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.

Clinical outcomes of first-line combination therapy with immune checkpoint inhibitor for metastatic non-clear cell renal cell carcinoma: a multi-institutional retrospective study in Japan.

BACKGROUND: In metastatic clear cell renal cell carcinoma (ccRCC), recent studies have shown promising efficacy of immune checkpoint inhibitor (ICI) combination therapy. However, there are insufficient evidences about clinical efficacy and safety of ICI combination therapy in metastatic non-ccRCC (nccRCC). METHODS: We retrospectively investigated 44 patients treated with nivolumab plus ipilimumab (ICI + ICI group) or anti-PD-1/PD-L1 inhibitor plus tyrosine kinase inhibitors (TKI) (ICI + TKI group), and assessed clinical efficacy in both groups. RESULTS: Of all patients, overall response rate and disease control rate for ICI combination treatments were 36.3% and 75%, respectively. The median progression-free survival (PFS) and overall survival (OS) was 8.8 and 23.9 months, respectively. Multivariate analysis revealed that the presence of liver metastasis significantly affected worse PFS and OS (p = 0.035 and p = 0.049). Importantly, PFS and OS seemed similar in ICI + ICI group and ICI + TKI group (p = 0.778 and p = 0.559). Although the discontinuation rate of the combination therapy due to adverse effects in patients aged ≥ 75 years was significantly higher compared to that in patients aged < 75 years (45% versus 12%, p = 0.017), there were no significant differences in PFS and OS between two groups (p = 0.290 and p = 0.257, respectively). CONCLUSION: This study confirms clinical benefit of ICI combination therapy for metastatic nccRCC patients in real-world settings. Furthermore, the effectiveness of combination therapy was comparable between patients aged < 75 and those ≥75 years with respect to clinical prognosis.

A comparative study on nivolumab and axitinib as secondary treatment in patients with metastatic renal cell carcinoma: A multi-institutional retrospective study in Japan.

OBJECTIVES: When primary treatment has been inadequate, nivolumab and axitinib are often used as a secondary treatments for patients with metastatic renal cell carcinoma (mRCC). However, there have been few reports comparing the efficacy and safety of these drugs. METHODS: We retrospectively investigated 58 patients treated with nivolumab and 57 patients treated with axitinib as secondary treatment between April 2013 and December 2019. We then assessed the clinical efficacy and safety of the treatments in both groups. RESULTS: The most common primary therapy was sunitinib (61.7%). Both nivolumab and axitinib groups showed no significant differences in terms of the objective response rate and disease control rate (p = 0.280 and p = 0.518, respectively). Importantly, progression-free survival (PFS) and overall survival (OS) seemed to be similar in patients treated with nivolumab and axitinib (p = 0.527 and p = 0.266, respectively), irrespective of the objective response to primary therapy. Furthermore, a Cox proportional hazards model showed that pretreatment Karnofsky Performance Status was significantly associated with PFS and OS. Although the incidence of adverse events was significantly higher in the patients treated with axitinib, there was no significant difference in time to treatment failure between the two groups. CONCLUSIONS: Nivolumab and axitinib showed similar clinical benefits as secondary treatment in patients with mRCC; thus, they should be an option in sequential therapy following treatment with tyrosine kinase inhibitors (TKIs). Future studies and feasible therapeutic biomarkers would help predict the clinical response to TKIs or immune checkpoint inhibitors in patients with mRCC.

Real-world efficacy and safety of nivolumab plus ipilimumab in untreated metastatic renal cell carcinoma, and the impact of previous nephrectomy on clinical outcome: Japanese multi-institutional retrospective study.

