Avelumab first-line maintenance treatment for advanced urothelial carcinoma: review of evidence to guide clinical practice.

The JAVELIN Bladder 100 phase III trial led to the incorporation of avelumab first-line (1L) maintenance treatment into international guidelines as a standard of care for patients with advanced urothelial carcinoma (UC) without progression after 1L platinum-based chemotherapy. JAVELIN Bladder 100 showed that avelumab 1L maintenance significantly prolonged overall survival (OS) and progression-free survival in this population compared with a 'watch-and-wait' approach. The aim of this manuscript is to review clinical studies of avelumab 1L maintenance in patients with advanced UC, including long-term efficacy and safety data from JAVELIN Bladder 100, subgroup analyses in clinically relevant subpopulations, and 'real-world' data obtained outside of clinical trials, providing a comprehensive resource to support patient management. Extended follow-up from JAVELIN Bladder 100 has shown that avelumab provides a long-term efficacy benefit, with a median OS of 23.8 months measured from start of maintenance treatment, and 29.7 months measured from start of 1L chemotherapy. Longer OS was observed across subgroups, including patients who received 1L cisplatin + gemcitabine, patients who received four or six cycles of 1L chemotherapy, and patients with complete response, partial response, or stable disease as best response to 1L induction chemotherapy. No new safety signals were seen in patients who received ≥1 year of avelumab treatment, and toxicity was similar in those who had received cisplatin or carboplatin with gemcitabine. Other clinical datasets, including noninterventional studies conducted in Europe, USA, and Asia, have confirmed the efficacy of avelumab 1L maintenance. Potential subsequent treatment options after avelumab maintenance include antibody-drug conjugates (enfortumab vedotin or sacituzumab govitecan), erdafitinib in biomarker-selected patients, platinum rechallenge in suitable patients, nonplatinum chemotherapy, and clinical trial participation; however, evidence to determine optimal treatment sequences is needed. Ongoing trials of avelumab-based combination regimens as maintenance treatment have the potential to evolve the treatment landscape for patients with advanced UC.

Imaging findings of granular cell tumours of the head and neck.

AIM: To review the imaging characteristics of granular cell tumours in the head and neck and assess their associations with pathological findings. MATERIALS AND METHODS: Eleven patients (10 [91%] women, mean age 43 years) with histopathologically confirmed granular cell tumours were included in this study. Preoperative imaging studies were performed, including computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound. The location of the tumours, their imaging features, and histopathological findings were analysed. RESULTS: Among the 11 granular cell tumours, four (36%), three (27%), and two (18%) tumours were found in the submucosal layer, subcutaneous layer, and intramuscular area, respectively. On CT, all tumours exhibited homogeneous iso-attenuating enhancement compared with adjacent muscle, and nine out of the 11 tumours (81%) demonstrated well-defined margins. On T2-weighted imaging (T2WI), four out of five tumours (80%) demonstrated iso-signal intensity compared with adjacent muscles, and four tumours (80%) exhibited homogeneous signal intensity. The apparent diffusion coefficient (ADC) values ranged from 0.68-0.81 × 10-3 mm2/s. Histopathological examination revealed densely packed tumour cells with variable amounts of fibrous stroma. CONCLUSION: Granular cell tumours were characterised by well-defined and iso-signals on T2WI and low mean ADC values, and were predominantly located in the submucosal, subcutaneous, or intramuscular areas in middle-aged women. The characteristic locations, demographic characteristics, and imaging findings can help to differentiate granular cell tumours from other soft-tissue tumours in the head and neck.

Early Vs Late Liver Retransplantation: Different Characteristics and Prognostic Factors.

