Clear Cell Histological Subtype Research Articles

Global Incidence of Ovarian Cancer According to Histologic Subtype: A Population-Based Cancer Registry Study.

Ovarian cancer can be categorized into distinct histologic subtypes with varying identifiable risk factors, molecular composition, clinical features, and treatment. The global incidence of ovarian cancer subtypes remains limited, especially in low- and middle-income countries (LMICs) without high-quality cancer registry systems. We used data from population-based cancer registries of the Cancer Incidence in Five Continents project to calculate the proportions of serous, mucinous, endometrioid, clear cell, and other histologic subtypes of ovarian cancer. Proportions were applied to the estimated numbers of patients with ovarian cancer from Global Cancer Observatory 2020. Age-standardized incidence rates were calculated. Globally, an estimated 133,818 new patients of serous cancer, 35,712 new patients of mucinous cancer, 29,319 new patients of endometrioid cancer, and 17,894 new patients of clear cell cancer were identified in 2020. The distribution of ovarian cancer histologic subtypes exhibited regional variation. Eastern Europe had the highest rate of serous and mucinous carcinomas, whereas Northern Africa and Eastern Asia had the highest burden of endometrioid and clear cell carcinomas, respectively. This study provides a global incidence landscape of histologic subtypes of ovarian cancer, particularly in LMICs lacking comprehensive registry systems. Our analysis offers valuable insights into disease burden and guidance for tailored strategies for prevention of ovarian cancer.

Uptake and Outcomes of Neoadjuvant Chemotherapy Among US Patients With Less Common Epithelial Ovarian Carcinomas

ImportanceRandomized clinical trials examining the effectiveness of neoadjuvant chemotherapy (NACT) for advanced ovarian cancer predominantly included patients with high-grade serous carcinomas. The use and outcomes of NACT in less common epithelial carcinomas are understudied.ObjectiveTo investigate the uptake and survival outcomes in treatment with NACT for less common histologic subtypes of epithelial ovarian cancer.Design, Setting, and ParticipantsA retrospective cohort study and systematic literature review with meta-analysis was conducted using the National Cancer Database from 2006 to 2017 and the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from 2006 to 2019. Data analysis was performed from July 2022 to April 2023. The evaluation included patients with stage III to IV ovarian cancer with clear cell, mucinous, or low-grade serous histologic subtypes who received multimodal treatment with surgery and chemotherapy.ExposuresExposure assignment per the sequence of treatment: primary debulking surgery (PDS) followed by chemotherapy (PDS group) or NACT followed by interval surgery (NACT group).Main Outcomes and MeasuresTemporal trends and characteristics of NACT use were assessed using multivariable analysis, and overall survival (OS) was assessed with the inverse probability of treatment weighting propensity score.ResultsA total of 3880 patients were examined in the National Cancer Database including 1829 women (median age, 56 [IQR, 49-63] years) with clear cell, 1156 women (median age, 53 [IQR, 42-64] years) with low-grade serous, and 895 women (median age, 57 [IQR, 48-66] years) with mucinous carcinomas. NACT use increased in patients with clear cell (from 10.2% to 16.2%, 58.8% relative increase; P < .001 for trend) or low-grade serous (from 7.7% to 14.2%, 84.4% relative increase; P = .007 for trend) carcinoma during the study period. This association remained consistent in multivariable analysis. NACT use also increased, but nonsignificantly, in mucinous carcinomas (from 8.6% to 13.9%, 61.6% relative increase; P = .07 for trend). Across the 3 histologic subtypes, older age and stage IV disease were independently associated with NACT use. In a propensity score–weighted model, the NACT and PDS groups had comparable OS for clear cell (4-year rates, 31.4% vs 37.7%; hazard ratio [HR], 1.12; 95% CI, 0.95-1.33) and mucinous (27.0% vs 26.7%; HR, 0.90; 95% CI, 0.68-1.19) carcinomas. For patients with low-grade serous carcinoma, NACT was associated with decreased OS compared with PDS (4-year rates, 56.4% vs 81.0%; HR, 2.12; 95% CI, 1.55-2.90). Increasing NACT use and histologic subtype–specific survival association were also found in the Surveillance, Epidemiology, and End Results Program cohort (n = 1447). A meta-analysis of 4 studies, including the current study, observed similar OS associations for clear cell (HR, 1.13; 95% CI, 0.96-1.34; 2 studies), mucinous (HR, 0.93; 95% CI, 0.71-1.21; 2 studies), and low-grade serous (HR, 2.11; 95% CI, 1.63-2.74; 3 studies) carcinomas.Conclusions and RelevanceDespite the lack of data on outcomes of NACT among patients with less common carcinomas, this study noted that NACT use for advanced disease has gradually increased in the US. Primary chemotherapy for advanced-stage, low-grade serous ovarian cancer may be associated with worse survival compared with PDS.

