Efficacy of abiraterone acetate for high-risk hormone-naïve metastatic prostate cancer: A comparison with combined androgen blockade therapy with bicalutamide and androgen deprivation therapy alone.

BACKGROUND: The treatment landscape for men with metastatic hormone-naïve prostate cancer (mHNPC) has dramatically changed with the approval of next-generation anti-androgen drugs. We compared the treatment efficacy of abiraterone with that of combined androgen blockade (CAB) therapy and androgen deprivation therapy (ADT) alone in men with high-risk mHNPC. METHODS: In total, 146 Japanese men with high-risk mHNPC were retrospectively analyzed. As initial hormonal therapy, 30, 83, and 33 men were treated with ADT plus abiraterone (ABI group), ADT plus bicalutamide (CAB group), and ADT alone (ADT group), respectively. Treatment efficacy was compared using time to castration resistance (TTCR) and prostate-specific antigen (PSA) response among the groups. Propensity score matching analysis was also performed to adjust for baseline differences. RESULTS: The median (95% confidence interval [CI]) TTCR in the ABI, CAB, and ADT groups were not reached, 10.7 (7.6-13.8) months and 11.0 (7.9-12.4) months, respectively, and it was significantly longer in the ABI group than in the other groups (p = 0.0012, p = 0.0008). In propensity score matching analysis, the median TTCR was also significantly longer in the ABI group than in the other groups (hazard ratio [HR], 0.47; 95% CI, 0.22-0.98; p = 0.010; HR, 0.32; 95% CI, 0.12-0.85; p = 0.004). The number of men who achieved PSA levels ≤0.2 ng/mL after propensity score matching were significantly higher in the ABI group than in the other groups. CONCLUSIONS: Our results provide important evidence regarding the superiority of abiraterone over CAB therapy and ADT alone for initial treatment for men with newly diagnosed mHNPC.

Rituximab maintenance improves outcomes of transformed diffuse large B-cell lymphoma: a retrospective study of 519 cases with de novo diffuse large B-cell lymphoma and 62 cases with concurrent diffuse large B-cell lymphoma and follicular lymphoma.

Although outcomes of transformed diffuse large B-cell lymphoma (DLBCL) from follicular lymphoma (FL) were improved using rituximab-combined immunochemotherapy, the efficacy of subsequent rituximab maintenance (RM) remains unclear. We retrospectively analyzed the prognoses of 519 patients with de novo DLBCL and 62 patients with concurrent DLBCL and FL (concurrent-DLBCL/FL). Progression-free survival (PFS) was shorter in patients with concurrent-DLBCL/FL than in de novo DLBCL (p=.030). Twenty-four patients with concurrent-DLBCL/FL received RM after induction therapy, and they achieved better OS and PFS (p=.010 and p<.001, respectively) with lower risk of relapse (p<.001) than the non-RM group. Moreover, concurrent-DLBCL/FL showed better subsequent OS and PFS after recurrence than de novo DLBCL (p=.0083 and p=.0044, respectively). Our study indicates that in the face of a high relapse rate, concurrent-DLBCL/FL is manageable and benefits from RM.

Test-retest repeatability of quantitative bone SPECT/CT.

OBJECTIVE: Technological innovations in single-photon emission computed tomography (SPECT) have enabled a more accurate quantitative evaluation of the uptake, and the standardized uptake value (SUV) can be measured as a semi-quantitative value, as in positron emission tomography. Nevertheless, the reliability of the SUV of bone SPECT has not been well established. The purpose of this study is to evaluate the test-retest repeatability of the SUV of bone SPECT/CT in clinical settings. METHODS: This prospective study recruited patients with prostate cancer planning to receive bone SPECT/CT for the evaluation of bone abnormality between August 2017 and September 2019. Bone images were acquired twice by an integrated SPECT/CT scanner (Symbia Intevo, Siemens) within a 4- to 10-day interval. The maximum SUV (SUVmax) and peak SUV (SUVpeak) were calculated for the volumes of interests on the normal bone areas, degeneration/fracture lesions, and metastatic lesions. To determine repeatability, we calculated statistical indicators, including intraclass correlation coefficient (ICC), repeatability coefficient (RC), and mean absolute percentage difference (MAPD). For the ICC, the 95% confidential interval (CI) was also calculated, and an ICC of ≥ 0.8 was defined as an almost perfect correlation. RESULTS: Twelve male patients were enrolled in the study (58-86 years; median, 71 years), and a total of 229 volumes of the interest were included in the analyses. The ICCs were 0.968 [95% CI (0.959, 0.975)] for SUVmax and 0.976 [95% CI (0.969, 0.981)] for SUVpeak. The RCs of the relative difference were 30.7% for SUVmax and 27.6% for SUVpeak, and the MAPDs (± standardized deviation) of all lesions were 12.3 ± 9.9% for SUVmax and 11.5 ± 8.3% for SUVpeak. The RCs and the MAPDs showed comparable value with the previous report regarding repeatability studies on PET. CONCLUSION: An almost perfect correlation was demonstrated by repeated SUVmax and SUVpeak measured by quantitative integrated SPECT/CT. The quantitative values could be reliable indicators in patient management.

