Osteoporotic fracture risk in women with breast cancer treated with aromatase inhibitors: a health insurance claims database study in Japan.

BACKGROUND: Hormone therapy with aromatase inhibitors (AIs) for estrogen receptor-dependent breast cancer may expose patients to an increased osteoporosis risk. This study was performed to estimate fracture risk in women with breast cancer to whom AIs were prescribed in Japan. METHODS: This retrospective study used data from the Japanese Medical Data Vision database. Women with breast cancer prescribed AIs over a 12-month period were identified and matched to women not prescribed AIs using a propensity score. Fracture rates were estimated by a cumulative incidence function and compared using a cause-specific Cox hazard model. The proportion of women undergoing bone density tests was retrieved. RESULTS: For all fractures sites combined, cumulative fracture incidence at 10 years was 0.19 [95%CI: 0.16-0.22] in women prescribed AIs and 0.18 [95%CI: 0.15-0.21] without AIs. AI prescription was not associated with any changes in risk (adjusted hazard ratio: 1.08 [95%CI: 0.99-1.17] p = 0.08). Women prescribed AI more frequently underwent bone density testing (31.9% [95% CI: 31.2%; 32.6%] versus 2.2% [95% CI: 2.0%; 2.4%]). CONCLUSIONS: The anticipated association between AI exposure and osteoporotic fracture risk in Japanese women with breast cancer was not seen clearly.

Androgen deprivation therapy-related fracture risk in prostate cancer: an insurance claims database study in Japan.

INTRODUCTION: Androgen deprivation therapy (ADT) is widely used for the treatment of prostate cancer. ADT is associated with reduced bone density leading to an increased risk of osteoporotic fracture. The objective of this retrospective cohort study was to quantify fracture risk in men treated with ADT for prostate cancer in real-world practice in Japan. MATERIALS AND METHODS: Data were extracted from the Japanese Medical Data Vision (MDV) database. Men initiating ADT for treatment of prostate cancer between April 2010 and March 2021 were identified and matched to a cohort of prostate cancer patients not taking ADT using a propensity score. Fracture rates were estimated by a cumulative incidence function and compared between cohorts using a Cox cause-specific hazard model. Information was extracted on demographics, comorbidities and bone densitometry. RESULTS: 30,561 men with PC starting ADT were matched to 30,561 men with prostate cancer not treated with ADT. Following ADT initiation, <5% of men underwent bone densitometry. Prescription of ADT was associated with an increased fracture risk compared to not taking ADT (adjusted hazard ratio: 1.63 [95% CI 1.52-1.75]). CONCLUSION: ADT is associated with a 1.6-fold increase in the risk of osteoporotic fracture in men with prostate cancer. Densitometry in this population is infrequent and monitoring urgently needs to be improved in order to implement effective fracture prevention.

Two cases of prostate cancer with disseminated carcinomatosis of the bone marrow treated with novel hormonal agents.

Introduction: Disseminated carcinomatosis of the bone marrow in prostate cancer is rare and has a poor prognosis. Although strong evidence suggests that novel hormonal agents improve the prognosis of metastatic prostate cancer, their effectiveness in cases of disseminated carcinomatosis of the bone marrow remains unclear. Case presentation: We encountered two cases of prostate cancer with disseminated carcinomatosis of the bone marrow at the time of initial diagnosis. One patient was treated with enzalutamide, abiraterone, docetaxel, cabazitaxel, denosumab, and radium-223 and died 38 months after the initial diagnosis. The other patient was treated with apalutamide and denosumab, and had progression-free survival for 17 months after the initial diagnosis. Conclusion: These results suggest that novel hormonal agents may improve the prognosis of prostate cancer even in patients with disseminated carcinomatosis of the bone marrow.

Validation of JSBMR's CTIBL manual for Japanese men receiving androgen deprivation therapy for prostate cancer.

