PADRES: a phase 2 clinical trial of neoadjuvant axitinib for complex partial nephrectomy.

OBJECTIVE: To report the results of PADRES (Prior Axitinib as a Determinant of Outcome of Renal Surgery, NCT03438708), a study investigating neoadjuvant axitinib for tumours of high complexity with imperative indication for partial nephrectomy (PN). METHODS: We conducted a single-arm phase II clinical trial of localized (cT1b-cT3M0) clear-cell renal cell carcinoma (RCC) patients with imperative indications for nephron preservation, where PN is a high-risk procedure due to complexity (RENAL score 10-12). Axitinib 5 mg was administered twice daily for 8 weeks with repeat imaging at completion, followed by surgery. The primary outcome was successful completion of planned PN following axitinib treatment. Secondary objectives included changes in tumour diameter, RENAL nephrometry score, renal function and Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, and surgical complications. RESULTS: Twenty-seven patients were enrolled (median age 69 years). Prior to therapy, twenty patients (74.0%) had ≥ clinical T3a staged tumours. Axitinib resulted in reductions in tumour diameter (7.5 vs 6.2 cm; P < 0.001) and RENAL score (11 vs 10; P < 0.001). Nine patients (33.3%) had partial response based on RECIST and nine (33.3%) were clinically downstaged. PN was performed in twenty patients (74.0%); twenty-five patients (96.2%) had negative margins. Six patients (22.2%) had Clavien III-IV complications. The median change in estimated glomerular filtration rate (preoperative to last follow-up) was 8.5 mL/min/1.73 m2 . CONCLUSION: Neoadjuvant axitnib resulted in reductions in tumour size and complexity, enabling safe and feasible PN and functional preservation in patients with complex renal masses and imperative indication.

Pathological Outcomes of Patients With Advanced Renal Cell Carcinoma Who Receive Nephrectomy Following Immunotherapy.

BACKGROUND: Even though cytoreductive nephrectomy (CN) was once the standard of care for patients with advanced renal cell carcinoma (RCC), its role in treatment has not been well analyzed or defined in the era of immunotherapy (IO). MATERIALS AND METHODS: This study analyzed pathological outcomes in patients with advanced or metastatic RCC who received IO prior to CN. This was a multi-institutional, retrospective study of patients with advanced or metastatic RCC. Patients were required to receive IO monotherapy or combination therapy prior to radical or partial CN. The primary endpoint assessed surgical pathologic outcomes, including American Joint Committee on Cancer (AJCC) staging and frequency of downstaging, at the time of surgery. Pathologic outcomes were correlated to clinical variables using a Wald-chi squared test from Cox regression in a multi-variable analysis. Secondary outcomes included objective response rate (ORR) defined by response evaluation criteria in solid tumors (RECIST) version 1.1 and progression-free survival (PFS), which were estimated using the Kaplan-Meier method with reported 95% CIs. RESULTS: Fifty-two patients from 9 sites were included. Most patients were male (65%), 81% had clear cell histology, 11% had sarcomatoid differentiation. Overall, 44% of patients experienced pathologic downstaging, and 13% had a complete pathologic response. The ORR immediately prior to nephrectomy was stable disease in 29% of patients, partial response in 63%, progressive disease in 4%, and 4% unknown. Median follow-up for the entire cohort was 25.3 months and median PFS was 3.5 years (95% CI, 2.1-4.9). CONCLUSIONS: IO-based interventions prior to CN in patients with advanced or metastatic RCC demonstrates efficacy, with a small fraction of patients showing a complete response. Additional prospective studies are warranted to investigate the role of CN in the modern IO-era.

Treatment Landscape of Renal Cell Carcinoma.

OPINION STATEMENT: The treatment landscape of renal cell carcinoma (RCC) has evolved significantly over the past three decades. Active surveillance and tumor ablation are alternatives to extirpative therapy in appropriately selected patients. Stereotactic body radiation therapy (SBRT) is an emerging noninvasive alternative to treat primary RCC tumors. The advent of immune checkpoint inhibitors (ICIs) has greatly improved the overall survival of advanced RCC, and now the ICI-based doublet (dual ICI-ICI doublet; or ICI in combination with a vascular endothelial growth factor tyrosine kinase inhibitor, ICI-TKI doublet) has become the standard frontline therapy. Based on unprecedented outcomes in the metastatic with ICIs, they are also being explored in the neoadjuvant and adjuvant setting for patients with high-risk disease. Adjuvant pembrolizumab has proven efficacy to reduce the risk of RCC recurrence after nephrectomy. Historically considered a radioresistant tumor, SBRT occupies an expanding role to treat RCC with oligometastasis or oligoprogression in combination with systemic therapy. Furthermore, SBRT is being investigated in combination with ICI-doublet in the advanced disease setting. Lastly, given the treatment paradigm is shifting to adopt ICIs at earlier disease course, the prospective studies guiding treatment sequencing in the post-ICI setting is maturing. The effort is ongoing in search of predictive biomarkers to guide optimal treatment option in RCC.

