Prognostic significance of absolute lymphocyte count in patients with metastatic renal cell carcinoma receiving first-line combination immunotherapies: results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: Lymphocytes are closely linked to mechanisms of action of immuno-oncology (IO) agents. We aimed to assess the prognostic significance of absolute lymphocyte count (ALC) in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Using the International mRCC Database Consortium (IMDC), patients receiving first-line IO-based combination therapy were analysed. Baseline patient characteristics, objective response rates (ORRs), time to next treatment (TTNT), and overall survival (OS) were compared. RESULTS: Of 966 patients included, 195 (20%) had lymphopenia at baseline, and they had a lower ORR (37% versus 45%; P < 0.001), shorter TTNT (10.1 months versus 24.3 months; P < 0.001), and shorter OS (30.4 months versus 48.2 months; P < 0.001). Among 125 patients with lymphopenia at baseline, 52 (42%) experienced ALC recovery at 3 months, and they had longer OS (not reached versus 30.4 months; P = 0.012). On multivariable analysis for OS, lymphopenia was an independent adverse prognostic factor (hazard ratio 1.68; P < 0.001). Incorporation of lymphopenia into the IMDC criteria improved OS prediction accuracy (C-index from 0.688 to 0.707). CONCLUSIONS: Lymphopenia was observed in one-fifth of treatment-naive patients with mRCC and may serve as an indicator of unfavourable oncologic outcomes in the contemporary IO era.

Application of Hereditary Renal Cell Carcinoma Risk Criteria to a Large Prospective Database.

AIMS: To evaluate the clinical impact of the Canadian criteria for identifying patients and families at risk for hereditary renal cell carcinoma (RCC). MATERIALS AND METHODS: The Canadian hereditary RCC risk criteria were applied to patients from 16 centres in the Canadian Kidney Cancer information system (CKCis) prospective database. The primary end point was the proportion of patients who met at least one criterion. RESULTS: Between January 2011 and May 2017, 8388 patients were entered in the database; 291 had inadequate risk data; 2827 (35%) met at least one criterion for genetic testing (at-risk population). Most (83%) met just one criterion. The criterion of non-clear cell histology contributed the largest proportion of at-risk patients (59%), followed by age ≤ 45 years (28%). Sixty-one patients had documentation of genetic testing, with 56 being classified at-risk (2% of at-risk). Twenty patients (35%) of the patients at risk and tested for hereditary RCC were found to harbour a germline mutation. CONCLUSIONS: Application of the Canadian hereditary RCC risk criteria to a large prospective database resulted in 35% of patients being identified at risk for hereditary RCC who could qualify for genetic testing. However, the true incidence of hereditary RCC in this population is unknown as most patients did not have documented genetic testing carried out and, thus, the sensitivity and specificity of the criteria cannot be determined. The low proportion of at-risk patients who underwent genetic testing is disappointing and highlights that there may be gaps in reporting, knowledge and/or barriers in access to genetic testing.

Renal cell carcinoma in the Canadian Indigenous population.

Background: Diagnosis and treatment of renal cell carcinoma (rcc) might be different in Indigenous Canadians than in non-Indigenous Canadians. In this cohort study, we compared rcc presentation and treatments in Indigenous and non-Indigenous Canadians. Methods: Patients registered in the Canadian Kidney Cancer Information System treated at 16 institutions between 2011 and 2018 were included. Baseline patient, tumour, and treatment characteristics were compared between Indigenous and non-Indigenous Canadians. The primary objective was to determine if differences in rcc stage at diagnosis were evident between the groups. The secondary objective was to determine if treatments and outcomes were different between the groups. Results: During the study period, 105 of the 4529 registered patients self-identified as Indigenous. Those patients were significantly younger at the time of clinical diagnosis (57.9 ± 11.3 years vs. 62.0 ± 12.1 years, p = 0.0006) and had a family history prevalence of rcc that was double the prevalence in the non-Indigenous patients (14% vs. 7%, p = 0.004). Clinical stage at diagnosis was similar in the two groups (p = 0.61). The disease was metastatic at presentation in 11 Indigenous Canadians (10%) and in 355 non-Indigenous Canadians (8%). Comorbid conditions that could affect the management of rcc-such as obesity, renal disease, diabetes mellitus, and smoking-were more common in Indigenous Canadians (p < 0.05). Indigenous Canadians experienced a lower rate of active surveillance (p = 0.01). Treatments and median time to treatments were similar in the two groups. Conclusions: Compared with their non-Indigenous counterparts, Indigenous Canadian patients with rcc are diagnosed at an earlier age and at a similar clinical stage. Despite higher baseline comorbid conditions, clinical outcomes are not worse for Indigenous Canadians than for non-Indigenous Canadians.

Inhibition of attaching and effacing lesion formation following enteropathogenic Escherichia coli and Shiga toxin-producing E. coli infection.

Enteropathogenic Escherichia coli (EPEC) and Shiga toxin-producing E. coli (STEC) induce cytoskeletal changes in infected epithelial cells. To further characterize host cytosolic responses to infection, a series of specific cell-signaling inhibitors were employed. Initial bacterial adhesion to HEp-2 epithelial cells was not reduced, whereas alpha-actinin accumulation in infected cells was blocked by a phosphoinositide-specific phospholipase C inhibitor (ET-18-OCH3), phosphoinositide 3-kinase inhibitors (wortmannin and LY294002), and a 5-lipoxygenase inhibitor, nordihydroguaretic acid. A cyclooxygenase-2 inhibitor (NS-398), however, did not block alpha-actinin reorganization in response to EPEC and STEC infections. Understanding signal transduction responses to enteric pathogens could provide the basis for the development of novel therapeutic strategies.