[A Case of Reactive Arthritis after BCG Intravesical Infusion Therapy Successfully Treated with Salazosulfapyridine].

The patient was a 70-year-old woman who underwent transurethral resection of bladder tumor in May 2020. She was diagnosed with urothelial carcinoma (high grade, pT1 by pathology). We started bacillus Calmette-Guerin (BCG) intravesical infusion (80 mg Tokyo strain) in August of the same year after a second transurethral resection. Pain during urination persisted during the administration of BCG, and it worsened after the completion of six doses. The patient was hospitalized with back and neck pain and difficulty in physical movement. At the time of admission, bilateral conjunctivitis was observed. The patient was diagnosed with reactive arthritis associated with BCG intravesical injection therapy, as three typical symptoms were observed (bilateral conjunctivitis, urethritis, polyarthritis). The patient was treated with prednisolone and non-steroidal anti-inflammatory drugs for arthritis, but the symptoms did not improve. We administered salazosulfapyridine and her reactive arthritis improved.

[False-Positive ¹²³I-Metaiodobenzylguanidine Scan in a Patient with Adrenocortical Cancer].

A 59-year-old woman presented with a left adrenal tumor 4 cm in diameter. The ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy showed apparent accumulation in the left adrenal tumor. However, the patient had no sign or symptoms suggesting pheochromocytoma. No biochemical evidence of catecholamine excess was noticed. Computed tomography (CT) revealed relatively strong enhancement in the arterial phase, which persisted until the portal phase. The computed tomography (CT) and magnetic resonance imaging showed 2 liver nodule suspected to be metastatic tumors. No ¹²³I-MIBG accumulation was seen in these nodules. CT also showed thyroid nodules with calcification, which suggested papillary thyroid cancer. Based on the findings, open left adrenalectomy, partial hepatectomy and segmentectomy were performed under the clinical diagnosis of pheochromocytoma and metastatic liver tumors. Histopathological diagnosis was adrenocortical cancer. There was only lymphocyte infiltration in the liver nodules. Postoperative recovery was uneventful, and the patient underwent partial thyroidectomy 6 months later. The pathological diagnosis was papillary thyroid cancer. She has been without recurrence or metastases for 18 months after adrenalectomy. We found only 6 cases of MIBG scintigraphy-positive adrenocortical cancer in the literature. The mechanisms for MIBG uptake in adrenocortical cancer are discussed with a review of the literature.

Systemic transduction of p16INK4a antitumor peptide inhibits lung metastasis of the MBT-2 bladder tumor cell line in mice.

p16INK4a (p16) is a key molecule in bladder tumor (BT) development. We previously reported that a p16 antitumor peptide inhibited the growth of subcutaneous BT grafts in mice through restoration of p16 function using a Wr-T peptide transporter system. In the present study, the efficacy of mouse p16 peptide administration in a mouse lung metastasis model for BT and also the toxicity of peptides by cardiac peptide injection were evaluated. Mouse lung metastases were developed by tail vein injection of a p16-deficient MBT-2 cell line. Six-week-old C3H/He female mice were divided into three groups: A control group (n=12) receiving no treatment; a group treated once on the 3rd experimental day (n=12); and a group treated three times on the 3rd, 5th and 7th experimental days (n=10) with an injection of a mixture of 80 nmol mouse p16 peptide and 50 nmol Wr-T into the tail vein. At the 14th experimental day, the lung metastases were histologically evaluated. Lung metastases were observed in 100% (12/12), 41.7% (5/12) and 30% (3/10) of the aforementioned three groups, respectively. The number and area of metastatic lung tumors were significantly different between control and treatment groups (control vs. triple treatment group for the number and area, P=0.0029 and P=0.0296, respectively). Immunohistochemistry demonstrated that phosphorylated retinoblastoma (Rb) protein was decreased in lung tumors of the treatment groups, compared with the control group. The toxicity of p16 peptide transduction was evaluated by using low-dose treatment (three dosages) and high-dose treatment (two dosages) on three male and three female C3H/He mice in early and late experimental phases. In low and high dose groups, no notable change was determined in body weight or blood analyses in early or late phases following mouse p16 peptide administration. In addition, no notable change was observed histologically in bone marrow of treatment groups. To conclude, systemic p16 peptide administration decreased lung tumor development in a mouse metastatic BT model without severe adverse events, as assessed by blood analyses and histological evaluation.

