MODY5 Hepatocyte Nuclear Factor 1ß (HNF1ß)-Associated Nephropathy: experience from a regional monogenic diabetes referral centre in Singapore.

From our monogenic diabetes registry set-up at a secondary-care diabetes center, we identified a nontrivial subpopulation (~15%) of maturity-onset diabetes of the young (MODY) among people with young-onset diabetes. In this report, we describe the diagnostic caveats, clinical features and long-term renal-trajectory of people with HNF1B mutations (HNF1B-MODY). Between 2013 and 2020, we received 267 referrals to evaluate MODY from endocrinologists in both public and private practice. Every participant was subjected to a previously reported structured evaluation process, high-throughput nucleotide sequencing and gene-dosage analysis. Out of 40 individuals with confirmed MODY, 4 (10%) had HNF1B-MODY (harboring either a HNF1B whole-gene deletion or duplication). Postsequencing follow-up biochemical and radiological evaluations revealed the known HNF1B-MODY associated systemic-features, such as transaminitis and structural renal-lesions. These anomalies could have been missed without prior knowledge of the nucleotide-sequencing results. Interestingly, preliminary longitudinal observation (up to 15 years) suggested possibly 2 distinct patterns of renal-deterioration (albuminuric vs. nonalbuminuric chronic kidney disease). Monogenic diabetes like HNF1B-MODY may be missed among young-onset diabetes in a resource-limited routine-care clinic. Collaboration with a MODY-evaluation center may fill the care-gap. The long-term renal-trajectories of HNF1B-MODY will require further studies by dedicated registries and international consortium.

Folate-targeted intraoperative fluorescence, OTL38, in robotic-assisted laparoscopic partial nephrectomy.

OBJECTIVE: To investigate the safety and efficacy of OTL38, a folate-targeted, intraoperative fluorescence agent, in patients undergoing robotic-assisted laparoscopic partial nephrectomy. METHODS: Patients with proven or suspected localized renal cell carcinoma at a single academic institution were selected from 2016 to 2018. Patients received one dose of OTL38 at 0.025 mg/kg prior to robotic-assisted laparoscopic partial nephrectomy. The da Vinci Fluorescence Imaging Vision System was used to identify the tumor and inspect for residual disease after resection. Immunohistochemistry was performed to quantify folate receptor alpha in both the tumor and surrounding normal parenchyma. Patient follow-up was 1 month. Outcome data included descriptive statistics of the patient cohort and surgeon and pathologist surveys. RESULTS: Ten cases were performed. Mean patient age was 62.9 years (range = 50-70). Mean tumor size was 2.45 cm. Pathologic tumor stages ranged from T1a-T3a. Histologic tumor types included clear cell, chromophobe, type 1 papillary renal cell carcinoma and oncocytoma. The tumors did not fluoresce, while the surrounding normal parenchyma did show fluorescence. No adverse reactions were seen. Staining for folate receptor alpha was localized to the proximal renal tubules. Average staining in normal surrounding renal parenchyma was significantly greater than staining observed in tumor tissue (0.2086 vs 0.0467; p = 0.002). The mean difference in staining between tumor tissue and surrounding normal renal parenchyma was 0.1619 (95% CI = 0.0796-0.2442). CONCLUSIONS: Based on our initial experience, OTL38 shows potential as a safe, effective and easy to use tool to improve visualization and resection of renal tumors.

Robotic Partial Nephrectomy for a Peripheral Renal Tumor.

Partial nephrectomy (PN) is the preferred surgical treatment for T1 renal tumors whenever technically feasible. When properly performed, it allows preservation of nephron mass without compromising oncologic outcomes. This reduces the postoperative risk of renal insufficiency, which translates into better overall survival for the patients. PN can be technically challenging, because it requires the surgeon to complete the tasks of tumor excision, hemostasis and renorrhaphy, all within an ischemic time of preferably below 30 minutes. The surgeon needs to avoid violating the tumor margins while leaving behind the maximal parenchymal volume at the same time. Variations such as zero ischemia, early unclamping, and selective clamping have been developed in an attempt to reduce the negative impact of renal ischemia, but inevitably add to the steep learning curves for any surgeon. Being able to appreciate the fine details of each surgical step in PN is the fundamental basis to the success of this surgery. The use of the robotic assistance allows a good combination of the minimally invasive nature of laparoscopic surgery and the surgical exposure and dexterity of open surgery. It also allows the use of adjuncts such as concurrent ultrasound assessment of the renal mass and intraoperative fluorescence to aid the identification of tumor margins, all with a simple hand switch at the console. Robot-assisted laparoscopic PN is now the most commonly performed type of PN in the United States and is gaining acceptance on the global scale. In this video, we illustrate the steps of robot-assisted laparoscopic PN and highlight the technical key points for success.