The emerging use of immunotherapy as a treatment option in metastatic renal cell carcinoma: Real-world evidence from a single UK tertiary cancer centre.

e16509 Background: The landscape of systemic anticancer therapy (SACT) options for the treatment of metastatic renal cell carcinoma (mRCC) has recently evolved following results from the CheckMate 214 trial in 2018 which demonstrated improved overall survival in patients with International mRCC Database Consortium (IMDC) intermediate- and poor-risk mRCC clear cell histological subtype receiving combination immunotherapy (Ipilimumab/Nivolumab) in the first-line setting compared to Sunitinib. This is in addition to other treatment options including: vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) (e.g. Sunitinib, Pazopanib, Tivozanib, Cabozantinib, etc.), combination immunotherapy/TKI (e.g. Avelumab/Axitinib), VEGF/mammalian target of Rapamycin (mTOR) inhibitors (e.g. Lenvatinib/Everolimus) and single-agent immunotherapy (e.g. Nivolumab) in both first- and second-line settings. Methods: An audit of SACT prescribing practices in mRCC between 2019-2022 in a single UK tertiary cancer centre (Castle Hill Hospital, Hull, UK) was conducted as part of a national collaboration multi-centre UK audit looking into the real-world landscape and treatment choices in mRCC. Information was derived from the Somerset Cancer Registry and a dataset containing 87 patients with a coded diagnosis of ‘malignant neoplasm of kidney, except renal pelvis (CX64X)’ and ‘secondary malignant neoplasm of kidney & renal pelvis (C790)’ was generated. Results: Of the 81 patients included in the final analysis, 65% (n = 53) were male and 81% (n = 66) had a clear cell histological subtype. The main sites of metastases were lung (n = 58) and lymph nodes (n = 45). Most of the patients (n = 72) received either one or two lines of SACT. Of those with clear cell mRCC, 74% (n = 51/69) were classed as having IMDC intermediate- or poor-risk features with almost half (n = 34/69) receiving combination Ipilimumab/Nivolumab. Comparing overall survival (OS) and progression-free survival (PFS) to the published Kaplan-Meier curves in the CheckMate 214 trial, no significant differences in OS (p = 0.6) and PFS (p = 0.13) were observed, although there was an overall trend towards improved PFS in the first 6 months (82.4% vs 63.3%) in our local dataset. Conclusions: The results of our real-world evaluation of prescribing practices in mRCC favoured the use of combination immunotherapy in the first-line setting for the treatment of IMDC intermediate- and poor-risk clear cell mRCC with similar outcomes to the published data in the CheckMate 214 trial. The overall trend towards improved PFS in the first 6 months in our local dataset highlights the importance of patient selection when using immunotherapy.

Histological features suggestive of survival in patients with renal cell carcinoma and tumor thrombus: A single-center experience.

PurposeTo evaluate the impact of histological subtype on the survival of patients with renal cell carcinoma (RCC) and tumor thrombus (TT).Patients and methodsWe retrospectively analyzed 350 patients with RCC and TT admitted to Chinese People’s Liberation Army General Hospital between January 2006 and June 2021. The patients underwent radical nephrectomy and thrombectomy using robot-assisted laparoscopic, laparoscopic, or open surgery. The clinical and pathological parameters of the patients were taken from their medical records. Survival was calculated with the Kaplan–Meier method. Univariate and multivariate Cox regression analyses were performed to evaluate the prognostic significance of variables on overall survival (OS) and progression-free survival (PFS).ResultsTT levels 0–IV were observed in 132 (37.71%), 43 (12.29%), 134 (38.29%), 20 (5.71) and 21 (6.00%) patients, respectively. Papillary (pRCC), clear cell, and other histological subtypes of RCC were detected in 28 (8.00%), 286 (81.71%), and 36 (10.29%) patients, respectively. Compared to the clear cell cohort, collecting systemic invasion (46.43 vs. 25.17%; p = 0.030) and lymph node metastasis (39.29 vs. 11.54%; p < 0.01) were more common in the pRCC cohort. Kaplan–Meier analyses showed that patients with pRCC and other subtypes had significantly worse OS and PFS compared to patients with the clear cell subtype (p < 0.05). Multivariate analyses revealed that histology was independently associated with reduced OS and PFS, including among patients without lymph node and distant metastasis (N0M0).ConclusionPapillary or other subtypes have a considerably shorter OS and PFS compared to clear cell subtype in RCC patients with TT. Strict follow-up and surveillance should be performed for papillary or other subtypes RCC with TT.

