Nomogram for overall survival of Japanese patients with bone-metastatic prostate cancer.

BACKGROUND: We analyzed the relationship between prostate cancer outcomes and pretreatment clinical factors and developed a prognostic nomogram of overall survival (OS) of patients with bone metastasis. METHODS: From 1993 to 2011, 463 consecutive patients were treated for bone-metastatic prostate cancer. Data sets from 361 patients were used to develop a nomogram (training data), and data sets of 102 patients were used for validation of the nomogram (validation data). Using the external validation data set, the nomogram was assessed for discriminatory ability, and the predictions were assessed for calibration accuracy by plotting actual survival against predicted risk. RESULTS: Of the 361 patients in the training data set, 205 (56.8%) patients died, 169 (46.8%) deaths of which were due to prostate cancer. The median follow-up period was 55.2 months. In the multivariate analysis, patient age, serum prostate-specific antigen level, clinical T stage, extent of disease on bone scan, and biopsy Gleason sum were independent prognostic factors. We developed a prognostic model comprising these five factors for patients with bone-metastatic prostate cancer. This nomogram can be used to estimate 1-, 3-, and 5-year survival probability. External validation of this model using 102 validation data sets showed reasonable accuracy (concordance index, 0.719). CONCLUSION: Our pretreatment prognostic nomogram might be useful for Japanese patients with bone-metastatic prostate cancer.

Androgen deprivation therapy prevents bladder cancer recurrence.

Although accumulating preclinical evidence indicates the involvement of androgen receptor signals in bladder cancer (BC) development, its clinical relevance remains unclear. We aimed to evaluate the predictive role of androgen deprivation therapy (ADT) in BC recurrence in prostate cancer (PC) patients. We retrospectively reviewed 20,328 patients with PC diagnosed during 1991-2013 and identified 239 (1.2%) men having primary BC. After excluding ineligible patients, 162 patients made up a final cohort. With a median follow-up of 62 months, 38 (50%) of 76 control patients without ADT experienced BC recurrence, while 19 (22%) of 86 did in ADT group. Thus, patients having received ADT for their PC showed a significantly lower risk of BC recurrence (5-year actuarial recurrence-free survival: 76% v 40%; P < 0.001) and also had a significantly smaller number of recurrence episodes (5-year cumulative recurrence: 0.44 v 1.54; P < 0.001), compared to the control patients. A multivariable analysis revealed ADT as an independent prognosticator (hazard ratio, 0.29; 95% confidence interval, 0.17-0.49) for BC recurrence. This is the first clinical study showing that ADT significantly reduces the risk of BC recurrence.

Possible anti-tumor activity of initial treatment with zoledronic acid with hormonal therapy for bone-metastatic prostate cancer in multicenter clinical trial.

BACKGROUND: To ascertain the anti-tumor effect of zoledronic acid (ZOL) treatment on clinical outcomes in patients with bone metastatic prostate cancer, we examined the effect of ZOL started simultaneously with hormonal therapy as initial treatment in these patients. METHODS: Forty-seven patients with bone-metastatic prostate cancer who received a luteinizing hormone releasing-hormone (LHRH) analogue and an anti-androgen [maximal androgen blockade (MAB)] were assigned to receive ZOL (4 mg intravenous administration every month for 2 years). The time to progression (TTP) of the prostate-specific antigen (PSA), the overall survival (OS), and the rate of PSA decrease in patients with MAB and ZOL treatment (ZOL group) were compared with these parameters in patients who received only MAB at one institute as a control group (non-ZOL group). RESULTS: Although the nadir PSA level and the rate of PSA normalization showed no significant differences between the ZOL and non-ZOL groups, the time to nadir PSA in the ZOL group was significantly shorter than that in the non-ZOL group (P < 0.05, Mann-Whitney U-test). There was a significant difference in TTP (P = 0.017, log-rank test) between the ZOL and non-ZOL groups, and statistically significant differences in TTP and OS between the ZOL and non-ZOL groups (P = 0.044 and 0.035, log-rank test) were recognized particularly in patients with advanced disease (extension of disease, grade 3 and 4). CONCLUSIONS: Simultaneous administration of ZOL and MAB as initial treatment delayed TTP in bone-metastatic prostate cancer patients. Initial treatment with ZOL has the possibility of anti-tumor activity to delay disease progression.

[Clinical studies of inverted papilloma of the bladder].