BACKGROUND: East Asia is a known endemic area for hepatitis B, and living donor liver transplantation is mainly performed. Liver retransplantation (ReLT) is expected to become an increasing problem because of a shortage of organs. This study aimed to compare early and late ReLT with consideration of specific circumstances and disease background of East Asians. METHODS: Between October 1996 and January 2015, 51 patients underwent ReLT; we performed a retrospective analysis of data obtained from medical records of the patients. Clinical characteristics, indication, causes of death, survival rate, and prognostic factors were investigated. RESULT: The survival rate for early ReLT (n = 18) was 51.5% and that for late ReLT (n = 33) was 50.1% at 1 year postoperatively. Continuous venovenous hemodialysis and the use of mechanical ventilators were more frequent, and pre-retransplant intensive care unit stay and prothrombin time was longer in early ReLT than in late ReLT. Operation time was longer and the amount of intraoperative blood loss was greater in late ReLT than in early ReLT. Multivariate analysis showed that a higher C-reactive protein level increased mortality in early ReLT (P = .045), whereas a higher total bilirubin level increased the risk of death in late ReLT (P = .03). CONCLUSION: Patients with early ReLT are likely to be sicker pre-retransplantation and require adequate treatment of the pretransplant infectious disease. On the other hand, late ReLT is likely to be technically more difficult and should be decided before the total bilirubin level increases substantially.

Single-Center Experience of Consecutive 522 Cases of Hepatic Artery Anastomosis in Living-Donor Liver Transplantation.

OBJECTIVE: The aim of this study was to clarify risk factors and outcome of hepatic arterial complication after living-donor liver transplantations (LDLT). METHODS: From 2004 to 2010, 522 consecutive LDLTs were performed. We used univariate and multivariate analysis to identify the risk factor on a retrospective basis, and then analysis was performed for adult cases. Hepatic arterial complication included thrombosis, stenosis, and pseudoaneurysm. RESULTS: The arterial complication rate was 4.79% (25 cases). Each complication was 9 thromboses, 14 stenoses, and 2 pseudoaneurysms. Preoperative hemoglobin was significantly associated with thrombosis (P = .021), and arterial size with stenosis (P = .037). We could not find any association between arterial complications and biliary stricture. However, the outcome of biliary stricture treatment was associated with arterial stenosis. Of 9 cases with thrombosis, 7 patients underwent rearterialization and 2 were treated with low-molecular-weight heparin (LMWH). Of 14 stenosis cases, 2 patients were treated with the use of balloon dilatation, 10 patients were observed under LMWH, and 2 patients underwent retransplantation. In cases of pseudoaneurysm, 1 patient underwent revision of the aneurysm and the other was observed. CONCLUSIONS: In our cohort, preoperative low hemoglobin level was a risk factor for thrombosis and artery size a risk factor for stenosis.

Implication of donor-recipient age gradient in the prognosis of graft outcome after deceased-donor kidney transplantation.

PURPOSE: Successful kidney transplantation leads to greater survival and improved quality of life for patients with end-stage renal disease. Among the most important influences on graft outcomes is donor age. We evaluated the relationships between the donor-recipient age gradient (DRAG) and the graft outcomes after deceased-donor kidney transplantation (DDKT). METHODS: From February 1995 to March 2011, a consecutive series of 526 adult DDKT recipients were analyzed. DRAG values were divided into two groups (negative versus positive years) and then four groups (≤-21, -20 to -1, 0 to 20, and ≥21 years). RESULTS: Median age of donors and recipients were 39 (range, 1-75) and 41 (range, 18-74) years, respectively. The degree of DRAG was not associated with episodes of allograft rejection. High or low DRAG had no effect on posttransplant serum creatinine levels or estimated glomerular filtration rates. However, negative levels of DRAG, particularly less than -20 years, were significantly correlated with superior 10-year death-censored graft survival (86.4% and 83.1% vs 72.2% vs 53.9%; overall P = .031), but not increased overall graft or patient survival. CONCLUSION: This study demonstrated that DRAG is a prognostic indicator of long-term graft outcomes after DDKT.

Can the kidney weight and recipient body weight ratio predict long-term graft outcome in living donor kidney transplantation?

