butterflies and moths. However, little attention has been focused on differences in floral cue learning abilities among species and sexes. We examined the associative learning of flower colour with nectar in four butterfly species: Idea leuconoe, Argyreus hyperbius, Pieris rapae and Lycaena phlaeas. All butterflies that were trained learned the flower colours associated with food. The flower colour learning rates were significantly higher in I. leuconoe and A. hyperbius than in P. rapae and L. phlaeas. Among the four species examined, the larger and longer-lived species exhibited higher learning rates. Furthermore, female butterflies showed a significantly higher learning rate than males. This study provides the first evidence that learning abilities related to floral cues differ among butterfly species. The adaptive significance of superior learning abilities in the larger and longer-lived butterfly species and in females is discussed.

Primary seminoma of the prostate.

Abstract A 54-year-old gentleman was suspected of having sarcoma of the prostate because of his low serum prostate-specific antigen level (1.9 ng/mL) and an enlarged heterogeneous mass on computed tomography and magnetic resonance imaging scans. Pathological examination of the prostate needle biopsy indicated seminoma, which was confirmed with immunohistochemical staining. There was no evidence of disease in other areas on physical examination or on radiographic tests. Therefore, we diagnosed the case as a primary seminoma of the prostate, which was consequently treated with a total of three courses of bleomycin, etoposide and cisplatin chemotherapy. Complete response was obtained on computed tomography, magnetic resonance imaging and prostate needle re-biopsy. To our knowledge, there have only been five cases of primary seminoma of the prostate reported.

[Case of renal cell carcinoma metastasized to iliopsoas muscle].

Skeletal muscle metastasis is a rare event in renal cell carcinoma (RCC). Only thirty-two cases have been reported until now. A 69-year-old female had a nephrectomy for right RCC (clear cell carcinoma, grade 2, pT1) in 1994. She has been followed up every three months after nephrectomy. After twelve years from nephrectomy, computed tomography (CT) showed a 3 cm mass in the right iliopsoas muscle. CT guided needle biopsy revealed tumor cells suspicious of renal cell carcinoma metastasis. The tumor was surgically removed and histologically diagnosed as renal cell carcinoma metastasized to the iliopsoas muscle.

Characterization and gene expression analysis of novel matched primary and metastatic renal cell carcinoma cell lines.

Despite recent advances in molecular biology that have clarified the mechanisms involved in the metastasis of several types of cancer, the molecular mechanism underlying the metastasis of renal cell carcinoma (RCC) remains unclear. Two RCC cell lines were successfully established from the surgical specimens of a matched primary tumor and adrenal metastasis from the same RCC patient, and were designated as TMK-1P and TMK-1M, respectively. Extensive characterization was accomplished using various methods, including the Matrigel invasion assay, DNA microarray analysis and real-time reverse transcriptase (RT)-polymerase chain reaction (PCR). While TMK-1P grew faster than TMK-1M, the invasive ability of TMK-1M was higher than that of TMK-1P. DNA microarray analysis showed a large differential expression of genes related to cell adhesion and the extracellular matrix molecules of which hexabrachion (tenascin-C), epidermal growth factor receptor, cadherin-6, and beta1-catenin were down-regulated, and the 67 kDa laminin receptor 1 and transforming growth factor-beta-induced 68 kDa protein (betaig-h3) were up-regulated in TMK-1M. Real-time RT-PCR analysis confirmed this differential gene expression between the two cell lines. The RCC cell lines may be useful in studying tumor invasion and screening markers for metastasis.

[First 24 Japanese cases of robotic-assisted laparoscopic radical prostatectomy using the daVinci Surgical System].

