Current Status of Prostate-specific Membrane Antigen-targeted Alpha Radioligand Therapy in Prostate Cancer.

Prostate cancer (PCa) is the most prevalent malignancy and leading cause of mortality in men. Despite the development of various drugs, such as novel androgen receptor signaling inhibitors and poly adenosine diphosphate-ribose polymerase inhibitors targeting homologous recombination repair-related genetic mutations, prognosis of metastatic castration-resistant prostate cancer remains unfavorable. However, recent advances in nuclear medicine have allowed for both imaging diagnostics and therapeutic interventions by targeting molecules specifically expressed in cancer cells with radioisotopes (RI). γ-rays are used in nuclear medicine imaging, whereas in therapy, α or ß-emitting RIs are administered to target cells in radiation therapy. PCa, in particular, exhibits the characteristic features of radioligand therapy, as the membrane protein prostate-specific membrane antigen (PSMA) is proportionally highly expressed in malignancy compared to normal tissues. The administered RI-labeled compound binds to PSMA, enabling specific targeting of PCa for treatment. Unlike ß-rays, α-rays have a shorter range and impart stronger energy to DNA, allowing α-particles to exhibit a higher linear energy transfer. Due to such characteristics, PSMA-targeted α radiotherapy is expected to have potent cytotoxic effects and fewer side effects on normal organs, making them more likely to be widely adopted in the future. However, reports on PSMA-targeted α radiotherapy differ in aspects, such as prior PSMA-targeted ß radiotherapy, the administered doses, and the number of treatment cycles. Therefore, in this review, we compile the reports on treatments utilizing α-emitting isotopes targeting PSMA in patients with PCa.

Detection support of lesions in patients with prostate cancer using 18 F -PSMA 1007 PET/CT.

PURPOSE: This study proposes a detection support system for primary and metastatic lesions of prostate cancer using 18 F -PSMA 1007 positron emission tomography/computed tomography (PET/CT) images with non-image information, including patient metadata and location information of an input slice image. METHODS: A convolutional neural network with condition generators and feature-wise linear modulation (FiLM) layers was employed to allow input of not only PET/CT images but also non-image information, namely, Gleason score, flag of pre- or post-prostatectomy, and normalized z-coordinate of an input slice. We explored the insertion position of the FiLM layers to optimize the conditioning of the network using non-image information. RESULTS: 18 F -PSMA 1007 PET/CT images were collected from 163 patients with prostate cancer and applied to the proposed system in a threefold cross-validation manner to evaluate the performance. The proposed system achieved a Dice score of 0.5732 (per case) and sensitivity of 0.8200 (per lesion), which are 3.87 and 4.16 points higher than the network without non-image information. CONCLUSION: This study demonstrated the effectiveness of the use of non-image information, including metadata of the patient and location information of the input slice image, in the detection of prostate cancer from 18 F -PSMA 1007 PET/CT images. Improvement in the sensitivity of inactive and small lesions remains a future challenge.

Evaluation of testicular stiffness in boys with unilateral cryptorchidism after orchiopexy by ultrasound strain elastography.

PURPOSE: We assessed the stiffness of unilateral undescended testes after orchiopexy, examining its value in tracking histopathological changes and fertility potential during postoperative follow-up. Additionally, we explored the optimal timing for surgery based on testicular stiffness. PATIENTS AND METHODS: Thirty-six boys who had been diagnosed with unilateral undescended testis and treated with orchiopexy were included in the study. Testicular stiffness was evaluated several times over respective follow-up periods by ultrasound strain elastography after orchiopexy. The strain ratios were measured as the ratios of the elasticities of the descended testis to those of the operated testes. The patients were divided into two groups based on the age at which they underwent orchiopexy:under < 2 years (Group A) and ≥ 2 years (Group B). RESULTS: The mean strain ratios were 0.90 ± 0.32 and 0.92 ± 0.20 in Groups A and B, respectively. In Group A, the strain ratio was constant regardless of postoperative months (r = 0.01, p = 0.99); however, in Group B, it tended to increase with postoperative months (r = 0.42, p = 0.07). CONCLUSIONS: Evaluation of testicular stiffness may be useful for the estimation of histopathological changes and fertility potential in boys with unilateral undescended testes at follow-up appointments after orchiopexy. Our data indicate that performing orchiopexy as early as possible may be recommended to avoid testicular damage.

Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

Downregulation of TCF7 and LEF1 is a key determinant of tumor-infiltrating regulatory T-cell function.

Forkhead box P3 (Foxp3)-expressing regulatory T (Treg) cells play essential roles in immune homeostasis but also contribute to establish a favorable environment for tumor growth by suppressing anti-tumor immune responses. It is thus necessary to specifically target tumor-infiltrating Treg cells to minimize effects on immune homeostasis in cancer immunotherapy. However, molecular features that distinguish tumor-infiltrating Treg cells from those in secondary lymphoid organs remain unknown. Here we characterize distinct features of tumor-infiltrating Treg cells by global analyses of the transcriptome and chromatin landscape. They exhibited activated phenotypes with enhanced Foxp3-dependent transcriptional regulation, yet being distinct from activated Treg cells in secondary lymphoid organs. Such differences may be attributed to the extensive clonal expansion of tumor-infiltrating Treg cells. Moreover, we found that TCF7 and LEF1 were specifically downregulated in tumor-infiltrating Treg cells both in mice and humans. These factors and Foxp3 co-occupied Treg suppressive function-related gene loci in secondary lymphoid organ Treg cells, whereas the absence of TCF7 and LEF1 accompanied altered gene expression and chromatin status at these gene loci in tumor-infiltrating Treg cells. Functionally, overexpression of TCF7 and LEF1 in Treg cells inhibited the enhancement of Treg suppressive function upon activation. Our results thus show the downregulation of TCF7 and LEF1 as markers of highly suppressive Treg cells in tumors and suggest that their absence controls the augmentation of Treg suppressive function in tumors. These molecules may be potential targets for novel cancer immunotherapy with minimum effects on immune homeostasis.

The activated complement pathway in the fibrous process of benign prostatic hyperplasia.

BACKGROUND: To elucidate the changes in activated complement pathway in the fibrous process of benign prostatic hyperplasia (BPH), we analyzed the correlation between complement component expression and histological types of fibrosis using human BPH tissue. METHODS: Fifty-six histological BPH patients who underwent prostate needle biopsy at our institution (mean age 68.6 ± 6.5 years), divided into two histological groups, fibromuscular and fibrous, were compared. Inflammatory cell infiltration in BPH tissue was evaluated by immunohistochemical staining using CD45, with complement expression analysis performed using C3, factor B, and C5b-9 antibody, and the occupancy ratio of the stained region was calculated. Further, correlation between the histological types of fibrous components in BPH tissue and lower urinary tract symptoms questionnaires was analyzed. RESULTS: Twenty-seven (48.2%) and 29 (51.8%) cases were classified in the fibromuscular and fibrous groups, respectively. The proportion of CD45-positive cells in BPH tissue was significantly higher in the fibromuscular group. In complement component analysis, factor B did not significantly differ between groups, while C3 (fibromuscular group; 10.7 ± 8.2%, fibrous group; 16.4 ± 12.7%) and C5b-9 (fibromuscular group; 15.9 ± 6.2%, fibrous group; 17.6 ± 9.2%) were significantly higher in the fibrous group (p = 0.04, p = 0.04, respectively). International Prostate Symptom Score Q5 subscore, indicating slow stream, was significantly higher in the fibrous group (p = 0.04). CONCLUSIONS: In fibrous BPH with abundant fibrosis, the late complement pathway in addition to alternative pathway was activated compared to fibromuscular BPH. These results suggested that the alternative and late complement pathways were involved in the histological fibrous process of BPH.

Second-line Pembrolizumab for Metastatic Urothelial Carcinoma: Differences in Treatment Outcomes According to the Primary Site.

