ABSTRACT
Background: Clear cell renal cell carcinoma (ccRCC) is the main component of renal cell carcinoma (RCC), and advanced ccRCC frequently indicates a poor prognosis. The significance of the CCCH-type zinc finger (CTZF) gene in cancer has been increasingly demonstrated during the past few years. According to studies, targeted radical therapy for cancer treatment may be a revolutionary therapeutic approach. Both lncRNAs and CCCH-type zinc finger genes are essential in ccRCC. However, the predictive role of long non-coding RNA (lncRNA) associated with the CCCH-type zinc finger gene in ccRCC needs further elucidation. This study aims to predict patient prognosis and investigate the immunological profile of ccRCC patients using CCCH-type zinc finger-associated lncRNAs (CTZFLs). Methods: From the Cancer Genome Atlas database, RNA-seq and corresponding clinical and prognostic data of ccRCC patients were downloaded. Univariate and multivariate Cox regression analyses were conducted to acquire CTZFLs for constructing prediction models. The risk model was verified using receiver operating characteristic curve analysis. The Kaplan-Meier method was used to analyze the overall survival (OS) of high-risk and low-risk groups. Multivariate Cox and stratified analyses were used to assess the prognostic value of the predictive feature in the entire cohort and different subgroups. In addition, the relationship between risk scores, immunological status, and treatment response was studied. Results: We constructed a signature consisting of eight CTZFLs (LINC02100, AC002451.1, DBH-AS1, AC105105.3, AL357140.2, LINC00460, DLGAP1-AS2, AL162377.1). The results demonstrated that the prognosis of ccRCC patients was independently predicted by CTZFLs signature and that the prognosis of high-risk groups was poorer than that of the lower group. CTZFLs markers had the highest diagnostic adequacy compared to single clinicopathologic factors, and their AUC (area under the receiver operating characteristic curve) was 0.806. The overall survival of high-risk groups was shorter than that of low-risk groups when patients were divided into groups based on several clinicopathologic factors. There were substantial differences in immunological function, immune cell score, and immune checkpoint expression between high- and low-risk groups. Additionally, Four agents, including ABT737, WIKI4, afuresertib, and GNE 317, were more sensitive in the high-risk group. Conclusion: The Eight-CTZFLs prognostic signature may be a helpful prognostic indicator and may help with medication selection for clear cell renal cell carcinoma.
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Background: Nivolumab (NIVO), a programmed death-1 immune checkpoint inhibitor, has demonstrated clinical efficacy across patients with different tumor types, including clear cell renal cell carcinoma (ccRCC), when administered via IV infusion. As an alternative to IV infusion, subcutaneous (SC) administration alleviates the need for IV ports, thereby lowering the risk of associated complications such as infections and phlebitis. SC formulation also reduces the time for dose preparation and administration, which may decrease overall treatment burden and reduce patient time in the clinic, benefiting patients and healthcare providers and improving overall healthcare resource utilization. SC-administered NIVO consists of NIVO co-formulated with the recombinant human hyaluronidase PH20 enzyme (NIVO + rHuPH20), which aims to increase the dispersion and absorption of NIVO within the SC space. SC NIVO + rHuPH20 was shown to be safe and well tolerated in a phase 1/2 study, warranting further investigation (Lonardi S et al. J Clin Oncol 2021;39(suppl 15):2575). Methods: CheckMate 67T is a multicenter, randomized, open-label, phase 3 study that will evaluate the noninferiority of SC NIVO + rHuPH20 versus IV NIVO in patients with advanced or metastatic ccRCC who have progressed after receiving ≤ 2 prior systemic treatment regimens. Key inclusion criteria are age ≥ 18 years, histologically confirmed advanced or metastatic ccRCC, measurable disease by RECIST v1.1 within 28 days prior to randomization, and a Karnofsky performance status ≥ 70. Key exclusion criteria are untreated symptomatic metastases to the central nervous system, other malignancy, autoimmune diseases, HIV-positive status with AIDS-defining infection within past year or current CD4 count < 350 cells/μL, other serious or uncontrolled disorders including severe, acute SARS-CoV-2 infection, and prior treatment with immune checkpoint inhibitors, other T-cell-targeting antibody drugs, or live attenuated vaccines within 30 days of first study treatment. At least 454 eligible patients will be randomized to receive SC NIVO + rHuPH20 or IV NIVO. The primary objectives are to demonstrate pharmacokinetic (PK) noninferiority of SC NIVO versus IV NIVO, as measured by time-averaged serum concentration over the first 28 days (Cavgd28) and trough serum concentration at steady state (Cminss) (co-primary endpoints). Secondary endpoints include objective response rate by blinded independent central review, additional PK parameters, safety, efficacy, and immunogenicity of SC NIVO and IV NIVO. This study is currently enrolling patients globally.
