Bone-modifying agents are protective for symptomatic skeletal events in Radium-223 treatment.

INTRODUCTION: Radium-223 (Ra-223) dichloride therapy increases overall survival and delays time to the first symptomatic skeletal event (SSE) in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Bone-modifying agents (BMA) reduce SSE in patients with bone metastasis, but there is little information on their use with Ra-223. This study aimed to investigate the effect of BMA on SSE in patients with bone metastatic CRPC treated with Ra-223 in real-world practice. METHODS: We included 73 patients treated with Ra-223 from 10 institutions in Japan. Time to the first SSE was estimated using the Kaplan-Meier method and compared between groups using the log-rank test. We used univariate analysis to ascertain the association between variables and SSE. RESULTS: During a median follow-up of 12.7 months (interquartile range, 7-21.7), 12 (16.4%) patients presented SSE. Age and BMA use were different between men with and without SSE. The 1-year SSE-free survival rate from Ra-223 treatment initiation was 82.4% (95% CI, 69.4%-90.2%). BMA use was associated with favorable SSE-free survival (hazard risk, 0.23; 95% confidence interval, 0.061-0.85; p = 0.027). Two (4.7%) and seven (23.3%) patients presented symptomatic pathological bone fracture in groups with and without BMA use, respectively (p = 0.017). CONCLUSION: This study stresses the importance of BMA use in patients with CRPC and bone metastases in Ra-223 treatment.

Effectiveness and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and bone metastases in real-world practice: A multi-institutional study.

OBJECTIVE: Radium-223 (Ra-223) dichloride is the bone-targeted radioligand therapy that prolongs overall survival (OS) in patients with bone-metastatic castration-resistant prostate cancer (CRPC). We aimed to evaluate the safety and effectiveness of this treatment in real-world practice. METHODS: We included Japanese men treated with Ra-223 for bone-metastatic CRPC from 10 institutions, retrospectively. Primary endpoint was OS. Secondary endpoint was maximum decline of alkaline phosphatase (ALP), lactate dehydrogenase, and prostate-specific antigen values, the rate of adverse events, and time to pathological fracture after Ra-223 treatment. Exploratory endpoint was the associations between clinical parameters and OS. RESULTS: In total, 73 men with bone metastatic CRPC treated with Ra-223 were enrolled. The median OS was 20.9 months. ALP levels decreased significantly from pre-treatment (p = 0.03). Anemia occurred in three (4.1%) patients. Grade ≥ 3 non-pathological fractures occurred in four (5.5%) men. Nine (12.3%) patients presented pathological fracture; 7/30 (23.3%) were in men without concomitant use of a bone-modifying agent (BMA) while 2/43 (4.7%) were in patients with concomitant BMA (p = 0.03). The median OS in patients with ≥3 cycles treatment (27.2 months, p < 0.001) or hemoglobin ≥12 g/dl (27.2 months, p = 0.001) or absence of bone pain (36.3 months, p = 0.004) was significantly longer compared to those who with ≤2 cycles or hemoglobin<12 g/dl or presence of bone paint, respectively. CONCLUSIONS: This study has shown the outcomes of Ra-223 treatment in real-world practice, where the number of treatment cycles, baseline anemia and bone pain may be useful to predict OS in Ra-223 treatment.

Nationwide surveillance of the antimicrobial susceptibility of Chlamydia trachomatis from male urethritis in Japan: Comparison with the first surveillance report.