In Japan, as of September 2007, prostatectomy is conducted with open surgical procedures in more than 90% of the cases. Following the first reported robotic prostatectomy by Binder, et al. in 2000, a robotic-assisted laparoscopic radical prostatectomy (RALP) using the daVinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, California, USA) has been extensively used as a standard procedure with gratifying results in the United States. In the Asian region, in contrast, RALP is still in an introductory phase. Recently, we introduced RALP in Japan. A total of 24 patients received robotic surgery within a year since August 2006. RALP was completed in all patients without conversion to open surgery, except for the first patient in whom a restriction to a 2-hour operation had been imposed by the Ethical Committee. The mean operative time using the daVinci device and the mean estimated blood loss were 232.0 (range; 136-405) minutes and 313.0 (range; 10-1,000) ml, respectively. The training program we recently developed proved remarkably effective in reducing the learning curve of robotic surgery in Japan, where there is no person with expertise in this operating procedure. In particular, the intraoperative guidance given by the expert was useful after relevant problematic points were delineated by operators who received comprehensive video-based image training and actually performed robot surgery in several cases. With direct intraoperative guidance by the mentor during cases 13 and 14, both the operation time and estimated blood loss was markedly reduced.

[Retroperitoneal dedifferentiated liposarcoma: a case report].

A 64 year-old female visited our outpatient clinic with left dull flank pain. The ultrasonography and CT scans showed the large solid mass in 12 cm in maximum diameter, containing large area of fatty element, in the left retroperitoneal space. Under the diagnosis of retroperitoneum liposarcoma, the mass and left kidney was completely removed. Pathological examination revealed the dedifferentiated liposarcoma which contained the distinct two patterns of well differentiated lipoma and dedifferentiated fibrotic sarcomatoid tissue.

Levels of formaldehyde vapor released from embalmed cadavers in each dissection stage.

Formaldehyde (FA) is an aldehyde used in antiseptics and adhesives. The World Health Organization (WHO) and other institutes have linked FA to sick building syndrome and allergic diseases. Recent studies have reported that cadavers embalmed using formalin and ethanol-based preservative solutions release FA vapor during dissection and that FA vapor may adversely affect students and lecturers in gross anatomy laboratories. However, few details have been reported correlating dissection stage with increased FA vapor release. In this study, we evaluated the vapor level of FA released in each dissection stage. Six cadavers for which consent was given for use in anatomy research and education were examined in this study. Using an active sampling method, FA vapor was collected above the thoracoabdominal region of each dissected cadaver. FA was eluted from each sampler using acetonitrile and analyzed by high-performance liquid chromatography. Our data show that FA levels significantly increase after skin incision and that the vapor level of FA released differs between male and female cadavers. We also found that subcutaneous adipose tissues of the thoracoabdominal-region release FA vapor and that female cadavers release significantly higher levels of FA per kilogram of subcutaneous adipose tissue than do male cadavers. Based on these data, we propose the methods be developed to prevent exposure to FA vapors released from cadavers.

Interpretation of multi-detector computed tomography images before dissection may allow detection of vascular anomalies: a postmortem study of anomalous origin of the right subclavian artery and the right vertebral artery.

The Graduate School of Medicine at Chiba University is planning to introduce computed tomography (CT) images of donated cadavers to the gross anatomy laboratory. Here we describe an anomaly of the right subclavian artery that was detected by interpretation of CT images prior to dissection. The anomaly was verified to be the right subclavian artery, as the last branch of the aortic arch, by subsequent dissection of the cadaver. We also identified an anomalous origin of the right vertebral artery by dissection. This anomaly was also visible on CT images, although it had not been recognized in the first interpretation of the CT images. Our results suggest that branching anomalies of arteries with a diameter of >1 cm are detectable on CT images even without the injection of contrast medium. We also discuss the utility of interpreting CT images prior to dissection as a means by which medical students can gain a better understanding of human body during the gross anatomy laboratory.

Dual targeting of Bcl-2 and VEGF: a potential strategy to improve therapy for prostate cancer.