[A Case of Upper Urinary Tract MALT Lymphoma with Remarkable Thickness of Renal Pelvis and Ureter Wall].

A 78-year-old man was referred to Tsukuba University Hospital for right hydronephrosis. He had undergone ureteroscopy and ureteral stenting in another hospital, but no tumor was revealed in renal pelvis and ureter. The urinary cytology was negative. Computed tomography (CT) revealed remarkable thickening of right renal pelvis and ureter wall. CT also showed para-aortic, iliac, supraclavicular and mediastinal lymph node (LN) swelling. 18F-fluoro-2-deoxy-D-glucose positron emission tomography (PET) revealed high uptake at thickened right renal pelvis and ureter wall and enlarged LNs. The soluble interleukin-2 receptor was elevated to 1,110 U/ml (normal range: 613 U/ml). Those findings suggested that the malignant lymphoma originated from the renal pelvis and ureter rather than urothelial cancer. Therefore we performed open biopsy of iliac LN and periureteral tissue. The pathological diagnosis was mucosa associated lymphoid tissue (MALT) lymphoma. The patient was trasferred to the department of hematology, and treated with rituximab and bendamustine. After 6 courses of chemotherapy, swelling of renal pelvis, ureter and LN was markedly reduced. The ureteral sent could be removed. MALT lymphoma of the upper urinary tract is extremely rare and pretreatment diagnosis is difficult. In 8 of 11 reported cases, the diagnosis was made by nephroureterectomy. In our cases, open biopsy could avoid nephroureterectomy.

[Metachronous Development of Mantle Cell Lymphoma during Active Surveillance in a Patient with Stage I Testicular Cancer].

A 78-year-old man presented with swelling of para-aortic and left iliac lymph nodes (LNs). He had undergone left high orchiectomy 10 years ago. He was diagnosed with stage I seminoma, and was managed with active surveillance. Eight years later, the follow-up computed tomography (CT) revealed para-aortic LN swelling, but the patient refused further treatment. He complained of left lower extremity edema 10 years after orchiectomy. CT showed enlargement of both LNs, especially, diameter of left iliac lymph nodes was up to 9 cm. He was referred to our hospital. LDH was slightly increased to 261 IU/1, but α-fetoprotein, and total and free beta human chorionic gonadotropin were within normal limits. Results of pathological review of the testicular tumor was also seminoma. The treatment with etoposide and cisplatin (EP) was started under the diagnosis of late relapse of seminoma. However, CT after 1 course of EP showed no shrinkage of LN metastases. At this time, soluble interleukin-2 receptor (sIL-2R) was elevated up to 5,090 U/ml (normal range: 613 U/ml). Needle biopsy from pelvic LN was performed on suspicion of metachronous malignant lymphoma. The pathological diagnosis was mantle cell lymphoma. The patient was transferred to the department of hematology, and treated successfully with rituximab and bendamustine. When LN swelling is seen after long-term active surveillance, there is a possibility of late relapse. However, metachronous malignant lymphoma also should be considered in an elderly patient.

Possible risk of overestimation of renal function using cystatin C-based eGFR in testicular cancer survivors treated with cisplatin-based chemotherapy.

BACKGROUND: Chronic kidney disease (CKD) is a major long-term morbidity of testicular cancer (TC) survivors cured by cisplatin-based chemotherapy. We conducted the present study to elucidate the usefulness of cystatin-based estimated glomerular filtration rates (eGFRcys) for diagnosis of CKD compared to creatinine-based eGFR (eGFRcreat) in those patients. METHODS: eGFRcys and eGFRcreat were measured in 53 TC survivors. The 24-h creatinine clearance (CrCl) was measured in 12 TC survivors and 17 CKD patients with medical disease; all of them had eGFRcreat <60 m/min/1.73 m2. Also, urinary beta2-microglobulin and albumin concentrations in spot urine specimens were measured. RESULTS: The mean eGFRcreat was significantly lower than eGFRcys, at 67.9 and 95.2 ml/min/1.73 m2, respectively (p < 0.05). The prevalence of stage 3-5 CKD differed by GFR estimation methods. It was 47.2% with eGFRcreat and only 7.5% with eGFRcys. There were 21 patients with eGFRcreat <60 ml/min/1.73 m2 and eGFRcys ≥60 ml/min/1.73 m2. In all 12 TC survivors, the eGFRcys values were higher than both eGFRcreat and GFR (24-h CrCl). In contrast, no difference was observed among eGFR values in the 17 patients with CKD due to medical disease. Ten of 21 patients with eGFRcreat <60 ml/min/1.73 m2 and eGFRcys ≥60 ml/min/1.73 m2 showed significant beta2-microglobulinuria: a higher prevalence than that in patients with both eGFRs ≥60 ml/min/1.73 m2. Also, the incidence of microalbuminuria tended to be high in those patients. CONCLUSIONS: The present study suggests that eGFRcys may overestimate renal function in TC survivors cured by cisplatin-based chemotherapy.