Analysis of RAS protein interactions in living cells reveals a mechanism for pan-RAS depletion by membrane-targeted RAS binders.

HRAS, NRAS, and KRAS4A/KRAS4B comprise the RAS family of small GTPases that regulate signaling pathways controlling cell proliferation, differentiation, and survival. RAS pathway abnormalities cause developmental disorders and cancers. We found that KRAS4B colocalizes on the cell membrane with other RAS isoforms and a subset of prenylated small GTPase family members using a live-cell quantitative split luciferase complementation assay. RAS protein coclustering is mainly mediated by membrane association-facilitated interactions (MAFIs). Using the RAS-RBD (CRAF RAS binding domain) interaction as a model system, we showed that MAFI alone is not sufficient to induce RBD-mediated RAS inhibition. Surprisingly, we discovered that high-affinity membrane-targeted RAS binding proteins inhibit RAS activity and deplete RAS proteins through an autophagosome-lysosome-mediated degradation pathway. Our results provide a mechanism for regulating RAS activity and protein levels, a more detailed understanding of which should lead to therapeutic strategies for inhibiting and depleting oncogenic RAS proteins.

Effects of the 2012 and 2018 US preventive services task force prostate cancer screening guidelines on pathologic outcomes after prostatectomy.

BACKGROUND: In May 2018, the US Preventive Services Task Force (USPSTF) recommended prostate cancer (PCa) screening for ages 55-69 be an individual decision. This changed from the USPSTF's May 2012 recommendation against screening for all ages. The effects of the 2012 and 2018 updates on pathologic outcomes after prostatectomy are unclear. METHODS: This study included 647 patients with PCa who underwent prostatectomy at our institution from 2005 to 2018. Patient groups were those diagnosed before the 2012 update (n = 179), between 2012 and 2018 updates (n = 417), and after the 2018 update (n = 51). We analyzed changes in the age of diagnosis, pathologic Gleason grade group (pGS), pathologic stage, lymphovascular invasion (LVI), and favorable/unfavorable pathology. Multivariable logistic regression adjusting for pre-biopsy covariables (age, prostate-specific antigen [PSA], African American race, family history) assessed impacts of 2012 and 2018 updates on pGS and pathologic stage. A p  < 0.05 was statistically significant. RESULTS: Median age increased from 60 to 63 (p = 0.001) between 2012 and 2018 updates and to 64 after the 2018 update. A significant decrease in pGS1, pGS2, pT2, and favorable pathology (p < 0.001), and a significant increase in pGS3, pGS4, pGS5, pT3a, and unfavorable pathology (p < 0.001) was detected between 2012 and 2018 updates. There was no significant change in pT3b or LVI between 2012 and 2018 updates. On multivariable regression, diagnosis between 2012 and 2018 updates was significantly associated with pGS4 or pGS5 and pT3a (p < 0.001). Diagnosis after the 2018 update was significantly associated with pT3a (p = 0.005). Odds of pGS4 or pGS5 were 3.2× higher (p < 0.001) if diagnosed between 2012 and 2018 updates, and 2.3× higher (p = 0.051) if after the 2018 update. Odds of pT3a were 2.4× higher (p < 0.001) if diagnosed between 2012 and 2018 updates and 2.9× higher (p = 0.005) if after the 2018 update. CONCLUSIONS: The 2012 USPSTF guidelines negatively impacted pathologic outcomes after prostatectomy. Patients diagnosed between 2012 and 2018 updates had increased frequency of higher-risk PCa and lower frequency of favorable disease. In addition, data after the 2018 update demonstrate a continued negative impact on postprostatectomy pathology. Thus, further investigation of the long-term effects of the 2018 USPSTF update is warranted.

A randomised clinical trial of single or extended dosing ciprofloxacin versus no intervention for prevention of ventilation tube otorrhoea and obstruction (PreVenTO2).