The Urogenital Sub-committee and the Surveillance Committee of the Japanese Society of Chemotherapy, The Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology conducted the second nationwide surveillance of the antimicrobial susceptibility of Chlamydia trachomatis. In this second surveillance study, clinical urethral discharge specimens were collected from patients with urethritis in 26 hospitals and clinics from May 2016 to July 2017. Based on serial cultures, the minimum inhibitory concentration (MIC) could be determined for 41 isolates; the MICs (MIC90) of ciprofloxacin, levofloxacin, tosufloxacin, sitafloxacin, doxycycline, minocycline, erythromycin, clarithromycin, azithromycin and solithromycin were 2 µg/ml (2 µg/ml), 1 µg/ml (0.5 µg/ml), 0.25 µg/ml (0.25 µg/ml), 0.125 µg/ml (0.063 µg/ml), 0.125 µg/ml (0.125 µg/ml), 0.25 µg/ml (0.25 µg/ml), 0.031 µg/ml (0.031 µg/ml), 0.25 µg/ml (0.125 µg/ml), and 0.016 µg/ml (0.008 µg/ml), respectively. In summary, this surveillance project did not identify any strains resistant to fluoroquinolone, tetracycline, or macrolide agents in Japan. In addition, the MIC of solithromycin was favorable and lower than that of other antimicrobial agents. However, the MIC of azithromycin had a slightly higher value than that reported in the first surveillance report, though this might be within the acceptable margin of error. Therefore, the susceptibility of azithromycin, especially, should be monitored henceforth.

Simultaneous deep inferior epigastric and bilateral anterolateral thigh perforator flap reconstruction of an extended perineoscrotal defect in Fournier's gangrene: A case report.

Fournier's gangrene is lethal necrotizing fasciitis that involves the perineum and external genitalia. We describe the case of a 52-year-old man with Fournier's gangrene who underwent reconstruction of an extensive perineoscrotal defect using three pedicled perforator flaps. Three debridement procedures resulted in a skin and soft tissue defect of 36 × 18 cm involving the perineum, scrotum, groin, medial thigh, buttocks, and circumferential perianal area and left the perforating arteries originating from these locations unavailable for reconstruction. We repaired the defect using left deep inferior epigastric artery perforator (DIEP) (29 × 8 cm) and bilateral anterolateral thigh perforator (ALT) flaps (35 × 8 cm and 22 × 7 cm). The flaps reached the defect without tension, and the defect was successfully covered without a skin graft. No postoperative complications occurred except for epidermal necrosis involving a tiny part of the DIEP flap tip. Nine months postoperatively, the patient experienced no impairment of bowel function or hip joint movement. There was also no avulsion or ulceration of the reconstructed perineal skin, and the cosmetic appearances of the healed wound and donor site were satisfactory. The combination of these three perforator flaps enabled us to achieve a satisfactory outcome while avoiding skin grafts.

Suppressed Recurrent Bladder Cancer after Androgen Suppression with Androgen Deprivation Therapy or 5α-Reductase Inhibitor.

PURPOSE: We determined whether intravesical recurrence is affected by inhibition of androgen signaling among men with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: We examined the intravesical recurrence rate among men treated with or without androgen suppression therapy by androgen deprivation therapy for prostate cancer or 5α-reductase inhibitor dutasteride for benign prostatic hyperplasia. RESULTS: We studied 228 men, including 32 with and 196 without androgen suppression therapy. During a median followup of 3.6 and 3.0 years intravesical recurrence developed in 4 (12.5%) and 59 men (30.1%) with and without androgen suppression therapy, respectively. On multivariate analysis multiple tumors (HR 1.82, p = 0.027), a large tumor (HR 2.13, p = 0.043) and ever smoking (HR 2.45, p = 0.020) as well as the presence of androgen suppression therapy (HR 0.36, p = 0.024) were independent risk factors for intravesical recurrence. Notably, tumor progressed to muscle invasive bladder cancer in 6 men (3.1%) without androgen suppression therapy. No man with androgen suppression therapy progressed to muscle invasive bladder cancer. CONCLUSIONS: Our study suggests the possibility of androgen suppression therapy as prophylaxis for intravesical recurrence of bladder cancer. Further explorations are warranted of the prophylactic effect of androgen suppression therapy on bladder cancer pathogenesis.

The Differential Impact of Body Mass Index and the Feature of Metabolic Syndrome on Oncological Outcomes Following Different Surgical Procedures in Japanese Men with Prostate Cancer.