Intraoperative Mannitol Not Essential During Partial Nephrectomy.

OBJECTIVE: Intraoperative mannitol is routinely administered for renoprotection in partial nephrectomy (PN). However, there is a paucity of evidence supporting mannitol's renoprotective effect. We performed a retrospective study of mannitol's efficacy in PN. MATERIALS AND METHODS: Using an institutional database, patients undergoing PN from 2006 to 2016 were retrospectively identified and divided into two groups based on mannitol use. Cases with missing serum creatinine measurements were excluded. Mannitol use was dependent on surgeon preference. An independent-samples t-test was used to compare 6-month postoperative estimated glomerular filtration rate (eGFR) between mannitol groups and to compare 6-month eGFR between mannitol dose for patients who received mannitol. Multivariate linear regression was used to estimate 6-month eGFR when adjusting for multiple covariates that were considered clinically relevant to postoperative renal function. RESULTS: Of the patients, 476 patients were eligible for analysis and 286 received mannitol. Preoperative eGFR (7.8 ± 21.4 mL/minute/1.73 m2 vs 75.3 ± 23.1 mL/minute/1.73 m2, p = 0.223) and tumor size (3.5 ± 1.7 cm vs 3.4 ± 1.5 cm, p = 0.532) were matched between the mannitol (M+) and no mannitol (M-) groups, whereas warm ischemic time (22.5 ± 11.2 minutes vs 15.0 ± 10.2 minutes, p < 0.001) was longer in the M+ group. There was no significant difference in 6-month eGFR between mannitol groups (70.6 ± 22.2 mL/minute/1.73 m2 vs 68.0 ± 23.9 mL/minute/1.73 m2, p = 0.225). No significant association between mannitol dose and 6-month eGFR was found. Covariates that significantly predicted 6-month eGFR in our multivariate model were age (ß = 0.052, p = 0.042) and preoperative eGFR (ß = 0.843, p < 0.001). In addition, neither the use of renal cooling nor the surgical approach (open vs minimally invasive) was significantly associated with 6-month eGFR. CONCLUSION: Mannitol did not demonstrate renoprotective effects based on analysis of 6-month postoperative eGFR. In addition, neither the surgical approach nor the use of renal cooling significantly predicted postoperative renal function.

Impact of positive surgical margins on overall survival after partial nephrectomy-A matched comparison based on the National Cancer Database.

INTRODUCTION: The impact of positive surgical margins (PSM) in partial nephrectomy (PN) has been a controversy. Previous studies on the relationship between PSM and overall survival (OS) were either underpowered or had highly dissimilar groups. We used the National Cancer Database with propensity score matching to determine the association between PSM and OS after PN. MATERIALS AND METHODS: We identified patients with T1/T2 N0M0 renal cancer treated with PN between 2004 and 2009, and divided them into 2 groups based on their margin status. We used propensity score matching to ensure similarities in age, comorbidity score (CCI), tumor size, histology, and grade between groups. Covariates were compared by χ2 test. Cox multiple regression was used to estimate the hazard ratios (HR) for all-cause mortality. OS between matched groups were compared by log-rank, Breslow and Tarone-Ware tests. RESULTS: After excluding those with missing data on margin or survival status, 20,762 patients were eligible for matching. Each matched group had 1,265 patients, similar in age, sex, race, CCI, tumor size, histology, and grade. There were 386 recorded all-cause mortalities over a median follow-up duration of 72.6 months. Cox multiple regression showed a higher risk of all-cause mortality among cases with PSM (HR: 1.393, P = 0.001). Old age, high CCI, and large tumors had higher risks, while papillary and chromophore histologic subtypes had lower risks. PSM was associated with significantly worse OS by log-rank, Breslow, and Tarone-Ware tests. CONCLUSION: PSM is associated with significantly worse OS after PN.

Medical therapy for clinical benign prostatic hyperplasia: α1 Antagonists, 5α reductase inhibitors and their combination.