The clonal evolution during long-term clinical course of multiple myeloma.

Somatic gene mutations related to acceleration disease and clonal evolution in multiple myeloma strongly influence severe clinical outcomes. In this study, we traced the transition of somatic mutations during the clinical course of myeloma patients over a long-term follow-up period (8.5 year average). Seven myeloma cases treated with immuno-chemotherapy at our institution were analyzed with clinical courses and the results of FISH and G-band analyses. Furthermore, the target sequences in regard to 121 genes, related to driver mutations or acceleration of disease in myeloma, were performed using bone marrow myeloma samples by next-generation sequencing, Ion Proton™ System. We detected a relationship between an increase in the dominant mutated gene (e.g., TP53, DIS3, FAM46C, KDM6B, and EGR1) and poor prognosis. In particular, clonal escalation of the TP53 mutation could not be overcome by any treatment. The selection of a combination treatment conducted in conjunction with the monitoring of gene mutations is appropriate for long-term survival. Our data demonstrate that long-term follow-up of somatic gene mutations during the clinical course of myeloma is helpful in the development of an effective treatment strategy.

Pembrolizumab-induced myasthenia gravis with myositis and presumable myocarditis in a patient with bladder cancer.

INTRODUCTION: Pembrolizumab cause immune-related adverse events. We herein report a case of advanced bladder cancer, who treated with pembrolizumab and exhibited intriguing clinical course. CASE PRESENTATION: A 63-year-old man with bladder carcinoma was treated by radical cystectomy, however, the bladder carcinoma recurred and invaded to the rectum. He was treated by combination therapy using gemcitabine and cisplatin, which were not effective for the tumor. He subsequently underwent treatment with pembrolizumab. In several 30 days, he suffered from the symptoms of myasthenia gravis. Serum levels of creatine kinase, its isozyme creatine kinase-myocardial band, and troponin I were elevated. Electrocardiography showed a right bundle branch block. These findings suggested that he was myasthenia gravis with general myositis and presumable myocarditis. Oral prednisolone administration significantly attenuated these findings. The tumor drastically shrunk only by the single injection of pembrolizumab. CONCLUSION: Early intervention with corticosteroid was effective for neuromuscular complications due to pembrolizumab.

Efficacy of Nivolumab Plus Ipilimumab in a Patient With Renal Cell Carcinoma Concomitant With Cardiac Metastasis: A Case Report.

BACKGROUND/AIM: Patients with metastatic renal cell carcinoma (RCC) with cardiac metastasis have had poor outcomes in the era of molecular targeted therapy. There are few reported outcomes for patients with cardiac metastasis of RCC treated with immune checkpoint inhibitors (ICIs). CASE REPORT: A 32-year-old female presented with metastatic RCC (unclassified type) with contralateral renal and cardiac metastases, as well as renal hilar lymph node metastases (cT4N2M1). An 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) computed tomographic (CT) scan was useful in diagnosing cardiac metastasis. Nivolumab plus ipilimumab achieved prominent shrinkage of almost all tumors except for one cardiac tumor. FDG-PET/CT scan also revealed the marked attenuation of FDG uptake in each tumor. In addition, a needle biopsy of the remaining primary renal tumor was pathologically observed to have no viable cancer cells. CONCLUSION: This successful case suggests that ICIs might provide a better outcome even for patients with cardiac metastasis of RCC, and that FDG-PET/CT scan might be useful for therapeutic assessment, as well as diagnosis.