OBJECTIVES: To determine the effectiveness of ciprofloxacin .3% antibiotic eardrops in preventing clinically significant postoperative otorrhoea and tube obstruction following grommet insertion in children. DESIGN: Three-arm parallel assessor-blinded randomised controlled trial. Randomisation in 1: 1: 1 ratio to single intraoperative application of ciprofloxacin drops, extended 5 day postoperative application and no drops. Patients were assessed by blinded assessors at 6 weeks postoperatively. SETTING: The study was conducted in a large tertiary health network in Melbourne, Australia. PARTICIPANTS: All children, 17 years and under, undergoing bilateral middle ear ventilation tube surgery with or without concurrent upper airway surgery for recurrent acute otitis media and chronic otitis media with effusion were approached. MAIN OUTCOME MEASURES: Presence of postoperative otorrhoea and ventilation tube obstruction at 6 weeks postoperatively. RESULTS: Two-hundred and fifty-six paediatric patients completed the study with a median age of 4.02 years. One-hundred and fifty-three participants were male. Ear analysis (n = 512) showed intraoperative antibiotics were more effective than no drops in preventing otorrhoea (RR = .341, 95% CI .158-.738, NNT =11.25, p = .006). Postoperative antibiotics were more effective than no drops in preventing ventilation tube obstruction (RR = .424, 95% CI .193 to .930, NNT =14.7, p = .032). CONCLUSION: Intraoperative topical ciprofloxacin was effective at preventing early postoperative otorrhoea, and a prolonged course was effective at preventing ventilation tube obstruction. Future studies on this topic should seek to clarify whether particular subgroups of patients benefit more from prophylactic topical antibiotics and model for cost-effectiveness.

Indolent T Cell Lymphoproliferation of the Gastrointestinal Tract: An Evolving Disease Entity.

Background: Indolent T cell lymphoproliferation of the gastrointestinal tract is a novel entity recently added to the 2016 WHO classification of lymphoid neoplasms. Classically, these patients demonstrate an immunophenotype consistent with T cell proliferation and can be either CD4-positive or CD8-positive but with a low Ki67 index, highlighting the indolent nature of this disease compared to its more aggressive T cell lymphoma counterparts such as enteropathy-associated T cell lymphoma and monomorphic epitheliotropic intestinal T cell lymphoma. Methods: Here, we describe one rare case of such a neoplasm under our care, initially presenting with non-specific signs and symptoms and requiring extensive investigations to diagnose. Available cases in the literature reflect a wide variety of ages and ethnicities affected, and any part of the gastrointestinal sites can be affected, which makes diagnosis difficult and prolonged; however, progression beyond lymph nodes is rare, and prognosis is otherwise favourable, particularly if CD8-positive. The optimal management of these patients remains yet to be defined, given the paucity of available cases currently. The current evidence suggests the utility of steroids, cyclosporine, radiotherapy, and a potential role for JAK inhibitors. Conclusions: Our case showed an excellent response to the initial course of steroids, with a subsequent successful transition to cyclosporine, keeping symptoms at bay with ongoing stable disease.

Combined Charlson comorbidity/C-Reactive Protein Index Is a Novel Predictor in Renal Cell Carcinoma: Analysis of the International Marker Consortium for Renal Cancer (INMARC) Registry.

OBJECTIVE: To evaluate predictive ability of a novel combined index, Charlson comorbidity index and C-reactive protein (CCI-CRP), for outcomes in renal cell carcinoma (RCC), and compare predictive outcomes with of CCI-CRP to its separate components and to the UCLA integrated staging system (UISS). PATIENTS AND METHODS: We retrospectively analyzed INMARC registry of RCC patients. Receiver Operator Characteristics (ROC) analysis was fitted to identify threshold defining low-CRP (LCRP) and high-CRP (HCRP). Patients were stratified according to CCI [low-CCI ≤ 3 (LCCI); intermediate-CCI 4-6 (ICCI); high-CCI > 6 (HCCI)] and CRP level. Kaplan-Meier analysis (KMA) was conducted for overall (OS) and cancer-specific survival (CSS). Based on survival analysis distribution we proposed a new stratification: CCI-CRP. Model performance was assessed with ROC/area under the curve (AUC) analysis and compared to CCI and CRP alone, and UISS. RESULTS: We analyzed 2,890 patients (median follow-up 30 months). ROC identified maximum product sensitivity and specificity for CRP at 3.5 mg/L. KMA revealed 5-year OS of 95.6% for LCRP/LCCI, 83% LCRP/ICCI, 73.3% LCRP/HCCI, 62.6% HCRP/LCCI, 51.6% HCRP/ICCI and 40.5% HCRP/HCCI (P < .001). From this distribution, new CCI-CRP is proposed: low CCI-CRP (LCRP/LCCI and LCRP/ICCI), intermediate CCI-CRP (LCRP/HCCI and HCRP/LCCI), and high CCI-CRP (HCRP/ICCI and HCRP/HCCI). AUC for CCI-CRP showed improved performance for predicting OS/CSS vs. CCI alone (0.73 vs. 0.63/0.77 vs. 0.60), CRP alone (0.73 vs. 0.71/0.77 vs. 0.74) and UISS (0.73 vs 0.67/0.77 vs 0.73). CONCLUSIONS: CCI-CRP, exhibits increased prognostic performance for survival outcomes in RCC compared to CCI and CRP alone, and UISS. Further investigation is requisite.