BACKGROUND: In metastatic renal-cell carcinoma (mRCC), recent clinical trials have shown efficacy of first-line combination therapy, as evidenced by better clinical outcome over target therapy. However, there are insufficient real-world evidences in mRCC patients in Japan. METHODS: We performed a multicenter retrospective study of 72 mRCC patients who received nivolumab plus ipilimumab as first-line treatment between September 2018 and July 2021. Patient's characteristics, clinical outcomes and safety were retrospectively reviewed. We analyzed overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in patients treated with combination therapy. RESULTS: Of all patients, the median age was 70 years (range, 36-86) and the major type of histology was clear cell RCC (n = 55; 76.4%). Progressive disease (n = 25; 34.8%) and irAEs (n = 22; 30.6%) were the most common causes for discontinuing treatment. Median PFS and OS seemed similar between patients who discontinued treatment because of irAEs and for patients who did not (p = 0.360 and p = 0.069, respectively). Importantly, for patients with synchronous metastatic disease at diagnosis (n = 56), nephrectomy before initiating nivolumab plus ipilimumab had a significantly positive impact on better OS when compared to that in patients without nephrectomy (p = 0.028). CONCLUSION: This study confirms efficacy and safety of nivolumab plus ipilimumab for mRCC patients in real-world settings. Furthermore, nivolumab plus ipilimumab was associated with a better outcome in patients who had undergone nephrectomy at diagnosis for synchronous mRCC.

[A Long-Term Survival Case of Paraganglioma Treated with Repeated Surgical Resection].

We report a case of long-term survival in paraganglioma treated with repetitive surgery. A 32-year-old man was seen at the hospital because of hypertension and headache. On biochemical tests, elevated serum and urinary levels of noradrenaline were noted. Abdominal computed tomographic (CT) scan revealed a tumor 50 mm in diameter on the dorsal region of the inferior vena cava, superior to the renal artery. Our diagnosis was paraganglioma and we performed open resection of the tumor. Six years later, hypertension and headache appeared and abdominal computed tomography revealed tumors located in right renal hilus and para-aortic regions superior to aortic bifurcation, and ¹²³I-MIBG scintigraphy revealed uptake at the same sites. Therefore, we diagnosed the patient with recurrent pheochromocytoma and performed laparoscopic resection of the tumor. Surgical treatment was repeatedly performed for recurrence, and the symptoms due to hypersecretion of catecholamines could be controlled over a long period.

The prognostic impact of immune-related adverse events in metastatic renal cell carcinoma patients treated with nivolumab: a real-world multi-institutional retrospective study.

BACKGROUND: Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) were correlated with favorable clinical outcome in patients with melanoma. However, in metastatic renal cell carcinoma (mRCC) patients, there have been few reports about the correlation between irAEs and clinical efficacy of anti-programmed cell death protein-1 (PD-1) therapy. METHODS: We retrospectively investigated 160 mRCC patients who started nivolumab monotherapy between September 2016 and July 2019. IrAEs were defined as patients' AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy. We compared the data of patients who received nivolumab into two groups based on the occurrence of irAEs and assessed clinical efficacy in both groups. RESULTS: Of all mRCC patients, 47 patients (29.4%) developed irAEs. In patients who developed irAEs, the objective response rate and disease control rate were 38.8% and 77.6%, which were significantly higher when compared to that in patients without irAEs (p = 0.012 and p < 0.001, respectively). Furthermore, the incidence of irAEs was significantly associated with an increase in progression-free survival (PFS) [Hazard ratio (HR) = 0.4867; p = 0.0006] and overall survival (OS) (HR = 0.526; p = 0.0252). Importantly, PFS and OS seemed to be similar in patients who discontinued treatment because of irAEs and in those who did not discontinue because of irAEs (p = 0.36 and p = 0.35, respectively). CONCLUSION: Development of irAEs strongly correlates with clinical benefit for mRCC patients receiving nivolumab monotherapy in real-world settings.

[Primary Pulmonary Cryptococcosis Mimicking Lung Metastases of Bladder Cancer : A Case Report].

A 70-year-old woman was diagnosed with bladder cancer (muscle invasive adenocarcinoma) via transurethral resection of bladder tumor in 2013. A month after the procedure, she underwent total cystectomy and ileal conduit diversion. Histopathological diagnosis was adenocarcinoma pTis pN0. In 2019, a computed tomography showed multiple nodules, each up to 1 cm in diameter, mainly in the right lower lobe. Metastatic lung cancer was suspected. She underwent thorascopic partial resection of the right lung, and was diagnosed with primary pulmonary cryptococcosis.

