Very high-risk locally advanced prostate ductal adenocarcinoma cured using low-dose-rate brachytherapy, with seminal vesicle implantation in combination with external beam radiotherapy at a biologically effective dose ≥ 220 Gy: two case reports with a long-term follow-up.

Purpose: Prostate ductal adenocarcinoma (PDA) is an aggressive, rare variant of histologic sub-type of prostate cancer. Patients with PDA present with more aggressive clinical features and have a poorer prognosis than patients with acinar adenocarcinoma. So far, an optimal treatment for PDA has yet to be established. Furthermore, the effectiveness of low-dose-rate (LDR) brachytherapy for PDA has not been reported previously. Case presentation: In this paper, we present two case reports on very high-risk locally advanced PDA, in which patients were successfully treated with LDR brachytherapy, with seminal vesicle implantation in combination with external beam radiotherapy (EBRT) at a biologically effective dose (BED) ≥ 220 Gy and short-term androgen deprivation therapy (ADT). There was no grade 2 genitourinary (GU) and gastrointestinal (GI) toxicities during follow-up, and no evidence of hematuria nor rectal bleeding during follow-up. The patients stay healthy without biochemical failure and without bowel or urinary difficulties at 11.5 years and 8 years, respectively. Conclusions: High-BED LDR-based radiotherapy in combination with EBRT (BED ≥ 220 Gy) may be an ideal treatment for very high-risk locally advanced PDA patients.

Prostate cancer with nodular bladder invasion (stage T4N1) cured by low-dose-rate brachytherapy with seminal vesicle implantation in combination with external beam radiotherapy of biologically effective dose ≥ 220 Gy: a case report.

PURPOSE: Prostate cancer with nodular bladder invasion (stage T4 prostate cancer) is an extremely difficult clinical entity to achieve complete cure. So far, there has been no clear report demonstrating complete cure of prostate cancer with nodular bladder invasion, stage T4 prostate cancer. CASE PRESENTATION: In this case report, the author presents a 55-year-old man with a diagnosis of advanced prostate cancer invading into the bladder wall with pelvic lymph node metastasis (T4N1M0 disease). The patient was treated with biologically effective dose (BED) ≥ 220 Gy of high-dose radiotherapy, using low-dose-rate (LDR) brachytherapy in combination with whole pelvis (WP) external beam radiotherapy (EBRT) and short-term androgen deprivation therapy (ADT): neo-adjuvant six months plus adjuvant six months ADT. There was no grade 2 genitourinary (GU) and gastrointestinal (GI) toxicity during follow-up. There was no evidence of hematuria, nor rectal bleeding in the follow-up. The patient stays healthy without biochemical failure and without bowel and urinary troubles at six years. CONCLUSIONS: Along with previous outstanding data of BED ≥ 220 Gy LDR-based radiotherapy for high-risk and very high-risk prostate cancer patents, including pelvic lymph node metastasis, the present report, in which the patient was treated with BED ≥ 220 Gy of high-dose radiotherapy, LDR brachytherapy in combination with WP EBRT may be an optimal treatment for prostate cancer with nodular bladder invasion with lymph node metastasis (T4N1disease).

Ten-step method of high-dose LDR 125 I brachytherapy for intermediate-risk prostate cancer.

Dose escalation is key for improved outcomes in intermediate-risk prostate cancer, including unfavorable intermediate-risk (UIR) cases. This educational report is designed to provide information about our quality high-dose 125 I seed implantation monotherapy technique in which a biologically effective dose (BED) â‰§ 200 Gy is applied for treatment of intermediate-risk prostate cancer. This protocol is named the "Ten-step Method," where the rationale and principle of the method are based on the following four goals: (1) The entire prostate should be covered by the prescription isodose distribution with a sufficient margin from the prostatic capsule, achieving high D90 and V100 values by 125 I seed implantation. (2) The high-dose cloud (240 Gy) should not invade the urethra or rectum. (3) In order to achieve goals (1) and (2), make the high-dose cloud intentionally along the periphery (bilateral wall to anterior wall) away from the urethra and rectum. (4) In order to achieve goal (3), seeds at the periphery, except those anterior to the rectal wall, should be placed just 1mm inside the capsule. The data obtained from a total of 137 patients with intermediate-risk prostate cancer treated with low-dose-rate (LDR) monotherapy are shown. The dosimetry parameters were monitored at 1 month after seed implantation by using CT and MRI fusion guidance. The data at 1 month after LDR were: Average D90, BED, and V100 of 125 I LDR monotherapy were 194.1 Gy, 207.3 Gy, and 99%, respectively. This ten-step method was reproducible in 137 patients with intermediate-risk prostate cancer, allowing administration of high-dose monotherapy with excellent clinical outcomes.