Association of Elevated C-Reactive Protein with Worsened Outcomes in Different Histologies of Renal Cortical Tumors: Analysis of the INMARC Registry.

BACKGROUND: To evaluate relationship between histological subtypes of renal cell carcinoma (RCC) and preoperative c-reactive protein (CRP). PATIENTS AND METHODS: We queried the International Marker Consortium for Renal Cancer database for patients affected by RCC. Patients were classified according to their histology: benign tumors, clear cell (cc) RCC, chromophobe (ch) RCC, papillary (p) RCC, and variant histology (vh) RCC; and according to CRP (mg/L): low CRP ≤5 and high CRP >5. Primary outcome was all-cause mortality (ACM). Secondary outcomes were cancer-specific mortality (CSM), recurrence and association between CRP and histology. Multivariable analysis (MVA) via Cox regression and multivariable logistic regression were fitted to elucidate predictors of outcomes. RESULTS: Total 3902 patients (high CRP n = 1266) were analyzed; median follow up 51 (IQR 20-91) months. On MVA elevated CRP was an independent risk factor associated with increased risk of ACM in benign tumors (HR 5.98, P < .001), ccRCC (HR 2.69, P < .001), chRCC (HR 3.99, P < .001), pRCC (HR 1.76, P = .009) and vhRCC (HR 2.97, P =.007). MVA for CSM showed CRP as risk factor in ccRCC (HR 2.77, P < .001), chRCC (HR 6.16, P = .003) and pRCC (HR 2.29, P = .011), while in vhRCC was not (P = .27). MVA for recurrence reported CRP as risk factor for ccRCC (HR 1.30, P = .013), while in chRCC (P = .33), pRCC (P = .34) and vhRCC (P = .52) was not. On multivariable logistic regression CRP was a predictor of pRCC (OR 1.003, P = .002), while decreasing CRP was associated with benign tumors (OR 0.994, P = .048). CONCLUSION: Elevated CRP was a robust predictor of worsened ACM in all renal cortical neoplasms. While most frequently observed in pRCC patients, elevated CRP was independently associated with worsened CSM in non-vhRCC. Conversely, elevated CRP was least likely to be noted in benign tumors, and elevation in this subgroup of patients should prompt further consideration for surveillance given increased risk of ACM. Further investigation is requisite.

Unraveling the BMI paradox in different renal cortical tumors: insights from the INMARC registry.

OBJECTIVE: To investigate impact of body mass index (BMI) on survival across different histologies and stages of renal cell carcinoma (RCC). METHODS: We conducted a retrospective multicenter analysis of clear cell (ccRCC) and non-ccRCC. Obesity was defined according to the WHO criteria (non-Asian BMI >30 Kg/m2, Asian BMI >27.5 Kg/m2). Multivariable analysis (MVA) via Cox regression model was conducted for all-cause (ACM), cancer-specific mortality (CSM) and recurrence. RESULTS: A total of 3,880 patients with a median follow-up of 31 (IQR 9-64) months were analyzed. Overall, 1,373 (35.3%) were obese; 2,895 (74.6%) were ccRCC and 985 (25.3%) were non-ccRCC (chRCC 246 [24.9%], pRCC 469 [47.6%] and vhRCC 270 [27.4%]). MVA in ccRCC revealed obesity associated with decreased risk of ACM, CSM and recurrence (hazard ratio [HR] 0.80, P = 0.044; HR 0.71, P = 0.039; HR 0.73, P = 0.012, respectively), while in non-ccRCC was not associated with decreased risk of ACM, CSM, and recurrence (P = 0.84, P = 0.53, P = 0.84, respectively). Subset analysis in stage IV ccRCC demonstrated obesity as associated with a decreased risk of ACM, CSM, and recurrence (HR 0.68, P = 0.04; HR 0.59, P = 0.01; HR 0.59, P = 0.01, respectively), while in stage I-III ccRCC was not (P = 0.21; P = 0.30; P = 0.19, respectively). CONCLUSION: Our findings refute a broad "obesity paradox" for RCC. Obesity was not associated with improved survival in non-ccRCC and in nonmetastatic ccRCC, while metastatic ccRCC patients with obesity had improved survival outcomes.

