Avelumab plus axitinib therapy for renal cell carcinoma in a patient with pulmonary alveolar proteinosis: A case report.

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the abnormal accumulation of surfactant-derived substances in the lungs. To the best of our knowledge, the successful treatment of metastatic renal cell carcinoma in patients with PAP has not been reported. Here, we describe such treatment of a patient via avelumab plus axitinib therapy. After four courses of treatment, computed tomography showed size reduction of the pulmonary metastatic nodule and improvement of PAP. This study highlights that avelumab plus axitinib therapy is a safe and effective treatment option for metastatic renal cell carcinoma, even in patients with PAP.

Patient-reported outcomes following neoadjuvant endocrine therapy, external beam radiation, and adjuvant continuous/intermittent endocrine therapy for locally advanced prostate cancer: A randomized phase III trial.

BACKGROUND: We evaluated patient-reported outcomes (PRO) during neoadjuvant androgen deprivation therapy (ADT) plus external beam radiation therapy (EBRT) followed by either adjuvant continuous ADT (CADT) or intermittent ADT (IADT) for patients with locally advanced prostate cancer (Pca). METHODS: A multicenter, randomized phase III trial enrolled 303 patients with locally advanced Pca. The patients were treated with 6 months (M) of ADT followed by 72 Gy of EBRT, and were randomly assigned to CADT or IADT after 14 M. The PROs were evaluated at sic points: baseline, 6 M, 8 M, 14 M, 20 M, and 38 M using FACT-P questionnaires and EPIC urinary, bowel, and sexual bother subscales. RESULTS: The FACT-P total scores were significantly better (p < 0.05) in IADT versus CADT at 20 M (121.6 vs.115.4) and at 38 M (119.9 vs. 115.2). The physical well-being scores (PWB) were significantly better (p < 0.05) in IADT versus CADT at 38 M (25.4 vs. 24.0). The functional scores were significantly better in IADT than those in CADT at 14 M (20.2 vs18.7, p < 0.05) and at 20 M (21.0 vs.18.9, p < 0.05). CONCLUSION: The PRO was significantly favorable in IADT on FACT-P total score at 20 M and 38 M, PWB and functional scores at 38 M.

Oncological outcomes for patients with locally advanced prostate cancer treated with neoadjuvant endocrine and external-beam radiation therapy followed by adjuvant continuous/intermittent endocrine therapy in an open-label, randomized, phase 3 trial.

BACKGROUND: To date, research has not determined the optimal procedure for adjuvant androgen deprivation therapy (ADT) in patients with locally advanced prostate cancer (PCa) treated for 6 months with neoadjuvant ADT and external-beam radiation therapy (EBRT). METHODS: A multicenter, randomized, phase 3 trial enrolled 303 patients with locally advanced PCa between 2001 and 2006. Participants were treated with neoadjuvant ADT for 6 months. Then, 280 patients whose prostate-specific antigen levels were less than pretreatment levels and less than 10 ng/mL were randomized. All 280 participants were treated with 72 Gy of EBRT in combination with adjuvant ADT for 8 months. Thereafter, participants were assigned to long-term ADT (5 years in all; arm 1) or intermittent ADT (arm 2). The primary endpoint was modified biochemical relapse-free survival (bRFS) with respect to nonmetastatic castration-resistant prostate cancer (nmCRPC) progression, clinical relapse, or any cause of death. RESULTS: The median follow-up time after randomization was 8.2 years. Among the 136 and 144 men assigned to trial arms 1 and 2, respectively, 24 and 30 progressed to nmCRPC or clinical relapse, and 5 and 6 died of PCa. The 5-year modified bRFS rates were 84.8% and 82.8% in trial arms 1 and 2, respectively (hazard ratio, 1.132; 95% confidence interval, 0.744-1.722). CONCLUSIONS: Although modified bRFS data did not demonstrate noninferiority for arm 2, intermittent adjuvant ADT after EBRT with 14 months of neoadjuvant and short-term adjuvant ADT is a promising treatment strategy, especially in a population of responders after 6 months of ADT for locally advanced PCa.

[CLINICAL OUTCOMES OF ABIRATERONE ACETATE FOR TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER: A RETROSPECTIVE ANALYSIS].