Clinical outcomes of low-dose-rate brachytherapy based radiotherapy for intermediate risk prostate cancer.

PURPOSE: To monitor the outcomes for intermediate-risk prostate cancer patients treated with biologically effective dose (BED) ≥ 200 Gy radiotherapy using low-dose-rate (LDR) brachytherapy. MATERIAL AND METHODS: Between 2005 and 2016, a total of 397 patients with intermediate-risk prostate cancer were treated by LDR-based radiotherapy with a BED ≥ 200 Gy. Treatments consisted of LDR brachytherapy alone (177 cases) or LDR and external beam radiotherapy (EBRT) (220 cases). Short-term androgen deprivation therapy (ADT) was used in 186 patients (46.9%). The median follow-up period was 72 months (range 29-165 months). Dosimetric parameters and BED were studied in each case. The numbers of intermediate-risk features were: 163 patients with 1 intermediate-risk feature (41%), 169 patients with 2 intermediate-risk features (43%), and 65 patients with 3 intermediate-risk features (16%). A total of 145 cases were diagnosed as having primary Gleason pattern 4: Gleason score 4 + 3 (36.5%). RESULTS: Three patients developed biochemical failure, thus providing a 7-year actual biochemical failure-free survival (BFFS) rate of 99.1%. Biochemical failure was observed exclusively in cases with distant metastasis: two cases with lymph node metastasis and one case with bone metastasis, thus yielding a 7-year freedom from clinical failure (FFCF) rate of 99.1%. We observed eight deaths, but there was no death from prostate cancer, thus yielding a 7-year cause-specific survival (CSS) rate of 100%, and an overall survival (OS) rate of 98.4%. CONCLUSIONS: This study highlights excellent outcomes for intermediate-risk prostate cancer patients, including unfavorable intermediate-risk cases, treated with BED ≥ 200 Gy radiotherapy using LDR brachytherapy. LDR alone with a BED of 200 Gy may be an optimal treatment for both favorable and unfavorable intermediate-risk prostate cancer patients, although a longer follow-up is mandatory to confirm the present findings.

High biologically effective dose radiation therapy using brachytherapy in combination with external beam radiotherapy for high-risk prostate cancer.

PURPOSE: To evaluate the outcomes of high-risk prostate cancer patients treated with biologically effective dose (BED) ≥ 220 Gy of high-dose radiotherapy, using low-dose-rate (LDR) brachytherapy in combination with external beam radiotherapy (EBRT) and short-term androgen deprivation therapy (ADT). MATERIAL AND METHODS: From 2005 to 2013, a total of 143 patients with high-risk prostate cancer were treated by radiotherapy of BED ≥ 220 Gy with a combination of LDR brachytherapy, EBRT, and androgen deprivation therapy (ADT). The high-risk patients in the present study included both high-risk and very high-risk prostate cancer. The number of high-risk features were: 60 patients with 1 high-risk factor (42%), 61 patients with 2 high-risk factors (43%), and 22 patients with 3 high-risk factors (15%) including five N1 disease. External beam radiotherapy fields included prostate and seminal vesicles only or whole pelvis depending on the extension of the disease. Biochemical failure was defined by the Phoenix definition. RESULTS: Six patients developed biochemical failure, thus providing a 5-year actual biochemical failure-free survival (BFFS) rate of 95.2%. Biochemical failure was observed exclusively in cases with distant metastasis in the present study. All six patients with biochemical relapse had clinical failure due to bone metastasis, thus yielding a 5-year freedom from clinical failure (FFCF) rate of 93.0%. None of the cases with N1 disease experienced biochemical failure. We observed four deaths, including one death from prostate cancer, therefore yielding a cause-specific survival (CSS) rate of 97.2%, and an overall survival (OS) rate of 95.5%. CONCLUSIONS: High-dose (BED ≥ 220 Gy) radiotherapy by LDR in combination with EBRT has shown an excellent outcome on BFFS in high-risk and very high-risk cancer, although causal relationship between BED and BFFS remain to be explained further.

Testicular germ cell tumours.

Testicular germ cell tumours are at the crossroads of developmental and neoplastic processes. Their cause has not been fully elucidated but differences in incidences suggest that a combination of genetic and environment factors are involved, with environmental factors predominating early in life. Substantial progress has been made in understanding genetic susceptibility in the past 5 years on the basis of the results of large genome-wide association studies. Testicular germ cell tumours are highly sensitive to radiotherapy and chemotherapy and hence have among the best outcomes of all tumours. Because the tumours occur mainly in young men, preservation of reproductive function, quality of life after treatment, and late effects are crucial concerns. In this Seminar, we provide an overview of advances in the understanding of the epidemiology, genetics, and biology of testicular germ cell tumours. We also summarise the consensus on how to treat testicular germ cell tumours and focus on a few controversies and improvements in the understanding of late effects of treatment and quality of life for survivors.