[Malignant Mesothelioma of the Tunica Vaginalis Testis : A Case Report].

A 56-year-old man presented with a painless swelling of the left scrotum. Cytologic examination of blood stained hydrocele fluid suggested malignancy. Left high orchiectomy was performed under the suspicion of malignant tumor of the tunica vaginalis testis. The final pathologic report revealed malignant mesothelioma of the tunica vaginalis testis. There is no evidence of recurrence after 114 months followup. It is important to perform en bloc resection for this disease to prevent recurrence.

[A Case Report : FDG Uptake to Brown Adipose Tissue Activated by Elevated Serum Catecholamine in a Patient with Pheochromocytoma].

A 69-year-old woman was admitted to the previous hospital because of a right adrenal tumor detected by a medical checkup. Although the tumor was diagnosed as non-functional adrenal adenoma, abdominal computed tomography (CT) revealed a left renal mass which was suspected to be renal cell carcinoma. Chest CT seeking for metastatic lesions revealed lung cancer of the left lung. First, laparoscopic radical nephrectomy was performed. After the surgery, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) CT performed for staging of the lung cancer demonstrated FDG uptake to the left lung mass, the heart, the right adrenal mass and perirenal regions of the right kidney. The patient showed elevated serum catecholamine level and hypertensive emergency. She was admitted to our hospital with a suspicion of pheochromocytoma of the right adrenal gland and multiple paraganglioma. CT and magnetic resonance imaging showed that the heart and the perirenal regions had no tumors. We considered these lesions brown adipose tissue. Under the diagnosis of pheochromocytoma of the right adrenal gland, laparoscopic partial adrenalectomy was performed. The clinical course after the surgery was uneventful. FDG PET-CT revealed that FDG uptake to brown adipose tissue disappeared 6 months after the partial adrenalectomy.

[Inflammatory Pseudotumor of the Ureter : A Case Report and a Review].

We report a case of inflammatory pseudotumor of the ureter. An 81-year-old man who had an operation of pelvic exenteration with ileal conduit presented with right flank pain. Computed tomography revealed a 16 mm mass of the right ureter with right hydronephrosis and renal atrophy. The mass increased in size during follow up. Right nephroureterectomy was performed with suspicion of ureteral cancer. Histopathological finding showed an inflammatory pseudotumor. No obvious recurrence has been observed for 33 months after the surgery.

[A Case of Retroperitoneal Cavernous Hemangioma Difficult to Differentiate from Retroperitoneal Liposarcoma].

We report a case of retroperitoneal cavernous hemangioma. A 77-year-old woman complaining of nausea was admitted to a different hospital in September 2013. Computed tomography (CT) detected a retroperitoneal mass in the left pararenal space. Three years later, repeated CT showed that the tumor had gradually grown in size. On dynamic contrast-enhanced magnetic resonance imaging (MRI), the tumor demonstrated radiographic signs of a liposarcoma. Resection of the mass with left nephrectomy was performed in June 2016, and histopathology showed cavernous hemangioma. Clinical diagnosis of cavernous hemangioma is difficult, and imaging modalities, including CT and MRI, may not be conclusive. The final diagnosis in most cases is established through surgery. This is the 29th case of retroperitoneal cavernous hemangioma to be reported in Japan.

Prostate-specific antigen measured 3 months after radical prostatectomy as a new predictor of biochemical recurrence.