Abstract 982: A new transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma

Abstract Introduction: Renal cell carcinoma, particularly the clear cell histological subtype (ccRCC), is the most common kidney cancer in adults, accounting for 75-85% of all cases. When it is localized to the kidney, it is often cured with surgical resection or thermal ablation. One quarter of the patients have evidence of metastatic disease at the time of diagnosis, and in this setting ccRCC still is a highly lethal disease with few effective treatment options. In this study we used single-cell RNA-sequencing to characterize tumor cell clonality, metastatic signatures and the tumor microenvironment in ccRCC at the single-cell level. Methodological approach: Here we took advantage of fresh patient samples that included treatment-naive primary tumor tissue, matched adjacent normal kidney tissue, as well as tumor samples collected from patients with bone metastases. We used single cell RNA sequencing (10X Genomics, Chromium 3’ v2 kit, 10x Genomics), that was analyzed with PAGODA and CONOS. Summary of new unpublished data: Our analysis revealed a distinct transcriptional signature that predicts metastatic potential and patient survival was disclosed through the single-cell analysis. In-depth exploration of the supporting stromal cells displayed a phenotype of vascular remodeling within the endothelial cells. The fibroblasts showed a proliferative signature that was associated with poor survival. An in silico cell-to-cell interaction analysis highlighted the CXCL9/CXCL10-CXCR3 axis and the CD70-CD27 axis as potential therapeutic targets. Conclusions: Our discoveries in ccRCC provide complementary biological insights, specifically in the interplay between tumor cells and their microenvironment in ccRCC. We demonstrate important biological insights into ccRCC biology including: (1) identification of a distinct metastatic signature that predicts survival outcome, (2) discovery of a proximal tubule cell population that may represent the ccRCC cell of origin, and (3) a detailed exploration in the immunosuppressive environment and the stromal alterations in treatment-naïve patients. In addition, we stress potential therapeutic targets for further evaluation in preclinical models. Citation Format: Adele Mirna Alchahin, Shenglin Mei, Ioanna Tsea, Taghreed Hirz, Youmna Kfoury, Douglas Dahl, Chin-Lee Wu, Alexander O. Subtelny, Shulin WU, David T. Scadden, John H. Shin, Philip J. Saylor, David B. Sykes, Peter V. Kharchenko, Ninib Baryawno. A new transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 982.

RAMPART: A phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse

Background20–60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting. Methods/designRAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3–11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART). Trial registrationISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017–002329-39, CTA #: 20363/0380/001–0001, MREC #: 17/LO/1875, ClinicalTrials.gov Identifier: NCT03288532, RAMPART grant number: MC_UU_12023/25, TransRAMPART grant number: A28690 Cancer Research UK, RAMPART Protocol version 5.0.

Metastatic nonclear renal cell carcinoma current review in evolving treatment strategies.

Renal cell carcinoma (RCC) is the 6th most often diagnosed cancer in men and the 10th in women. Nearly 75% of the renal cancer cases are clear cell histologic subtype, whereas nonclear cell histologies represent the remaining 25%. Treatment options for clear renal type are well established. However, as nonclear RCC represents a heterogenous and less frequent group. Current treatment options for these tumors are limited and mostly based on evidence derived from small phase II clinical trials. The present review aims to provide an update of the available treatment options for nonclear RCC. In the past decade, the vascular endothelial growth factor tyrosine kinase inhibitor, sunitinib, and mammalian target of rapamycin inhibitors, everolimus, and temsirolimus, have demonstrated limited efficacy in nonclear RCC. Recent studies with MET inhibitors and immunotherapy-based combinations have proven promising activity, especially in certain subgroups of patients, such as patients with MET-driven disease or patients with sarcomatoid features RCC. Here, we report currently available data about biology and treatment of nonclear cell RCC.