INTRODUCTION: Androgen deprivation therapy (ADT) for prostate cancer causes cancer treatment-induced bone loss (CTIBL), increases the fracture risk 2-3 times, and worsens life prognoses. The Japan Society of Bone and Mineral Research (JSBMR) created a CTIBL treatment manual in 2020; however, no study has validated its use in patients with ADT/CTIBL prostate cancer. MATERIALS AND METHODS: This study classified 124 patients with prostate cancer without bone metastasis who received ADT into high- and low-risk groups using the JSBMR CTIBL algorithm. Comparisons were made with the period to incident vertebral fracture and the existing International Osteoporosis Foundation (IOF) classification. RESULTS: The median age was 74 years; the median observation period was 81 months. At 1, 3, 5, 7, and 9 years, the prevalence of incident vertebral fractures was, respectively, 3.3%, 10.7%, 17.9%, 21.4%, and 31.2% in the entire population; 13%, 27%, 36%, 42%, and 58% in the high-risk group (19%); and 1%, 7%, 14%, 17%, and 25% in the low-risk group (81%). The hazard ratio between the two groups was 3.57 (p = 0.0004). Based on multivariate analysis, age, previous vertebral fracture and femoral neck bone density were significant risk factors for incidental vertebral fracture. The JSBMR had a hazard ratio of 3.26 (p = 0.04) relative to 1.13 (p = 0.84) for the IOF, indicating the JSBMR classification performed better. CONCLUSION: Taking preventive measures against fractures is necessary, including starting bone-modifying agents early in patients with a high fracture risk. The JSBMR CTIBL manual may be useful for this purpose.

Unmet needs in non-metastatic castration-resistant prostate cancer from the Japanese patient perspective: a discrete choice experiment.

OBJECTIVES: With novel antiandrogen treatments of varying clinical benefits and risks becoming available, this study investigates how patients with castration-resistant prostate cancer (CRPC) value differences in treatment characteristics. DESIGN: Cross-sectional observational study. SETTING: A discrete choice experiment was conducted. Patients chose between two hypothetical non-metastatic CRPC (nmCRPC) treatments defined by six attributes: risk of fatigue, falls or fracture, cognitive impairment, hypertension, rashes as side effects to treatment and extension of time until cancer-related pain occurs. PARTICIPANTS: A total of 137 adult male patients with CRPC with no prior experience with chemotherapy and with Eastern Cooperative Oncology Group status 0-1 were recruited. Patients were excluded if they participated in an investigational programme outside of routine clinical practice, had a clinically relevant medical or psychiatric condition, or diagnosis of visceral/other metastases not related to the prostate, or were otherwise deemed ineligible by the referring physician. PRIMARY OUTCOME MEASURES: Relative preference weights and relative importance of the attributes was estimated by hierarchical Bayesian logistic regression. RESULTS: Among the treatment attributes, 'risk of cognitive impairment as a side effect of treatment' was the most important attribute (relative importance (RI) (95% CI): 27.47% (24.80% to 30.14%)), followed by 'extension of time until cancer-related pain occurs' (RI (95% CI): 17.87% (15.49% to 20.25%)) and the 'risk of falls or fracture' (RI (95% CI): 15.99% (14.73% to 17.25%)). The 'risk of hypertension as a side effect of treatment' (RI (95% CI): 13.77% (12.73% to 14.81%)) had similar RI as 'risk of rashes as a side effect of treatment' (RI (95% CI): 13.17% (12.15% to 14.19%)), followed by the 'risk of fatigue as a side effect of treatment' (RI (95% CI): 11.74% (10.75% to 12.73%)). CONCLUSIONS: Patients consider the risk of cognitive impairment as a side effect of treatment as the most important attribute in nmCRPC, followed by the extension of time until cancer-related pain occurs, and the risk of falls and fracture. These features should be considered in treatment decision making for nmCRPC in Japan.

Efficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a sub-group analysis of the phase III ARAMIS trial.