BACKGROUND/AIM: To evaluate the difference in the clinical efficacy and safety of pembrolizumab between patients with metastatic upper tract urothelial carcinoma (UTUC), which includes renal pelvic urothelial carcinoma (UC) and ureteral UC, and those with metastatic lower tract urothelial carcinoma (LTUC). PATIENTS AND METHODS: A total of 752 patients who received pembrolizumab for the treatment of chemoresistant UC were retrospectively analyzed. We compared progression-free survival (PFS), overall survival (OS) and adverse events (AEs) in patients with renal pelvic UC, ureteral UC, and LTUC. RESULTS: The median follow-up period was 42.5 [interquartile range (IQR)=35.1-47.4] months. The primary tumor site was in the upper tract in 362 (48.1%) patients [renal pelvis, n=219 (60.5%); ureter, n=143 (39.5%)] and in the lower tract in 390 (51.9%) patients. The estimated glomerular filtration rate before pembrolizumab treatment in the UTUC group was significantly lower than that in the LTUC group (p<0.001). The median PFS in the UTUC and LTUC groups was 3.4 months, respectively (p=0.271). The median OS in the UTUC and LTUC groups was 10.1 months and 11.7 months, respectively (p=0.195). In an analysis of UTUC divided into renal pelvic UC, ureteral UC, and LTUC, patients with renal pelvic UC had a significantly poorer prognosis in comparison to the other two groups (p=0.041). The incidence of any-grade AEs (51.7% vs. 47.9%, p=0.343) and grade ≥3 AEs (12.2% vs. 12.8%, p=0.826) in the two groups was not statistically significantly different. CONCLUSION: No significant differences were found between the UTUC and LTUC groups with regard to the oncological outcomes and safety of pembrolizumab. Patients with renal pelvic UC had a significantly poorer prognosis than those with other ureteral UCs and LTUCs.

Efficacy and safety of axitinib for metastatic renal cell carcinoma: Real-world data on patients with renal impairment.

OBJECTIVES: Limited information is currently available on the efficacy and safety of axitinib for metastatic renal cell carcinoma (mRCC) patients with renal impairment. Therefore, the present study investigated the efficacy and toxicity of axitinib in patients with chronic kidney disease. METHODS: Post-hoc analyses were performed on a Japanese multicenter cohort study of 477 mRCC patients who received axitinib followed by 1 or 2 regimens of systemic antiangiogenic therapy between January 2012 and December 2016. Differences in clinical characteristics and the efficacy and safety of axitinib were assessed based on pretreatment renal function. RESULTS: Patients were categorized into the following 5 renal function groups according to baseline renal function: estimated glomerular filtration rate (eGFR) ≥60 ml/min (n = 133), 45 ml/min ≤eGFR <60 ml/min (n = 153), 30 ml/min ≤eGFR< 45 ml/min (n = 130), eGFR <30 ml/min (n = 45), and dialysis (n = 16). Median progression-free survival (PFS) (95% confidence interval [CI]) in the 5 groups was 11 (8-16), 14 (11-19), 14 (10-19), 12 (8-24), and 6 (3-NR) months, respectively (p = 0.781). After adjustments for treatment-related confounders, the renal function group was not a significant prognostic factor for PFS. Objective response rates in the 5 groups were 22%, 23%, 23%, 18%, 20%, and 38%, respectively (p = 0.468). Regarding adverse events of all grades, hypertension (p = 0.0006) and renal and urinary disorders (p < 0.0001) were more frequently observed in the eGFR <30 ml/min group than in the other groups. CONCLUSIONS: Since renal function at the initiation of treatment with axitinib does not adversely affect the efficacy of VEGF-TKI therapy, clinicians do not need to avoid its administration to mRCC patients with impaired renal function in consideration of the risk of progression to end-stage renal disease.

PSMA Targeted Molecular Imaging and Radioligand Therapy for Prostate Cancer: Optimal Patient and Treatment Issues.