A case of castration-resistant prostate cancer with liver metastases achieved a complete response by docetaxel chemotherapy.

Castration-resistant prostate cancer (CRPC) patients with liver metastases have an extremely poor prognosis. Herein, we report a rare patient who achieved a complete response by docetaxel chemotherapy for this aggressive disease. A 67-year-old Japanese male diagnosed with local prostate cancer [initial prostate specific antigen (PSA) of 10.3 ng/mL, a highest Gleason score of eight] received radical prostatectomy (RP) followed by salvage radiotherapy for PSA recurrence without distant metastases. After four years, androgen deprivation therapy was commenced for both local recurrence and elevated PSA. After a further four years, despite good control of PSA (1.2 ng/mL), other clinical findings including radiographic images revealed CRPC with multiple liver metastases. Ten cycles of docetaxel chemotherapy achieved a complete response for more than five years. In conclusion, even if a patient has CRPC with liver metastases, early diagnostic imaging irrespective of the PSA level may provide a better response to early docetaxel chemotherapy.

The pretreatment neutrophil-to-lymphocyte ratio is a novel biomarker for predicting clinical responses to pembrolizumab in platinum-resistant metastatic urothelial carcinoma patients.

PURPOSE: We investigated the relationship between pretreatment neutrophil-to-lymphocyte ratio (pre-NLR) levels just before the initiation of treatment with pembrolizumab and clinical outcomes in platinum-resistant metastatic urothelial carcinoma (UC) patients treated with pembrolizumab. METHODS: Our study population comprised 78 patients diagnosed with metastatic UC and treated with pembrolizumab after platinum-based chemotherapy at our institutions between December 2017 and April 2019. We examined the relationships between pre-NLR levels just before pembrolizumab treatment and clinical outcomes. A pre-NLR level of ≥3.35 was defined as elevated according to a calculation by a receiver-operating curve analysis. RESULTS: The high pre-NLR group consisted of 33 patients (42.3%). Overall, 29.5% of patients had a clinical response and the sum of the target lesion longest diameter was decreased in 18.8% of the high pre-NLR group, which was significantly lower than that in the low pre-NLR group (58.1%, P = 0.005). Six-month progression-free survival and cancer-specific survival rates for the high pre-NLR group were 9.1 and 58.0%, which were significantly lower than those for their counterpart (45.9 and 89.1%, P < 0.001 and P = 0.002, respectively). The pre-NLR level was an independent indicator of disease progression and cancer-specific death (P < 0.001 and P = 0.003). Furthermore, patients with a postpembrolizumab NLR level that had decreased ≥25% from the pre-NLR level had significantly lower disease progression and cancer-specific death rates than their counterparts (P = 0.01 and P = 0.022, respectively). CONCLUSIONS: Elevated pre-NLR may be a novel biomarker for identifying poor responders to pembrolizumab among platinum-resistant metastatic UC patients.

Thiamine deficiency in a patient with recurrent renal cell carcinoma who developed weight loss with normal appetite and loss of energy soon after nivolumab treatment.

BACKGROUND: Nivolumab has become an effective treatment option for cancer in various sites; however, this drug may cause immune-related adverse effects due to its mechanism of action. Furthermore, little has been reported on thiamine deficiency (TD) in patients receiving nivolumab treatment. METHOD: From a series of cancer patients, we reported a patient with recurrent renal cell carcinoma who developed TD after the start of nivolumab treatment. RESULTS: A 74-year-old man with recurrent renal cell carcinoma was referred to the psycho-oncology department as he had lost about 4 kg and displayed a loss of energy after four cycles of nivolumab treatment. Psychiatric interviews revealed a decrease in energy. Neurological examination did not reveal any impairment in consciousness, ataxia, or ocular symptoms. He did not develop appetite loss. The malabsorption or overconsumption of some nutrients is thought to occur due to the rapid loss of weight; thus, a reduction in vitamin B1, which has a short storage period in the body and is often deficient in cancer patients, was suspected. The diagnosis of TD was supported by the patient's abnormally low serum thiamine level. SIGNIFICANCE OF RESULTS: In patients treated with nivolumab, it is necessary to pay careful attention to TD when proceeding with the treatment. It is hoped that future research may reveal the link between nivolumab administration and TD.