(Objective) We retrospectively evaluated the clinical efficacy and safety of abiraterone acetate (AA) in patients with castration-resistant prostate cancer (CRPC). (Methods) We analyzed the clinical records of 50 patients who had received AA in Gunma Cancer Center between October 2014 and June 2017. We assessed the response of prostate-specific antigen (PSA) to AA, and analyzed the association between overall survival and various parameters, including the types of primary hormonal therapy, PSA level, Gleason score, time to CRPC, prior treatment with enzalutamide (Enz) and docetaxel, and sites of metastases. (Results) The median patient age was 74.5 years and median PSA level at baseline was 15.9 ng/ml; 39 (78%) patients had Gleason score ≥8. Eleven (45.8%) of the 24 docetaxel-naïve patients achieved >50% reduction in PSA level from baseline as opposed to one (4.5%) of the 22 patients previously treated with docetaxel.Eleven (55%) of the 20 Enz-naïve patients achieved >50% reduction in PSA level from baseline compared to one (3.8%) of the 26 patients previously treated with Enz. The overall survival of the group with time to CRPC >12 months was significantly longer than that of the group with time to CRPC <12 months (p=0.035). In general, AA was tolerated; the most frequently reported adverse events included liver dysfunction (22%) and fatigue (6%). (Conclusion) Our results suggest that AA is tolerated and may be suitable for patients with time to CRPC >12 months.

Renal primitive neuroectodermal tumor with elevated plasma adrenocorticotropic hormone levels: A case report.

INTRODUCTION: Primitive neuroectodermal tumors are small round-cell tumors - Ewing sarcoma family, frequently occurring in the extremities, but rarely in the kidney. CASE PRESENTATION: A 58-year-old woman presented with whole-body edema and weakness of lower limb muscles. Computed tomography revealed a left renal tumor, and the plasma adrenocorticotropic hormone level was elevated. The tumor was surgically removed without complications, her plasma adrenocorticotropic hormone reverted to normal levels, and symptoms disappeared after surgery. Histopathological examination revealed a primitive neuroectodermal tumor arising in her kidney. The patient was alive without metastasis 3 years after the surgery. CONCLUSION: We report the first case of renal primitive neuroectodermal tumor accompanying elevated plasma adrenocorticotropic hormone levels which are thought to be produced and secreted in an ectopic fashion.

[USEFULNESS OF VIVID (VISUALIZATION OF VARIOUS INTEGRATION WITH DIFFUSION) ON COGNITIVE FUSION PROSTATE BIOPSY].

(Purpose) We created an image reconstructing multiparametric MRI system called VIVID (Visualization of Various Integration with Diffusion) and examined the efficacy of VIVID in detecting prostate cancer. (Methods and materials) The subjects were 80 patients who underwent one target biopsy with reference to MRI images in addition to 8-20 biopsies. (Results) The significant cancer detection rate was 61%, the significant cancer detection rate of PI-RADS 4 or 5 was 55%, and the significant cancer detection rate of VIVID score 4 or 5 was 55%. Three cases with PI-RADS 4 at TZ lesion with positive T2WI only were evaluated as having VIVID scores 1 or 2. Cancer was not detected with target biopsy from the site. (Conclusion) Our finding suggest that VIVID correctly excludes TZ lesions with only T2WI positively in multiparametric MRI.

Psychological distress in men with prostate cancer and their partners before and after cancer diagnosis: a longitudinal study.