PURPOSE: This study aimed to examine the differential impact of body mass index and the feature of metabolic syndrome (MetS; obesity, hypertension, diabetes mellitus, and dyslipidemia) on biochemical recurrence (BCR) following radical prostatectomy (RP) treatment for prostate cancer using different surgical procedures. METHODS: This study included 283 Japanese patients with clinically localized prostate cancer who were treated with RP between 2008 and 2012. The prognostic significance of overweight and the feature of MetS were analyzed according to surgical procedures. RESULTS: BCR occurred in 68/283 (24.0%) men. Overweight and the feature of MetS were predictors of BCR in patients who had undergone open RP (ORP), but not in those treated with laparoscopic surgery. Multivariate analyses incorporating preoperative and postoperative risk factors revealed that overweight and the feature of MetS were independent BCR risk factors when treated with ORP. CONCLUSIONS: In Japanese men, overweight and the feature of MetS were associated with worse outcomes following RP, particularly ORP, compared with those following laparoscopic surgery. These results suggest that laparoscopic surgery can overcome the surgical challenges associated with abdominal obesity.

Co-introduction of a steroid with docetaxel chemotherapy for metastatic castration-resistant prostate cancer affects PSA flare.

OBJECTIVE: To investigate the potential relationship of steroid usage with prostate-specific antigen (PSA) flare as well as the prognostic impact of PSA flare, which is known to occur in 10-20% of patients with metastatic castration-resistant prostate cancer during docetaxel chemotherapy. PATIENTS AND METHODS: This study included 71 patients with metastatic castration-resistant prostate cancer treated by docetaxel chemotherapy with co-introduction of a steroid. PSA flare was defined as a transient PSA increase followed by a PSA decrease. RESULTS: PSA flare was recognized in 7.0-23.9% of patients according to the definition used. Intriguingly, men with steroid intake before the initiation of docetaxel chemotherapy experienced significantly fewer PSA flares. The progression-free survival rate in men with PSA flare was equivalent to that of PSA responders, but significantly better than men with PSA failure. CONCLUSIONS: Our results suggest that de novo steroid co-introduction with docetaxel chemotherapy induces the PSA flare phenomenon. This novel finding may account for the mechanism of PSA flare as well as being valuable for distinguishing PSA elevation attributable to PSA flare from that attributable to PSA failure.

The feature of metabolic syndrome is a risk factor for biochemical recurrence after radical prostatectomy.

BACKGROUND AND OBJECTIVE: To examine the association between the features of metabolic syndrome (MetS) (obesity, hypertension, diabetes mellitus, and dyslipidemia) and the risk of biochemical recurrence (BCR) after radical prostatectomy in patients with prostate cancer. METHODS: This study included 283 Japanese patients with localized prostate cancer who were treated with radical prostatectomy between 2008 and 2012. Their oncological outcomes and the prognostic significance of several clinicopathological factors, as well as the features of MetS, were analyzed. RESULTS: Of 283 men who underwent radical prostatectomy, 49 (17.2%) subsequently developed BCR with a median postoperative follow-up of 14.8 months. Among the clinicopathological factors, prostate-specific antigen (PSA) level at diagnosis, pathological stage, pathological Gleason score, and lymph-node involvement were independent risk factors for BCR in multivariate analysis. In addition, the number of metabolic risk factors was also an independent risk factor for BCR. CONCLUSIONS: The features of MetS were linked with poorer outcome after radical prostatectomy among Japanese men. Further investigations are needed to determine the effect of improving MetS on prostate cancer prognosis.

The oncological outcomes and risk stratification in docetaxel chemotherapy for castration-resistant prostate cancer.