Predictive factors for recurrence and outcomes in T1a renal cell carcinoma: Analysis of the INMARC (International Marker Consortium for Renal Cancer) database.

OBJECTIVE: Stage migration in renal cell carcinoma (RCC) has led to an increasing proportion of diagnosed small renal masses. Emerging knowledge regarding heterogeneity of RCC histologies and consequent impact on prognosis led us to further explore outcomes and predictive factors in surgically-treated T1a RCC. METHODS: The INMARC database was queried for T1aN0M0 RCC. Patients were stratified into groups based on recurrence. Primary outcome was overall survival (OS). Multivariable analyses (MVA) were performed for factors associated with recurrence, cancer-specific (CSM), and all-cause mortality (ACM). Kaplan-Meier analyses (KMA) assessed survival by histology and grade. Subset analysis for time to recurrence was conducted for grade and histologic groups and compared with recent AUA follow-up guidelines [low-risk (AUA-LR), intermediate-risk (AUA-IR), high-risk (AUA-HR), and very-high risk (AUA-VHR) groups]. RESULTS: We analyzed 1,878 patients (median follow-up 35.2 months); 101 (5.4%) developed recurrence. MVA for recurrence demonstrated increasing age (P = 0.026), male sex (P = 0.043), diabetes (P = 0.007), high/unclassified grade (P < 0.001-0.007), and variant histology (P = 0.017) as independent risk factors for increased risk, while papillary (P = 0.016) and chromophobe (P = 0.049) were associated with decreased risk. MVA identified high/unclassified grade (P = 0.003-0.004) and pT3a upstaging (P = 0.043) as predictive factors for worsened risk of CSM while papillary (P = 0.034) was associated with improved risk. MVA for ACM demonstrated increasing age (P < 0.001), non-white (P < 0.001), high-grade (P = 0.022), variant histology (P = 0.049), recurrence (P = 0.004), and eGFR<45 at last follow-up (P < 0.001) to be independent risk factors. KMA comparing clear cell, chromophobe, papillary, and variant RCC revealed significant differences for 5-year CSS (P = 0.018) and RFS (P < 0.001), but not OS (P = 0.34). Median time to recurrence was 23.8 months for low-grade (AUA-LR), 17.3 months for high-grade (AUA-IR), 18 months for pT3a upstaging (AUA-HR), and 12 months for variant histology (AUA-VHR; P < 0.001). CONCLUSION: We noted differential outcomes in T1a RCC based on histology and grade for recurrence and CSM, while renal functional decline in addition to pathological factors and recurrence were predictive for ACM. Our findings support recently promulgated AUA follow-up guidelines for low-grade and variant histology pT1a RCC, but call for consolidation of follow-up protocols for high-grade pT1a and pT3a upstaged patients, with intensification of frequency of imaging follow-up in pT1a high-grade RCC.

Recent Advances in the Management of Localized and Locally Advanced Renal Cell Carcinoma: A Narrative Review.

Purpose: To review the current status of surgical and procedural treatments for renal cell carcinoma (RCC), focusing on oncological and functional outcomes, and the use of techniques for advanced disease over the last 10 years. Findings: Partial nephrectomy (PN) has become the reference standard for most T1 and T2 masses. In cT2 RCC, PN exhibits oncological equivalence and improved functional outcomes compared to radical nephrectomy (RN). Additionally, emerging data suggest that PN may be used to treat cT3a RCC. The robot-assisted platform is increasingly used to treat locally advanced RCC. Studies suggest safety and feasibility of robotic RN and robotic inferior vena cava tumor thrombectomy. Additionally, single-port robot-assisted laparoscopic approaches are comparable to multiport approaches in select patients. Long-term data show that cryoablation, radiofrequency ablation, and microwave ablation are equipotent in management of small renal masses. Emerging data suggest that microwave may effectively treat cT1b masses.

Comparison of Capture Rates of the National Cancer Database Across Race and Ethnicity.