OBJECTIVE: To examine the relative risk of psychological distress of men with prostate cancer and their partners during the period before and after prostate cancer diagnosis compared with men without prostate cancer and their partners. METHODS: The participants reported questionnaires on psychological distress at four time points: before prostate cancer biopsy, and at 1, 3 and 6 months following prostate cancer diagnosis. We performed multiple logistic regression analyses to examine the relative risk of psychological distress. RESULTS: A total of 115 couples answered the questionnaires at all four time points. Men with prostate cancer showed a significantly higher risk of psychological distress compared to men without prostate cancer at 1 (odds ratio [OR] = 4.8, 95% confidence interval [CI] = 1.9-13.1), 3 (OR = 3.2, 95% CI = 1.1-10.2) and 6 months following prostate cancer diagnosis (OR = 6.9, 95% CI = 2.3-25.7). Their partners showed a significantly higher risk of psychological distress compared to the partners of men without prostate cancer at 1 month following prostate cancer diagnosis (OR = 2.6, 95% CI = 1.1-6.6). CONCLUSIONS: Men with prostate cancer showed psychological distress during the 6 months following the cancer diagnosis. Their partners also showed psychological distress at 1 month following the cancer diagnosis. Inviting both men with prostate cancer and their partners to speak to their concerns, empathizing with them, finding the solutions together and monitoring of their psychological status regularly should be regarded as important following prostate cancer diagnosis.

Psychosocial longitudinal study profile and distress of couples in relation to the conduct of prostate biopsy.

OBJECTIVE: Partners of prostate cancer patients have been reported to suffer from high levels of psychological distress, although there are few reports of the changes in their distress levels observed before and after the diagnosis and the factors influencing them. This study constructed a longitudinal psychosocial database of prostate cancer biopsy subjects and their partners. This paper describes a summary of the database and the nature and severity of the psychological distress and cancer-related worry. METHODS: We distributed self-administered questionnaires to subjects scheduled for a prostate cancer biopsy and their partners on four occasions: prior to the biopsy, and 1, 3 and 6 months after being informed whether the diagnosis was cancer or not. The questionnaires included questions pertaining to the psychological distress, cancer-related worry and correlational factors. RESULTS: Of the 240 couples who agreed to participate in the database project, 184 couples completed the first and second surveys; thus, the database consists of them. While no significant differences in the levels of psychological distress were found among the participants before the biopsy, the prostate cancer patients and their partners had significantly higher levels of psychological distress as compared with the non-prostate cancer patients at 1 month after being informed whether the diagnosis was cancer or not. CONCLUSIONS: This study constructed a longitudinal psychosocial database of prostate cancer biopsy subjects and their partners. Our findings suggest that partners of prostate cancer patients might experience a similar psychological impact to the prostate cancer patients before and after the diagnosis.

Long-term survival and onset of granulomatous pneumonia after lung metastasectomy in a patient with non-muscle-invasive bladder cancer.

AIMS: This case report describes a first case of granulomatous pneumonia occurring at the same site of the previous lung metastasectomy in a patient with high-grade non-muscle-invasive bladder cancer (NMIBC), which was treated with bladder preservation therapy despite multiple recurrences and failure of intravesical bacillus Calmette-Guerin (BCG) therapy. CLINICAL CASE: We report a 52-year-old woman who underwent transurethral surgery and BCG therapy for pT1, G3 bladder cancer. Although cystectomy was recommended after BCG failure, the operation was not performed because of the patient's wish for bladder preservation. Eighteen months after the first surgery, computed tomography (CT) revealed solitary lung mass. Partial lobectomy which the patient underwent after chemotherapy revealed G3 metastatic urothelial carcinoma. Three years after lung metastasectomy, CT revealed lung mass at the same site of the previous lung metastasectomy. Dynamic contrast-enhanced magnetic resonance imaging showed the significantly enhanced lung mass, which indicated lung metastasis. However, lobectomy of the remnant lobe revealed that the lung mass was granulomatous pneumonia. Although no additional specific treatment was carried out, the patient remains free of disease for 53 months after surgery. CONCLUSIONS: Lung metastasis from NMIBC rarely occurs. Our case report confirms that lung metastasectomy in highly selected patients may contribute to long-term disease control. Moreover, our case report suggests that mycobacterial lung infections along the staple-suture line rarely occur, and percutaneous biopsy should be considered under these circumstances to avoid the unnecessary operation.

[Clinical study on poor PSA response to initial endocrine therapy with MAB or estrogenic drugs for treatment of prostate cancer].