Medical therapy for clinical benign prostatic hyperplasia (BPH) has advanced significantly in the last 2 decades. Many new α1 antagonists and 5α reductase inhibitors (5ARi) are now commercially available. The practicing urologist must decide on the most appropriate medication for his patients, taking into consideration various factors like efficacy, dosing regime, adverse effects, cost, patient's socioeconomic background, expectations, drug availability and his own clinical experience. The use of combination therapy added further to the complexity in clinical judgment when prescribing. We highlight some of the key points in prescribing α1 antagonists, 5ARi and their combination, based on our viewpoints and experience as urologists in an Asian clinical setting.

Matched Comparison Between Partial Nephrectomy and Radical Nephrectomy for T2 N0 M0 Tumors, a Study Based on the National Cancer Database.

OBJECTIVES: To compare overall survival (OS) and immediate postoperative outcomes between partial and radical nephrectomy (RN) for T2 N0 M0 tumors and identify significant factors for poor OS. PATIENTS AND METHODS: Using the National Cancer Database, we identified patients with T2 N0 M0 renal cancer between 2004 and 2009 who were treated with partial or radical nephrectomy. The partial and RN groups were statistically matched by demographics and tumor characteristics. We used Cox multiple regression to identify significant factors for all-cause mortality and plotted survival curves for both groups. We compared immediate postoperative outcomes between groups by χ2 test and independent samples t-test. RESULTS: After statistical matching, there were 527 patients in each group, with high similarities in age, gender, race, comorbid status, tumor size, histology, and grade. RN was associated with a higher risk of all-cause mortality (hazard ratio: 5.289; p < 0.001) than partial nephrectomy (PN), after adjusting for all available covariates. PN had significantly better OS than RN, with log-rank, Breslow, and Tarone-Ware tests consistently showing p-values of <0.001. Old age, high comorbidity index, and high Fuhrman grade were associated with increased risks of all-cause mortality, while papillary and chromophobe tumors had decreased risks. PN was associated with more positive surgical margins (PSM) than RN (4.4% vs 2.5%, p < 0.001). CONCLUSION: T2 N0 M0 tumors treated with PN had better OS than those treated with RN, despite more PSM. Age, comorbidity index, histologic subtypes, and Fuhrman grade had significant impacts on OS.

Preoperative Nomograms for Predicting Renal Function at 1 Year After Partial Nephrectomy.

INTRODUCTION: Partial nephrectomy (PN) reduces the risk of postoperative chronic renal insufficiency (CRI). However, some patients still develop CRI after PN, and may eventually require dialysis. Being able to predict renal function before PN helps in counseling patients and managing expectations. We aimed to construct nomograms that predict estimated glomerular filtration rates (eGFRs), defined by the modification of diet in renal disease (MDRD) and the chronic kidney disease epidemiology collaboration (CKD-EPI) formulae, at 1 year after PN, using only preoperative covariates as predictors. PATIENTS AND METHODS: We identified patients who underwent PN in our institution between 2004 and 2016, with known postoperative serum creatinine levels at 1 year. The preoperative covariates included patients' demographics, chronic comorbid conditions, tumor characteristics, and preoperative renal status. The endpoints were eGFRs at 1 year after PN, calculated using the MDRD and the CKD-EPI formulae. We first identified preoperative covariates with significant associations with the endpoints by Pearson correlation and independent samples t-test. Suitable covariates were then included in two multivariate linear regression models, for constructing and internally validating two nomograms. RESULTS: 461 patients were eligible for analysis. The percentage of patients with eGFR below 60 mL/min/1.73 m2 increased from 25% before PN to 35% at 1 year after PN. We included age, gender, African American race, body mass index, preoperative creatinine level, ipsilateral renal volume, solitary kidney status, tumor diameter, hypertension, diabetes, ischemic heart disease, and previous stroke in the multivariate linear regression models for nomogram construction. Internal validation showed bootstrap-corrected coefficients of determination of 0.61 and 0.70, for predicting eGFRs defined by the MDRD and CKD-EPI formulae, respectively. CONCLUSIONS: We constructed and internally validated two nomograms to predict eGFRs at 1 year after PN, using only preoperative covariates as predictors.

OTL-38-Guided Fluorescent Imaging in Renal Cell Cancer Robotic Partial Nephrectomy.