Theranostics (therapy + diagnosis) targeting prostate-specific membrane antigen (PSMA) is an emerging therapeutic modality that could alter treatment strategies for prostate cancer. Although PSMA-targeted radioligand therapy (PSMA-RLT) has a highly therapeutic effect on PSMA-positive tumor tissue, the efficacy of PSMA-RLT depends on PSMA expression. Moreover, predictors of treatment response other than PSMA expression are under investigation. Therefore, the optimal patient population for PSMA-RLT remains unclear. This review provides an overview of the current status of theranostics for prostate cancer, focusing on PSMA ligands. In addition, we summarize various findings regarding the efficacy and problems of PSMA-RLT and discuss the optimal patient for PSMA-RLT.

Role of puboperinealis and rectourethralis muscles as a urethral support system to maintain urinary continence after robot-assisted radical prostatectomy.

The present study investigated the role of a urethral support system to maintain urinary continence after robot-assisted radical prostatectomy (RARP), with a focus on pelvic floor muscles, such as the puboperinealis muscle (PPM) and rectourethralis muscle (RUM). Finally, 323 patients who underwent RARP were analyzed in this study. All patients performed a one-hour pad test 1, 3, 6, 9, and 12 months after RARP to assess urinary incontinence and MRI before and 9 months after RARP to evaluate the pelvic anatomical structure. The preoperative cross-sectional area of PPM (2.21 ± 0.69 cm2) was significantly reduced by 19% after RARP (1.79 ± 0.60 cm2; p < 0.01). Positive correlations were observed between the amount of urinary leakage according to the 1-h pad test 1, 3, 6, 9, and 12 months after RARP and the change in the cross-sectional area of PPM by RARP (p < 0.01, < 0.001, < 0.001, < 0.001, and < 0.001, respectively). A positive correlation was also noted between the amount of urinary leakage 6 and 12 months after RARP and the preoperative RUM diameter (p < 0.05). The amount of urinary leakage 1, 3, 6, 9, and 12 months after RARP negatively correlated with the change in the antero-posterior diameter of the membranous urethra (MU diameter) from the static to dynamic phases during the Valsalva maneuver by cine MRI. Furthermore, the change in the MU diameter negatively correlated with the change in the cross-sectional area of PPM (p < 0.05). PPM and RUM play significant roles as a supportive mechanism to maintain urinary continence by functioning as a urethral support.

SMARCB1-deficient basal cell carcinoma of the prostate controlled using radiation therapy.

Introduction: Basal cell carcinoma of the prostate is rare, with no established treatment for its recurrence or metastasis. We report a case involving basal cell carcinoma of the prostate controlled using radiotherapy. Case presentation: A 57-year-old man complained of perineal pain. Although his prostate-specific antigen was 0.657 ng/mL, a digital rectal examination revealed his prostate was stone hard. Prostate needle biopsy showed basal cell carcinoma of the prostate. The patient then underwent radical prostatectomy. Local recurrence and sacral bone metastasis appeared 2 months after surgery. OncoGuide™ NCC Oncopanel System showed deletion of SMARCB1; however no recommended treatment was identified. Thus, we decided to perform radiotherapy, which reduced all lesions. Conclusion: Basal cell carcinoma of the prostate may have a poor prognosis with recurrence or metastasis, hence evaluation of prognostic factors is important. In this case, the genomic profiling test suggested that SMARCB1 deletion may be a prognostic factor associated with disease progression.

The current status of prostate cancer treatment and PSMA theranostics.