Factors contributing to the ceiling effect of the EQ-5D-5L: an analysis of patients with prostate cancer judged "no-problems".

PURPOSE: The goal of the present study was to determine factors related to a ceiling effect (CE) on the EQ-5D-5L among Japanese patients with prostate cancer (PC). METHODS: An existent cross-sectional observational study dataset was used. Patients were ≥ 20 years of age and diagnosed with PC. For CE determinants on the EQ-5D-5L, we excluded possible "full-health" patients flagged by the EQ-VAS (score = 100) and/or FACT-P (score = 156) instruments. We then divided them into binary variables: A CE group (EQ-5D-5L score = 1) and others (< 1). The associations between CE, sociodemographic and medical characteristics, and FACT-P subscale scores were examined using a multivariate LASSO selection followed by a binomial logistic regression analysis performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 362 patients were analyzed. The LASSO selection variables, including all obtained variables, were as follows: age, palliative treatment, FACT-P physical well-being, and PC subscale score. Statistically significant variables predicting CE were palliative treatment (OR 0.23; 95% CI 0.09-0.60), physical well-being (OR 1.54; 95% CI 1.34-1.76), and PC subscale (OR 1.08; 95% CI 1.03-1.14). CONCLUSIONS: This study revealed that palliative treatment and two FACT-P physical well-being and PC subscale scores were positively related to CE on the EQ-5D-5L. To our knowledge, this is the first study to examine predictors of CE on the EQ-5D-5L. The present results may be helpful for facilitating the consideration of "bolt-on" studies from the standpoint of PC patients.

Health utility and health-related quality of life of Japanese prostate cancer patients according to progression status measured using EQ-5D-5L and FACT-P.

PURPOSE: To obtain health utility data to allow for cost-effectiveness analysis in groups stratified by disease progression along with health-related quality of life (HRQoL) information in Japanese prostate cancer (PC) patients. METHODS: In this cross-sectional observational study, EuroQol-5 Dimension- 5 Level (EQ-5D-5L), EuroQol Visual Analog Scale (EQ-VAS), and Functional Assessment of Cancer Therapy-Prostate (FACT-P) measures were used to examine utility, VAS scores, and disease-specific HRQoL, respectively. Scores obtained were statistically examined for the correlation among measures and domains. Parameter estimates of statistically significant factors were assessed using generalized linear models (GLM). RESULTS: A total of 380 patients stratified by their disease progression status were analyzed. The numbers (%) of patients in groups stratified as having localized (L), localized progression (LP), distant metastatic (DM), and DM-castration-resistant PC (CRPC) were 275 (72.4), 40 (10.5), 27 (7.1), and 38 (10.0), respectively. EQ-5D-5L mean (standard deviation, SD) scores of L, LP, DM, and DM-CRPC in study participants were 0.87 (0.15), 0.86 (0.15), 0.85 (0.18), and 0.84 (0.17), respectively. The mean (SD) scores assessed by EQ-5D-5L, EQ-VAS, and FACT-P instruments were 0.86 (0.16), 74.6 (16.8), and 110.8 (19.6), respectively. Utility scores correlated well with FACT-P scores. Eastern Cooperative Oncology Group performance status had significant influences on all instruments' scores. CONCLUSIONS: We obtained health utility and HRQoL scores of Japanese PC patients stratified by disease progression in detail. Our results will be useful for establishing cost-effectiveness analyses in Japanese PC settings.

Usefulness of Implementing Comprehensive Pharmaceutical Care for Metastatic Renal Cell Carcinoma Outpatients Treated with Pazopanib.

