Prevention and management of diarrhea associated with naldemedine among patients receiving opioids: a retrospective cohort study.

BACKGROUND: Naldemedine, a novel peripherally-acting mu-opioid receptor antagonist, has improved opioid-induced constipation in randomized controlled trials. The most frequent adverse event of naldemedine is diarrhea, which can cause abdominal pain and often leads to treatment discontinuation. We aimed to identify risk factors and appropriate management strategies for key adverse events including diarrhea associated with naldemedine, since those have not been extensively studied. METHODS: We conducted a multi-center retrospective cohort study. Eligible patients had cancer, had undergone palliative care at participating centers, had been prescribed regular opioids, and had taken at least one dose of naldemedine between June 2017 and March 2018. The primary endpoint was the incidence of diarrhea according to baseline characteristics. Secondary endpoints included the duration of naldemedine administration, daily defecation counts before and after starting naldemedine, duration and severity of diarrhea as an adverse event of naldemedine, other adverse events, and the incidence of constipation within 7 days after recovery from diarrhea. We defined patients who started naldemedine within three days of starting a regularly prescribed opioid as the early group, and the remainder as the late group. RESULTS: Among 103 patients who received naldemedine, 98 fulfilled the eligibility criteria. The median age was 68 years and 48% of the patients were female. Median performance status was 3, and the median oral intake was 50%. The median duration of naldemedine administration and overall survival were 25 and 64 days, respectively. The incidence of diarrhea in the early group (n = 26) was significantly lower than in the late group (n = 72) (3.9% vs. 22.2%, p = 0.02). Daily defecation counts increased after late (median 0.43 to 0.88, p < 0.001), but remained stable after early naldemedine administration (median 1.00 to 1.00, p = 0.34). Constipation after the diarrhea was resolved was common (53%), especially among patients who stopped naldemedine (78%). The diarrhea was improved within three days in 92% of patients who stopped other laxatives. CONCLUSIONS: The early administration of naldemedine is beneficial because it reduces adverse events including diarrhea. Diarrhea caused by naldemedine can be effectively managed by stopping other laxatives while continuing naldemedine.

Clinical and pathological analyses of interstitial fibrosis and tubular atrophy cases after kidney transplantation.

AIM: We carried out a clinicopathological analysis of cases presenting with interstitial fibrosis and tubular atrophy (IF/TA) after renal transplantation in an attempt to clarify the mechanisms underlying the development and prognostic significance of IF/TA. METHODS: IF/TA was diagnosed in 35 renal allograft biopsy specimens (BS) obtained from 35 renal transplant recipients under follow up at the Department of Transplant Surgery, Kidney Center, Toda Chuo General Hospital, between January 2014 and March 2015. RESULTS: IF/TA was diagnosed at a median of 39.9 months after the transplantation. Among the 35 patients with IF/TA, 19 (54%) had a history of acute rejection. Among the 35 BS showing evidence of IF/TA, the IF/TA was grade I in 25, grade II in 9, and grade III in 1. Arteriosclerosis of the middle-sized arteries was observed in 30 BS (86%). We then classified the 35 BS showing evidence of IF/TA according to their overall histopathological features, as follows; IF/TA alone (6 BS; 17%), IF/TA + medullary ray injury (12 BS; 34%), and IF/TA + rejection (12 BS; 34%). Loss of the renal allograft occurred during the observation period in one of the patients (3%). Of the remaining patients with functioning grafts, deterioration of the renal allograft function after the biopsies occurred in 15 patients (43%). CONCLUSIONS: The results of our study suggests that rejection contributes to IF/TA in 30-40% of cases, medullary ray injury in 30-40% of cases, and nonspecific injury in 20% of cases. IF/TA contributes significantly to deterioration of renal allograft function.

Possible role of template-based lymphadenectomy in reducing the risk of regional node recurrence after nephroureterectomy in patients with renal pelvic cancer.

