Naoya Niwa

Acquired platinum resistance involves epithelial to mesenchymal transition through ubiquitin ligase FBXO32 dysregulation

To identify the molecules involved in epithelial to mesenchymal transition (EMT) in urothelial carcinoma (UC) after acquisition of platinum resistance, here we examined the changes in global gene expression before and after platinum treatment. Four invasive UC cell lines, T24, 5637, and their corresponding sublines T24PR and 5637PR with acquired platinum resistance, were assessed by microarray, and the ubiquitin E3 ligase FBXO32 was newly identified as a negative regulator of EMT in UC tumors after acquisition of platinum resistance. In vitro and in vivo studies showed an intimate relationship between FBXO32 expression and EMT, demonstrating that FBXO32 dysregulation in T24PR cells results in elevated expression of the mesenchymal molecules SNAIL and vimentin and decreased expression of the epithelial molecule E-cadherin. The association between FBXO32 expression and EMT was further validated using clinical samples. Knockdown of MyoD expression, a specific target of FBXO32 polyubiquitination, revealed upregulation of E-cadherin expression and downregulation of SNAIL and vimentin expression in T24PR cells. Comparative genomic hybridization array analysis demonstrated loss of heterozygosity at 8q24.13 in T24PR cells, which harbors FBXO32. Our findings suggest the importance of the association between EMT and ubiquitin-proteasome regulation when tumors develop acquired platinum resistance.

Determining When to Stop Prostate Specific Antigen Monitoring after Radical Prostatectomy: the Role of Ultrasensitive Prostate Specific Antigen

Purpose: We analyzed long‐term followup data after radical prostatectomy to determine how long we should follow patients in whom the serum prostate specific antigen level measured by an ultrasensitive assay was consistently low. Materials and Methods: We retrospectively reviewed clinicopathological data for 582 consecutive patients who underwent open or laparoscopic radical prostatectomy between 1995 and 2004, excluding 4 patients who received adjuvant therapy. We stratified the patients according to prostate specific antigen at 3 and 5 years after surgery, and examined subsequent biochemical recurrence (elevation of prostate specific antigen to greater than 0.2 ng/ml) during followup. Mean followup was 9.7 years. Results: At 3 years after surgery prostate specific antigen levels were measured by an ultrasensitive assay in 323 patients who had not experienced biochemical recurrence. In 187 patients with undetectable prostate specific antigen levels (less than 0.01 ng/ml) the 10 and 15‐year biochemical recurrence‐free survival rates were 99% and 96%, respectively. At 5 years after surgery prostate specific antigen was measured in 315 patients by the ultrasensitive assay. In 162 patients with undetectable prostate specific antigen levels the 10 and 15‐year biochemical recurrence‐free survival rates were both 100%. In this group the prostate specific antigen level at last followup was less than 0.01 ng/ml in 132 patients, 0.01 to 0.03 ng/ml in 27 patients, and 0.06 ng/ml, 0.07 ng/ml and 0.11 ng/ml in 1 patient each. Conclusions: This long‐term review indicates that if patients have continuously undetectable prostate specific antigen levels by an ultrasensitive assay for 5 years, prostate specific antigen monitoring can be stopped with an extremely low risk of subsequent biochemical recurrence.

Comparison of outcomes between ultrasonography and cystoscopy in the surveillance of patients with initially diagnosed TaG1-2 bladder cancers: A matched-pair analysis