Comparison between small renal masses 0-2 cm vs. 2.1-4 cm in size: A population-based study

BackgroundThe NCCN guidelines recommend active surveillance (AS) as an option for the initial management of cT1a 0-2 cm renal lesions. However, data about comparison between renal cell carcinoma (RCC) 0-2 cm vs. 2.1-4 cm are scarce. MethodsWithin the Surveillance, Epidemiology, and End Results database (2002–2016), 46,630 T1a NanyMany stage patients treated with nephrectomy were identified. Data were tabulated according to histological subtype, tumor grade (low [LG] vs. high [HG]), as well as age category and gender. Additionally, rates of synchronous metastases were quantified. ResultsOverall, 69.3 vs. 74.1% clear cell, 21.4 vs. 17.6% papillary, 6.9 vs. 6.8% chromophobe, 2.0 vs. 1.1% sarcomatoid dedifferentiation, 0.2 vs. 0.2% collecting duct histological subtype were identified for respectively 0-2 cm and 2.1-4 cm RCCs. In both groups, advanced age was associated with higher rate of HG clear cell and HG papillary histological subtype. In 0-2 cm vs. 2.1-4 cm RCCs, 13.8% vs. 20.2% individuals operated on harbored HG tumors and were more prevalent in males. Lower synchronous metastases rates were recorded in 0-2 cm RCC and ranged from 0 in respectively multilocular cystic to 0.9% in HG papillary histological subtype. The highest synchronous metastases rates were recorded in sarcomatoid dedifferentiation histological subtype (13.8% and 9.7%) in both groups. ConclusionsRelative to 2.1-4 cm RCCs, 0-2 cm RCCs harbored lower rates of HG tumors, lower rates of aggressive variant histology and lower rates of synchronous metastases. The indications and demographics of patients selected for AS may be expanded in the future to include younger and healthier patients.

Small Renal Masses With Tumor Size 0 to 2 cm: A SEER-Based Study and Validation of NCCN Guidelines.

The NCCN Clinical Practice Guidelines in Oncology for Kidney Cancer recommend active surveillance as an option for initial management of T1a 0- to 2-cm renal lesions, in addition to partial nephrectomy, radical nephrectomy, and focal ablation. However, contemporary data regarding the distribution of patient and renal cell carcinoma characteristics within this special patient group are scarce. Within the SEER database (2002-2016), 13,364 patients with T1aNanyMany 0- to 2-cm renal lesions treated with nephrectomy were identified. Data were tabulated according to histologic subtype, Fuhrman grade (FG1-2 vs FG3-4), age category, and sex. In addition, rates of synchronous metastases were quantified. Overall, clear-cell (69.3%), papillary (21.4%), chromophobe (6.9%), multilocular cystic (2.0%), sarcomatoid dedifferentiation (0.2%), and collecting-duct histologic subtypes (0.2%) were identified. Advanced age was associated with a lower rate of FG1-2 clear cell histologic subtype (70.8%-50.3%) but higher rates of FG1-2 papillary (11.1%-23.9%) and chromophobe histologic subtypes (6.2%-8.5%). Overall, 14.5% individuals harbored FG3-4 clear cell (9.8%) or FG3-4 papillary histologic subtypes (4.8%), and both were more prevalent in men. FG3-4 clear-cell and FG3-4 papillary histologic subtypes increased with age, more so in women than in men. The overall rate of synchronous metastases was 0.4% and ranged from 0 in the multilocular cystic subtype to 0.9% in the FG3-4 papillary histologic subtype, respectively, except for 13.8% in the sarcomatoid dedifferentiation histologic subtype. Most T1a 0- to 2-cm renal cell carcinoma represents the low-grade clear-cell or low-grade papillary histologic subtype, with an FG3-4 minority. Even in patients with the FG3-4 histologic subtype, rates of synchronous metastases are virtually zero.