OBJECTIVE: It remains unclear whether lymphadenectomy alters regional node recurrence after nephroureterectomy in patients with urothelial carcinoma of the renal pelvis. The predictive factors for regional node recurrence are still unclear. In this study, we retrospectively examined how the extent of lymphadenectomy influences regional node recurrence in patients with urothelial carcinoma of the renal pelvis. METHODS: From January 1988 through July 2013, we performed nephroureterectomy in 180 patients with non-metastatic (cN0M0) urothelial carcinoma of the renal pelvis at two Japanese institutes. Regional nodes were determined according to our previous mapping study: complete lymphadenectomy designates that all regional sites were dissected; incomplete lymphadenectomy that all sites were not dissected. A third group included those without lymphadenectomy. RESULTS: The 5-year cancer-specific and recurrence-free survival was significantly higher in the complete lymphadenectomy group than in the incomplete lymphadenectomy or without lymphadenectomy groups (P = 0.03). The incidence of regional node recurrence was significantly lower in the complete lymphadenectomy group at 2.9% (2/67) than in the incomplete lymphadenectomy at 18.1% (4/22) or without lymphadenectomy at 10.9% (10/91) groups (P = 0.03). In patients with incomplete lymphadenectomy, 75% of regional node recurrence occurred outside of the dissected sites. Complete lymphadenectomy is shown to be a likely predictive factor of reduced risk of recurrence at the regional nodes by multivariate analysis, after adjusting for patient age, pathological T stage, and pathological nodal metastases. CONCLUSIONS: This study shows that template-based lymphadenectomy reduced the risk of regional node recurrence in patients with urothelial carcinoma of the renal pelvis and appears to result in improved survival.

Clinical symptoms predict poor overall survival in chronic-dialysis patients with renal cell carcinoma associated with end-stage renal disease.

OBJECTIVE: To evaluate which clinical symptoms predict the survival of patients with renal cell carcinoma associated with end-stage renal disease under chronic dialysis. METHODS: We retrospectively evaluated 401 patients with renal cell carcinoma associated with end-stage renal disease who underwent radical nephrectomy at our institute up through December 2012. Patients were divided into two groups: the symptomatic group and the incidental group, by diagnosis. We compared the clinicopathologic features and patient survival of the two groups and investigated prognostic factors using Cox multivariate analysis. RESULTS: Of the 401 patients, 124 (30.9%) were in the symptomatic group and 277 (69.0%) in the incidental group. The symptomatic group included more advanced tumors in terms of larger tumor size, higher stage and higher grade compared with the incidental group. The 5-year cancer-specific survival and overall survival of the symptomatic and incidental groups were 76.9 vs. 95.3% (P < 0.001) and 64.2 vs. 84.9% (P < 0.001), respectively. On multivariate analysis, the presence of symptoms, higher age, higher stage, diabetic nephropathy and longer hemodialysis duration were independent prognostic factors. CONCLUSIONS: Symptomatic detection was significantly associated with worse overall survival in patients with renal cell carcinoma associated with end-stage renal disease as well as sporadic renal cell carcinoma. The high incidence of renal cell carcinoma as well as the poor oncologic outcome in patients with longer dialysis therapy may suggest an important role for routine screening in these patients.

Superior tolerability of altered dosing schedule of sunitinib with 2-weeks-on and 1-week-off in patients with metastatic renal cell carcinoma--comparison to standard dosing schedule of 4-weeks-on and 2-weeks-off.

OBJECTIVE: Poor tolerability to sunitinib with the standard dosing schedule has become an issue. We retrospectively analyzed the treatment efficacy and the profile of adverse events of 2 weeks of sunitinib treatment followed by 1-week-off (Schedule 2/1) and compared the results with the standard dosing schedule with 4 weeks of treatment followed by 2-weeks-off (Schedule 4/2). METHODS: From January 2010 until December 2012, 48 patients with metastatic renal cell carcinoma who received at least two cycles of sunitinib as first-line therapy were the subjects of this study. After 2011, we switched to Schedule 2/1 for most patients. RESULTS: Schedule 2/1 included 26 patients and Schedule 4/2 had 22. The incidence of most adverse events was not significantly different between the two groups except for hand-foot syndrome and diarrhoea, which were observed more frequently in Schedule 4/2 and reached statistical significance. A dose interruption due to adverse events in the first three cycles was significantly lower in Schedule 2/1 patients than in those on Schedule 4/2 (27 versus 53% P = 0.04). With respect to treatment efficacy, the objective response rate tended to be higher in Schedule 4/2 than in Schedule 2/1 (50 versus 32%), and median progression-free survival was longer in patients on Schedule 2/1 than those on Schedule 4/2 (18.4 versus 9.1 months). These differences, however, did not reach statistical significance (P = 0.14, P = 0.13). CONCLUSIONS: Alteration in dosing schedule of sunitinib with 2-weeks-on and 1-week-off showed a lower incidence of dose interruption and a similar oncological outcome compared with the standard dosing schedule of 4-weeks-on and 2-weeks-off.