In the treatment of cancer, understanding the disease status, or accurate staging, is extremely important, and various imaging techniques are used. Computed tomography (CT), magnetic resonance imaging, and scintigrams are commonly used for solid tumors, and advances in these technologies have improved the accuracy of diagnosis. In the clinical practice of prostate cancer, CT and bone scans have been considered especially important for detecting metastases. Nowadays, CT and bone scans are called conventional methods because positron emission tomography (PET), especially prostate-specific membrane antigen (PSMA)/PET, is extremely sensitive in detecting metastases. Advances in functional imaging, such as PET, are advancing the diagnosis of cancer by allowing information to be added to the morphological diagnosis. Furthermore, PSMA is known to be upregulated depending on the malignancy of the prostate cancer grade and resistance to therapy. Therefore, it is often highly expressed in castration-resistant prostate cancer (CRPC) with poor prognosis, and its therapeutic application has been attempted for around two decades. PSMA theranostics refers to a type of cancer treatment that combines both diagnosis and therapy using a PSMA. The theranostic approach uses a radioactive substance attached to a molecule that targets PSMA protein on cancer cells. This molecule is injected into the patient's bloodstream and can be used for both imaging the cancer cells with a PET scan (PSMA PET imaging) and delivering radiation directly to the cancer cells (PSMA-targeted radioligand therapy), with the aim of minimizing damage to healthy tissue. Recently, in an international phase III trial, the impact of 177Lu-PSMA-617 therapy was studied in patients with advanced PSMA-positive metastatic CRPC who had previously been treated with specific inhibitors and regimens. The trial revealed that 177Lu-PSMA-617 significantly extended both progression-free survival and overall survival compared to standard care alone. Although there was a higher incidence of grade 3 or above adverse events with 177Lu-PSMA-617, it did not negatively impact the patients' quality of life. PSMA theranostics is currently being studied and used primarily for the treatment of prostate cancer, but it has the potential to be applied to other types of cancers as well.

Sexual function using the EORTC QLQ-TC26 in testicular cancer survivors: A multi-institutional, cross-sectional study.

OBJECTIVE: To evaluate sexual function after treatment using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 (EORTC QLQ-TC26) questionnaire in Japanese testicular cancer (TC) survivors in a multi-institutional, cross-sectional study. METHODS: This study enrolled TC survivors who visited any of eight high-volume institutions in Japan from 2018 to 2019. After obtaining informed consent, participants completed the EORTC QLQ-TC26 questionnaires. We evaluated sexual function after treatment for TC using the EORTC QLQ-TC26 and analyzed the impact of treatment on sexual function in TC survivors. RESULTS: A total of 567 TC survivors responded to the EORTC QLQ-TC26. Median age at the time of response was 43 years (interquartile range [IQR] 35-51 years), and median follow-up period after treatment was 5.2 years (IQR 2.2-10.0 years). Sexual function, particularly ejaculatory function, was significantly lower after post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) than after Surveillance or Chemotherapy groups (p < 0.05). In the PC-RPLND group, nerve-sparing procedure preserved postoperative ejaculatory function after RPLND compared with the non-nerve-sparing and offered improved ejaculatory function with time. On multivariate analysis, RPLND was a significant predictor of post-treatment ejaculatory dysfunction, particularly without nerve-sparing (odds ratio 3.0, 95% CI 1.2-7.7, p < 0.05). In addition, TC survivors with nerve-sparing RPLND had higher sexual activity than those without. CONCLUSION: This survey of the EORTC QLQ-TC26 showed that sexual function and activity in TC survivors after RPLND was reduced in the absence of nerve-sparing techniques.

Mechanism of Androgen-Independent Stromal Proliferation in Benign Prostatic Hyperplasia.

Benign prostatic hyperplasia (BPH) is a chronic proliferative disease showing stromal-dominant proliferation. However, the detailed proliferation mechanism has remained unclear. Although aging and androgen have been reported as definitive risk factors for BPH, recent studies have focused on the involvement of androgen-independent factors. Androgen-independent factors include ischemia, oxidative stress, metabolic syndrome, infection, autoimmune reactions, and inflammation, with inflammation in BPH tissues playing a central role in the BPH proliferative process. Inflammation in BPH tissues by various factors finally leads to tissue remodeling and stromal proliferation through the wound healing process of the prostate. To elucidate the proliferative mechanism of BPH, a study using whole-genome gene expression analysis in a stromal-dominant BPH rat model was performed and showed that immune response-related pathways and complement classical pathways are activated. Furthermore, expression analysis using this BPH rat model showed that the autoimmune reaction triggered complement pathway activation in the proliferative process of BPH. BPH is a multifactorial disease, and understanding the role of androgen-independent factors including immune responses contributes to elucidating the pathogenesis of BPH. Androgen-independent factors may lead to new therapeutic targets for BPH, and further development of this research is expected.