BACKGROUND: Darolutamide, an oral androgen receptor inhibitor, has been approved for treating nonmetastatic castration-resistant prostate cancer (nmCRPC), based on significant improvements in metastasis-free survival (MFS) in the ARAMIS clinical trial. Efficacy and safety of darolutamide in Japanese patients are reported here. METHODS: In this randomized, double-blind, placebo-controlled phase III trial, 1509 patients with nmCRPC and prostate-specific antigen (PSA) doubling time ≤ 10 months were randomized 2:1 to darolutamide 600 mg twice daily or matched placebo while continuing androgen deprivation therapy. The primary endpoint was MFS. RESULTS: In Japan, 95 patients were enrolled and randomized to darolutamide (n = 62) or placebo (n = 33). At the primary analysis (cut-off date: September 3, 2018), after 20 primary end-point events had occurred, median MFS was not reached with darolutamide vs. 18.2 months with placebo (HR 0.28, 95% CI 0.11-0.70). Median OS was not reached due to limited numbers of events in both groups but favored darolutamide in the Japanese subgroup. Time to pain progression, time to PSA progression, and PSA response also favored darolutamide. Among Japanese patients randomized to darolutamide vs. placebo, incidences of treatment-emergent adverse events (TEAEs) were 85.5 vs. 63.6%, and incidences of treatment discontinuation due to TEAEs were 8.1 vs. 6.1%. CONCLUSIONS: Efficacy outcomes favored darolutamide in Japanese patients with nmCRPC, supporting the clinical benefit of darolutamide in this patient population. Darolutamide was well tolerated; however, due to the small sample size, it is impossible to conclude with certainty whether differences in the safety profile exist between Japanese and overall ARAMIS populations.

Fine structure of Aldrovanda vesiculosa L: the peculiar lifestyle of an aquatic carnivorous plant elucidated by electron microscopy using cryo-techniques.

The aquatic carnivorous plant Aldrovanda vesiculosa L. is critically endangered worldwide; its peculiar lifestyle raises many questions and poses problems both intriguing on their own and relevant to conservation. While establishing a culture system for its propagation and restoring its natural habitat in Hozoji pond in Saitama, Japan, we conducted ultrastructural observations to examine the various aspects of Aldrovanda's way of life. Electron microscopic observation in combination with cryo-techniques produced novel information which could not be obtained by other methods. Some of the results are: phosphorous is stored in petiole cells of turions during winter; mucilaginous guides are provided for pollen tubes in parietal placental ovaries; storage of potassium in the vicinity of the midrib of carnivorous leaves may contribute to the rapid closing of the carnivorous leaves; dynamic sequential changes of the ultrastructure of digestive glands are involved in the synthesis and secretion of digestive enzymes, including protease and acid phosphatase. These results should contribute significantly to our understanding of Aldrovanda and the detailed mechanisms of its life.

Management manual for cancer treatment-induced bone loss (CTIBL): position statement of the JSBMR.

Androgen deprivation therapy and aromatase inhibitors are known to cause a decrease in bone mineral density and an increase in fractures. Patients receiving these treatments have been shown to have a fracture risk equal to or greater than that of patients with osteoporosis with prevalent fractures. This manual was created to prevent fractures in patients with cancer treatment-induced bone loss with high fracture risks who cannot be treated under the current Japanese guideline for the prevention and treatment of osteoporosis. This manual recommends drug treatment for patients with BMD - 2.0 ≤ T score < - 1.5 with the family history of hip fracture or 15% or more 10-year probability of major osteoporotic fractures by FRAX®; or in patients with BMD T score < - 2.0. It is important to verify whether the use of this manual can reduce fractures and improve the quality of life of patients with cancer treatment-induced bone loss by prospective studies.

Variations in antibiotic susceptibility of group B Streptococcus in Japanese women: A long-term population-based cohort study.