Importance: The National Cancer Database (NCDB) is an invaluable and widely used resource for cancer research, but the current state of representation of different racial and ethnic groups compared with the United States Cancer Statistics (USCS) database is unknown. Objective: To examine whether Hispanic and American Indian or Alaska Native individuals have lower representation in the NCDB compared with the USCS database. Design, Setting, and Participants: This multicenter, retrospective cohort study assessed individuals diagnosed with breast, colorectal, lung, and prostate cancer from January 1, 2004, to December 31, 2006, and January 1, 2017, to December 31, 2019, in the NCDB and USCS databases. Data analysis was performed from September 2022 to October 2023. Exposure: Time. Main Outcomes and Measures: The primary outcome was the absolute percentage change (APC) in capture rate across the study period. Results: The cohort included 5 175 007 individuals (0.50% American Indian or Alaska Native, 3.10% Asian or Pacific Islander, 12.01% Black, 6.58% Hispanic, and 77.81% White) who were diagnosed with breast, colorectal, lung, and prostate cancer. Capture rates were the lowest for individuals who were Hispanic (40.83% in 2004-2006 and 54.75% in 2017-2019; P < .001) or American Indian or Alaska Native (20.72% in 2004-2006 and 41.41% in 2017-2019; P < .001). The APCs were positive for both racial categories across all 4 cancers. However, overall APCs for Hispanic individuals (13.92%) remained lower than the overall APCs of White individuals (22.23%; P < .001). The APCs were greater for American Indian or Alaska Native individuals than for White individuals for prostate (14.68% vs 11.57%) and breast (21.61% vs 17.90%) cancer (P < .001), but the APCs for American Indian or Alaska Native individuals were lower than for White individuals for lung cancer (24.54% vs 33.03%; P < .001). Conclusions and Relevance: In this cohort study of individuals diagnosed with cancer in the NCDB, Hispanic and American Indian or Alaska Native individuals diagnosed with breast, colorectal, lung, and prostate cancer were undercaptured in the NCDB, but their representation improved over time. Increased study is needed to determine where these populations predominantly seek cancer care.

Age-Related Differences in Oncological Outcomes in Renal Cell Carcinoma: Impact of Functional Conservation as Measured by Postoperative eGFR.

INTRODUCTION: We sought to determine whether loss of renal function increases risk of recurrence and metastases in renal cell carcinoma (RCC), and whether this impact was age-related. MATERIALS AND METHODS: We performed a retrospective analysis of the International Marker Consortium for Renal Cancer (INMARC) registry. Patients were separated into younger (<65 years old) and elder (≥65 years old) age groups, and rates of de novo estimated glomerular filtration rate (eGFR<45 mL/min/1.73m2 [eGFR<45]) were calculated. Multivariable analysis (MVA) was conducted for predictors of progression-free survival (PFS) and all-cause mortality (ACM). Kaplan-Meier Analysis (KMA) was conducted for PFS and overall survival (OS) in younger and elder age groups stratified by functional status. RESULTS: We analyzed 1805 patients (1113 age<65, 692 age≥65). On MVA in patients <65, de novo eGFR<45 was independently associated with greater risk for worsened progression (HR=1.61, P=.038) and ACM (HR=1.82, P=.018). For patients ≥65, de novo eGFR<45 was not independently associated with progression (P=.736), or ACM (P=.286). Comparing patients with de novo eGFR<45 vs. eGFR ≥45, KMA demonstrated worsened 5-year PFS and OS in patients <65 (PFS: 68% vs. 86%, P<.001; OS: 73% vs. 90%, P<.001), while in patients ≥65, only 5-year OS was worsened (77% vs. 81%, P<.021). CONCLUSION: Development of de novo eGFR<45 was associated with more profound impact on patients <65 compared to patients ≥65, being an independent risk factor for PFS and ACM. The mechanisms of this phenomenon are unclear but underscore desirability for nephron preservation when safe and feasible in younger patients.

Partial versus radical nephrectomy for complex renal mass: multicenter comparative analysis of functional outcomes (Rosula collaborative group).

