Differential impact of proton pump inhibitor on survival outcomes of patients with advanced urothelial carcinoma treated with chemotherapy versus pembrolizumab.

OBJECTIVES: We clarified the effect of concomitant proton pump inhibitor use on oncological outcomes in patients with advanced urothelial carcinoma treated either with chemotherapy or immune checkpoint inhibitor. METHODS: We retrospectively reviewed patients with advanced urothelial carcinoma who received paclitaxel-gemcitabine therapy or pembrolizumab after platinum-based chemotherapy. The patients were divided into four groups based on the treatment regimen and the concomitant use of proton pump inhibitor. We compared survival outcomes between the groups and determined which factors predicted overall survival. RESULTS: Among the 60 and 75 patients treated with paclitaxel-gemcitabine and pembrolizumab, 15 and 29 used a concomitant proton pump inhibitor. Progression-free and overall survival was significantly shorter in patients who were administered pembrolizumab with concomitant proton pump inhibitor compared to those without. The use of a concomitant proton pump inhibitor had no effect on survival outcomes in patients who received paclitaxel-gemcitabine therapy. Furthermore, progression-free and overall survival were significantly shorter in patients treated with paclitaxel-gemcitabine therapy compared to those treated with pembrolizumab among patients without concomitant proton pump inhibitor. In contrast, there was no difference in survival outcomes between the two regimens among patients with concomitant proton pump inhibitor. Concomitant proton pump inhibitor use was associated with poor overall survival only in patients treated with pembrolizumab. CONCLUSION: The use of a concomitant proton pump inhibitor use had no impact on oncological outcomes in patients with advanced urothelial carcinoma treated with paclitaxel-gemcitabine therapy, different from those treated with pembrolizumab.

Association Between Body Mass Index and Outcomes in Patients With Urothelial Carcinoma Treated With Pembrolizumab.

BACKGROUND/AIM: We aimed to clarify the association between body mass index (BMI) and clinical outcomes of pembrolizumab treatment for advanced urothelial cancer (UC). PATIENTS AND METHODS: We retrospectively reviewed the records of patients with advanced UC who received pembrolizumab after chemotherapy between March 2018 and December 2021. Patients were divided according to BMI into the non-overweight group (BMI <25 kg/m2) and the overweight group (BMI ≥25 kg/m2). We compared the two groups' tumour response, survival rates, and incidence of immune-related adverse events (irAEs) and investigated the factors predicting survival. RESULTS: Of 84 eligible patients, 63 (75%) and 21 (25%) were in the non-overweight and overweight groups, respectively. Although the objective response rate was higher in the overweight group (55%) than that in the non-overweight group (29%), the difference was not significant. Progression-free survival (PFS) was significantly longer in the overweight group (median 15.2 months) than that in the non-overweight group (median 4.8 months; p=0.01). Overall survival was also longer in the overweight group (median 36.1 months) compared to that in the non-overweight group (13.4 months), but the difference was not significant (p=0.11). Multivariable analysis showed that overweight was significantly associated with favourable PFS. Any and severe (grade 3) irAEs were observed in 15 (24%) and 5 (7.9%) patients in the non-overweight group, respectively, and in 8 (38%) and 2 (9.5%) patients in the overweight group, respectively, but the differences were not significant. CONCLUSION: BMI was associated with oncological outcomes in patients with advanced UC who received pembrolizumab but not with the development of irAEs.

Combination therapy with paclitaxel and gemcitabine after platinum-based chemotherapy in patients with advanced urothelial cancer.

OBJECTIVES: To evaluate the efficacy and tolerability of paclitaxel and gemcitabine therapy after platinum-based chemotherapy for patients with advanced urothelial carcinoma. METHODS: Consecutive patients with advanced urothelial carcinoma who received paclitaxel and gemcitabine therapy from December 2003 to March 2018 were retrospectively reviewed. The objective response for paclitaxel and gemcitabine therapy, progression-free survival and overall survival, and adverse events were evaluated. The reduction rate among each metastatic site and the associations between the clinical parameters and overall survival or progression-free survival were also assessed. RESULTS: We enrolled 58 patients. Complete and partial responses were observed in two (3.4%) and 15 patients (26%), respectively. The median progression-free survival and overall survival were 4.3 months (95% confidence interval 2.9-5.2) and 11.5 months (95% confidence interval 7.7-14.8), respectively. The objective response rates of primary site and metastases in lymph nodes, lung, bone, and liver were 6.0%, 37%, 23%, 0%, and 22%, respectively. Poor performance status (≥1), prior use of gemcitabine and the number of metastatic sites (≥2) were significantly associated with poor overall survival. Although three patients discontinued the treatment because of adverse events, there was no therapy-related death. CONCLUSIONS: Paclitaxel and gemcitabine therapy seems to be a valid option as a subsequent treatment after platinum-based chemotherapy for urothelial carcinoma, especially in patients with favorable performance status and no prior use of gemcitabine.