Inverted papilloma of the bladder is an uncommon urothelial neoplasm. Although it is traditionally regarded as a benign tumor, there are conflicting data on multiplicity, reoccurrence rate, and association with urothelial carcinoma. From 2005 to 2011, 14 cases of inverted papilloma of the bladder were diagnosed at our hospital. Clinical features of 14 cases were summarized. These patients ranged in age from 25 to 81 years (mean, 61 years). The most frequently occurring symptom was gross hematuria. Eleven bladder tumors arose from the trigone or near the bladder neck. One case was associated with urothelial carcinoma. One was suspected to be a case of tumor recurrence. All other patients were free of tumor recurrence during the mean follow-up of 16.4 months (range, 0-75 months). This study does not suggest the malignant potential of inverted papilloma. However, since inverted papilloma may correlate with urothelial carcinoma. Post-treatment follow up for inverted papilloma should include cystoscopic follow up.

Coexpression of aPKCλ/ι and IL-6 in prostate cancer tissue correlates with biochemical recurrence.

Atypical protein kinase C λ/ι (aPKCλ/ι) and interleukin-6 (IL-6) have been implicated in prostate cancer progression, the mechanisms of which have been demonstrated both in vitro and in vivo. However, the clinical significance of the correlation between the expressions of these factors remains to be clarified. In the present study, we report a significant correlation between aPKCλ/ι and IL-6 proteins in prostate cancer tissue by immunohistochemical staining. We evaluated the association of both proteins by analyzing clinicopathological parameters using chi-square test, Kaplan-Meier with log-rank test, and a Cox proportional hazard regression model in univariate and multivariate analyses. The results again showed that the expression of aPKCλ/ι and IL-6 correlates in prostate cancer tissue (P < 0.001). Atypical protein kinase C λ/ι was also found to correlate with the Gleason score (P < 0.001) and with biochemical recurrence after prostatectomy (P = 0.02). Furthermore, aPKCλ/ι correlated with biochemical recurrence in a Kaplan-Meier and log-rank test (P = 0.01) and Cox analysis (P = 0.02 in the univariate analysis, P = 0.02 in the multivariate analysis). The coexpression of aPKCλ/ι and IL-6 also correlated with biochemical recurrence by Kaplan-Meier and log-rank test (P = 0.005) and Cox analysis (P = 0.01 in the univariate analysis, P = 0.03 in the multivariate analysis). These results indicate a strong correlation between aPKCλ/ι and IL-6 in prostate tumors, and that the aPKCλ/ι-IL-6 axis is a reliable prognostic factor for the biochemical recurrence of this cancer.

[A case of recurrent intracaval renal cell carcinoma effectively treated with sunitinib].

A 67-year-old man received left radical nephrectomy for left renal cell carcinoma (RCC) (clear cell carcinoma, G2, pT3bN0M0). After 9 months, he presented with an acute onset of left extremity edema. A computed tomographic (CT) scan and magnetic resonance imaging reveal recurrent renal cell carcinoma in the inferior vena cava (IVC) and the left renal fossa, thrombus in the left external vein and acute pulmonary embolism. We performed treatment with sunitinib for 5 months after anticoagulant therapy for 3 weeks. A new CT scan showed disappearance of RCC in the IVC and reduction in the size of RCC in the renal fossa. Only 11 cases are reported as recurrent RCC in the IVC. We report the first case of recurrent intracaval RCC in which sunitinib treatment was effective.

ETS family-associated gene fusions in Japanese prostate cancer: analysis of 194 radical prostatectomy samples.

The incidence and clinical significance of the TMPRSS2:ERG gene fusion in prostate cancer has been investigated with contradictory results. It is now common knowledge that significant variability in gene alterations exists according to ethnic background in various kinds of cancer. In this study, we evaluated gene fusions involving the ETS gene family in Japanese prostate cancer. Total RNA from 194 formalin-fixed and paraffin-embedded prostate cancer samples obtained by radical prostatectomy was subjected to reverse-transcriptase polymerase chain reaction to detect the common TMPRSS2:ERG T1-E4 and T1-E5 fusion transcripts and five other non-TMPRSS2:ERG fusion transcripts. We identified 54 TMPRSS2:ERG-positive cases (54/194, 28%) and two HNRPA2B1:ETV1-positive cases (2/194, 1%). The SLC45A3-ELK4 transcript, a fusion transcript without structural gene rearrangement, was detectable in five cases (5/194, 3%). The frequencies of both TMPRSS2:ERG- and non-TMPRSS2:ERG-positive cases were lower than those reported for European, North American or Brazilian patients. Internodular heterogeneity of TMPRSS2:ERG was observed in 5 out of 11 multifocal cases (45%); a frequency similar to that found in European and North American cases. We found a positive correlation between the TMPRSS2:ERG fusion and a Gleason score of ≤7 and patient age, but found no relationship with pT stage or plasma prostate-specific antigen concentration. To exclude the possibility that Japanese prostate cancer displays novel TMPRSS2:ERG transcript variants or has unique 5' fusion partners for the ETS genes, we performed 5' RACE using fresh-frozen prostate cancer samples. We identified only the normal 5' cDNA ends for ERG, ETV1 and ETV5 in fusion-negative cases. Because we identified a relatively low frequency of TMPRSS2:ERG and other fusions, further evaluation is required before this promising molecular marker should be introduced into the management of Japanese prostate cancer patients.