We investigated the effect of the donor kidney weight (Kw) to recipient body weight (Rw) ratio (Kw/Rw) on long-term graft function. To investigate the impact of the Kw/Rw ratio on the graft function, we retrospectively collected data from 213 kidney transplant recipients at least 5 years Post-transplantations. Renal function showed a positive correlation with the Kw/Rw ratio until 5 years after transplantation (at 60 months after transplantation, R = 0.158, P = .023); however, this ratio does not affect graft survival (P = .794). We used the mixed-effect model to identify the factors that affect the estimated glomerular filtration rate (eGFR) over time. In univariate analysis, donor age, BSA, kidney weight, and Kw/Rw ratio were associated with eGFR. To identify independent factors that affect to the eGFR, multivariate analysis using a mixed model was applied. Donor age (P < .001) and Kw/Rw ratio (P < .001) were independent factors that affected the eGFR. To identify the cutoff values of the Kw/Rw ratio and donor age that affect long-term graft function, multiple testing using a mixed model was applied. The cutoff value for the Kw/Rw ratio was 3.16 (P = .0104) and the cutoff value of donor age was 44 years (P = .0001). Based on our results, we conclude that the Kw/Rw ratio and donor age are important factors for the long-term function of graft.

Monitoring and treatment for BK virus after kidney transplantation.

BACKGROUND: The BK nephropathy (BKN) shows a 10% prevalence among cases of kidney transplantation (KT). We assessed the incidence of BK replication in KT recipients as well as our updated screening strategy and the impact of interventions on BK virus infections. METHODS: Since September 2007, our screening protocol for BK virus included examination of urine cytology or BK virus DNA real-time polymerase chain reaction (PCR) detection on postoperative days 1, 5, 9, 16, 24, 36, 48 weeks up to 1 year. IR present, we tested urine BK virus DNA PCR quantitation. We applied the updated screening protocol from August 2010. It urine BK DNA PCR quantification was above 10(7) copies/mL, we checked regularly blood the BK virus DNA PCR quantification. In addition, if the blood BK virus DNA load was above 10(4) copies/mL and the serum creatinine elevated, we was performed an allograft biopsy. Between September 2007 and December 2011, the 58 recipients who showed BK viremia were enrolled in the present study in 2 groups according to the period of screening protocol (era I, era II). RESULTS: The time between kidney transplantation and BK viremia detection of era II was shorter than that of era I (16 vs 29 weeks; P = .001). Viremia clearance rate at 6 months in era II was significant higher than that of era I (82% vs 36.8%; P = .001) as well as at 12 months (100% vs 61.1%, P < .001) after intervention. Interestingly, viremia clearance at 12 months after intervention was 100% in era II. CONCLUSION: An updated screening protocol for BK virus allowed early detection and accurate diagnosis of BKN. Early detection of BK virus infection enabled early intervention and improved viral clearance rate.

Presence of vesicoureteral reflux in the graft kidney does not adversely affect long-term graft outcome in kidney transplant recipients.

INTRODUCTION: We studied the incidence of vesicoureteral reflux (VUR) in the graft kidney and its effect on the occurrence of urinary tract infection (UTI) and long-term graft function. METHODS: We performed a retrospective analysis of 64 adult kidney transplant recipients based upon voiding cystourethrography at 12 months post-transplantation. Patients underwent analysis of survival, incidence of UTIs beyond 1 year, and graft function. RESULTS: Thirty-seven male and 27 female patients in the study populations showed a mean age 42 years. VUR in the transplanted kidney at 12 months post-transplant occurred among 78.1% (50/64) of subjects: grade I (n = 6), grade II (n = 30), or grade III (n = 14) reflux. Patients followed for a median 61 months (range 44-74s) showed 11 cases of UTIs in 9 subjects. There were no significant differences in clinical characteristics or incidence of, UTIs according to the presence or severity of VUR (P = .81) or the Serum creatinine and estimated glomerular filtration rate values at 12, 36, 48, or 60 months post-transplantation. CONCLUSIONS: VUR present in 78.1% of patients after kidney transplantation affected neither graft functions or graft survival. The incidence of UTI did not differ according to the presence of VUR.