OBJECTIVE: To clarify the risk factors and develop a refined risk-stratification model to help in the appropriate selection of docetaxel chemotherapy in patients with castration-resistant prostate cancer. METHODS: This study included 97 Japanese patients with castration-resistant prostate cancer who were treated with 70-75 mg/m(2) docetaxel and 10 mg prednisone every 3 or 4 weeks from 2008 to 2013. The oncological outcomes and prognostic significance of clinicopathological factors were analyzed, and significant prognostic factors were used to develop a risk-stratification model. RESULTS: Prostate-specific antigen decline was observed in 75 patients (77.3%), including 43 (44.3%) who achieved a prostate-specific antigen decline of ≥ 50%. The median progression-free survival and overall survival were 5.1 and 20.8 months, respectively. Univariate analysis identified performance status, alkaline phosphatase value, visceral metastasis, duration from diagnosis, duration from initiation of hormone treatment and prior treatment with estramustine as significant predictors of overall survival. Among these, alkaline phosphatase value, visceral metastasis and duration from initiation of hormone treatment were independent prognostic factors in multivariate analysis. Furthermore, risk classification according to the number of independent risk factors present effectively stratified survival among docetaxel-treated castration-resistant prostate cancer patients. CONCLUSIONS: Oncologic outcomes in Japanese patients with castration-resistant prostate cancer receiving docetaxel chemotherapy were comparable to or slightly better than those in Western populations, and the risk-stratification model developed in this study may help to predict prognosis and contribute to the selection of suitable therapy after castration resistance.

Risk factors for febrile neutropenia in patients receiving docetaxel chemotherapy for castration-resistant prostate cancer.

PURPOSE: Docetaxel is a standard therapy for patients with castration-resistant prostate cancer (CRPC). However, docetaxel-associated adverse events (AEs) such as febrile neutropenia (FN) can impair quality of life and may become life-threatening. In this study, we clarified the AEs and risk factors associated with FN in clinical settings. METHODS: This study included 37 Japanese patients with CRPC who were treated with 70-75 mg/m(2) docetaxel and 10 mg prednisone every 3 or 4 weeks between 2008 and 2012. AEs, risk factors for FN, and the prognostic significance of several clinicopathological factors were analyzed. RESULTS: Hematological AEs of ≥grade 3 included neutrocytopenia in 36 patients (97.3 %), leukopenia in 24 patients (64.9 %), lymphopenia in 10 patients (27.0 %), and FN in 4 patients (10.8 %). In addition, severe non-hematological AEs included colonic perforation, interstitial pneumonia, and acute respiratory distress syndrome in 1 patient each. Severe lymphopenia was positively associated with the incidence of FN. Low serum albumin and low lymphocyte count were identified as possible pre-treatment risk factors, while severe lymphopenia was identified as a post-treatment risk factor. CONCLUSIONS: Non-hematological AEs as well as substantial hematological AEs were recognized in the Japanese population treated with docetaxel chemotherapy against CRPC. Pre- and post-treatment lymphopenia and pre-treatment serum albumin should be considered in order to minimize the risk of FN when selecting patients with prostate cancer for docetaxel therapy, and when considering dose modifications, and the prophylactic use of granulocyte colony-stimulating factor.

Change in the Neutrophil-to-Eosinophil Ratio After Avelumab Maintenance for Advanced Urothelial Carcinoma: The UROKYU Study.

BACKGROUND/AIM: The association between clinical outcomes and posttreatment changes in the neutrophil-to-lymphocyte ratio (NLR) and neutrophil-to-eosinophil ratio (NER) in patients receiving avelumab maintenance therapy for advanced urothelial carcinoma (UC) is unclear. PATIENTS AND METHODS: We retrospectively analyzed data from advanced UC patients who received avelumab and had not progressed with first-line platinum-based chemotherapy. The association between the changes in NLR and NER from pretreatment to week 6 of avelumab treatment and therapeutic efficacy was evaluated. RESULTS: Thirty-two patients were enrolled in this study (male, n=25; female, n=7; median age, 71 years). At six weeks, 19 patients (59.4%) had a decreased NLR and 18 patients (56.3%) had a decreased NER. When the change in NER from pretreatment to six weeks was compared, there was a significant decrease in responders (without progressive disease) (p=0.008); however, there was no significant decrease in non-responders (progressive disease) (p=0.855). The NLR showed no significant change in either group (p=0.099, 0.358). When patients were compared according to the change in the NLR at six weeks, progression-free survival (PFS) and overall survival (OS) did not differ between the decreased NLR and increased NLR groups (p=0.116, 0.256). When patients were compared according to the change in the NER, the decreased and increased groups showed significant differences in PFS and OS (p<0.001, 0.030). CONCLUSION: In the present real-world study, the responders showed a significantly decreased NER at six weeks. This was associated with improved PFS and OS in patients with advanced UC.