Involvement of estrogen in the pathogenesis of cyclophosphamide-induced cystitis in rats.

We examined the effects of ovariectomy and castration on the histology of cyclophosphamide (CP)-induced cystitis in rats. The animals were injected with CP (100 mg/kg) or saline intraperitoneally twice with an intervening 4 d and were euthanized at 1 or 2 wk after the initial CP administration. Saline treatment did not cause an apparent histological change in the bladder regardless of surgery, i.e., ovariectomy, castration, and sham-operation. CP treatment resulted in submucosal edema, urothelial damage, hemorrhage, and leukocyte infiltration in the bladder at 1 wk after the initial CP administration regardless of surgery. However, these histological changes were more severe in ovariectomized rats than in the sham-operated rats. In contrast, there were no significant differences in CP-induced histological changes in the bladder between castrated and sham-operated groups. We further examined the role of estrogen and progesterone on the CP-induced histology in the bladder by the replacement with estrogen only or estrogen plus progesterone for 2 wk in overiectomized rats. Estrogen treatment ameliorated CP-induced histological changes compared to oil treatment, whereas estrogen plus progesterone treatment did not produce any differences in the histology of the bladder compared to estrogen treatment. These results suggest that estrogen may play a role in the pathogenesis of bladder inflammation.

Upregulation of corticotropin-releasing hormone gene expression in the paraventricular nucleus of cyclophosphamide-induced cystitis in male rats.

We examined the effects of cyclophosphamide (CP)-induced cystitis on the expression of corticotropin-releasing hormone (CRH) mRNA in the paraventricular nucleus (PVN) and the serum levels of adrenocorticotropic hormone (ACTH) using in situ hybridization histochemistry and radioimmunoassay. In addition, the expression of AVP heteronuclear (hn) RNA and neuronal nitric oxide synthase (nNOS) mRNA was also examined in the PVN of a CP-induced cystitis model. We found that the levels of CRH mRNA were significantly increased in the PVN at 2 h after intraperitoneal administration of CP compared to those in saline-treated rats. The CRH mRNA levels in the PVN peaked at 12 h after CP administration and the levels were still significantly higher than those in saline-treated group at 24 h after CP administration. The serum ACTH levels in CP-treated group were also significantly higher compared to those in saline-treated group at any of the time points examined. Unlike previous findings showing upregulation of nNOS mRNA and AVP hnRNA under somatic nociceptive states, the levels of nNOS mRNA and AVP hnRNA were unchanged in the PVN following CP-induced cystitis, visceral nociceptive stimulation. These results suggest that visceral nociceptive stimulation as well as somatic nociceptive stimulation may activate the hypothalamo-pituitary axis but the hypothalamic neuroendocrine responses produced by visceral nociceptive stimulation may be different from those produced by somatic nociceptive stimulation.

Multiple biopsies of normal-looking urothelium in patients with superficial bladder cancer: Are they necessary?

BACKGROUND: The objective of the study presented here was to assess the usefulness and indications of multiple biopsies of normal-appearing urothelium in patients with superficial bladder cancer. METHODS: Between December 1996 and December 2002, multiple biopsies of normal-appearing bladder mucosa were performed in 100 patients with superficial bladder transitional cell carcinoma. Biopsy specimens were taken from seven different sites in females and nine different sites in males. RESULTS: In eight of 100 patients, bladder cancers were detected in the biopsy specimens. Three cases were Ta and five were Tis. All of the five patients with carcinoma in situ (CIS) in their biopsy specimens had multiple papillary broad-base tumors and positive urinary cytology. The detection ratio of CIS in patients with these findings was 17.9% (5/28). No concomitant CIS was detected in the 72 patients who had a solitary tumor, pedunculated tumor(s), or negative urinary cytology. CONCLUSION: Multiple mucosal biopsies of normal-appearing urothelium are not necessary for all patients with superficial bladder cancer. They are, however, necessary for patients with multiple papillary broad-base tumors and positive urinary cytology.