OBJECTIVE: To investigate the long-term antibiotic susceptibility of group B Streptococcus (GBS) present in the vagina. MATERIALS AND METHODS: A population-based retrospective cohort study was performed. A total of 19,899 women who underwent vaginal swab examination between 2005 and 2017 was enrolled. Specimens were cultured on modified Drigalski agar, blood agar, and chocolate agar media. Antibiotic susceptibilities of GBS were assessed using eight antibiotics, namely penicillin-G (PC-G), cefotiam (CTM), cefditoren (CDTR), ceftriaxone (CTRX), meropenem (MEPM), chloramphenicol (CP), levofloxacin (LVFX), and azithromycin (AZM), by the broth microdilution method when GBS was positive in the culture. The main outcome was antibiotic sensitivity based on the culture results. RESULTS: GBS was 100% susceptible to PC-G, CTM, CTRX, CDTR, and MEPM. However, the susceptibility trend showed a considerable decrease for CP (99%-81%), LVFX (91%-70%), and AZM (87%-57%). CONCLUSIONS: Our study demonstrated a significant decrease in the antibiotic sensitivity of GBS in Japan in the past 13 years. Based on these results, current policies on antibiotic resistance of GBS in maternal and neonatal care may need to be reassessed.

Detection rate of clinically significant prostate cancer in magnetic resonance imaging and ultrasonography-fusion transperineal targeted biopsy for lesions with a prostate imaging reporting and data system version 2 score of 3-5.

OBJECTIVES: To evaluate the detection rates of clinically significant prostate cancer classified according to the prostate imaging reporting and data system scoring system using magnetic resonance imaging/ultrasound rigid fusion targeted biopsy. METHODS: A total of 339 patients underwent transperineal magnetic resonance imaging/ultrasound rigid fusion targeted biopsy in our institution between January 2015 and July 2017. Patients with prostate imaging reporting and data system category 1 or 2 and those with a pre-biopsy prostate-specific antigen value of >30 ng/mL were excluded from this study. Finally, 310 patients were recruited. RESULTS: The detection rates of clinically significant prostate cancer with prostate imaging reporting and data system category 3, 4, and 5 were 1.0% (1/98), 35.1% (47/134) and 73.1% (57/78), respectively. The factors affecting the detection of clinically significant prostate cancer with prostate imaging reporting and data system categories 4 and 5 were: (i) prostate imaging reporting and data system category 5; (ii) prostate volume <40 cc; (iii) no previous biopsy; (iv) lesion located in the peripheral zone; and (v) prostate-specific antigen density >0.35 ng/mL/mL. CONCLUSIONS: The detection rate of clinically significant prostate cancer on magnetic resonance imaging/ultrasound rigid fusion targeted biopsy is very low in patients with prostate imaging reporting and data system category 3; therefore, patients with this classification should not undergo targeted biopsy. Prostate-specific antigen density, prostate volume, locations of suspected cancer and history of biopsy should be considered to predict the detection rate of clinically significant prostate cancer with prostate imaging reporting and data system categories 4 and 5.

[Bone and calcium metabolism associated with malignancy. Bone management of prostate cancer in the novel anti-androgen era.]

Androgen deprivation therapy(ADT)is a standard systemic therapy for prostate cancer. ADT induces bone loss(ADTIBL)and muscle loss(sarcopenia)leading to falls and farctures. There are 2 aims in bone management of prostate cancer:one is to prevent fragility fractures in patients without bone metastasis and the other is to prevent symptomatic skeletal events(SSE)which are pathologic fractures, spinal compression, radiation to bones and surgery to bones. Bone fractures and SSE are both correlated with worse overall survival(OS). Concomitant use of novel anti-androgens further increases the risk of falls and fractures. The earlier and appropiriate intervention with vitamin D and bone modifying agents(BMA)is necessary to prevent treatment related bone fractures and SSE. Bone management algorithm aids to decide the timing and doses of BMA. As for sarcopenia physical exercise and life style advices are important. Because abiraterone with glucocorticoid therapy induces stronger bone resorption, it is recommended to start denosumab simultaneously. Ra-223, bone seeking radiopharmaceuticals should not be used with abiraterone and predonisone because of high incidence of fracture and death.