Prognostic Impact of Histologic Subtype and Divergent Differentiation in Patients with Metastatic Urothelial Carcinoma Treated with Enfortumab Vedotin: A Multicenter Retrospective Study.

Subtype of urothelial carcinoma (SUC), defined here as urothelial carcinoma with any histologic subtype or divergent differentiation, is a clinically aggressive disease. However, the efficacy of enfortumab vedotin (EV) against SUC remains unclear. Hence, this study aimed to assess the oncological outcomes of patients with SUC treated with EV for metastatic disease. We retrospectively evaluated consecutive patients with advanced lower and upper urinary tract cancer who received EV after platinum-based chemotherapy and immune checkpoint blockade therapy at six institutions. The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between patients with pure urothelial carcinoma (PUC) and those with SUC. We identified 44 and 18 patients with PUC and SUC, respectively. Squamous differentiation was the most common subtype element, followed by glandular differentiation and sarcomatoid subtype. Although patients with SUC had a comparable ORR to those with PUC, the duration of response for SUC was short. Patients with SUC had poorer PFS than those with PUC; however, no significant difference was observed in OS. Multivariate analysis revealed that SUC was significantly associated with shorter PFS. Although the response of metastatic SUC to EV was similar to that of PUC, SUC showed faster progression than PUC.

Cutaneous and Renal Toxicities of Enfortumab Vedotin for Advanced Urothelial Carcinoma: The UROKYU Study.

BACKGROUND/AIM: The clinical outcomes associated with cutaneous toxicity and changes in the renal function of patients receiving enfortumab vedotin (EV) for advanced urothelial carcinoma (UC) is unclear. PATIENTS AND METHODS: We retrospectively analyzed the relationship between clinical outcomes and EV-related cutaneous toxicity, and the influence on the renal function in 58 patients with advanced UC who received EV after the failure of platinum-based chemotherapy and immune checkpoint inhibitors from December 2021 to July 2023. RESULTS: There were no differences in the overall response and disease control rates between patients with any grade of EV-related cutaneous toxicity and without (p=0.605 and p>0.99, respectively) nor of grade ≥3 (p>0.99 and p=0.173, respectively). Progression-free survival was not significantly associated with EV-related cutaneous toxicity of any grade (5.4 vs. 5.6 months, p=0.557) nor of grade ≥3 (2.7 vs. 5.6 months, p=0.053). Overall survival was not significantly associated with EV-related cutaneous toxicity of any grade (11.8 vs. 8.9 months, p=0.389), nor of grade ≥3 (4.6 vs. 11.4 months, p=0.168). The incidence of EV-related cutaneous toxicity of any grade was significantly higher in patients with any grade of ICI-related cutaneous toxicity (88.9% vs. 36.7%, p=0.008). There was no significant difference in the serum creatinine levels after EV treatment (p=0.211). Divided into two groups according to their renal function, using a serum creatinine cut-off of 2 mg/dl, there were no significant changes after EV treatment in either group (p=0.187 and p=0.938). CONCLUSION: EV-related cutaneous toxicity did not affect clinical outcomes, although it occurred in patients who experienced immune checkpoint inhibitor-related cutaneous toxicity. EV did not affect renal function.