PURPOSE: The prostate specific antigen (PSA) level usually is lowered in response to initial endocrine therapy even in advanced cases of prostate cancer, but in some cases, it is not. We examined the cases in which the PSA level was not sufficiently lowered by initial endocrine therapy with maximal androgen blockade (MAB) or estrogenic drugs. MATERIALS AND METHODS: The subjects were 20 patients with prostate cancer diagnosed between January 1992 and December 2005 whose PSA level was not lowered below 10 ng/ml after initial endocrine therapy with MAB or estrogenic drugs. We investigated the frequency of cases, pretreatment PSA levels, PSA nadir levels after initial endocrine therapy and throughout the therapy, PSA response to second line therapy, and the prognosis. RESULTS: The PSA level was not lowered below 10 ng/ml after initial endocrine therapy with MAB or estrogenic drugs in 4.9% of the cases. Cancer-specific survival rates in all cases were extremely poor, 75.0% at 1 year and 14.7% at 3 years. Prognosis tended to be worse in patients with a higher PSA nadir level throughout the therapy and on whom second therapy was not effective, although the difference was not statistically significant. CONCLUSION: The patients whose PSA levels were not lowered sufficiently by MAB or estrogenic drugs had an extremely poor prognosis. These results are useful in planning the therapy, and in explaining the status or future prospective of the disease to patients and their families.

Correlation between the Banff 97 classification of renal allograft biopsies and clinical outcome.

The 1997 fourth Banff meeting revised the consensus for describing transplant biopsies. We have conducted a retrospective analysis of biopsies correlated between the Banff 97 classification and clinical outcome. The patients ( n=149), who had a total of 404 biopsy-proven rejections, were assessed and the biopsies taken from these patients were re-examined and classified according to the Banff 97 classification. Morphological changes in the glomeruli (g), interstitium (i), tubules(t), and arterial vessels (v) were scored. Severity of acute rejection was statistically associated with unresponsiveness to anti-rejection treatment ( P<0.0001) and predicted an increased risk of graft failure ( P<0.05). Each quantitative criterion (g, i, t, and v) was also statistically associated with unresponsiveness to anti-rejection treatment. Mean serum creatinine levels were significantly higher in the groups graded Banff 97 type I-III after 1 and 2 years of follow-up. The Banff 97 classification correlated with reversibility of rejection episodes and long-term graft survival.

The combination of multi-voxel MR spectroscopy with MR imaging improve the diagnostic accuracy for localization of prostate cancer.

BACKGROUND: We assessed the usefulness of combined multi-voxel magnetic resonance spectroscopy (MRS) and MR imaging (MRI) in the diagnosis of prostate cancer localization. PATIENTS AND METHODS: MRS and MRI were performed in 21 patients with prostate cancer. On T2-weighted images, tumor localization was based on low signal intensity in the peripheral zone. At MRS, cancer patterns were diagnosed when the ratio of choline plus creatine to citrate was greater than 0.86. The results were analyzed with reference to pathological confirmation of prostate cancer at bilateral or unilateral lobe. RESULTS: Six out of 11 patients with unilateral positive biopsy specimens were diagnosed as unilateral cancer, and 9 of 10 patients with bilateral positive biopsy specimens were diagnosed as bilateral cancer on MRI. Two of 4 patients with unilateral cancer, who were not detected on MRI alone, were diagnosed as unilateral cancer on combined MRI and MRS. The accuracy of MRI alone was 71.4%, while that of combined MRI and MRS was 81.0%. CONCLUSION: Combined MRI and MRS improved the diagnostic accuracy for localization of prostate cancer.

Placental growth factor gene expression in human prostate cancer and benign prostate hyperplasia.

BACKGROUND: Angiogenesis plays a crucial role in normal development and carcinogenesis of prostate glands. Placental growth factor (PlGF) belongs to the same family as the vascular endothelial growth factor. The presence of PlGF in human prostate has not been studied. In the current study, we investigated the gene expression profiles of PlGF in human prostate. MATERIALS AND METHODS: Gene expression of PlGF-1 and PlGF-2 was assessed by RT-PCR and direct sequencing. Gene expression levels were quantified by real-time PCR, and we compared the transcript levels among benign prostate hyperplasia (BPH), prostate caner (CAP) and CAP after androgen deprivation therapy (CAP-Tx). RESULTS: Human prostate cancer cells, LNCaP, PC-3 and DU-145, expressed both PlGF-1 and -2 mRNAs. Human prostate tissues, BPH, CAP and CAP-Tx, also expressed both types of PlGF mRNA. BPH and CAP-Tx expressed similar levels of PlGF, however, CAP expressed significantly lower levels of PlGF than BPH or CAP-Tx (p < 0.01). CONCLUSION: PlGF mRNA was expressed in human prostate. Significantly lower levels of PlGF in CAP in comparison with those in BPH or CAP-Tx suggested that PlGF might have effects on vasculogenesis and angiogenesis in prostate disease.