BACKGROUND: Utility of partial nephrectomy (PN) for complex renal mass (CRM) is controversial. We determined the impact of surgical modality on postoperative renal functional outcomes for CRM. METHODS: We retrospectively analyzed a multicenter registry (ROSULA). CRM was defined as RENAL Score 10-12. The cohort was divided into PN and radical nephrectomy (RN) for analyses. Primary outcome was development of de-novo estimated glomerular filtration rate (eGFR)<45 mL/min/1.73 m2. Secondary outcomes were de-novo eGFR<60 and ΔeGFR between diagnosis and last follow-up. Cox proportional hazards was used to elucidate predictors for de-novo eGFR<60 and <45. Linear regression was utilized to analyze ΔeGFR. Kaplan-Meier Analysis (KMA) was performed to analyze 5-year freedom from de-novo eGFR<60 and <45. RESULTS: We analyzed 969 patients (RN=429/PN=540; median follow-up 24.0 months). RN patients had lower BMI (P<0.001) and larger tumor size (P<0.001). Overall postoperative complication rate was higher for PN (P<0.001), but there was no difference in major complications (Clavien III-IV; P=0.702). MVA demonstrated age (HR=1.05, P<0.001), tumor-size (HR=1.05, P=0.046), RN (HR=2.57, P<0.001), and BMI (HR=1.04, P=0.001) to be associated with risk for de-novo eGFR<60 mL/min/1.73 m2. Age (HR=1.03, P<0.001), BMI (HR=1.06, P<0.001), baseline eGFR (HR=0.99, P=0.002), tumor size (HR=1.07, P=0.007) and RN (HR=2.39, P<0.001) were risk factors for de-novo eGFR<45 mL/min/1.73 m2. RN (B=-10.89, P<0.001) was associated with greater ΔeGFR. KMA revealed worse 5-year freedom from de-novo eGFR<60 (71% vs. 33%, P<0.001) and de-novo eGFR<45 (79% vs. 65%, P<0.001) for RN. CONCLUSIONS: PN provides functional benefit in selected patients with CRM without significant increase in major complications compared to RN, and should be considered when technically feasible.

Outcomes of Consolidative Nephrectomy following Primary Immunotherapy in Advanced Renal Cell Carcinoma: A Multicenter Analysis.

BACKGROUND: To evaluate effect and outcomes of combination primary immunotherapy (IO) and nephrectomy for advanced renal cell carcinoma (RCC). METHODS: We conducted a multicenter, retrospective analysis of patients with advanced/metastatic RCC who received IO followed by nephrectomy. Primary outcome was Bifecta (negative surgical margins and no 30-day surgical complications). Secondary outcomes included progression-free survival (PFS) following surgery, reduction in tumor/thrombus size, RENAL score, and clinical/pathologic downstaging. Cox regression multivariable analysis was conducted for predictors of Bifecta and PFS. Kaplan-Meier analysis assessed PFS, comparing Bifecta and non-Bifecta groups. RESULTS: A total of 56 patients were analyzed (median age 63 years; median follow-up 22.5 months). A total of 40 (71.4%) patients were intermediate IMDC risk. Patients were treated with immunotherapy for median duration of 8.1 months. Immunotherapy resulted in reductions in tumor size (P < .001), thrombus size (P = .02), and RENAL score (P < .001); 38 (67.9%) patients were clinically downstaged on imaging (P < .001) and 25 (44.6%) patients were pathologically downstaged following surgery (P < .001). Bifecta was achieved in 38 (67.9%) patients. Predictors for bifecta achievement included decreasing tumor size (HR 1.08, P = .043) and pathological downstaging (HR 2.13, P = .047). Bifecta (HR 5.65, P = .009), pathologic downstaging (HR 5.15, P = .02), and increasing reduction in tumor size (HR 1.2, P = .007) were associated with improved PFS. Bifecta patients demonstrated improved 2-year PFS (84% vs. 71%, P = .019). CONCLUSIONS: Primary immunotherapy reduced tumor/thrombus size and complexity. Pathologically downstaged patients were more likely to achieve bifecta, and these patients displayed improved 2-year PFS. Our study supports further inquiry in the use of CRN following primary immunotherapy for advanced renal cancer.

Epidemiological trends of gallbladder cancer in Australia between 1982 to 2018: A population-based study utilizing the Australian Cancer Database.

Backgrounds/Aims: Gallbladder cancer (GBC) is a rare neoplasm. The epidemiology of GBC has not been updated in Australia for over five decades. Methods: Data of all Australian patients diagnosed with GBC at any age from 1982 to 2018 were identified from the Australian Cancer Database. Age-standardized rates were calculated and joinpoint analysis was performed to ascertain the trends of incidence and mortality of GBC. Results: Between 1982 and 2018, there were 22,745 cases of GBC and 11,054 GBC-related deaths in Australia. There were three distinct periods showing changed incidence. Period 1 (1982-1995) was stable. Period 2 (1996-2006) showed reduced incidence in females (3.6 to 2.8/100,000; p < 0.01) and all Australians (3.7 to 2.8/100,000, p < 0.01). Period 3 (2006-2017) demonstrated significantly increased incidence in all groups (males: 2.7 to 4.0/100,000, p < 0.01; females: 2.8 to 3.5/100,000, p < 0.01; all Australians: 2.8 to 3.7/100,000, p < 0.01). Incidence between females and males had declined from 1.10 : 1 in 1982 to 0.87 : 1 in 2017. There was a 71% reduction in mortality (3.1 to 0.9/100,000; p < 0.01). Median age at diagnosis increased from 69.7 to 74.3 years for females and from 67.2 to 73.3 years for males. Increasing incidence in the 6th to 8th decade of life in males, compared to previous years, was noted. Conclusions: Incidence, mortality, sex, and age of GBC have significantly changed in Australia since 1982. Rising incidence of GBC in Australia warrants further investigation.