Organ-specific Tumor Response to Avelumab Maintenance Therapy for Advanced Urothelial Carcinoma: A Multicenter Retrospective Study.

BACKGROUND/AIM: The organ-specific therapeutic effects of avelumab for the maintenance treatment of advanced urothelial carcinoma (UC) are unclear. PATIENTS AND METHODS: Patients who received avelumab for advanced UC that had not progressed with first-line platinum-based chemotherapy and who had measurable disease were retrospectively analyzed. The organ-specific response was evaluated, and progression-free survival (PFS) and overall survival (OS) were estimated. RESULTS: We analyzed 42 patients (male, n=31; median age, 72 years). The overall response rate [complete response (CR)+ partial response (PR)] and disease control rate (CR+PR+stable disease) were 2.4% and 47.6%, respectively. In total, 27, 11, 8 and 5 patients had measurable lymph node [organ-specific response rate (OSRR) 7.4%, organ-specific disease control rate (OSDCR) 59.3%], lung (OSRR 18.2%, OSDCR 36.4%), primary tumor organ (OSRR 0%, OSDCR 100%) and liver (OSRR 0%, OSDCR 100%) disease, respectively. The median PFS and OS was 3.8 months and 20.2 months, respectively. Regarding organ-specific PFS, a log-rank test confirmed significant differences between patients with and without primary tumor organ disease (p=0.009) and patients with and without liver metastasis (p=0.015). Regarding organ-specific OS, a log-rank test revealed no significant differences between patients with and without metastatic disease for all organs (lung: p=0.835; lymph node: p=0.914; bone: p=0.257; primary tumor: p=0.057; liver: p=0.893). CONCLUSION: In patients receiving avelumab maintenance therapy, no significant differences in OS were observed between patients with and without metastasis to any organ, including the primary organ, although metastases and the primary tumor organ disease showed different responses.

Depth and origin of prostatic involvement by urothelial carcinoma: prognostic significance and staging interpretation.

OBJECTIVE: To investigate the prognostic significance of prostatic involvement by bladder urothelial carcinoma using the new 2009 TNM staging system. METHODS: From 1993 to 2008, 77 consecutive men who were clinically and/or pathologically diagnosed with bladder cancer underwent radical cystectomy. Patients were classified into several groups, according to the presence, extent and invading pathway of prostatic involvement by urothelial carcinoma, whether there was stromal or non-stromal involvement, and whether there was contiguous or non-contiguous involvement. Cause-specific survivals were calculated in each group and they were compared. RESULTS: Prostatic involvement was observed in 23 (30%) patients: 10 had non-contiguous non-stromal involvement, 5 had non-contiguous stromal involvement and 8 had contiguous stromal involvement. Patients with stromal involvement (both contiguous and non-contiguous) showed significantly shorter cause-specific survival compared with those without prostatic stromal involvement (P= 0.002). The survival of patients with contiguous prostatic stromal involvement was similar to that of patients with non-contiguous prostatic stromal involvement (P= 0.79). Multivariate analysis showed that prostatic stromal involvement (both contiguous and non-contiguous) (hazard ratio, 8.4; P< 0.001), lymph node involvement (hazard ratio, 4.4; P= 0.016) and perivesical fat involvement (hazard ratio, 3.8; P= 0.029) were predictive of cause-specific survival. CONCLUSIONS: The depth of prostatic involvement has a significant impact on survival for patients with bladder urothelial carcinoma; however, whether its origin is contiguous or non-contiguous does not appear to be important.

Mechanism of synergistic antitumor effect of sorafenib and interferon-α on treatment of renal cell carcinoma.