Negative impact of papillary histological subtype in patients with renal cell carcinoma extending into the inferior vena cava: single-center experience.

OBJECTIVES: To investigate the impact of histological subtypes on the survival of patients presenting with renal cell carcinoma extending into the inferior vena cava. METHODS: From January 1985 until October 2011, 68 patients with renal cell carcinoma extending into the inferior vena cava underwent radical nephrectomy and inferior vena cava thrombectomy at Tokyo Women's Medical University, Tokyo, Japan. Their clinical and pathological parameters were reviewed from the medical charts. RESULTS: The median follow up was 19 months (range 0.1-144 months). The tumor thrombus level was I in four patients (6%), II in 38 patients (56%), III in 12 patients (18%) and IV in 14 patients (20%). Papillary histological subtype was found in seven patients (10%), and clear cell in 61 patients (90%). Patients with a papillary subtype had a significantly worse survival outcome than the patients with the clear cell subtype (median survival time 9.0 vs 36.1 months, P < 0.001). Multivariate analysis also showed that the papillary subtype was the only independent prognostic factor for unfavorable cancer-specific survival (P = 0.03). When the patients presented with metastases to lymph nodes or distant metastases, the median survival of the patients with a papillary subtype was extremely short, at just 5.2 months compared with those with a clear cell subtype (24.0 months, P = 0.001). CONCLUSIONS: Patients with renal cell carcinoma extending into the inferior vena cava with a papillary subtype show a considerably shorter survival compared with those with a clear cell subtype. The papillary renal cell carcinoma extending into the inferior vena cava patient might be an inappropriate candidate for extensive surgery when metastases to nodes or distant organs are found.

Similar functional outcomes after partial nephrectomy for clinical T1b and T1a renal cell carcinoma.

OBJECTIVES: To examine the medium-term functional outcomes of partial nephrectomy for clinical T1b renal cell carcinoma, and to compare them with those of radical nephrectomy for clinical T1b and with those of partial nephrectomy for clinical T1a tumors. METHODS: The participants of this study were patients operated for clinical T1a and clinical T1b tumors operated at Tokyo Women's Medical University, Tokyo, Japan, between January 1979 and June 2011. A total of 67 patients underwent partial nephrectomy for clinical T1b tumor, 195 patients underwent radical nephrectomy for clinical T1b tumors and 324 underwent partial nephrectomy for clinical T1a tumors. The outcomes of these three groups were compared. RESULTS: Partial nephrectomy provided better preservation of residual renal function compared with radical nephrectomy for clinical T1b, and the postoperative estimated glomerular filtration rate was similar in the patients who underwent partial nephrectomy for clinical T1b and those who underwent partial nephrectomy for clinical T1a. Postoperative renal function was steadily maintained after partial nephrectomy during the medium-term follow up. The probability of freedom from new onset of chronic kidney disease after partial nephrectomy for clinical T1b tumors was significantly higher from that after radical nephrectomy for clinical T1b tumors, and similar to that after partial nephrectomy for clinical T1a tumors. CONCLUSIONS: The higher anatomical complexity of clinical T1b tumors is unlikely to provide a significant influence on postoperative renal function after partial nephrectomy, when compared with the clinical T1a tumors. These findings support the beneficial role of partial nephrectomy in the preservation of renal function of clinical T1b renal cell carcinoma patients undergoing surgery.

Decompressive surgery in combination with preoperative transcatheter arterial embolization: successful improvement of ambulatory function in renal cell carcinoma patients with metastatic extradural spinal cord compression.

We analyzed the results of direct decompressive surgery plus stabilization of the vertebrae involved (DDSS) in six non-ambulatory patients with metastatic extradural spinal cord compression (MESCC) due to renal cell carcinoma (RCC). Transcatheter arterial embolization (TAE) was performed prior to surgery to reduce intraoperative blood loss. Radiotherapy and systemic therapy, including cytokine or targeted therapy and zoledronic acid, were added to the surgery. The DDSS procedure was performed successfully in all patients, with an estimated mean blood loss of 1726 mL. After surgery, all patients regained ambulatory function within 2 months. Patients were ambulatory with the use of assisting apparatus for 4-29 months (median 10.5 months). Median overall survival time after surgery was 15 months (range 4-38 months). In conclusion, DDSS with preoperative TAE can be performed safely and significantly improves the ambulatory function of non-ambulatory RCC patients with MESCC.