[A clinical study for intravesical recurrence after surgical therapy of urotherial carcinoma of the upper urinary tract].

To identify the risk factors for developing subsequent bladder carcinoma in patients undergoing surgical management of urothelial carcinoma (UC) of the upper urinary tract, we retrospectively studied 119 (median age 69, 81 males and 38 females) patients who underwent surgical resection at Yokohama Municipal Citizen's Hospital, Yokosuka Kyousai Hospital and Chigasaki Municipal Hospital from August 1980 to September 2006. After a median follow up of 37.7 months, 42 cases (35.3%) developed recurrent bladder cancer and the intravesical recurrence-free survival rate at 5 years (Kaplan-Meier method) was 57.7%. Bladder cancer was significantly more common in patients who had smaller primary tumors (less than 3 cm: p0.0444) by univariate analysis. This factor was also identified as independent predictor for the intravesical recurrence by multivariated analysis (p0.0495, Hazard ratio 2.099). In 42 intravesical recurrence cases, invasive recurrence was seen in 9 cases (21.4%). Invasive recurrence appeared to occur in the patients who were older and had longer interval by intravesical recurrence.

[Rupture of renal angiomyolipoma during pregnancy: a case report].

A 39-year-old woman, who was followed because of a 4 cm asymptomatic angiomyolipoma (AML) in the left kidney, presented with an acute onset of lower left back pain in the 38th week of her first pregnancy. An ultrasound revealed an 8 cm mass suggestive of AML rupture and retroperitoneal hemorrhage. An emergency caesarean delivery was performed. A post-delivery computed tomographic scan confirmed the AML rupture and selective embolization was performed. This was a case in which the AML grew rapidly during the pregnancy ; therefore, we discuss the relationship between AML and pregnancy.

[Segmental infarction of the testis presenting as acute scrotum: a case report].

We report a case of segmental testicular infarction that is a rare and usually idiopathic. The patient is a 36-year-old man who presented with acute right scrotal pain and swelling. Scrotal ultrasound demonstrated a round hypoechoic lesion and magnetic resonance imaging (MRI) findings could not rule out intratesticular hemorrhage or necrotic tissue associated with malignant neoplasm. Therefore right high orchiectomy was performed. The histopathological examination revealed segmental infarction of the testis at the upper and middle pole with coagulation necrosis.

[A clinical study concerning survival of operative cases for the transitional cell carcinoma of the upper urinary tract].

To identify prognostic factors influencing survival in transitional cell carcinoma (TCC) of the upper urinary tract, we retrospectively studied 189 (median age 70, 130 males and 59 females) patients who underwent surgical resection at our 3 hospitals from August 1980 to September 2006. After a median follow up of 47.8 months, 45 cases (23.8%) died of cancer and the 5-year and 10-year disease-specific survival rate (Kaplan-Meier method) was 70.5 and 67.1%. Because lymphatic and vascular involvements, pattern of infiltration and location of tumor had loss of data, only the univariate analysis was done. They were observed to be significantly different by the univariate analysis. The significant prognostic factors for survival using Cox-proportional hazard models were tumor stage, tumor grade, lymph node metastasis, and surgical margin status. Adjuvant chemotherapy was not the prognostic factor in our multivariate analysis.

Alterations of p16 and p14ARF genes and their 9p21 locus in oral squamous cell carcinoma.