PURPOSE: The multikinase and tyrosine kinase inhibitor sorafenib has antitumor activity in patients with advanced renal cell carcinoma. Recent reports show the ability of sorafenib to synergize with interferon-α, leading to greater antitumor activity. We examined the underlying mechanism of sorafenib and interferon-α synergism for renal cell carcinoma treatment in vitro and in tumor bearing murine models. MATERIALS AND METHODS: We used murine and human renal cell carcinoma cell lines for in vitro cell proliferation assay. ACHN (ATCC®) and RENCA tumors were subcutaneously transplanted into NCr-nu/nu and syngeneic BALB/c mice (Charles River Laboratories, Yokohama, Japan), respectively. Mice were treated with sorafenib and/or interferon-α, and tumor growth was monitored. Immunological assays were done in the RENCA model. RESULTS: In the ACHN and RENCA cell lines combination index analysis clearly revealed the synergistic antiproliferative effects of interferon-α and sorafenib in vitro. In the ACHN NCr-nu/nu model we clearly noted the synergistic antitumor effects of interferon-α and sorafenib, indicating the synergistic direct effects of each drug on tumor growth. In the RENCA BALB/c model flow cytometry showed no change in the proportion of lymphocytes. However, while sorafenib alone did not induce natural killer or cytotoxic T-lymphocyte activity against RENCA in that model, interferon-α alone or combined with sorafenib induced natural killer and cytotoxic T-lymphocyte activity. CONCLUSIONS: Our results show the synergistic activity of interferon-α and sorafenib. These findings provided the rationale for combination therapy with interferon-α and sorafenib in patients with advanced renal cell carcinoma.

Posttransplant administration of cyclophosphamide and donor lymphocyte infusion induces potent antitumor immunity to solid tumor.

PURPOSE: Nonmyeloablative allogeneic stem cell transplantation (SCT) has been increasingly used for the treatment of hematologic and solid malignancies, and mature donor T cells are considered to be the main effectors of the graft-versus-tumor (GVT) activity. However, the association between degree of donor chimerism and intensity of GVT effects has not been fully elucidated. We recently proposed a unique nonmyeloablative cell therapy using posttransplant cyclophosphamide and donor lymphocyte infusion, by which a significant antitumor effect against murine renal cell carcinoma, RENCA, was induced, although the level of mixed chimerism was relatively low. In this study, we attempted to clarify a role of chimerism for in vivo antitumor effects on GVT effects in radiation-associated nonmyeloablative SCT. EXPERIMENTAL DESIGN: We assessed antitumor effects on RENCA tumors and the degree of donor chimerism after several doses of irradiation followed by allogeneic SCT and compared the results with those of cyclophosphamide-based cell therapy. RESULTS: Allogeneic SCT following sublethal irradiation (6 Gy) induced almost complete donor chimerism, whereas cyclophosphamide-based cell therapy produced low levels of donor chimerism. Nonetheless, GVT activity was much more potent in cyclophosphamide-based cell therapy than irradiation-conditioned SCT. Furthermore, cyclophosphamide-conditioned SCT induced more potent immune reconstitution with less severe graft-versus-host disease than irradiation-conditioned SCT. CONCLUSIONS: Our results indicate that a high level of chimerism is not essential for the in vivo antitumor effect of nonmyeloablative allogeneic cell therapy against solid tumor and that the recovery of peripheral lymphocytes after the initial immunosuppression might be a critical event for the elicitation of in vivo antitumor effects of that treatment modality.

Cyclophosphamide-using nonmyeloablative allogeneic cell therapy against renal cancer with a reduced risk of graft-versus-host disease.