We previously demonstrated that Bcl-2 overexpression stimulates angiogenesis in PC-3 human prostate cancer cells, thus giving these tumors a growth advantage. To further elucidate the relationship between Bcl-2 and vascular endothelial growth factor (VEGF) in PC-3-Bcl-2 cells, tumorigenicity and angiogenesis were evaluated in our in vitro and in vivo model treated with antisense Bcl-2 oligodeoxynucleotide (ASO) and bevacizumab. In vitro and in vivo angiogenesis assays, as well as a xenograft tumor model of the human prostate cancer cell line PC-3-Bcl-2, were subjected to ASO alone, bevacizumab alone, or the combination of ASO and bevacizumab. Protein-based assays (e.g., immunohistochemical staining and enzyme-linked immunosorbent assay [ELISA]) were utilized to detect molecular changes. Interestingly, targeting Bcl-2 with ASO resulted in the inhibition of in vitro tube formation and inhibition of angiogenesis in Matrigel plugs similar to treatment with bevacizumab. In our PC-3-Bcl-2 xenograft model, ASO alone resulted in 41% reduction in tumor size, bevacizumab alone resulted in a 50% reduction in tumor size, whereas the combination of ASO with bevacizumab was associated with >95% reduction in tumor volume. Reduction in tumor size in all groups was associated with reduction in Bcl-2 and VEGF expression, induction of apoptosis, and inhibition of angiogenesis and its associated chemokine production. These findings confirm that Bcl-2 is a pivotal target for cancer therapy and thus, further study of this novel combination of Bcl-2 reduction and angiogenic targeting in human tumors is warranted.

Contact investigation in a primary school using a whole blood interferon-gamma assay.

OBJECTIVES: To evaluate the usefulness of QuantiFERON-TB Gold (QFT-G) for children. METHODS: Students in a primary school exposed to a tuberculosis patient were investigated using the tuberculin skin test (TST), chest X-ray examination and sequential QFT-G tests. RESULTS: The first QFT-G test was conducted one month after the end of exposure for 308 of the 313 children, with 6 (1.9%) positive. TST results were obtained from 306 of the students at 2 months after exposure, and 200 (65.4%) had induration > or =5mm. A second QFT-G test, a further month later, and a third QFT-G test, six months after exposure, found an additional 2 positive and one weakly positive, respectively. Overall, the rate of QFT-G positivity was 9.8% (4/41) for close contact children (> or =90h exposure), significantly higher than for casual contacts (< or =18h exposure; 1.8%, 5/272; p=0.020), whereas there was no significant difference in TST positive rates (p=0.078). CONCLUSIONS: These data suggest that QFT-G has the same performance characteristics in BCG vaccinated children as it does in adults. The observation that none of the 297 students who were QFT-G negative had developed active TB after 3 years of follow-up suggests that QFT-G has a very high negative predictive value.

Persistent exposure to Mycoplasma induces malignant transformation of human prostate cells.

Recent epidemiologic, genetic, and molecular studies suggest infection and inflammation initiate certain cancers, including those of the prostate. The American Cancer Society, estimates that approximately 20% of all worldwide cancers are caused by infection. Mycoplasma, a genus of bacteria that lack a cell wall, are among the few prokaryotes that can grow in close relationship with mammalian cells, often without any apparent pathology, for extended periods of time. In this study, the capacity of Mycoplasma genitalium, a prevalent sexually transmitted infection, and Mycoplasma hyorhinis, a mycoplasma found at unusually high frequency among patients with AIDS, to induce a malignant phenotype in benign human prostate cells (BPH-1) was evaluated using a series of in vitro and in vivo assays. After 19 weeks of culture, infected BPH-1 cells achieved anchorage-independent growth and increased migration and invasion. Malignant transformation of infected BPH-1 cells was confirmed by the formation of xenograft tumors in athymic mice. Associated with these changes was an increase in karyotypic entropy, evident by the accumulation of chromosomal aberrations and polysomy. This is the first report describing the capacity of M. genitalium or M. hyorhinis infection to lead to the malignant transformation of benign human epithelial cells and may serve as a model to further study the relationship between prostatitis and prostatic carcinogenesis.