PURPOSE To examine the clinical outcomes of regular use of ultrasonography when compared with those of cystoscopy in the follow-up of patients with TaG1-2 bladder tumors. PATIENTS AND METHODS Between 1990 and 2012, 197 patients with TaG1-2 bladder tumors from a retrospective 2-institution cohort were included. We assessed clinical outcomes in 83 patients followed up by ultrasonography, matched for propensity score calculated from clinicopathological variables including age, gender, tumor multiplicity, size, grade, postoperative immediate chemoinstillation, and adjuvant intravesical treatment. RESULTS Among the 166 patients identified using the one-to-one propensity score analysis, the 5- and 10-year recurrence-free survival rates were both 63.3% in the cystoscopy group and 69.1% and 58.4%, respectively, in the ultrasonography group (P = 0.762). A total of 54 patients experienced disease recurrence, and 18 patients acquired progressive disease such as tumor grade 3, pT1 tumors, and the appearance of concurrent carcinoma in situ. There were no significant differences in the characteristics of recurrent tumors between both the groups, whereas time to first recurrence in the cystoscopy group was significantly shorter than that in the ultrasonography group (P = 0.021). In a subgroup analysis using 111 patients without adjuvant intravesical treatments, the 5- and 10-year recurrence-free survival rates were both 56.9% in the cystoscopy group and 71.9% and 60.3%, respectively, in the ultrasonography group (P = 0.282). CONCLUSIONS This retrospective study suggests that ultrasonography may be one of the follow-up substitutes when considering the management of low-risk bladder tumors such as TaG1-2 bladder tumors.

Acute aortic dissection in a patient with metastatic renal cell carcinoma treated with axitinib

axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptor (VEgFr) 1, 2, and 3, and has been approved for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy. Compared with first-generation tyrosine kinase inhibitors (TKis), such as sorafenib, axitinib is a more specific VEgFr inhibitor. The toxicity profile of axitinib is tolerable. Common adverse events of axitinib include diarrhea, hypertension, and fatigue, and they have also been reported after using other TKis. Other adverse events, such as palmar-plantar erythrodysesthesia, cutaneous toxicity, and myelosuppression, are less commonly reported after using axitinib than after using other TKis [1]. a 51-year-old man with a renal tumor, but without any other comorbidities including hypertension, underwent left radical nephrectomy. Pathological examination revealed the tumor as a pT3aN0M0 clear cell renal cell carcinoma. six months after surgery, multiple lung metastases were detected via thoracic computed tomography (CT), after which sunitinib was administered as a four-weeks-on and two-weeks-off schedule. sunitinib was discontinued owing to grade 3 palmar-plantar erythrodysesthesia after two cycles of treatment, and the patient was switched to axitinib. Ten days after receiving axitinib, he presented to the urology outpatient department with sudden midsternal pain. He looked well, and his blood pressure was 127/66 mmHg. an electrocardiogram showed sT-segment elevation in all leads. Contrast-enhanced thoracoabdominal CT revealed acute aortic dissection (stanford type a) from the ascending aorta to the left external iliac artery (Figure 1). The patient underwent emergency reconstruction of the ascending aorta. acute aortic dissection is a life-threatening entity. The most common predisposing factor is hypertension, followed by atherosclerosis, history of cardiac surgery, Marfan syndrome, and iatrogenic causes [2]. Hypertension is a frequent adverse event with axitinib and other small-molecule TKis. Other cardiovascular toxicities including heart failure, left ventricular systolic dysfunction, and QT prolongation have also been reported. The mechanism of TKiassociated cardiotoxicity remains poorly understood. Possible mechanisms include the loss of vascular stability because of endothelial cell damage or decreased production of nitric oxide through inhibition of VEgF pathways [3]. To our knowledge, this is the first case of acute aortic dissection in a patient treated with axitinib. Only two cases of aortic dissection during treatment with small-molecule multitargeted TKis (1 with sorafenib [4] and 1 with sunitinib [5]) were

Purified Protein Derivative Skin test prior to bacillus Calmette-Guérin Therapy May have Therapeutic Impact in Patients with Nonmuscle Invasive Bladder Cancer