Gastric neuroendocrine carcinoma with positive staining for prostate cancer markers including prostate-specific antigen and alpha-methylacyl-CoA racemase.

We report a case with prostate cancer and gastric neuroendocrine carcinoma. A 72-year old male presented with a gastric lesion 5 months after radical prostatectomy. The lesion was immunohistochemically positive for PSA, alpha-methylacyl-CoA racemase, synaptophysin, and chromogranin A, but negative for androgen receptor (AR). Differentiating gastric neuroendocrine carcinoma from gastric metastasis of prostate cancer is difficult, as both lesions exhibit similar acinar cell proliferation with prominent nucleoli.1 We discuss the diagnostic process of this case and how AR was a useful specific marker for diagnosing primary gastric neuroendocrine carcinoma.

A prospective study of magnetic resonance imaging and ultrasonography (MRI/US)-fusion targeted biopsy and concurrent systematic transperineal biopsy with the average of 18-cores to detect clinically significant prostate cancer.

BACKGROUND: This study compared the detection rates for clinically significant prostate cancer (CSPC) between magnetic resonance imaging and ultrasonography (MRI/US)-fusion-targeted biopsy (TB), systematic biopsy (SB) and combination of TB and SB. METHODS: This prospective study evaluated simultaneous TB and SB for consecutive patients with suspicious lesions that were detected using pre-biopsy multiparametric MRI. A commercially available real-time virtual sonography system was used to perform the MRI/US-fusion TB with the transperineal technique. The prostate imaging reporting and data system version 2 (PI-RADS v2) was assigned to categorize the suspicious lesions. RESULTS: A total of 177 patients were included in this study. The detection rate for CSPC was higher using SB, compared to TB (57.1% vs 48.0%, p = 0.0886). The detection rate for CSPC was higher using the combination of TB and SB, compared to only SB (63.3% vs 57.1%, p = 0.2324). Multivariate analysis revealed that PIRADS v2 category 4 and an age of <65 years were independent predictors for TB upgrading (vs. the SB result). CONCLUSIONS: PI-RADS v2 category 4 and an age of <65 years were predictive factors of upgrading the Gleason score by MRI/US-fusion TB. Thus, MRI/US-fusion TB may be appropriate for patients with those characteristics. TRIAL REGISTRATION: This study was retrospectively registered at the University Hospital Medical Information Network ( UMINID000025911 ) in Jan 30, 2017.

[Prostate cancer and Cancer Treatment-Induced Bone Loss(CTIBL)].

Osteopenia and osteoporosis often become the long term complications in cancer treatment and is defined as cancer treatment-induced bone loss(CTIBL). Hormonal therapy is the main factor for CTIBL in both men and women. Androgen deprivation therapy(ADT)is a mainstay in the systemic therapy for prostate cancer(PC)and often persists for a long term. ADT induces bone loss and increases the risk of osteoporosis and bone fractures, which reduces QOL of the patients, results in the need of nursing care state and a serious adverse event to be connected for shortening of the overall survival. It is important that we prevent a fracture above all in the bone management of patients with PC. According to the results of overseas large-scale clinical trials, denosumab is a drug having the highest evidence level. And it is necessary to set a clear treatment objective depending on the clinical condition of the PC patients, and to use it. In the non-bone metastatic, castration-sensitive PC patients, we do it with a dose for the purpose of the prevention of osteoporosis and bone fractures, and it is demanded what a dose for the purpose of prevention and in bone metastatic, castration resistant PC patients, the reduction of symptomatic skeletal events. However, There is no benefit in prolongation of overall survival by addition of denosumab or zoledronic acid. Care for oral hygiene should be considered to avoid osteonecrosis of the jaw, oral infection and hypocalcemia.