BACKGROUND: This study was undertaken to investigate if the prostate-specific antigen (PSA) level measured 3 months after radical prostatectomy (RP) is a predictor of biochemical recurrence (BCR)-free survival. METHODS: We retrospectively reviewed the clinicopathologic data of 174 patients with a follow-up of at least 3 years after RP for clinically localized prostate cancer. None of the patients received neoadjuvant/adjuvant therapy. Subjects were categorized according to PSA level 3 months after RP (3M-PSA): <0.010 ng/mL (group 1; n = 119) or 0.010-0.100 ng/mL (group 2; n = 55). BCR was defined as two consecutive rises in PSA level ≥0.2 ng/mL. RESULTS: At a median follow-up of 69.5 months (range 36-113 months), 32 (18.4 %) patients experienced BCR. The median time to BCR was 16 months (range 4-98 months) after RP. The 5-year BCR-free survival rate was 92.6 and 57.4 % in groups 1 and 2, respectively. Patients in group 1 had a significantly higher BCR-free survival rate than those in group 2 (log-rank P < 0.001). According to the Cox proportional hazards model, patients with a 3M-PSA level of <0.010 ng/mL were at lower risk for BCR (P < 0.001), along with pathologic Gleason sum 6 (P = 0.028). PSA nadir level after RP was also a risk factor for BCR (log-rank P < 0.001). Area under the receiver operating characteristic curve for 3M-PSA to predict BCR was almost equivalent to that for the PSA nadir level (0.855 vs. 0.849). CONCLUSIONS: 3M-PSA is an independent predictor of BCR-free survival. Our findings might be used for a risk-adjusted follow-up protocol.

[Stromal Tumors of Uncertain Malignant Potential (STUMP) of the Prostate : A Case Report].

A 77-year-old man was seen at our hospital with the chief complaint of pollakisuria. Magnetic resonance imaging (MRI) showed a 25 mm cystic tumor with solid components behind the prostate. A transrectal biopsy for the prostate showed no evidence of malignancy. Two years later, he complained of weak urinary stream, and the MRI diagnosis demonstrated an increase of the tumor size to 67 mm. Since prostatic sarcoma was diagnosed by the transrectal biopsy for the prostate, a tumor resection and prostatectomy were performed. At 19 months after the operation, there was no evidence of metastasis or recurrence, and he has had no dysuria. The final pathological diagnosis was of a prostatic STUMP.

[Two Cases of Intrapelvic Schwannoma].

A 67-year-old man (case 1) and 65-year-old man (case 2) were incidentally found to have a tumor in the retrovesical region. Computed tomography and magnetic resonance imaging demonstrated a solid tumor at the right side of the rectum. 2-Deoxy-2-[fluorine-18] fluoro-D-glucose (FDG) -positron emission tomography revealed uptake at the tumor. Both patients were cured by tumor resection. Histological diagnosis was benign schwannoma. In case 2, it was difficult to diagnose the tumor as schwannoma by imaging studies. We made a histological diagnosis by transrectal needle biopsy of the tumor before the operation. Schwannoma is located mostly in the limbs and the head and neck, but rarely in the intrapelvic cavity. We expect that the transrectal needle biopsy is valuable for diagnosing the retrovesical tumor.

Development of nomogram to non-steroidal antiandrogen sequential alternation in prostate cancer for predictive model.

OBJECTIVES: To clarify clinical predictors for a prostate-specific antigen decrease ≥50% in response to alternative non-steroidal antiandrogen therapy and to develop a nomogram to predict the prostate-specific antigen decrease ≥50% in response to alternative non-steroidal antiandrogen therapy in patients with advanced prostate cancer that relapsed after initial combined androgen blockade. We previously reported that combined androgen blockade with an alternative non-steroidal antiandrogen is effective for advanced prostate cancer that has relapsed after initial combined androgen blockade. METHODS: We enrolled 161 patients from 14 medical institutions with histologically confirmed prostate cancer who had been treated with combination therapy and in whom cancer progressed after first-line combined androgen blockade therapy. A nomogram for the prostate-specific antigen decrease ≥50% from baseline prostate-specific antigen in response to alternative non-steroidal antiandrogen therapy was developed based on the final logistic regression model. RESULTS: Overall prostate-specific antigen decreased ≥50% in 75 of 161 patients (46.6%) in response to alternative non-steroidal antiandrogen therapy. Using five independent risk factors (initial serum level of prostate-specific antigen, hemoglobin, C-reactive protein, prostate-specific antigen nadir to second hormone therapy and Gleason sum), a nomogram was developed for the prediction of prostate-specific antigen decrease ≥50% in response to alternative non-steroidal antiandrogen therapy. The receiver operating characteristic curve showed that the accuracy of the predicted probability was 72.5% for the model. CONCLUSIONS: This predictive nomogram could predict the prostate-specific antigen decrease ≥50% in response to alternative non-steroidal antiandrogen therapy and might be of benefit to determine the sequential treatment strategy in patients with relapse after first combined androgen blockade.