Dimethyl sulfoxide induces chemotherapeutic resistance in the treatment of testicular embryonal carcinomas.

Dimethyl sulfoxide (DMSO) is an amphipathic molecule that is used as a solvent in biological studies and as a vehicle for drug therapy. The present study was designed to evaluate the potential effects of DMSO as a solvent in the treatment of testicular embryonal carcinomas (ECs). DMSO was applied to two human EC cell lines (NEC8 and NEC14), with the treated cells evaluated in relation to cisplatin (CDDP) resistance, differentiation (using Vimentin, Fibronectin, TRA-1-60, and SSEA-1 and -3 as markers) and stemness (denoted by expression of SOX2 and OCT3/4). Furthermore, DNA methyltransferase (DNMT-1, -3A and -3L) expression and methylation status were analyzed. DMSO induced resistance to CDDP, aberrant differentiation and reduction of stemness-related markers in each of the EC cell lines. The expression levels of DNMT-3L and -3A were reduced in response to DMSO, while this treatment also affected DNA methylation. The data demonstrated that DMSO perturbed differentiation, reduced stemness and induced resistance to CDDP in human EC cells. Therefore, DMSO could reduce drug efficacy against EC cells and its use should be carefully managed in the clinical application of chemotherapy.

Advanced childhood testicular yolk sac tumor with bone metastasis: a case report.

We report a case of advanced childhood testicular yolk sac tumor with bone metastasis, which was successfully treated by multimodal treatment. Optimal management of bone metastases from testicular yolk sac tumor in childhood is discussed.

Assessment of Sunitinib-Induced Toxicities and Clinical Outcomes Based on Therapeutic Drug Monitoring of Sunitinib for Patients With Renal Cell Carcinoma.

BACKGROUND: Sunitinib has been approved for the treatment of metastatic renal cell carcinoma (RCC). Sunitinib pharmacokinetics shows a large interpatient variability. PATIENTS AND METHODS: A retrospective, observational clinical study of 21 patients with RCC was performed. Sunitinib was administered for 4 weeks of a 6-week cycle for the first cycle. We evaluated the association of sunitinib-induced toxicities and clinical outcomes with the trough total sunitinib concentration in a steady state during the first cycle. RESULTS: The median total sunitinib concentration was 91.8 ng/mL (range, 49.8-205 ng/mL). There was an association between total sunitinib concentration and the severity of thrombocytopenia, anorexia, and fatigue. Patients with ≥ 100 ng/mL total sunitinib (n = 8), compared with patients with < 100 ng/mL (n = 13), had a greater incidence of Grade ≥ 3 toxicities (6 patients [75.0%] vs. 3 patients [23.1%]). Patients with < 100 ng/mL total sunitinib had significantly longer time to treatment failure (TTF) and progression-free survival (PFS) time than patients with ≥ 100 ng/mL (median TTF, 590 vs. 71 days; P = .04; median PFS, 748 vs. 238 days; P = .02). CONCLUSION: Results of this study suggest that therapeutic drug monitoring of sunitinib could be useful for avoiding severe toxicities. Dose reduction might be needed, especially when the total sunitinib concentration is ≥ 100 ng/mL, to avoid unnecessary early discontinuation of treatment.

[PREPUBERTAL MATURE TERATOMA OF THE TESTIS MASQUERADING OF A SIMPLE CYST OF THE TESTIS].

A 6-month-old boy was referred to our hospital with left scrotal swelling. Scrotal ultrasound examination revealed a 2 cm cystic mass without solid component in left testicular parenchyma. Serum AFP, hCG and LDH levels were within normal limits. Although we suspected a simple cyst of the testis or a benign testicular tumor, the left testicle was explored via an inguinal incision in case of malignancy. Since intraoperative frozen section revealed benign, we preserved the remaining testis. The wall of cystic mass had a small solid lesion. The definitive pathological examination of the cyst wall showed mature teratoma including squamous epithelium, glandular epithelium of enteric type and cartilage. At 4 years of follow up, he was free of recurrence without testicular atrophy.

Magnetic resonance voiding cystourethrography (MRVCUG): a potential alternative to standard VCUG.