[A case of bladder cancer arising after augmentation cystoplasty using ileal patch for interstitial cystitis].

A 62-year-old man, who was refractory to repeated hydrodistentions for interstitial cystitis, underwent augmentation cystoplasty using ileal patch. Pathological examination revealed no malignancy. Computed tomography (CT) scan showed multiple pelvic and para-aortic lymph-node swellings at 14 months after the operation. CT-guided lymph-nodes biopsies and transurethral bladder biopsies revealed invasive urothelial carcinoma with lymph node metastasis. In patients with symptoms of interstitial cystitis, bladder cancer should be kept in mind despite negative findings of cytology and bladder biopsies.

[Ductal adenocarcinoma of the prostate: a report of 7 cases].

Ductal adenocarcinoma of the prostate is a rare subtype of prostatic adenocarcinoma, defined by morphological criteria as one that has papillary or cribriform architecture composed of high columnar cells with pseudostratified nuclei. We clinically evaluated 7 cases of ductal adenocarcinoma of the prostate in our hospital. The median age was 69 years old and median initial serum PSA level was 22.8 ng/ml. Two cases presented with dysuria, two with macrohematuria and one with abnormality on chest radiograph. Five cases were diagnosed on prostate biopsy, one on TUR-P and one on radical prostatectomy. Two had pure ductal adenocarcinoma and five had mixed ductal adenocarcinoma. Four had metastatic disease, and were treated by hormonal therapy. Among three with non-metastatic disease, two underwent radical prostatectomy with adjuvant radiotherapy and one underwent external beam radiotherapy with hormonal therapy. Three cases with non-metastatic disease have no biochemical recurrence. Among four with metastatic disease, one underwent chemotherapy of Docetaxel and one had found a new lesion in lung.

Naftopidil vs silodosin in medical expulsive therapy for ureteral stones: a randomized controlled study in Japanese male patients.

The aim of the present study was to compare the efficacy of the selective α(1D) -adrenoceptor antagonist naftopidil and the selective α(1A) -adrenoceptor antagonist silodosin (as an example) in the management of ureteral stones in Japanese male patients. A total of 74 patients with symptomatic ≤ 10 mm ureteral stones were enrolled in a prospective study and randomized into two groups: Group 1 received 50 mg naftopidil daily, whereas Group 2 received 8 mg silodosin daily. Patients were followed-up for up to 6 weeks. The primary endpoint was stone expulsion rate and secondary endpoints were stone expulsion time, the rate of interventions, such as transurethral ureterolithotripsy, extracorporeal shock wave lithotripsy, or ureteral stenting, and side effects. There were no significant differences between the two groups with respect to age, stone size, and location. The stone expulsion rate was 61% and 84% in the naftopidil and silodosin groups, respectively (P = 0.038). No significant differences were noted in stone expulsion time or the rate of interventions between the two groups. The findings suggest that α(1A)-adrenoceptor blockade was clinically superior for stone expulsion our study population.

[Tegafur-uracil markedly reduced pulmonary metastasis from renal cell carcinoma refractory to sorafenib, interferon and interleukin 2].

In September 2003, a 68-year-old man was with renal cell carcinoma(RCC)underwent left radical nephrectomy. The pathological diagnosis was renal cell carcinoma, clear cell type, grade 1, pT3bNxMx stage III. Seventeen months later, lung metastasis was detected by CT and treated with recombinant interferon(IFN) -α2b (Intron A®) 600×104 units until the regrowth lung metastasis in May, 2008. Sorafenib, an antiangiogenic molecular-targeted agent, at a dose of 800 mg per day, was administered as the second time treatment. Nevertheless, it was discontinued in 2 months because of an increase in tumor size, severe hand-foot syndrome and thrombocytopenia. Therefore, the treatment was switched to natural human IFNa with tegafur-uracil at 300 mg per day since February 2009. After that, a nearly complete disappearance of the lung lesion was obtained 7 months later and maintained for 9 months.