The p16 gene encodes a 16-kDa cyclin kinase inhibitor, and the p14ARF gene a 14-kDa protein, which acts as a cell cycle regulator or tumor suppressor in human cancer cells. Both genes are mapped on chromosome 9p21. Previous studies have suggested that the p16 gene has important roles in head and neck squamous cell carcinoma. To clarify carcinogenesis in oral squamous cell carcinoma (OSCC), we examined 44 primary OSCCs for alterations of p16 and p14ARF mRNA expression, the methylation status of the p16 gene promoter, the loss of heterozygosity (LOH) at the 9p21 locus, and p16 and p14ARF gene mutations. Alterations of p16 and p14ARF mRNA expression were seen in 27 (61.4%) of 44 and 10 (22.7%) of 44 of OSCC samples, respectively. Methylation of the p16 gene promoter region was detected in 28 (63.6%) of 44 samples, and LOH at 9p21 locus was found in 30 (68.2%) of 44. p16 and p14ARF gene mutations were observed in 4 (9.0%) of 44 and 2 (4.5%) of 44 samples, respectively. Suspected homozygous deletion (HD) was seen in 9 (20.5%) of 44. All cases except one (97.7%) showed alterations in p16, p14ARF, and their locus. These data indicate that the status of p16 and p14ARF genes in OSCC is frequently influenced by methylation, gene mutation, and allelic deletions. Furthermore, these genes and their 9p21 locus have various roles in the pathogenesis of OSCC.

[A case of hormone/docetaxel-refractory prostate cancer in which PSA level decreased after docetaxel+zoledronic acid treatment].

The patient was a 63-year-old man who had a recurrence and bone metastasis of prostate cancer after total prostatectomy. He was diagnosed with prostate cancer refractory to hormones. Subsequently, the PSA level decreased after docetaxel therapy, but then gradually increased. Thus, he was diagnosed with bone metastasis of prostate cancer refractory to therapy with hormones or docetaxel. The PSA level decreased after the start of therapy with docetaxel+ zoledronic acid. Zoledronic acid seems to be effective not only for the prevention but also for the treatment of skeletal related events(SRE)in patients with prostate cancer with bone metastases.

[Retroperitoneal Castleman's disease presenting characteristic image finding].

A 30-year-old woman was hospitalized in our institute with fever up and abdominal pain. Computerized tomography showed a retroperitoneal mass (8 cm in diameter) with arborizing calcification, which was enhanced homogeneously in the arterial phase. The operation was performed and parthological diagnosis revealed hyaline vascular type Castleman's disease. This characteristic calcification pattern is considered unique to Castleman's disease, and could be useful for future diagnosis.

[Massive residual stones after ESWL for staghorn cystine calculi were completely dissolved by oral administration of alkaline citrate: a case report].

A 62-year-old woman was referred to our hospital for bilateral renal stones. Ultrasonography (US) and computed tomography (CT) revealed bilateral staghorn calculi and atrophic left kidney. She had extracorporeal shock-wave lithotripsy (ESWL) for right renal stone during the first 6 months. However, ESWL was not effective and the patient did not want to continue this treatment. Her stone was composed of cystine. We started oral administration of alkaline citrate. Then massive residual stones were completely dissolved during the next 32 months.

[Significance of thcg assay in the management of testicular cancer--the possibility of a standard assay in testicular cancer as an alternative to FbetahCG assay].

PURPOSE: There are three kind of assays related to human chorionic gonadotropin (hCG) : free beta hCG (fbetahCG), which is the standard assay for the management of testicular cancer in Japan, intact hCG (ihCG), which detects hCG only, and total hCG (thCG), which detects hCG free-betahCG and possibly other degradation products. We examined the efficacy of thCG assay for the management of testicular cancer. MATERIALS AND METHODS: The simultaneous determination of serum thCG (DPC IMMULYZE hCG), ihCG (hCG [SRL] or (ECLusys hCG STAT)) and fbetahCG (BALL ELSA F-betahCG) was performed in 21 patients with germ-cell tumor (18 gonadal tumors and 3 extra-gonadal tumors; 8 seminomatous germ-cell tumors [SGCTs] and 13 non-seminomatous germ-cell tumors [NSGCTs]) during treatment. We examined the correlation, diagnostic sensitivity and efficacy of management with three assays. RESULTS: There was no correlation between fbetahCG and the other two assays in SGCTs, while there was good correlation among the three assays in NSGCTs. In SGCTs, diagnostic sensitivity was higher in thCG, whereas in NSGCTs diagnostic sensitivity was higher in thCG and ihCG. In 7 patients whose hCG assays were positive at diagnosis, serum fbetahCG became negative first during treatment in all patients, but serum thCG and ihCG became negative after about 4 weeks. CONCLUSIONS: In this study, thCG assay was significant for the diagnosis and management of patients with testicular cancer especially NSGCTs compared with fbetahCG assay. This study revealed that thCG assay is appropriate as the standard assay in NSGCTs.