BACKGROUND: Pazopanib is an effective treatment option for renal cell carcinoma (RCC). However, the therapy is often limited by the appearance of adverse events (AEs), including nausea/vomiting, hepatic impairment, hand-foot syndrome, diarrhea, hypertension and oral mucositis. Early management of AEs is, therefore, extremely important in order to maximize treatment outcomes. PATIENTS AND METHODS: This non-randomized controlled before-and-after study was carried out to evaluate the effectiveness of our comprehensive pharmaceutical interventions in 37 outpatients receiving pazopanib for RCC (experimental group). Data were compared with those obtained from 13 patients before the start of pharmaceutical intervention (control group). RESULTS: The incidence rates of grade 2 or more nausea and anorexia were significantly lower in the experimental, than in the control group (3% versus 38% for nausea, respectively, p=0.003; 8% versus 46% for anorexia, respectively, p=0.005). Importantly, non-adherence based on patient self-assessment was not observed with intervention (0% versus 38%, p<0.001). Consequently, the median total dose of pazopanib was increased by the intervention (72,600 versus 18,200 mg, p=0.002). Moreover, the median time to treatment failure was significantly longer with intervention than before (10.2 versus 1.7 months, HR=0.23, 95% CI=0.110-0.499, p<0.001). These findings suggest that our interventions are highly effective for enhancing treatment outcomes.

Early tumor shrinkage as a predictive factor of metastatic renal cell carcinoma in molecular targeted therapy: A single institutional study.

The aim of the present study was to investigate the impact of metastatic sites and early tumor shrinkage (eTS) as prognostic predictive factors of metastatic renal cell carcinoma (mRCC) in molecular targeted therapy. A total of 209 advanced RCC cases treated with sorafenib, sunitinib, axitinib, pazopanib, temsirolimus and everolimus from our single institution were included in the present study. Several known prognostic predictive factors, including metastatic sites and the rate of eTS, were analyzed by Kaplan-Meier survival estimate analysis followed by Cox's proportional hazards model analysis. eTS was measured by three independent physicians. Four metastatic sites in the liver, bone, lymph nodes and brain as well as greater eTS were identified as potential independent predictors of overall survival (OS) in several cohorts: i) Metastatic RCC (n=194); ii) metastatic clear cell RCC (n=119); and iii) mRCC patients with eTS data (n=127). In sub-analyses of patients treated with each 1st line tyrosine kinase inhibitor, eTS was identified as a potentially potent predictor of OS in patients treated with axitinib. The liver, bone, lymph nodes, brain metastases and eTS were identified as independent predictive factors of OS by analyzing a limited Japanese cohort.

Delayed nivolumab-induced hepatotoxicity during pazopanib treatment for metastatic renal cell carcinoma: An autopsy case.

INTRODUCTION: Pazopanib, a tyrosine kinase inhibitor, and nivolumab, an immune checkpoint inhibitor, are both considered to cause hepatotoxicity with different pathophysiology. We report a case in which a patient died of severe hepatotoxicity who was presumed to have been caused by the administration of nivolumab followed by pazopanib for metastatic renal cell carcinoma. CASE PRESENTATION: A 74-year-old male with metastatic renal cell carcinoma was treated with nivolumab as a third-line treatment. However, nivolumab was subsequently discontinued, as it caused severe thyroiditis. About 2 months after the final dose of nivolumab was administered, pazopanib was initiated as a fourth-line treatment. The patient suffered from lethal hepatic failure and died 18 days after the initiation of pazopanib treatment. An autopsy revealed that CD8-positive lymphocytes had infiltrated the thyroid gland and liver. CONCLUSION: The patient was considered to have died of severe hepatic failure due to the aggravation of mild nivolumab-induced immune-related hepatitis by pazopanib.

A case in which bladder cancer invaded the ureteral orifice and was resected via photodynamic diagnosis-assisted transurethral resection involving orally administered 5-aminolevulinic acid.

INTRODUCTION: Transurethral resection of bladder tumor is widely used in combination with photodynamic diagnosis to treat non-muscle invasive bladder cancer. We experienced an intriguing case, in which bladder cancer infiltrated into the right ureteral orifice and was resected via photodynamic diagnosis-assisted transurethral resection involving the oral administration of 5-aminolevulinic acid. CASE PRESENTATION: This case was a 71-year-old Japanese man. He was diagnosed with bladder carcinoma, which had infiltrated into the right ureter (clinical classification: T1, N0, M0). He underwent transurethral resection involving the oral administration of 5-aminolevulinic acid. We successfully resected the tumor in the ureteral orifice, which was accomplished by resecting the ureteral orifice until the non-luminescent lumen was exposed. After the surgery, to prevent recurrence, Bacillus Calmette-Guérin was administered intravesically after right ureteral stent placement. CONCLUSION: Photodynamic diagnosis-assisted transurethral resection involving the oral administration of 5-aminolevulinic acid has the potential to treat ureteral tumors derived from bladder tumors.