Purpose: We investigated the clinical impact of the purified protein derivative skin test prior to bacillus Calmette‐Guérin therapy in patients with nonmuscle invasive bladder cancer treated with adjuvant bacillus Calmette‐Guérin therapy. Materials and Methods: A total of 498 patients with nonmuscle invasive bladder cancer treated with adjuvant bacillus Calmette‐Guérin were included in study, of whom 320 underwent the purified protein derivative skin test 1 to 2 weeks prior to therapy. Oncologic outcomes and the rate of bacillus Calmette‐Guérin related side effects were statistically evaluated. Results: The mean ± SD 5‐year recurrence‐free survival rate in patients who did vs did not undergo the purified protein derivative skin test was 66.6% ± 2.8% and 59.1% ± 4.1%, respectively, which was significantly different (p = 0.048). No significant difference was observed in the progression‐free survival rate between patients who did vs did not undergo the test. Multivariate Cox regression analysis revealed that a history of recurrence (HR 1.59, p = 0.02), multiple tumors (HR 1.95, p <0.01), the bacillus Calmette‐Guérin Connaught strain (HR 0.71, p = 0.04), 7 or more bacillus Calmette‐Guérin instillations (HR 0.70, p = 0.04) and undergoing the purified protein derivative skin test (HR 0.72, p = 0.04) were independently associated with tumor recurrence. Major bacillus Calmette‐Guérin related side effects were noted in 77 of the 320 patients (24.1%) who did vs 27 of the 178 (15.2%) who did not undergo the test, which was significantly different (p = 0.02). Conclusions: The purified protein derivative skin test prior to bacillus Calmette‐Guérin treatment enhances the therapeutic effects of this treatment and potentially results in a higher incidence of major bacillus Calmette‐Guérin related side effects. Combination therapy with bacillus Calmette‐Guérin using the purified protein derivative skin test may improve the oncologic outcomes of that therapy.

Purified protein derivative skin test reactions are associated with clinical outcomes of patients with nonmuscle invasive bladder cancer treated with induction bacillus Calmette-Guérin therapy

OBJECTIVES To investigate the relationship between purified protein derivative (PPD) skin test reactions before bacillus Calmette-Guérin (BCG) therapy and the clinical outcomes of BCG-naïve nonmuscle invasive bladder cancer patients treated with adjuvant BCG therapy. MATERIALS AND METHODS A total of 288 nonmuscle invasive bladder cancer patients subjected to the PPD skin test before BCG therapy were included. PPD skin test reactions were categorized into 3 groups: positive, slightly positive, and negative. The presence of an induration was positive. If an induration was absent, erythema of 10mm or more and less than 10mm corresponded to slightly positive and negative, respectively. RESULTS A total of 66 (22.9%), 149 (51.7%), and 73 (25.3%) patients exhibited a positive, slightly positive, and negative to PPD skin test, respectively. The 5-year recurrence-free survival rate of patients with positive PPD skin test reactions was 89.4 ± 4.1%, which was significantly higher than those of patients with slightly positive (65.5 ± 4.2%, P = 0.001) and negative reactions (56.4 ± 6.6%, P<0.001). A multivariate Cox regression analysis revealed that a positive PPD skin test reaction was independently associated with tumor recurrence (hazard ratio of 0.233, P<0.001), but not with stage progression. The incidence of fever persisting for more than 2 days or fever of ≥38°C was significantly higher in patients with a positive PPD skin test reaction (18.2%) than in patients with slightly positive (8.7%) and negative PPD skin test reactions (4.1%). CONCLUSIONS The PPD skin test reactions before BCG therapy may predict clinical outcomes following BCG therapy and help clinicians counsel patients exhibiting strong therapeutic effects with BCG therapy and potentially major BCG-related side effects.

Mucosa-associated lymphoid tissue lymphoma arising from the kidney

Primary renal lymphoma is rare, and most are intermediate- and high-grade lymphomas of B-cell lineage, such as diffuse large B-cell or Burkitt lymphoma. We report a case of low-grade B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) arising from the kidney. Only a few cases of primary renal MALT lymphoma have been published.