[A Case of Primary Schwannoma of the Urinary Bladder].

A 68-year-old woman presented with a bladder tumor. She was asymptomatic, and the tumor was incidentally detected with radiological imaging performed during treatment of cervical cancer. Magnetic resonance imaging and computed tomography revealed a solitary submucosal tumor located in the anterior wall of the urinary bladder, with homogeneous contrast enhancement. Cystoscopy showed a submucosal tumor covered by normal mucosa. A paraganglioma was considered in the differential diagnosis, but symptoms suggesting hypercatecholaminemia were not apparent. Moreover, she did not have a family history or symptoms associated with neurofibromatosis-1 (NF-1). She underwent partial cystectomy with a preliminary diagnosis of submucosal bladder tumor. Histopathological diagnosis confirmed a schwannoma arising from the bladder wall. She was followed up without intravesical recurrence or metastases for 6 months. In the literature, only 12 cases of bladder schwannoma have been reported. There was no reported family history or symptoms associated with NF-1 in any of the cases. Although the number of cases is limited, literature review showed a favorable prognosis for bladder schwannoma with local tumor resection in patients without NF-1.

[A Clinicopathologic Study of 6 Patients with Histologically Pure Seminoma But Elevated Serum Alpha-Fetoprotein].

Histologically pure seminoma with elevated alpha-fetoprotein (AFP), so-called AFP-positive seminoma, is rare. It is recommended that patients with AFP-positive seminoma be managed as non-seminoma, but the clinical features and prognosis of this disease are not fully understood. In this study, we retrospectively analyzed 6 cases of metastatic AFP-positive seminoma at Tsukuba University Hospital (TUH). AFP was elevated before induction chemotherapy in 4 patients with an average of 1,372 ng/ml. In the remaining 2 patients, AFP became elevated during or after induction chemotherapy. In all 4 patients examined, AFPL3% was abnormally increased. As induction chemotherapy, all patients received bleomycin, etoposide and cisplatin (BEP), which was then followed by etoposide, ifosfamide and cisplatin (VIP) in 3 patients. After or during induction chemotherapy, 3 patients suffered from disease progression accompanied by AFP elevation. All 3 were treated by salvage chemotherapy and surgery. Four patients underwent retroperitoneal lymph node dissection (RPLND) after induction chemotherapy ; the pathological findings were necrosis in 3 patients, and viable nonseminomatous cancer in 1 patient. Furthermore, RPLND was performed as salvage surgery in 3 patients ; the pathological findings were necrosis, viable nonseminomatous cancer and teratoma with malignant transformation, respectively. The 5-year progression-free survival rate of the 6 patients was 50%, which is somewhat inferior to that of poor-prognosis non-seminoma patients treated at TUH. One patient ultimately died of cancer, and the remaining 5 are in remission with a median follow-up of 58 months. The present study demonstrates that AFP-positive seminoma patients have a higher risk of relapse compared to non-seminoma patients.

Impact of acute kidney injury defined by CTCAE v4.0 during first course of cisplatin-based chemotherapy on treatment outcomes in advanced urothelial cancer patients.