PURPOSE: To evaluate the accuracy and feasibility of magnetic resonance voiding cystourethrography (MRVCUG), with or without contrast medium, in detecting vesicoureteral reflux (VUR) by comparison with conventional voiding cystourethrography (VCUG). MATERIALS AND METHODS: Seventy-five patients underwent a series of 55 indirect MRVCUG (I-MRVCUG) and 61 direct MRVCUG (D-MRVCUG) between 2003 and 2009. We retrospectively compared the results from I-MRVCUG and D-MRVCUG with those from VCUG on 150 kidney-ureter units. Ratios of successful completion of the two types of MRVCUG were analyzed in 116 examinations according to sex, age, and among the two groups, with or without sedation. RESULTS: D-MRVCUG was superior to I-MRVCUG in detecting VUR (sensitivity: 96.8% vs. 76.9%; specificity: 96.3% vs. 88.7%; agreement: 96.6% vs. 83.7%; kappa: 0.83 [95% confidence interval (CI): 0.72, 0.94] vs. 0.55 [95% CI: 0.41, 0.69]). The overall ratio of successful completion of the two types of MRVCUG was 76.7% (89/116): there was no significant difference between I-MRVCUG and D-MRVCUG. The successful completion rate was significantly lower in MRVCUG in toddlers compared with preschoolers, infants, schoolchildren, and adults (P < 0.001). CONCLUSION: The two types of MRVCUG (I-MRVCUG and D-MRVCUG) are promising tests without radiation exposure. Both I-MRVCUG and D-MRVCUG are feasible for children except for toddlers.

Recurrent rhabdomyosarcoma after adjuvant chemotherapy for stage I non-seminomatous germ cell tumor with malignant transformation.

We report a rare case of stage I non-seminomatous testicular germ cell tumor with malignant transformation. The patient received two cycles of chemotherapy (cisplatin, bleomycin and etoposide) tailored to testicular germ cell tumors as an adjuvant therapy after orchiectomy. However, 22 months later, the patient developed a metastasis in the occipital region that consisted of solely rhabdomyosarcoma through malignant transformation of a teratoma component. This case highlights an issue related to adjuvant chemotherapy for testicular germ cell tumors with components of malignant transformation.

Therapeutic potential of SOX2 inhibition for embryonal carcinoma.

PURPOSE: Some nonseminomatous germ cell tumors are resistant to any type of chemotherapy. Control of embryonal carcinoma cells is crucial to manage nonseminomatous germ cell tumors. We established SOX2 targeting therapy in an embryonal carcinoma model. MATERIALS AND METHODS: SOX2 expression was evaluated in a series of testicular germ cell tumor tissue samples. The antitumor effect of SOX2 knockdown was analyzed in vitro and in vivo using an embryonal carcinoma model. RESULTS: In testicular germ cell tumor tissue SOX2 was expressed in the foci of embryonal carcinoma but negative in seminoma and yolk sac tumors. In an embryonal carcinoma model SOX2-siRNA induced apoptotic cell death in vitro and significant growth suppression in vivo. CONCLUSIONS: This study shows the therapeutic potential of SOX2 silencing for embryonal carcinoma. However, further improvements are needed in SOX2-siRNA delivery to the tumor.

Epigenetics: a way to understand the origin and biology of testicular germ cell tumors.

Testicular germ cell tumors are neoplasms carrying two unique features. First, testicular germ cell tumors have a pluripotential nature and show protean histology ranging from that of germ cells to embryonal and differentiated somatic cells. Therefore, testicular germ cell tumors are interesting resources positioned at a crossroad in developmental and neoplastic processes. The second unique feature of testicular germ cell tumors is their exquisite sensitivity to cisplatin-based chemotherapy. This review summarizes recent research progress in the epigenetics of testicular germ cell tumors in an attempt to explain the abovementioned biological and clinical characteristics of testicular germ cell tumors.

Pharmacokinetic/Pharmacodynamic Analysis of a Hemodialyzed Patient Treated with 25 mg of Sunitinib.