Abstract IA23: Therapeutic approaches for ARID1A-mutated ovarian cancer

Abstract Ovarian cancer remains the most lethal gynecologic malignancy in the developed world. Despite the unprecedented progress in understanding the genetics of ovarian cancer, cures remain elusive due to a lack of insight into the mechanisms that can be targeted to develop new therapies. SWI/SNF chromatin remodeling complexes are genetically altered in ~20% of all human cancers. SWI/SNF alterations vary in different histologic subtypes of ovarian cancer, with ARID1A mutation occurring in ~50% of ovarian clear-cell carcinomas. Given the prevalence of ARID1A mutation, ovarian cancer represents a paradigm for investigating the molecular basis and exploring therapeutic strategies for SWI/SNF alterations. The presentation will discuss our recent efforts in understanding SWI/SNF alterations in ovarian cancer and specifically focuses on ARID1A mutation in endometriosis-associated clear cell and endometrioid histologic subtypes of ovarian cancer. Understanding the molecular underpinning of ARID1A mutation in ovarian cancer will provide mechanistic insights into how ARID1A inactivation contributes to ovarian cancer. In addition, how these newly gained insights can be leveraged to develop urgently needed therapeutic strategies in a personalized manner for ovarian cancer will be discussed. Citation Format: Rugang Zhang. Therapeutic approaches for ARID1A-mutated ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA23.

Prognostic Value of Histologic Subtype and Treatment Modality for T1a Kidney Cancers.

Introduction:To evaluate overall survival (OS) of T1a kidney cancers stratified by histologic subtype and curative treatment including partial nephrectomy (PN), percutaneous ablation (PA), and radical nephrectomy (RN).Materials and Methods:We queried the National Cancer Data Base (2004–2015) for patients with T1a kidney cancers who were treated surgically. OS was estimated by Kaplan-Meier curves based on histologic subtype and management. Cox proportional regression models were used to determine whether histologic subtypes and management procedure predicted OS.Results:46,014 T1a kidney cancers met inclusion criteria. Kaplan Meier curves demonstrated differences in OS by treatment for clear cell, papillary, chromophobe, and cystic histologic subtypes (all p < 0.001), but no differences for sarcomatoid (p = 0.110) or collecting duct (p = 0.392) were observed. Adjusted Cox regression showed worse OS for PA than PN among patients with clear cell (HR 1.58, 95%CI [1.44–1.73], papillary RCC (1.53 [1.34–1.75]), and chromophobe RCC (2.19 [1.64–2.91]). OS was worse for RN than PN for clear cell (HR 1.38 [1.28–1.50]) papillary (1.34 [1.16–1.56]) and chromophobe RCC (1.92 [1.43–2.58]). Predictive models using Cox proportional hazards incorporating histology and surgical procedure alone were limited (c-index 0.63) while adding demographics demonstrated fair predictive power for OS (c-index 0.73).Conclusions:In patients with pathologic T1a RCC, patterns of OS differed by surgery and histologic subtype. Patients receiving PN appears to have better prognosis than both PA and RN. However, the incorporation of histologic subtype and treatment modality into a risk stratification model to predict OS had limited utility compared with variables representing competing risks.

Y-box binding protein-1 is crucial in acquired drug resistance development in metastatic clear-cell renal cell carcinoma

BackgroundRenal cell carcinoma (RCC) is a highly vascular tumor and patients with low risk metastatic RCC of clear-cell histological sub-type (mccRCC) are treated with tyrosine-kinase inhibitors (TKIs), sunitinib, as the first-line of treatment. Unfortunately, TKI resistance eventually develops, and the underlying molecular mechanism is not well understood.MethodsRCC cell-line with metastatic clear-cell histology (Caki-1), and patient samples were analysed to identify the role of Y-box binding protein 1 (YB-1) and ATP-binding cassette sub-family B member 1 (ABCB-1) in acquired sunitinib-resistance development. Caki-1 was conditioned with increasing sunitinib doses to recapitulate acquired resistance development in clinics. Sunitinib-conditioned and wild-type Caki-1 were subjected to cell viability assay, scratch assay, chicken embryo chorioallantoic membrane engraftment and proteomics analysis. Classical biochemical assays like flow cytometry, immunofluorescent staining, immunohistochemical staining, optical coherence tomography imaging, Western Blot and RT-PCR assays were applied to determine the possible mechanism of sunitinib-resistance development and the effect of drug treatments. Publicly available data was also used to determine the role of YB-1 upregulation in ccRCC and the patients’ overall survival.ResultsWe demonstrate that YB-1 and ABCB-1 are upregulated in sunitinib-resistant in vitro, ex vivo, in vivo and patient samples compared to the sensitive samples. This provides evidence to a mechanism of acquired sunitinib-resistance development in mccRCC. Furthermore, our results establish that inhibiting ABCB-1 with elacridar, in addition to sunitinib, has a positive impact on reverting sunitinib-resistance development in in vitro, ex vivo and in vivo models.ConclusionThis work proposes a targeted therapy (elacridar and sunitinib) to re-sensitize sunitinib-resistant mccRCC and, possibly, slow disease progression.