Importance of donor-recipient age gradient to the prediction of graft outcome after living donor liver transplantation.

PURPOSE: Advanced donor age is a well-known risk factor for poor graft function after living donor liver transplantation (LDLT). In addition, advanced recipient age has a significant impact because of the high prevalence of comorbidities. We investigated the relationship between donor-recipient age gradient (DRAG) and the posttransplant outcomes in LDLT. METHODS: We included 821 consecutive adult recipients who underwent LDLT from June 1997 to May 2011. According to the value of DRAG, they were divided into 2 groups: Negative years (the donor was younger than the recipient) and positive years (the donor was older than the recipient). These groups were further divided into subgroups (≤-21, -20 to -1, 0 to 20, and ≥21 years). We collected retrospectively patient characteristics, laboratory results, medical and surgical complications, and graft loss. RESULTS: The positive DRAG group had higher level of posttransplant alkaline phosphatase, but a lower incidence of biliary complications. The negative DRAG group, particularly DRAG ≤ -21 years was associated with the superior 1-, 3-, 5-, and 10-year graft survivals. Recipients with DRAG ≥ 21 showed persistently inferior graft survival during the observation period. In cases of young donors, transplants utilizing lower DRAG seen between young donors and older recipients showed more favorable graft survival than that of young-to-young transplants. CONCLUSION: This study demonstrated that DRAG and a fixed donor age limit could be significant factors to predict graft survival after LDLT. Patients should carefully consider the worse graft survival if the donor is older than the recipient by ≥20.

Comparison of the incidence of de novo malignancy in liver or kidney transplant recipients: analysis of 2673 consecutive cases in a single center.

PURPOSE: An increased incidence of de novo malignancy (dM) is an established complication among solid organ transplant (SOT) recipients compared with the general population. The aims of this study were to describe the incidence and cumulative risk for development of dM among our transplanted population, depending on various clinical and pathologic variables. METHODS: We retrospectively reviewed the medical records and pathologic data of SOT recipients performed from February 1995 to December 2010. RESULTS: Among 2673 consecutive SOT recipients, the dM that developed in 66 (2.5%) patients included, 16 (0.6%; 24.2% of overall dM) lymphoid dM and 50 (1.9%; 75.8% of overall dM) nonlymphoid dM. Cumulative incidence of dM in liver was significantly higher than that in kidney transplant recipients. A significantly higher cumulative incidence of dM was observed among living donor versus deceased donor SOT. Although the more frequent development of lymphoid dM was observed during the first year posttransplantation, the cumulative risk of nonlymphoid dM increased year by year, reaching a substantially higher incidence than that of lymphoid dM beyond 5 years after SOT. Comparing the various immunosuppressive regimens, the cumulative incidence was greater among the group with basiliximab induction. However, the hazard of occurrence was unaffected by whether tacrolimus or cyclosporine was used for maintenance immunosuppression. The increased risk of dM was not dependent on recipient age or gender. CONCLUSION: This study demonstrated distinctive cumulative incidences of dM in different clinical and pathologic settings.

Characteristics of recipients who achieved spontaneous operational tolerance in adult liver transplantation.

BACKGROUND: Chronic immunosuppression is associated with unwanted adverse effects and increased morbidities. Long-term acceptance of transplanted organs without the requirement for immunosuppression, or operational tolerance, remains an important goal in clinical transplantation. METHODS: We reviewed the characteristics of recipients who achieved spontaneous operational tolerance after liver transplantation (OLT) among a consecutive series of 1014 adult recipients in a single center. RESULTS: We observed 5 cases (0.5%) of operational tolerance. All cases were men who underwent transplantations for hepatitis B virus-related liver cirrhosis. The mean time from OLT to achievement of spontaneous operational tolerance was 83.1 ± 62.9 months (range, 21.3-156.2). Characteristics common to all tolerant recipients were superior graft quality and good pretransplant recipient condition: specifically, high graft-recipient weight ratio (median, 1.18; range, 1.15-2.69), low hepatic macrosteatosis (median, 3; range, 0-15), low score of model for end-stage liver disease (median, 13; range, 7-21), and no history of preoperative intensive care.