Regulation of metallothionein and zinc transporter expression in human prostate cancer cells and tissues.

Prostate glands contain heavy metals such as zinc and cadmium, and epidemiological studies showed that both metals were associated with prostate cancer development. To understand the heavy metal metabolism in prostate glands, we investigated the regulation of metallothionein (MT), metal-responsive promoter element-binding transcription factor (MTF) and zinc transporter (ZnT) in human prostate cells and tissues. Growth of human prostate cancer cells, LNCaP and PC-3 cells, was suppressed by zinc or cadmium treatment in a dose-dependent manner. LNCaP cells expressed MT-1A, 1X and 2A mRNA, and PC-3 cells expressed MT-1X and 2A mRNA. Zinc or cadmium treatment up-regulated MTs, MTF-1 and ZnT-1 gene expression levels in both cell lines. In PC-3 cells, ZnT-1 protein was detected, and was up-regulated by the metal treatment. Human prostate cancer tissues expressed significantly lower levels of ZnT-1 gene in comparison with hyperplastic tissues. We demonstrated the ZnT-1 expression in human prostate for the first time. The present study showed that heavy metal-metabolizing proteins were involved in human prostate homeostasis, and that the metal metabolizing system might be different in malignant tissues.

Association of genetic polymorphisms of glutathione-S-transferase genes (GSTM1, GSTT1 and GSTP1) with familial prostate cancer risk in a Japanese population.

BACKGROUND: Glutathione-S-transferases (GSTs) are active in the detoxification of a wide variety of toxins and carcinogens. The genetic polymorphisms of GSTM1, GSTT1 and GSTP1 genes have been studied to estimate the relative risk of various cancers. In the current study, we examined the association of the GST gene polymorphisms with familial prostate cancer in a Japanese population by performing a case-control study consisting of 81 familial prostate cancer cases and 105 normal controls. MATERIALS AND METHODS: No significant association of the GSTM1 and GSTT1 gene polymorphisms with familial prostate cancer risk was found; however, the Val/Val genotype of the GSTP1 gene significantly increased risk (OR = 9.31, 95% CI = 0.47-184, p = 0.030). The combination analysis of genotypes of the three genes showed that presence of two high-risk genotypes, i.e., null genotype of the GSTM1 or GSTT1 gene, or any Val genotypes of the GSP1 gene, significantly increased the risk of prostate cancer (OR = 2.67, 95% CI = 1.08-6.59, p = 0.03). Stratification of cases according to the pathological grade or the clinical stage showed no significant differences among categories. CONCLUSION: In the present study, we found that genotypes of GSTs, especially the Val-allele of the GSTP1 gene and the combination of three genotypes, were associated with familial prostate cancer risk.

Association of the genetic polymorphism in cytochrome P450 (CYP) 1A1 with risk of familial prostate cancer in a Japanese population: a case-control study.

Association between genetic polymorphisms of CYP1A1 and familial prostate cancer risk was examined by a case-control study of 185 individuals. Although the individual analysis of m1 or m2 genotype of CYP1A1 showed no significant association with prostate cancer risk, the presence of any mutated alleles significantly increased prostate cancer risk in comparison with wild-type genotypes by combination analysis (odds ratio [OR]=2.38; 95% confidence interval [CI]=1.72-3.29; P=0.0069). Furthermore, metastatic cancer had a significant association with mutated alleles of m1 and m2. These finding suggested that CYP1A1 polymorphisms has an association with prostate cancer risk, especially with progression of prostate cancer.

Vitamin D receptor gene polymorphism in familial prostate cancer in a Japanese population.