[Questionnaire on suitableness and acceptableness of cancer notification in aged Japanese prostate cancer patients].

PURPOSE: In Japan, sometimes a patient with malignant fatal disease is not informed the diagnosis. We tried to investigate if the informed consent of cancer notification is acceptable and suitable for aged Japanese prostate cancer patients. MATERIALS AND METHODS: From January to June 2003, we distributed a questionnaire to outpatients who had been followed up for more than 6 months after the diagnosis of prostate cancer. These patients declared a wish to be notified the true diagnosis in their first visit to our department and were informed that they had prostate cancer just after the diagnosis. Ninety-one per cent of patients (54 patients, mean age was 74.8 +/- 6.1 years old) answered to our questionnaire. Clinical stage consisted of 14 cases of B1, 13 cases of B2, 15 cases of C, 3 cases of D1, and 9 cases of D2. The histopathological grade consisted of 6 cases of well differentiated carcinoma, 32 cases of moderately differentiated carcinoma, and 16 cases of poorly differentiated carcinoma. Eleven cases underwent total prostatectomy (B1 and B2) and 44 cases had androgen deprivation therapy. RESULTS: Seventy-six per cent of patients understood and accepted their illness within a few days. However, 11% of patients took more than 3 months to accept their malignant disease. They answered that they could accept their illness given with a relationship of mutual trust between themselves as patients and the medical staff, effective medical treatment, and with the help of their family. They also answered that the most important emotional support was given by their wives (46.3%) and doctors (27.8%). In the early days following the diagnosis, they worried about their remaining days, the risks or side effects of the treatment, their family, and their job. Several months following the diagnosis, they were concerned about recurrence of the disease, their family, medical expenses, and their old age. Those who did not worry at all doubled from 11.1% immediately after the diagnosis to 22.2% several months later. More than 90% of the patients were satisfied with our medical care. And none answered that they might have been happier without cancer notification. CONCLUSIONS: Cancer notification is acceptable and suitable in aged Japanese prostate cancer patients who declare a wish to know their malignant illness. A good relationship between the patients and the medical staff, and emotional support from the wife are important.

[A case of therapy-related leukemia/myelodysplastic syndrome following treatment of refractory testicular germ cell tumor].

We report a patient with a refractory testicular non-seminomatous germ cell tumor (NSGCT) who developed therapy-related leukemia (TRL) after undergoing salvage chemotherapy and multiple operations for repeat recurrences. Fifty months after the initial therapy, pancytopenia and myeloblasts were observed in the patient's peripheral blood while the patient was undergoing salvage chemotherapy for a fifth recurrence. A bone marrow examination showed evidence of myelodysplastic syndrome (MDS) and refractory anemia with excess of blasts in transformation (RAEB in T) under French-America-British (FAB) classification. Cytogenetic 5q-/7q- abnormalities were also observed. The patient had received a total dose of 189g/m2 of Ifosfamide, 8,250mg/m2 of Etoposide and 1,450 mg/m2 of Cisplatin; therefore, he was diagnosed as having TRL/MDS. The patient has received induction chemotherapy for TRL with Cytarabine, Daunorubicin and Fludarabine while a bone marrow transplantation has been scheduled. Recently, TRL associated with chemotherapy are being reported with increasing frequency in the literature. Since early detection and treatment are necessary for the management of TRL, peripheral blood examinations should be performed after a diagnosis of refractory germ cell tumor has been made. If pancytopenia is detected, bone marrow and cytogenetic examinations should be immediately performed to rule out TRL.

[Two cases of testicular cancer with low human chorionic gonadotropin (hCG) levels after treatment].

Some patients with testicular cancer exhibit low human chorionic gonadotropin (hCG) levels even after successful treatment. We report 2 patients with testicular cancer (2 non-seminomatous germ cell tumors [NSGCTs]) and low betahhCG levels with no recurrence after successful treatment. The first patient is a 45-year-old man with pulmonary and retroperitoneal lymph node metastases. During the first chemotherapy the hCG level decreased but remained at a low level. Salvage chemotherapy had no effect on the hCG level, but a low betahCG level persisted for 16 months. The second case is a 19-year-old man with testicular cancer with retroperitoneal lymph node metastases. The patient underwent an operation for residual masses after chemotherapy. Pathological findings showed necrotic tissue, and a low betahCG level persist for 160 months. A low hCG level does not necessarily meen residual malignancy. Patients with a low hCG level should be monaged carefully avoiding needless treatment.