Ductal adenocarcinoma of the prostate forming a mass in the retrovesical space

Ductal adenocarcinoma of the prostate is a rare histologic variant of prostate cancer that often presents with normal prostate-specific antigen levels and is inherently aggressive enough to spread beyond the prostate gland. Here, we describe a case of prostatic ductal adenocarcinoma that formed a mass in the retrovesical space and presented with a high prostate-specific antigen level.

Establishment of the optimal follow-up schedule after radical prostatectomy

PURPOSE Monitoring the serum level of prostate specific antigen (PSA) is indispensable for surveillance after radical therapy, and the aim of this study was to establish the optimal follow-up schedule. MATERIALS AND METHODS We retrospectively reviewed the clinicopathological data of 1,010 consecutive patients who underwent radical prostatectomy. After excluding patients who received neoadjuvant or adjuvant therapy and those without a nadir PSA level<0.2ng/ml, the remaining 779 patients were enrolled. Biochemical recurrence (BCR) was defined as elevation of PSA to >0.2ng/ml. We investigated the PSA doubling time (PSA-DT) following BCR at various times after surgery. RESULTS During a mean follow-up of 8.8 years, BCR occurred in 180/779 patients. The annual BCR rate was 6% in the first year after surgery, 6% between 1 and 2 years, 3% between 2 and 3 years, 3% between 3 and 5 years, and 2% at >5 years postoperatively. During these periods, the minimum PSA-DT after BCR was 1.6, 2.4, 3.1, 6.1, and 6.4 months, respectively. These minimum PSA-DTs were used to determine the optimal follow-up interval during each period after surgery. If the baseline level is 0.1ng/ml, PSA should be measured at approximately 3-month intervals for the first year, at 4-month intervals between 1 and 2 years, at 6-month intervals between 2 and 3 years, and annually thereafter to definitely detect BCR before the serum PSA level exceeds 0.4ng/ml. CONCLUSION The PSA-DT following BCR varies according to the time after surgery. Our data on minimum PSA-DT values after BCR are useful for setting the optimal follow-up schedule.

Does switching the bacillus Calmette-Guérin strain affect clinical outcome in patients with recurrent non-muscle-invasive bladder cancer after initial bacillus Calmette-Guérin therapy?

PURPOSE It is still unknown whether switching the bacillus Calmette-Guérin (BCG) strain at the second induction course of BCG therapy has a therapeutic benefit in patients with tumor recurrence after the initial BCG therapy (BCG-relapsing tumor). MATERIALS AND METHODS We retrospectively reviewed the clinicopathological features of 97 patients treated with a second induction course of BCG therapy between 1986 and 2014. Among the patients initially treated with BCG Tokyo-172, the second course was either BCG Tokyo-172 in 56 (57.8%) or BCG Connaught in 15 (15.5%). Among those who were initially treated with BCG Connaught, the corresponding numbers were 13 (13.4%) or 13 (13.4%), respectively. Twenty-eight (28.9%) patients were given a different BCG strain at the 2 BCG therapies (switching group), and 69 (71.1%) patients were given the same BCG strain (non-switching group). RESULT The 5-year recurrence-free survival rate of the switching group was 64.7 ± 9.6%, which was not significantly different from that of the non-switching group (54.8 ± 6.9%, P = 0.427). Switching or not switching the BCG strain was not significantly associated with tumor recurrence after the second BCG therapy. The 5-year progression-free survival rate of the switching group was 95.4 ± 2.6%, which was also not significantly different from that of the non-switching group (96.0 ± 3.9%, P = 0.674). Patients treated with BCG Tokyo-172 to Tokyo-172 had significantly higher incidences of side effects during the second BCG therapy. CONCLUSIONS The results of this study indicate that in patients with a BCG-relapsing tumor after the initial BCG therapy, the same BCG strain as that administered at the initial BCG therapy could be utilized effectively for the second BCG therapy. Patients treated with BCG Tokyo-172 for an initial tumor had a higher incidence of side effects during the second BCG therapy using the same strain.