BACKGROUND: The Kidney Disease: Improving Global Outcomes group (KDIGO) defined acute kidney injury (AKI) as an elevation of serum creatinine (sCR) exceeding 0.3 mg/dl within 48 h. The widely used adverse events criteria for chemotherapy, Common Toxicity Criteria for Adverse Events Version 4.0 (CTCAE v4.0), also defined AKI as sCR exceeding 0.3 mg/dl, but with no provision of a time course. Here, we attempted to clarify the impact of AKI (CTCAE v4.0) during cisplatin-based chemotherapy on clinical outcome of patients with advanced urothelial cancer (UC). METHODS: This multicenter retrospective study included 230 UC patients who received cisplatin-based chemotherapy. RESULTS: During the first chemotherapy course, AKI (CTCAE v4.0) episodes were observed in 61 patients (26.5 %), whereas only four patients (1.5 %) experienced AKI (KDIGO) episodes. Both the pretreatment estimated glomerular filtration rate (eGFR) and creatinine clearance by Cockcroft-Gault formula were not efficient predictors for the development of AKI (CTCAE v4.0). AKI (CTCAE v4.0) impacted renal function: at the start of second-course chemotherapy, the average eGFR of the patients with AKI (CTCAE v4.0) was 54.1 ml/min/1.73 m2, significantly lower than that of patients without AKI (CTCAE v4.0) (63.4 ml/min/1.73 m2). As a result, only 57.4 % of patients with AKI (CTCAE v4.0) received the planned treatment at the second course. The survival of the patients who developed AKI (CTCAE v4.0) was significantly worse than that of the patients who did not. The 3-year OSs were 10.3 and 21.4 %, respectively (P = 0.02). CONCLUSION: The present study demonstrated that AKI (CTCAE v4.0) during chemotherapy had a negative impact on both the intensity of subsequent chemotherapy and oncological outcomes.

Long-term single-institute experience with trimodal bladder-preserving therapy with proton beam therapy for muscle-invasive bladder cancer.

OBJECTIVE: We retrospectively elucidated the oncological outcomes, prognostic factors and toxicities of proton beam therapy in trimodal bladder-preserving therapy for muscle-invasive bladder cancer at our institution. METHODS: From 1990 to 2015, 70 patients with cT2-3N0M0 muscle-invasive bladder cancer underwent trimodal bladder-preserving therapy consisting of maximal transurethral resection of the bladder tumor, small pelvis photon irradiation, intra-arterial chemotherapy and proton beam therapy. The overall survival rate, progression-free survival rate, time to progression, predictive factors for progression and toxicities were analyzed. Progression was defined as when muscle-invasive recurrence, distant metastasis or upper urinary tract recurrence was observed. RESULTS: The patients' median age was 65 (range 36-85) years. The median follow-up period was 3.4 (range 0.6-19.5) years. The 5-year cumulative overall survival rate, progression-free survival rate and time to progression rate were 82%, 77%, and 82%, respectively. In univariate and multivariate analyses, tumor multiplicity and tumor size (≥5 cm) were significant and independent factors associated with progression (hazard ratio 3.5, 95% confidence interval 1.1-12; hazard ratio 5.0, 95% confidence interval 1.3-17; P < 0.05 for all). As for toxicity, 26 (18%) patients had grade 3-4 acute hematologic toxicities and 2 (3%) patients had grade 3 late genitourinary toxicity. No patient had to discontinue the treatment due to acute toxicity. CONCLUSIONS: Our bladder-preserving therapy with proton beam therapy was well tolerated and achieved a favorable mortality rate. Tumor multiplicity and tumor size were important risk factors for progression. Our findings indicate that this therapy can be an effective treatment option for selected muscle-invasive bladder cancer patients.

Current status of systemic chemotherapy for octogenarians with advanced urothelial cancer in Japan: a Japanese multi-institutional study (CURE study).

BACKGROUND: The standard regimen of systemic chemotherapy for patients with advanced urothelial cancer (UC) changed from methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) to gemcitabine and cisplatin (GC) in 2008 when the use of gemcitabine for UC began to be reimbursed by public health insurance in Japan. We examined its influence on the chemotherapy trend in elderly patients aged ≥80 years. METHODS: Among 345 patients included in our previous multicenter retrospective cohort study (chemotherapy for urothelial carcinoma: renal function and efficacy study; CURE study), the outcome of 30 patients aged ≥80 years was reviewed before and after 2008 and compared with 315 young patients. RESULTS: There were only 7 (4.6 %) elderly individuals among all registered patients before 2008, whereas the number increased to 23 (12 %) after 2008. Before 2008, only one elderly patient received MVAC, while GC (whose rate was similar to the rate in young patients) was administered to 13 patients (56.5 %) after 2008. The chemotherapeutic effect and overall survival (OS) rate was not significantly different between young and elderly patients. In the elderly treated with the GC regimen, the renal impairment rate after the first cycle was significantly higher, and the presence of distant metastases and renal impairment were independent prognostic factors in a multivariate analysis. CONCLUSION: Since GC was approved as the standard regimen for first-line chemotherapy in UC, selected elderly patients have been able to safely receive systemic chemotherapy like young patients. The clinical response rate and OS rate were similar to the young, but we need to monitor changes in renal function more closely in the elderly treated with GC.