Real-world effectiveness of nivolumab and subsequent therapy in Japanese patients with metastatic renal cell carcinoma (POST-NIVO study): 36-month follow-up results of a clinical chart review.

OBJECTIVES: To examine the long-term effectiveness of nivolumab monotherapy and following subsequent therapies for metastatic renal cell carcinoma (mRCC) in Japanese real-world settings. METHODS: This was a multicenter, retrospective, observational study, with a 36-month follow-up, and conducted in Japanese patients with mRCC who initiated nivolumab monotherapy between 1 Feb 2017 and 31 Oct 2017. Endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). RESULTS: Of the 208 patients, 36.5% received nivolumab monotherapy as second-line, 30.8% as third-line, and 31.7% as fourth- or later-line therapy. By 36 months, 12.0% of patients continued nivolumab monotherapy; 88.0% discontinued, mainly because of disease progression (66.7%). The median (m) OS was not reached irrespective of treatment line, with a 36-month OS rate of 54.3% (second-line, 57.4%; third-line, 52.6%; fourth- or later-line, 52.9%). The ORR was 24.2% and five patients achieved complete response. The OS from first-line therapy was 8.9 years. In the 95 patients receiving therapy after nivolumab, 87.4% received vascular endothelial growth factor receptor-tyrosine kinase inhibitors, with mOS and mPFS of 27.4 and 8.1 months, respectively. Irrespective of treatment line, the mOS was not reached in patients with International Metastatic RCC Database Consortium (IMDC) favorable or intermediate risk at mRCC diagnosis. CONCLUSIONS: This 36-month real-world follow-up analysis showed a survival benefit of nivolumab monotherapy for patients with mRCC. The long-term effectiveness of sequential therapy from first-line therapy to therapy after nivolumab was also demonstrated. Additionally, nivolumab monotherapy was beneficial for patients with favorable IMDC risk at the time of mRCC diagnosis.

Increased toxicities associated with dose escalation of stereotactic body radiation therapy in prostate cancer: results from a phase I/II study.

BACKGROUND: This dose-escalation study evaluated the toxicity and efficacy of different stereotactic body radiation therapy (SBRT) doses for selecting an optimal dose for prostatic adenocarcinoma (PCa). MATERIALS AND METHODS: This clinical trial was registered at UMIN (UMIN000014328). Patients with low- or intermediate-risk PCa were equally assigned to 3 SBRT dose levels: 35, 37.5, and 40 Gy per 5 fractions. The primary endpoint was the occurrence rate of late grade ≥2 genitourinary (GU) and gastrointestinal (GI) adverse events at 2 years, while the secondary endpoint was the 2-year biochemical relapse-free (bRF) rate. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Seventy-five patients (median age, 70 years) were enrolled from March 2014 to January 2018, of whom 10 (15%) and 65 (85%) had low- and intermediate-risk PCa, respectively. The median follow-up time was 48 months. Twelve (16%) patients received neoadjuvant androgen deprivation therapy. The 2-year occurrence rates of grade 2 late GU and GI toxicities were 34 and 7% in all cohorts, respectively (35 Gy: 21 and 4%; 37.5 Gy: 40 and 14%; 40 Gy: 42 and 5%). The occurrence risk of GU toxicities significantly increased with dose escalation (p = 0.0256). Grades 2 and 3 acute GU toxicities were observed in 19 (25%) and 1 (1%), respectively. Grade 2 acute GI toxicity was observed in 8 (11%) patients. No grade ≥3 GI or ≥4 GU acute toxicity or grade ≥3 late toxicity was observed. Clinical recurrence was detected in 2 patients. CONCLUSIONS: An SBRT dose of 35 Gy per 5 fractions is less likely to cause adverse events in patients with PCa than 375- and 40-Gy SBRT doses. Higher doses of SBRT should be applied with caution.

Mucinous cystadenoma of the renal parenchyma presenting as a Bosniak IIF complex renal cyst.