Safety of nivolumab in metastatic renal cell carcinoma patients: A real-life experience in a Spanish urology setting

Introduction and objectivesNivolumab is an immunotherapy agent that has been an approved treatment for previously treated patients with advanced renal cell carcinoma (RCC). Experience in real-life settings, especially regarding immune-related adverse events, is scarce. We present our experience with reference to the safety of nivolumab in patients with metastatic RCC (mRCC) treated in 9 hospitals in Spain. Material and methodsRetrospective, multicenter study of patients with mRCC treated with nivolumab between 2016 and 2018. Data on baseline socio-demographic and clinical characteristics and drug-related adverse events were collected. ResultsThe mean age of the 26 patients included was 63.7±11.5 years; 96% were ECOG 0–1 and 78% had favorable or intermediate MSKCC risk scores; 73% had the clear cell histological subtype and 30% metastatic disease. Median follow-up was 9 months (range 1–14). All patients experienced an adverse event at different grades, with fatigue, fever and anemia being the most common (27%). Grade 3 adverse events occurred in 23% of patients. Adverse reactions led to treatment suspension in 3 patients (11%). ConclusionIn the real-life clinical setting, nivolumab shows favorable outcomes, similar to those reported by other studies.

Seguridad de nivolumab en pacientes con carcinoma de células renales metastásico: experiencia española en urología en la práctica clínica real

Introduction and objectivesNivolumab is an immunotherapy agent that has been an approved treatment for previously treated patients with advanced renal cell carcinoma (RCC). Experience in real-life settings, especially regarding immune- related adverse events, is scarce. We present our experience with reference to the safety of nivolumab in patients with metastatic RCC (mRCC) treated in 9 hospitals in Spain. Material and methodsRetrospective, multicentre study of patients with mRCC treated with nivolumab between 2016 and 2018. Data on baseline socio-demographic and clinical characteristics and drug-related adverse events were collected. ResultsThe mean age of the 26 patients included was 63.7±11.5 years; 96% were ECOG 0-1 and 78% had favourable or intermediate MSKCC risk scores; 73% had the clear cell histological subtype and 30% metastatic disease. Median follow-up was 9 months (range 1-14). All patients experienced an adverse event at different grades, with fatigue, fever and anaemia being the most common (27%). Grade 3 adverse events occurred in 23% of patients. Adverse reactions led to treatment suspension in 3 patients (11%). ConclusionIn the real-life clinical setting, nivolumab shows favourable outcomes, similar to those reported by other studies.

Effect of histopathologic characteristics on pseudocapsular invasion in the case of partial nephrectomy for renal tumours

It is aimed to define the existence of pseudocapsular structure on renal tumours, illuminate the relation between pseudocapsular invasion and Fuhrman grade histological type that are among histopathologic prognostic risk factors and determine the relation between surgical margin positivity and existence of pseudocapsular invasion. Sequential partial nephrectomy series and relevant pathological preparations were retrospectively reviewed in order to evaluate these issues. The study includes 123 patients diagnosed with T1 renal tumour and treated with partial nephrectomy in between January 2007 and June 2016. Benign angiomyolipoma was excluded due to complete non-existence of pseudocapsule. 99 T1 patients diagnosed with renal cell cancer whose pathological slides can be duly analysed were included in the study. Clinical and pathological details were evaluated for all patients. Existence of pseudocapsule was revealed for all patients. Pseudocapsule invasion was classified by existence of expansive and infiltrative type and non-existence of pseudocapsule invasion. The groups have been assessed by their histopathologic characteristics. Compared to the group in which pseudocapsular invasion was not detected, clear-cell histological subtype was observed more frequently in a statistically significant way in the group with expansive pseudocapsular invasion and infiltrative pseudocapsular invasion respectively (p=0.017 and p<0.001). Pathological tumour sizes were found out to be statistically similar (p=0.874). There was not a statistically significant difference in terms of Fuhrman grade (p=0.220). There was not a statistically significant difference in terms of surgical positive margin (p=0.609). It was indicated in our study that only the histological subtype affected pseudocapsular invasion in group of patients treated with partial nephrectomy but tumour size, tumour stage, tumour location as well as endophytic and exophytic character did not affect invasion. It has also been revealed that surgical margin positivity is not correlated with pseudocapsular invasion.