Introduction and Objective: The folate receptor (FR) protein is upregulated in numerous epithelial malignancies while having limited expression on normal tissues. This overexpression of FR in renal-cell carcinoma (RCC) can be exploited by attaching nearly any therapeutic or imaging agent for delivery to cancer cells. In one of its first applications, platinum-resistant ovarian cancer, folate was used to deliver pegylated liposomal doxorubicin (a folate-linked vinca alkaloid) and improved progression-free survival versus standard treatment. RCCs are thought to be the second highest FR-expressing cancer. OTL-38 is a folate analogue conjugated with a fluorescent dye that emits light in the near infrared spectrum. This longer wavelength allows for deeper penetration of the fluorescent light through tissues with the potential to better image tumors beneath adipose tissue or deeper into organ parenchyma. We are currently conducting a pilot, phase 2, nonrandomized study in patients with RCC, scheduled to undergo primary, partial, or radical nephrectomy. The aim is to explore the use of OTL-38 and fluorescence imaging to observe RCC at the margins of resection in partial nephrectomy and in lymph node(s) or other metastases for radical nephrectomy. Methods: Currently two patients have participated in the trial to date with an accrual target of 20 patients. The first was a 67-year-old male with an incidental 2.2 cm right-sided renal mass, and the second was a 70-year-old male with an enlarging 2 cm renal mass. Per protocol, both patients were administered OTL-38 in the preoperative area 1 hour before the procedure. Subsequently, both procedures were performed with robotic assistance as per normal routine with the use of Firefly fluorescence to aid in observation of OTL-38 uptake. Results: Intraoperative guidance through OTL-38 demonstrated minimal to no uptake of the OTL-38 as seen by Firefly fluorescence (green color). Surprisingly, the normal renal parenchyma showed strong uptake of OTL-38 as seen by Firefly fluorescence. Both pathology reports revealed conventional clear cell RCC. Immunohistochemistry slides of the tumor revealed only mild staining for folate. In contrast, immunohistochemistry slides of the normal renal parenchyma in the surgical margin revealed a strongly positive stain for folate. Conclusions: In conclusion, our first two patients' renal tumors did not stain strongly for folate; however, the normal renal parenchyma did, which served as an intraoperative guide to confirm a negative margin. Further study of patients will reveal whether folate receptors are, in fact, predominant or not in renal cell cancer. No competing financial interests exist. Runtime of video: 5 mins Presented at the World Congress of Endourology 2016 in Capetown, South Africa.

Novel Use of Folate-Targeted Intraoperative Fluorescence, OTL38, in Robot-Assisted Laparoscopic Partial Nephrectomy: Report of the First Three Cases.

Partial nephrectomy is now the preferred surgical option for small renal tumors because it allows nephron preservation without compromising oncologic clearance. Its outcomes depend on the surgeon's ability to continuously identify the edges of the tumor during resection, thus leaving an adequate margin around the tumor without excessive removal of normal parenchyma, as well as keeping a short ischemic time. Folate receptors are highly abundant in the normal kidney, and there is a difference in folate receptor expression between malignant and normal renal tissues. Thus, the use of fluorescent agents that target folate receptors should result in differential fluorescence between the tumor and surrounding parenchyma during partial nephrectomy, which, in turn, helps tumor demarcation for identification and resection. A phase 2 study on the novel use of OTL38 in robot-assisted laparoscopic partial nephrectomy is currently in progress in our institution. The outcomes of the first three cases have shown the possible advantages of OTL38 in intraoperative tumor identification before resection and recognition of residual disease in the surrounding parenchyma after resection. The tumors typically appeared dark while the surrounding parenchyma showed brighter fluorescence. Immediately after tumor resection, the margins of all the specimens appeared to have a uniformly bright fluorescence, suggestive of an intact margin of normal renal parenchyma along the plane of excision. The pattern of intraoperative fluorescence correlates well with immunohistochemistry. No OTL38-related adverse effects have been seen among these three patients. We present the outcomes of these three cases, illustrated with intraoperative and immunohistochemistry images.

Catheter-free discharge on first postoperative day after bipolar transurethral resection of prostate: clinical outcomes of 100 cases.