AIM: Vitamin D acts as an antiproliferative agent against prostate cells. Epidemiological study has shown that a low level of serum vitamin D concentration is a risk factor for prostate cancer. Vitamin D acts via vitamin D receptor (VDR), and an association of genetic polymorphisms of the VDR gene has been reported. In the current study, we examined the association of VDR gene polymorphisms with familial prostate cancer in a Japanese population. METHODS: We performed a case-control study consisting of 81 familial prostate cancer cases and 105 normal control subjects. Three genetic polymorphisms (BsmI, ApaI and TaqI) in the VDR gene were examined by the restriction fragment restriction length polymorphism method. RESULTS: Overall, there was no significant association of the VDR gene polymorphisms with familial prostate cancer risk in the cases and control subjects. However, a weak association between BsmI or TaqI genotypes and cancer risk was observed in subjects under 70 years of age. Stratification of cases by clinical stage or pathological grade did not show significant association between the VDR gene polymorphisms and prostate cancer risk. CONCLUSION: In the present study, we could not confirm any significant association between VDR gene polymorphisms with familial prostate cancer risk in a Japanese population. Further large-scale case-control studies are warranted to confirm the importance of VDR gene polymorphisms in familial prostate cancer.

Gene expression profiles of human BPH (II): Optimization of laser-capture microdissection and utilization of cDNA microarray.

Laser capture microdissection (LCM) enables the dissection of heterogeneous components of tissues, helping to investigate the molecular properties of these tissues. We have reported gene expression profiles in human benign prostatic hyperplasia (BPH) using LCM and quantitative real-time PCR. In the current work, we extended the previous observations. Firstly, we studied the relationship between the number of dissected acini and amplification by PCR, and found that androgen receptor (AR) and 18S rRNA transcripts were successfully amplified from total RNA obtained from one prostate acinus. Furthermore, LCM-dissected samples were applicable to methylation-specific PCR of E-cadherin promoter gene after bisulfite modification of genomic DNA. Next, we performed cDNA microarray analysis to screen gene expression profiles in the epithelium and stroma. RNA was amplified by T7-RNA polymerase and labeled with Cy3 and Cy5. Epithelium-related or stroma-related genes were identified through cDNA microarray. We confirmed true gene expression levels by quantitative real-time PCR. In epithelium, E-cadherin and serine protease 2, Kunitz-type gene expression levels were significantly elevated, while the connective tissue growth factor gene expression level was significantly elevated in stroma. Thus, LCM-dissected samples were applicable to various molecular examinations including methylation-specific PCR and cDNA microarray, and this will contribute to a precise understanding of the molecular profiles of prostate glands.

Association of the genetic polymorphism of the CYP19 intron 4[TTTA]n repeat with familial prostate cancer risk in a Japanese population.

BACKGROUND: Estrogen is crucial for development of benign prostate hyperplasia and prostate cancer. Aromatase (CYP19) is a key enzyme for estrogen synthesis in males. The genetic polymorphism of the CYP19 intron 4 [TTTA]n tetranucleotide has been studied in relation to breast cancer susceptibility. MATERIALS AND METHODS: We examined the association of the tetranucleotide repeat polymorphism of the CYP19 gene with familial prostate cancer risk in a Japanese population by performing a case-control study consisting of 99 familial prostate cancer cases and 116 normal controls. RESULTS: [TTTA] repeats ranged from 7 to 13 and were designated as A1 to A7 according to the repeat number. We did not observe any A3 allele among cases and controls, nor A7 among cases. Short repeat alleles, A1 and A2, had a tendency to be frequently observed in cases (odds ratio [OR] = 1.43, 95% confidence interval [CI] = 0.96-2.14, p = 0.080). Analysis of polymorphic genotypes showed that short genotypes, i.e., A1A1, A1A2 and A2A2, significantly increased prostate cancer risk in comparison with other longer genotypes (OR = 1.80, 95% CI = 1.04-3.11, p = 0.035). Stratification of cases according to the pathological grade or the clinical stage showed no significant differences among categories. CONCLUSIONS: In the present study, we found that short polymorphic genotypes of [TTTA]n repeats of the CYP19 gene were associated with familial prostate cancer risk.