Introduction: A primary retroperitoneal mucinous cystadenoma should be surgically resected because of the risk of malignant transformation. However, mucinous cystadenoma of the renal parenchyma is very rare, and preoperative imaging mimics complicated renal cysts. Case presentation: A 72-year-old woman presented with a right renal mass on computed tomography that was followed up as a Bosniak IIF complicated renal cyst. One year later, the right renal mass gradually increased in size. Abdominal computed tomography showed an 11 × 10 cm mass in the right kidney. A laparoscopic right nephrectomy was performed because cystic carcinoma of the kidney was suspected. Pathologically, the tumor was diagnosed as mucinous cystadenoma of the renal parenchyma. Eighteen months after resection, the disease has not recurred. Conclusion: Here, we experienced a case of a renal mucinous cystadenoma as a slowly enlarging Bosniak IIF complex renal cyst.

Seronegative rheumatoid arthritis after combination therapy with ipilimumab and nivolumab for postoperative pancreatic and liver metastases from renal cell carcinoma.

Introduction: Since the approval of immune checkpoint inhibitors for renal cell carcinoma treatment, therapeutic efficacy has been enhanced. However, although autoimmune-related side effects may occur, rheumatoid immune-related adverse events seldom develop. Case presentation: A 78-year-old Japanese man with renal cell carcinoma developed pancreatic and liver metastases after bilateral partial nephrectomy and was treated with ipilimumab and nivolumab. After 22 months, he developed arthralgia in limbs and knee joints, accompanied by limb swelling. The diagnosis was seronegative rheumatoid arthritis. Nivolumab was discontinued, and prednisolone was initiated, quickly improving symptoms. Although nivolumab was resumed after 2 months, arthritis did not recur. Conclusion: Immune checkpoint inhibitors may cause a wide variety of immune-related adverse events. When arthritis is encountered during immune checkpoint inhibitor administration, seronegative rheumatoid arthritis should be differentiated from other types of arthritis, despite being less frequent.

A case of mediastinal teratoma with malignant transformation into angiosarcoma and relapse with multiple bone metastases that was cured by a multidisciplinary treatment.

Introduction: Complete resection is essential for the treatment of teratoma with malignant transformation, and if metastasis occurs, it will be difficult to cure. We report a case of primary mediastinal teratoma with differentiation into angiosarcoma that caused bone metastases but was cured by multidisciplinary treatment. Case presentation: A 31-year-old man with a primary mediastinal germ cell tumor underwent primary chemotherapy followed by post-chemotherapy resection, with angiosarcoma due to malignant transformation found in the surgical specimen. Femoral diaphyseal metastasis was manifested, and he underwent femur curettage followed by radiation therapy of 60 Gy in parallel with 4 cycles of chemotherapy combining gemcitabine and docetaxel. Although thoracic vertebral bone metastasis emerged 5 months after treatment, intensity-modulated radiation therapy was successful, and metastatic lesions have remained shrunken for 39 months after treatment. Conclusion: Even if complete resection is difficult, teratoma with malignant transformation may be cured by multidisciplinary treatment based on histopathology.

Surgical resection of primary leiomyosarcoma of retro-hepatic inferior vena cava extending from bilateral renal veins across the diaphragm.

Vascular leiomyosarcoma of the inferior vena cava is a rare malignant soft tissue tumor that requires surgical treatment to prevent tumor-related symptoms such as pulmonary embolism and Budd-Chiari syndrome. However, a treatment strategy for surgical resection of advanced cases has not yet been determined. This report describes the case of advanced leiomyosarcoma of the inferior vena cava that was successfully treated with surgery and subsequent chemotherapy. A 44-year-old man was found to have a 12 × 10 cm retroperitoneal tumor on computed tomography. The tumor originated in the inferior vena cava and extended beyond the diaphragm into the renal vein. The surgical plan was determined in joint consultation with the multidisciplinary team. It was safely resected and the inferior vena cava was closed caudal to the porta hepatis without a synthetic graft. The tumor was diagnosed as leiomyosarcoma. Doxorubicin, followed by pazopanib were administered as treatment for metastatic disease. Eighteen months after the surgery, the patient's performance status was maintained.