OBJECTIVES: Our center has adopted a protocol for catheter-free first postoperative day discharge after bipolar transurethral resection of the prostate. We present the immediate, 1-month and 6-month outcomes of our first 100 cases following this protocol. METHODS: All bipolar transurethral resection of the prostate patients followed the protocol regardless of indications and background comorbid conditions. Bladder irrigation was stopped in the evening after transurethral resection of the prostate, and the catheter was removed at 06.00 hours. All patients were discharged on the first postoperative day. They were reviewed at 1 month and 6 months with the International Prostate Symptom Score and uroflowmetry. RESULTS: The mean age of the study population was 70.8 years. A total of 40 patients had urinary retention and were on an indwelling catheter before transurethral resection of the prostate. A total of 14 patients had other surgeries in the same setting as the transurethral resection of the prostate. The mean resection weight was 32.7 g. The mean irrigation time and catheter time were 4.2 h and 15.0 h, respectively. The improvement in terms of International Prostate Symptom Score, quality of life score, peak flow rate and post-void residual volume was comparable with those reported in the literature for bipolar transurethral resection of the prostate. Similarly, early and late complication rates also compared favorably with the literature. The perioperative cost was significantly reduced. CONCLUSIONS: Catheter-free first postoperative day discharge after bipolar transurethral resection of the prostate is safe with good clinical outcomes and cost savings.

Continuous femoral nerve block in total knee arthroplasty: immediate and two-year outcomes.

We conducted a prospective study to investigate the immediate and 2-year outcomes of total knee arthroplasty patients who received continuous femoral nerve block (FNB) for analgesia. Sixty patients undergoing unilateral total knee arthroplasty were randomized into 3 groups and received high-dose continuous FNB, low-dose continuous FNB, or no FNB. In the immediate postoperative period, we studied their pain scores, cumulative morphine use, any FNB-related complications, time of first ambulation, and patient satisfaction. At 2 years, we assessed their functional outcomes with Oxford knee questionnaire and Knee Society clinical rating system. Immediately after surgery, there was less pain, higher satisfaction, and lower morphine use among patients on continuous FNB regardless of ropivacaine dosage used. At 2 years, there were no significant differences in functional outcomes.

A case of adrenal cavernous hemangioma presenting with progressive enlargement and apparent hormonal hypersecretion.

OBJECTIVE: To report the case of a man with an adrenal cavernous hemangioma presenting as a progressively enlarging adrenal mass with apparent hormonal hypersecretion. METHODS: We report the clinical, laboratory, imaging findings, and clinical course of this patient, and we highlight the important atypical features of this case. The literature is reviewed for the typical presentations of adrenal cavernous hemangiomas. RESULTS: A 59-year-old man presented with an adrenal incidentaloma that had an imaging phenotype suggestive of a pheochromocytoma or an adrenal carcinoma. The hormonal profile also suggested a state of aldosterone and catecholamine hypersecretion. Surgery, however, proved the diagnosis to be an adrenal cavernous hemangioma. CONCLUSION: Although adrenal cavernous hemangioma is a rare entity, it should be considered in the differential diagnosis of an adrenal incidentaloma. Its radiologic features are not specific, and the presence of hormonal hypersecretion does not exclude the diagnosis.

On-table diagnostic accuracy and the clinical significance of routine exploration in open appendectomies.

INTRODUCTION: The current practice of further exploration for other intra-abdominal pathology only when a normal appendix is found may leave other organic causes of acute abdomen undetected if the surgeon's on-table diagnostic accuracy is low. METHODS: In this retrospective study in 518 patients who underwent surgery for acute appendicitis, the on-table operative diagnosis of surgeons was correlated with the histological diagnosis of pathologists. RESULTS: Surgeons were unable to make an accurate on-table diagnosis in 14.3% of cases. The sensitivity for diagnosing normal appendices was also low at 51.3%, suggesting that almost half of normal appendices were misdiagnosed as acute appendicitis and there was no further exploration for other pathology. It was also found that surgeon's experience, patient gender and patient age had no significant effect on diagnostic accuracy. CONCLUSION: Based on these results, it seems that the on-table diagnostic accuracy in open appendectomies is low and surgeons' on-table diagnosis should not be the determining factor for whether further exploration is necessary. Exploration for other intra-abdominal pathology should be routine irrespective of the on-table diagnosis, the surgeon's experience and patient gender and age. An alternative is minimal-access surgery in which inspection of other intra-abdominal organs can be performed more easily.