Predictors of postoperative complications in paediatric patients receiving grommets - A retrospective analysis.

BACKGROUND: Insertion of middle ear ventilation tubes (MEVT), tympanostomy tubes or grommets is one of the most common paediatric surgical procedures performed by ENT surgeons worldwide. Outcomes may be complicated by postoperative otorrhoea and ventilation tube blockage. OBJECTIVE: To identify risk factors associated with early postoperative complications of MEVT insertion. METHOD: In a case-control study, set in a tertiary hospital in Melbourne, Australia, 590 paediatric patients undergoing grommet insertion between February 2017 and February 2018, 311 patients (205 males & 106 females; median age of 3.86 years) met the inclusion criteria and had identical middle ear status bilaterally. INTERVENTION: Tympanostomy tube insertion and postoperative topical otic antibiotic drops. MAIN OUTCOME AND MEASURES: Patient age, gender, weight/BMI percentile, intraoperative middle ear status, number of previous grommets, type of surgery, season of surgery, diagnosis and time to first medical review were examined. The duration of topical otic antibiotic drops used and tube patency and presence of otorrhoea at 6-week postoperative review were also recorded. RESULTS: At the first medical review, 8.7% of patients (n = 27) developed otorrhoea from one or both ears, 6.4% of patients (n = 20) had an obstructed MEVT in one or both ears. Exposure to intraoperative [IO] and postoperative [PO] antibiotic drops were significantly less associated with developing postoperative otorrhoea compared to non-exposure (IO: Odds Ratio [OR] = 0.15, 95%CI 0.04 to 0.57, p = 0.005; PO: OR = 0.21, 95%CI 0.58 to 0.76, p = 0.017). There were no statistically significant associations between antibiotic drop exposure and grommet blockage (p > 0.05). There was a significant association between developing postoperative otorrhoea and patients receiving surgery during the colder months of Winter/Autumn (OR = 3.17, 95%CI 1.14 to 8.84, p = 0.028), as well as patients aged less than 3 years (OR = 2.66, 95%CI 1.01 to 7.03, p = 0.049). There was a statistically significant association between serous effusions and grommet blockage compared to no effusion (OR = 4.03, 95%CI 1.03 to 15.7, p = 0.045). There were no statistically significant associations identified between otorrhoea and gender, weight/BMI percentile, intraoperative middle ear status, number of previous grommets, type of surgery, diagnosis and time to first medical review. There were no statistically significant associations between grommet blockage and age, gender, indication for surgery, concurrent surgery, season or number of previous grommets. CONCLUSIONS: 8.7% of patients developed otorrhoea within 6 weeks post-operatively. Undergoing the procedure during winter/autumn, age <3 years were associated with developing otorrhoea. Topical antibiotic exposure was inversely associated with developing postoperative otorrhoea. 6.4% of patients had grommet blockage. Presence of serous middle ear effusion intraoperatively was a statistically significant indicator for developing grommet blockage.

Necrotising granulomatous mass of the foreskin with inguinal lymphadenopathy: a rare presentation of syphilis.

We report the case of a 24-year-old man who presented with a 5-week history of painful right inguinal lymphadenopathy, weight loss and non-ulcerative foreskin mass. The patient's symptoms progressed despite initial antibiotic therapy. The foreskin mass was clinically suspicious for squamous cell carcinoma; however, histopathology of both the foreskin mass and inguinal lymph node showed necrotising granulomatous inflammation. Extensive immunohistochemistry testing was inconclusive and could not identify a causative microorganism. Ultimately, serology was positive for Treponema pallidum and he was treated with intramuscular benzathine penicillin. This is an unusual case, which highlights the importance of extensive investigation for differential diagnoses of penile mass and exemplifies the resurgence of syphilis in developed countries.