SWI/SNF Complexes in Ovarian Cancer: Mechanistic Insights and Therapeutic Implications.

Ovarian cancer remains the most lethal gynecologic malignancy in the developed world. Despite the unprecedented progress in understanding the genetics of ovarian cancer, cures remain elusive due to a lack of insight into the mechanisms that can be targeted to develop new therapies. SWI/SNF chromatin remodeling complexes are genetically altered in approximately 20% of all human cancers. SWI/SNF alterations vary in different histologic subtypes of ovarian cancer, with ARID1A mutation occurring in approximately 50% of ovarian clear cell carcinomas. Given the complexity and prevalence of SWI/SNF alterations, ovarian cancer represents a paradigm for investigating the molecular basis and exploring therapeutic strategies for SWI/SNF alterations. This review discusses the recent progress in understanding SWI/SNF alterations in ovarian cancer and specifically focuses on: (i) ARID1A mutation in endometriosis-associated clear cell and endometrioid histologic subtypes of ovarian cancer; (ii) SMARCA4 mutation in small cell carcinoma of the ovary, hypercalcemic type; and (iii) amplification/upregulation of CARM1, a regulator of BAF155, in high-grade serous ovarian cancer. Understanding the molecular underpinning of SWI/SNF alterations in different histologic subtypes of ovarian cancer will provide mechanistic insight into how these alterations contribute to ovarian cancer. Finally, the review discusses how these newly gained insights can be leveraged to develop urgently needed therapeutic strategies in a personalized manner.

Vaginal Brachytherapy and External Beam Radiation therapy in Operable Stage II Endometrial Cancer: A National Cancer Database Study

We investigated the effect of radiotherapy modality for Federation of Gynecology and Obstetrics (FIGO) stage II endometrial cancer after hysterectomy using the National Cancer Database (NCDB). Between 2004 and 2013, FIGO Stage II endometrial cancer patients who received a total, modified radical or extended hysterectomy were selected from the NCDB. Patients with positive margins were excluded. Adenocarcinoma, clear cell, and papillary serous histological subtypes were allowed. Differences in outcomes between patients who received external beam radiation (EBRT), vaginal brachytherapy (VBT), or both (EBRT+VBT) were investigated. Lymph node number removed and receipt of chemotherapy were also examined. The primary endpoint of this study was overall survival (OS). A total of 4,497 patients were eligible for analysis with a median follow-up of 47.8 months and median age of 62. Adenocarcinomas comprised 88.4% of the population, and 66.0% received radiation, with 16.8% receiving chemotherapy. Univariate analysis revealed race, Charlson-Deyo Score (performance status), grade, lymphovascular invasion (LVSI), receipt of radiation, lymph node number removed (<10 vs ≥10), and age to each be significant for OS (p<0.01). On multivariable analysis (MVA) of all patients, African-American (vs White) race, not receiving radiation, Charlson-Deyo Score 2, grade 2-3 cancer (vs grade 1), <10 lymph nodes resected, and older age were associated (p < 0.01) with worse OS. Of patients who received radiation, VBT was associated with a significantly improved OS (p=0.03) when compared to EBRT (HR 1.38, 95% CI 1.10-1.73) or EBRT+VBT (HR 1.25, 95% CI 1.02-1.54). On MVA of those who received radiation, no differences in OS were observed between VBT (HR 1.00), EBRT (HR 1.11, 95% CI 0.86-1.41), or EBRT+VBT (HR 1.08, 95% CI 0.86-1.36), and chemotherapy was not associated with improved OS (HR 0.82, 95% CI 0.63-1.07, p = 0.14). When evaluating individual patient cohorts separated by grade and radiation therapy modality, there existed no difference in 5 year OS between groups (p=0.74). On stratification by presence of LVSI and radiation modality, there was no difference in 5 year OS when comparing each individual group (p=0.4). This study suggests that adjuvant radiation plays a key role in the management of operable Stage II endometrial cancer regardless of modality. VBT alone may be sufficient with stage II endometrial cancer regardless of grade or LVSI. Prospective data is required to further investigate and validate these results.Abstract TU_20_3520: Table 1Five-year Overall Survival (95% CI) of Stage II Endometrial Cancer by Grade and Radiation ModalityRadiation ModalityGradeVBTEBRTEBRT+VBT191.6% (87.0-94.7%)88.9% (82.2-93.2%)91.0% (86.2-94.2%)285.1% (80.4-88.7%)84.6% (79.0-88.8%)84.6% (80.7-87.8%)373.7% (67.0-79.3%)65.6% (58.5-71.8%)65.1% (59.0-70.5%) Open table in a new tab