Comparison between resection and transplantation in combined hepatocellular and cholangiocarcinoma.

OBJECTIVE: The treatment of choice for combined hepatocellular and cholangiocarcinoma (cHCC-CC) is surgical resection. However, the efficacy of liver transplantation is not clear. We compared the surgical outcome of hepatic resection and liver transplantation for cHCC-CC. PATIENTS AND METHODS: From 1995 to 2012, 89 patients were diagnosed with cHCC-CC after hepatic resection and 8 patients diagnosed with cHCC-CC after liver transplantation. We excluded 21 patients who were American Joint Committee on Cancer Staging Stage III or IV and lost to follow-up. The outcomes were reviewed retrospectively. RESULTS: The poor prognostic factors in cHCC-CC patients who underwent hepatectomy were large tumor size (>5 cm), small safety margin (<2 cm), and low preoperative albumin level. The disease-free survival (DFS) and overall survival (OS) between the hepatectomy group (n = 68) and the liver transplant group (n = 8) was not statistically different (5-year DFS: 26.2% vs 37.5%, P = .333; 5-year OS: 42.1% vs 50%, P = .591). In the small tumor subgroup (tumor size <5 cm), the DFS and OS between the 2 surgical procedures was not different, and in the adequate resection margin subgroup (safety margin >2 cm), survival was comparable. CONCLUSIONS: In well-selected cases with small tumor size and with preserved liver function, liver resection should be considered when complete resection is possible.

Jejunal artery can be a useful option for arterial reconstruction in living donor liver transplantation when the suitable arterial inflow is absent.

Successful arterial reconstruction is essential for liver transplantation. In the case of inadequate arterial inflow, an arterial conduit from the aorta using artery graft or re-establishment of arterial flow through other arteries such as the splenic artery, gastroepiploic, or sigmoid artery is considered. Herein we report our experience of 27 cases of hepatic artery reconstruction using alternative methods. The most common cause of hepatic artery reconstruction requiring alternative methods was intimal dissection for which we usually used the gastroepiploic artery. Many patients had a previous operation or transarterial chemoembolization history. Among these cases, hepatic artery reconstruction using the jejunal artery was performed for 2 cases of living donor liver transplantation due to the absence of suitable alternatives. These patients have been followed up with patent hepatic arterial flow until now. Thus, the jejunal artery can be a useful option for arterial reconstruction in living donor liver transplantation when suitable arterial inflow is absent.

Can immune function assay predict infection or recovery?

BACKGROUND: Recently, the ImmuKnow assay (Cylex Inc., Columbia, Md) has been reported to be a global immune monitoring tool for organ transplants recipients. We assessed whether immunKnow ATP values predicted infectious syndromes. METHODS: We prospectively enrolled 71 kidney transplant patients between September 2008 and May 2011. lmmuKnow assay monitoring was performed at one dav before as well as 4, 8, 12, 16, 20, 24, 36, and 52 weeks after the operation. ImmuKnow assay values were compared as well as BK viral infection pre-infection(PI), at first detection of infectious syndrome (DI), 4 weeks there after (4W), 8 weeks there after (8W) and 12 weeks there after (12W) and pre-recovery (PR), recovery (R) times. RESULTS: Serial ImmuKnow assays showed significant differences over time and BK viral infectious state (P = .026). Interestingly, PI was significantly lower than DI and PR but PR significant greater than PI, 8W and 12W. However, we did not observe an adequate or absolute cutoff value of ImmuKnow by ROC curve: 377 ng/mL ImmuKnow showed 0.471 of AUC and 57.1% and 56.2%, of sensitivity and specificity. CONCLUSION: Longitudinal evaluation and adjustment of the value of ImmuKnow assay seemed to be a favorable modality to monitor infectious syndromes especially those involving BK virus.