PURPOSE: Much attention has been paid to nonmyeloablative allogeneic stem cell transplantation for the treatment of renal cancer. We recently proposed a cyclophosphamide-using nonmyeloablative cell therapy in which donor lymphocyte infusion (DLI) was carried out after the tolerance induction to donor cells. In considering the clinical application of the cyclophosphamide-using cell therapy, attempts to reduce graft-versus-host disease (GVHD) are crucial. The aim of the present study was to modify the cyclophosphamide-using cell therapy to reduce the risk of GVHD while preserving the antitumor activity against renal cancer. EXPERIMENTAL DESIGN: We assessed whether a delay in performing DLI from day 1 to day 5 after the cyclophosphamide treatment could reduce the risk of GVHD while preserving antitumor activity against RENCA, a murine carcinogen-induced renal cell carcinoma, in the cyclophosphamide-using cell therapy. RESULTS: Regarding the in vivo antitumor effect, there was no difference between DLI on day 1 and day 5 after the cyclophosphamide treatment, whereas the histologic findings of the small intestine showed that the cyclophosphamide-using cell therapy with DLI on day 5 decreased the risk of GVHD. In addition, the acquired immunity against RENCA was also observed in the RENCA-rejected mice that had been treated with DLI on day 5. CONCLUSIONS: Our results show that a delay in DLI during cyclophosphamide-using nonmyeloablative cell therapy can dissociate graft-versus-tumor effects from GVHD by reducing the risk of GVHD.

Neoadjuvant androgen-deprivation therapy with radical prostatectomy for prostate cancer in association with age and serum testosterone.

BACKGROUND: We aimed to identify the candidate prostate cancer patients suitable for neoadjuvant androgen-deprivation therapy (ADT) with radical prostatectomy (RP). MATERIALS AND METHODS: This study included 711 Japanese patients with clinically localized prostate cancer who were treated with RP between 2000 and 2013. Patients were treated with or without neoadjuvant ADT before RP. The prognostic significance of neoadjuvant ADT on biochemical recurrence (BCR) was analyzed according to various clinicopathological characteristics. RESULTS: BCR occurred in 186 (26.2%) of 711 patients. The group treated with neoadjuvant ADT showed higher levels of prostate-specific antigen at diagnosis and advanced clinical T-stage, but suppressed pathological T-stage. Neoadjuvant ADT was not associated with the risk of BCR. In subgroup analysis, neoadjuvant ADT was significantly associated with increased BCR in patients aged >65 years [hazard ratio (95% confidence interval), 2.04 (1.13-3.43), P = 0.020]. Among the 53 patients with available serum testosterone levels, neoadjuvant ADT was associated with the risk of BCR according to serum testosterone levels. CONCLUSION: This study demonstrated that neoadjuvant ADT showed potential deleterious effects in older patients and patients with lower serum testosterone levels, while a possible improved prognosis in patients with high serum testosterone levels treated with neoadjuvant ADT was suggested, warranting further exploration.

A rational risk assessment for intravesical recurrence in primary low-grade Ta bladder cancer: A retrospective analysis of 245 cases.

The aim of the present study was to evaluate the prognostic impact of size and number of tumors in primary low-grade (LG) Ta bladder urothelial carcinoma (UC), and thus allow accurate risk stratification of low-risk non-muscle invasive bladder cancer (NMIBC). This study was a retrospective analysis of 245 patients with primary LG Ta UC of the urinary bladder who were treated with transurethral resection. Differences in intravesical recurrence-free survival (RFS) according to various cutoff values of tumor size and tumor number were calculated using Cox proportional hazards model. Median maximum size of tumor was 1.4 cm, and 153 patients (62.4%) had solitary tumors. Forty-nine patients experienced intravesical recurrence during a median 34 months of follow-up. Patients with solitary tumors had significantly longer RFS times compared with those with ≥8 tumors (P=0.003). Patients with larger tumors had significantly shorter RFS times for each cutoff value (P=0.01 for 1.0 cm, P<0.0001 for 1.5 and 2.0 cm, P=0.006 for 3.0 cm). On multivariate analysis, each cutoff value of tumor size was found to be a predictor of RFS; among them, the cutoff of 1.5 cm showed the strongest association (hazard ratio, 4.12; 95% confidence interval, 2.11-8.81; P<0.001). If we consider only lower risk NMIBC patients, such as primary LG Ta, the appropriate cutoff value of tumor size to predict intravesical recurrence might be 1.5 cm, but not 3.0 cm generally adopted in various guidelines. These findings suggest the need for rational risk assessment with consideration of the diversity of patients with NMIBC.