Effect of African-American race on cancer specific mortality differs according to clear cell vs. non-clear cell histologic subtype in metastatic renal cell carcinoma

AimTo test the effect of African-American race on cancer specific mortality (CSM) in clear cell metastatic renal cell carcinoma (ccmRCC) and non-ccmRCC. Patients and methodsWithin Surveillance, Epidemiology and End Results registry (2001–2014), we identified patients with ccmRCC and non-ccmRCC. We relied on propensity score (PS) matching to reduce the effect of inherent differences between African-American vs. Caucasian patients. After PS matching that included access to cytoreductive nephrectomy (CNT), cumulative incidence, competing-risks regression (CRR) models and landmark analyses tested the effect of race on CSM. ResultsBefore PS matching, African-American patients accounted for 7.0 and 24.5% of respectively ccmRCC (N = 6742) and non-ccmRCC patients (N = 766). After PS matching, African-American patients accounted for 22.3 and 33.5% of respectively ccmRCC (N = 2050) and non-ccmRCC (N = 391) matched cohorts. In multivariable CRR models focusing on ccmRCC, higher CSM was recorded in African-Americans (HR:1.27, p < 0.001). Conversely, in non-ccmRCC, lower CSM was recorded in African-Americans (HR:0.54, p < 0.001). Landmark analyses rejected the hypothesis of immortal time bias. ConclusionAfrican-Americans experienced higher CSM in ccmRCC. Conversely, African-Americans experienced lower CSM, when diagnosed with non-ccmRCC. These differences are independent of access to CNT and warrant further study since they may have an impact on efficacy or access to systemic therapies.

Evaluation of PD-1 and PD-L1 levels in clear cell histologic subtypes of ovarian and uterine malignancies and correlation with stage and survival

Evaluation of PD-1 and PD-L1 levels in clear cell histologic subtypes of ovarian and uterine malignancies and correlation with stage and survival

Differential expression of estrogen receptor subtypes and variants in ovarian cancer: effects on cell invasion, proliferation and prognosis

BackgroundDue to the presence of both classical estrogen receptor (ERα) and another ER subtype (ERβ) in ovarian cancer, hormonal treatment is an attractive option. However, response to tamoxifen in ovarian cancer is modest. The presence of ERβ variants further complicated the issue. We have recently shown that specifically targeting ER subtypes using selective ER modulators showed opposing functions of ER subtypes on cell growth. In the present study, the clinical significance of ERα and ERβ variants (β1, β2 and β5) and the functional effects of ERβ2 and ERβ5 in ovarian cancer was investigated.MethodsERα, ERβ1, ERβ2 and ERβ5 expression were evaluated by immunohistochemistry in 106 ovarian cancer tissues. The association between ERs expression and clinicopathological parameters or prognosis was analyzed. Ectopic expression of ERβ2 and ERβ5 followed by functional assays were performed in ovarian cancer cell lines in order to detect their effects on cell invasion and proliferation.ResultsWe found significantly higher nuclear (n)ERα and nERβ5 and lower cytoplasmic (c)ERα expression in advanced cancers. Significantly lower ERβ1 expression was also detected in high grade cancers. Significant loss of nERα and cERβ2 expression were observed in clear cell histological subtypes. Higher nERβ5 and lower cERβ5 expression were associated with serous/clear cell subtypes, poor disease-free and overall survival. Positive cERα and higher cERβ1 expression were significantly associated with better disease-free and overall survival. Furthermore, we found nERβ5 as an independent prognostic factor for overall survival. Functionally, overexpression of ERβ5 enhanced ovarian cancer cell migration, invasion and proliferation via FAK/c-Src activation whereas ERβ2 induced cell migration and invasion.ConclusionsSince tamoxifen binds to both ERα and ERβ1 which appear to bear opposing oncogenic roles, the histotypes-specific expression pattern of ERs indicates that personalized treatment for women based on ERs expression using selective estrogen receptor modulators may improve response rate. This study also suggests nERβ5 as a potential prognostic marker and therapeutic target in ovarian cancer.