A Case of Renal Oncocytoma with Renal Venous Tumor Thrombus.

Renal oncocytoma is generally regarded as a benign renal tumor. We herein report a case of large renal oncocytoma with renal venous tumor thrombus. The patient may need to be carefully followed up because hematogenous metastasis may occur.

[Occurrence of acquired factor V inhibitor during antibiotic therapy for a surgical wound infection].

Acquired factor V (FV) inhibitor is a rare disorder. Herein we report a case of an 82-year-old Japanese woman with FV inhibitor exhibiting a pseudo decline in the activities of the multiple coagulation factors. After rectal cancer surgery, she received antibiotic therapy for wound infection. As prothrombin and activated partial thromboplastin time was prolonged, heparin for atrial fibrillation was discontinued without improvement. Coagulation factor activity assays revealed deficiencies in II, V, VII, VIII, IX, X, XI, and XII factor activities; in particular, the FV activity was markedly decreased to <1%. The cross-mixing test findings revealed an inhibitor pattern, and multiple coagulation factor inhibitors were positive. The FV inhibitor level was high at 62 Bethesda U/ml. The patient exhibited no bleeding tendency with the prolonged wound infection without immunosuppressive therapy. The inhibitor disappeared four months after the onset.

Clinical Impact of Consolidative and Salvage Radiotherapy for Lymph Node Metastasis in Upper Urinary Tract Urothelial Carcinoma.

A 75-year-old Japanese male was referred to our institution for the evaluation of a left ureteral tumor in the ureterovesical junction. Computed tomography and pathologic examination under ureteroscopy revealed an invasive left ureteral urothelial carcinoma with left obturator nodal metastasis without distant metastasis. First, the patient underwent systemic chemotherapy (gemcitabine and cisplatin chemotherapy). We then performed left radical nephroureterectomy and extended lymph node dissection. Pathological examination revealed that the tumor was a high-grade invasive urothelial carcinoma with left common iliac and pelvic lymph node metastasis (pT3N2). Unfortunately, metastases appeared in the common iliac and para-aortic lymph nodes immediately after the operation; therefore, the previous first-line chemotherapy was readministered and second-line chemotherapy (gemcitabine and paclitaxel chemotherapy) was also performed. We also performed consolidative radiotherapy and salvage radiotherapy (boost, 20 Gy/10 fractions to the inferior para-aortic, and left common iliac regions containing swollen lymph nodes). The patient has shown no evidence of recurrence or metastasis even approximately 4 years after the initial diagnosis of advanced UUT-UC with lymph node metastasis. Our case suggests that consolidative or salvage radiotherapy combined with surgery and chemotherapy may provide clinical benefit for selected cases of advanced UUT-UC with lymph node metastasis.

Bridging-to-transplant with Azacitidine for Myelodysplastic Syndrome and Acute Myeloid Leukemia, Reduces the Incidence of Acute Graft-versus-host Disease.

Allogeneic stem cell transplantation (allo-SCT) is the only curative option for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Azacitidine (AZA) has a good toxicity profile compared with intensive chemotherapy and can be considered a pre-transplant regimen in elderly patients and in patients with comorbidities. To investigate the impact of pre-transplant AZA on patient outcome after allo-SCT, we conducted a retrospective analysis of AZA pre-treatment followed by allo-SCT in patients with high-risk MDS and AML. Twenty patients who were divided into two groups according to AZA treatment given prior to allo-SCT (AZA vs non-AZA group, 10 each). Overall survival, event-free survival and incidence of chronic graft-versus-host disease (GVHD) were not significantly different between the two groups. The overall incidence of grade II to IV acute GVHD in the AZA group was significantly lower than that in the non-AZA group (P=0.004). Bridging to transplant with AZA should be considered as an immunomodulator and effective treatment strategy for patients with MDS and AML.