[Port site recurrence after retroperitoneoscopic nephrectomy for renal cell carcinoma : a case report].

A 61-year-old woman was diagnosed with left renal cell carcinoma. Clinical stage was cT1bN0M0. She underwent retroperitoneoscopic radical nephrectomy. The pathological diagnosis was clear cell carcinoma, pT1b, G1＞G2, INFα, v(+). At 33 months postoperatively CT demonstrated an enhancing tumor just under the port site for evacuation route of the kidney. The tumor was removed by surgery. The pathological diagnosis was clear cell carcinoma. The patient had no recurrence or metastasis 21 months after the surgery.

Osteosarcoma of the bladder: a case report.

BACKGROUND: Osteosarcoma arising from the bladder is extremely rare, with only 38 cases reported to our knowledge. It is often detected owing to hematuria, and is treated by surgery (for example, total cystectomy), radiation therapy, and chemotherapy; however, the prognosis is extremely poor. CASE PRESENTATION: An 83-year-old Japanese man underwent cystoscopy for postoperative follow-up of urothelial carcinoma of the bladder, which revealed a 2-cm nodular tumor on the right wall. He had a history of abdominal aortic aneurysm and hypertension, and had been smoking 15 cigarettes per day for 45 years. Seven years previously, the patient underwent transurethral resection of bladder tumor for a 5-cm tumor on the right wall of the bladder. The histopathological diagnosis was urothelial carcinoma. No recurrence had been detected since then. Transurethral resection of bladder tumor was performed, and the histopathological diagnosis was cystosarcoma. Because of his advanced age, we decided that it would be difficult to perform total cystectomy. We therefore performed a second transurethral resection of bladder tumor and found no residual tumor. At 29 months after surgery, the patient remains alive without recurrence. CONCLUSION: Bladder osteosarcoma has a poor prognosis. However, our case was detected early, and treatment with transurethral resection of bladder tumor alone resulted in long-term survival without recurrence.

[Bilateral upper tract urothelial carcinoma eight years after total cystectomy and Indiana pouch urinary diversion for bladder cancer : a case report].

A 46-year-old man underwent total cystectomy and Indiana pouch urinary diversion for bladder cancer in 2001. Pathological examination revealed an urothelial carcinoma of the bladder (pT2N0M0). He was referred to our hospital for bilateral hydronephrosis in June 2009. Cytological examination of the urine was negative. Percutaneous nephrostomy was performed, and we suspected bilateral ureteral tumors from pyelo-ureterography. Percutaneous ureteroscopy revealed a papillary tumor in the right ureter. Since there appeared to be a papillary tumor in the left ureter, we decided to perform ureterectomy for bilateral ureteral tumors, and to keep the bilateral nephrostomy tube for urinary diversion. Pathological examination revealed urothelial carcinoma in bilateral ureters. There has been no sign of recurrence at 17 months after the operation.

Real-world Outcomes of Tyrosine Kinase Inhibitors Immediately After Immune Checkpoint Inhibitors in Renal Cell Carcinoma.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) have demonstrated a survival benefit for patients with cancer. However, the clinical outcomes of subsequent tyrosine kinase inhibitors (TKIs) after ICI failure in patients with metastatic renal cell carcinoma (mRCC) remain unclear. PATIENTS AND METHODS: We retrospectively examined 38 patients with mRCC who started TKIs immediately after nivolumab with (combination group) or without ipilimumab (nivolumab group) between September 2016 and July 2019. RESULTS: Of the 38 patients, 16 and 11 achieved partial response and stable disease, respectively, resulting in a 42.1% objective response rate and 71.1% disease control rate. The median progression-free survival (PFS) from TKI initiation was 8.8 and 12.9 months in the nivolumab and combination groups, respectively. PFS and overall survival were significantly longer in patients with long-term responses to previous ICI treatment (p=0.0152 and p=0.0155, respectively). CONCLUSION: TKIs demonstrate adequate anti-tumour activity after treatment with ICIs in real-world settings.