Sunitinib has been approved for the treatment of advanced and/or metastatic renal cell carcinoma (RCC). Information on the dosage adjustment of sunitinib for patients undergoing hemodialysis is limited. Especially, efficacy and tolerance of sunitinib at a low dose in such patients are not fully understood. Thus, we examined the effect of hemodialysis on the pharmacokinetics, safety and efficacy of 25 mg of sunitinib. The patient was a 66-year-old man diagnosed with RCC and undergoing hemodialysis. He was treated with sunitinib at 25 mg daily for 4 weeks of a 6-week cycle. There were little differences in the AUC(0-24 h) of sunitinib and its major active metabolite SU12662 on day 17 (on hemodialysis) and day 18 (off hemodialysis) of the first cycle. The total sunitinib concentration (sunitinib and SU12662) was approximately 50 ng/ml at a steady state in every cycle. The patient's genotype was wild type for ABCG2 421C>A, which is associated with increased sunitinib exposure. In the following two cycles of sunitinib, computed tomography scan showed a partial response of the lung metastasis. During the first cycle, the patient developed grade 2 thrombocytopenia and leukocytopenia. After four cycles of treatment, the patient developed grade 3 fatigue and the sunitinib treatment was discontinued. Our patient on hemodialysis could be safely and effectively treated with 25 mg of sunitinib, and a total sunitinib concentration of about 50 ng/ml was maintained. The pharmacokinetics of sunitinib and SU12662 were rarely affected by hemodialysis. Therapeutic drug monitoring could be helpful during sunitinib therapy, especially in a specific population.

Methylation profile of DNA repetitive elements in human testicular germ cell tumor.

Testicular germ cell tumors (TGCTs) have a unique epigenetic profile distinct from that of other types of cancer. To further evaluate epigenetics of TGCTs, this study examines DNA methylation patterns of DNA repetitive elements in TGCTs. Bisulfite genomic sequencing and combined bisulfite restriction analysis (COBRA) were used to analyze the methylation patterns of DNA repetitive elements (LINE1 and Alu repeats) in embryonal carcinoma (EC) derived cell lines, primary TGCT tissues, noncancerous testicular tissues adjacent to TGCTs and cancer cells derived from somatic tissues (testicular malignant lymphoma tissues and renal cell carcinoma cell lines). Through both bisulfite genomic sequencing and COBRA, LINE1 was extensively hypomethylated in both seminomatous and nonseminomatous TGCT tissues as well as EC cell lines. We studied two Alu repeats locating in the 5' end of E-cadherin and XIST by bisulfite genomic sequencing. These two Alu elements were extensively hypomethylated in seminomatous TGCTs, but methylated in nonseminomatous TGCTs, including two EC derived cell lines. This increased unmethylated profile in seminomatous TGCTs was observed also by COBRA for Alu repeats. Although partial demethylation of DNA repetitive elements was observed in cancer cells of somatic tissue origin, the degree of demethylation was more pronounced in TGCTs than in cancer cells of somatic tissue origin. We observed abnormal demethylation of DNA repetitive elements in some of the tissues adjacent to TGCTs. The results indicate that the underlying mechanisms to undergo or maintain demethylation of DNA repetitive sequences differ between TGCTs and cancer cells of somatic tissue origin.

A rare case of multiple schwannomas presenting with scrotal mass: a probable case of schwannomatosis.

We report a rare case of multiple schwannomas presenting with scrotal mass. In the present case, a scrotal schwannoma developed in a 66-year-old man with a history of brain tumor surgery. Investigating the patient's past history lead to the diagnosis as probable schwannomatosis. Patients with schwannomatosis are at increased risk of developing multiple schwannomas and these patients need regular surveillance. In this regard, the present case highlights the importance of thorough history taking in patients with scrotal schwannoma.

DNMT3L is a novel marker and is essential for the growth of human embryonal carcinoma.

PURPOSE: Testicular germ cell tumors (TGCT) have a unique epigenetic profile distinct from that of other types of cancer. Elucidation of these properties has a potential to identify novel markers for TGCTs. EXPERIMENTAL DESIGN: We conducted comprehensive analysis of DNA methyltransferase (DNMT) gene expression in TGCTs. Based on the expression profiles of DNMT genes in TGCTs, we generated a rabbit polyclonal anti-human DNMT3L antibody. We then studied the role of DNMT3L in TGCTs by the treatment of two embryonal carcinoma (EC) cell lines with a small interfering RNA system. Finally, we evaluated the immunohistochemical detection of DNMT3L in TGCT tissues. We also compared the patterns of DNMT3L immunohistochemistry with those of CD30 and SOX2. RESULTS: Among the DNMT genes, we found that mRNA for DNMT3L was specifically expressed in TGCTs, but neither in normal testicular tissues nor in cancer cells of somatic tissue origin. DNMT3L protein was strongly expressed in two EC cell lines, but not in the cell lines of somatic tissue origin. Transfection of small interfering RNA for DNMT3L significantly reduced DNMT3L expression and resulted in growth suppression and apoptosis in EC cells. Immunohistochemical analysis showed that DNMT3L protein was present only in EC cells, but not in the other types of TGCT components and cancer cells of somatic tissue origin. DNMT3L staining was more prominent and specific than CD30 or SOX2 staining for detecting EC cells. CONCLUSION: DNMT3L is a novel marker and is essential for the growth of human embryonal carcinoma.