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Background: Cabozantinib is a small molecule inhibitor of the tyrosine kinases c-Met, AXL and VEGFR2 that has been shown to reduce tumor growth, metastasis, and angiogenesis. After the promising results from the METEOR, CABOSUN and Checkmate-9ER trials, cabozantinib was approved for use in patients with advanced renal cell carcinoma (RCC). The increased response rates with cabozantinib in metastatic RCC, along with the other neoadjuvant TKI data, support an expanded role for cabozantinib in the neoadjuvant setting. Methods: Patients with clinical stage ≥ T3Nx or TanyN+ or deemed unresectable by the surgeon with biopsy-proven clear cell RCC were eligible for this study, and received cabozantinib at a starting dose of 60 mg daily for 12 weeks. The primary outcome was objective response rate per RECIST v1.1 (complete and partial responses) at week 12 after the administration of cabozantinib as determined by independent radiologist review. Secondary outcomes included safety, tolerability, clinical outcome (DFS, OS), surgical outcome and quality of life. Results: As of 20 September 2021, 16 biopsy-proven clear cell RCC patients were treated with neoadjuvant cabozantinib. The median age was 56 years (range: 41-84 years) and 81.2% male. All patients completed 12 weeks of treatment, and 15 of them underwent surgery as planned without any delay after completion of 4 weeks wash-out. One patient refused to undergo surgery due to personal reasons and received further systemic treatment. Five patients (31.2%) experienced a partial response, and 11 patients had stable disease. There was no progression of disease while on cabozantinib. Median reduction of primary renal tumor size was 24% (range: 6-45%). The one patient who was deemed to be unresectable became resectable at the end of treatment. Two patients were converted from radical to partial nephrectomy. The most common AEs were diarrhea, nausea, fatigue, hypertension, anorexia, and palmar-plantar erythrodysesthesia syndrome. Intraoperatively, we did not experience any immediate complications. Postoperatively, no surgical complications related to the drug were noted. No treatment related grade 4 or 5 AEs related to cabozantinib or surgery occurred. Two patients had died at the time of analysis (1 due to COVID and 1 unknown cause). Conclusions: Cabozantinib was clinically active and safe in the neoadjuvant setting in patients with locally advanced non-metastatic clear cell RCC. Additional data will be reported including long term outcomes, correlative studies, quality of life, and frailty/sarcopenia indices.
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Introduction & Objectives: The COVID-19 pandemic has forced disruptive changes in the prioritization of care in Urology worldwide. In response to the first peak of the outbreak, the European Association of Urology (EAU) Guidelines Office Rapid Reaction Group (GORRG) provided comprehensive recommendations to guide the prioritization of surgery for patients with non-metastatic renal cell carcinoma (RCC). Notably, to date, such priority groups have not been validated from a histopathological perspective. To fill this gap, in this study we sought to explore the diversity and predictors of histopathological findings across the EAU GORRG priority groups for renal tumors at a referral Academic Centre. Materials & Methods: After Ethical Committee approval, we queried our prospectively collected Institutional database to select consecutive patients undergoing elective surgery for cT1-4 N0-1 M0 renal masses between January 2017 and December 2020. The primary outcome measures at histopathological analysis were: a) benign histology;b) non-organ confined disease (pT3-4 and/or pN1);c) adverse pathologic features for both clear cell RCC (ccRCC) and papillary RCC (pRCC) according to validated prognostic models. Results: Overall, 940 (54.2%), 358 (20.6%) and 436 (25.2%) patients were classified as low-, intermediate- and high-priority, respectively. The three groups significantly differed regarding all primary histopathological outcomes: benign histology (21.6% vs 15.9% vs 6.4% for the low-, intermediate- and high-risk group, respectively, p<0.001);b) non-organ-confined disease (5.0% vs 19.0% vs 45.4%, p<0.001);c) adverse pathologic features according to validated prognostic models (including median Leibovich score for clear cell RCC: 0 vs 2 vs 4, p<0.001). At multivariable analysis, beyond the EAU GORRG priority groups, specific patient and/or tumor-related characteristics were independent predictors of the aforementioned histopathological outcomes. s EAU22 – 37th Annual EAU Congress (Figure Presented) Conclusions: To the best of our knowledge, our study showed for the first time the value of the EAU GORRG priority groups from a histopathological standpoint, prompting the implementation of such a prioritization scheme beyond the COVID-19 pandemic.
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Background: Often the onset symptoms of a disease don't easily direct towards the correct diagnosis. Furthermore, the CoViD-19 pandemic has often been an obstacle to obtaining a quick diagnosis. Description of the case: Male 49-year-old patient admitted to emergency room for persistent back pain, asthenia and weight loss. Physical examination revealed a palpable mass in the right gluteal region, chest X ray an enlargement of mediastinum. Nasopharingeal swab for CoViD-19 was positive (even if negative for CoViD-related symptoms);he was so hospitalized in our Internal Medicine CoViD Ward. Blood samples found microcytic anemia (thalassemic trait carrier);high ferritin (1072 ng/ml), aptoglobin (297 mg/dl, nv <200) and B2 microglobulin (3.25 mg/l, nv <2.53);K and L chains normal with K/L serum ratio reduction, increase in urine sample. Lymphocyte subpopulations were indicative of lymphopenia. Suspecting a lymphoproliferative disease, he performed a chest and abdomen CT scan that found: multiple bilateral pulmonary nodules, the largest one 10x9 cm in the left lung;a left renal lesion11x10 cm;a mass 9.5 cm of the sacroiliac left wing and splenomegaly (145 mm). We thus performed a US-assisted biopsy of the mass in the gluteal region. The histological examination allowed to identify metastasis from clear cell renal carcinoma. Conclusions: We report this case to highlight the peculiarity of onset of this renal carcinoma, in absence of genitourinary symptoms. Diagnostic autonomy can be a winning weapon in accelerating the diagnostic process, even more so in times of CoViD-19 pandemic.
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BACKGROUND: SARS-CoV-2 proteins binding human mRNAs (SPBRs) have been proven to regulate a variety of tumor-related functions in different types of cancer. However, their biological roles and potential mechanisms in clear cell renal cell carcinoma (ccRCC) are still elusive. Herein, we investigate the expression and prognostic value of SPBRs in ccRCC through bioinformatics methods. METHODS: Data downloaded from the Cancer Genome Atlas (TCGA) database was used to screen differentially expressed SPBRs (DE-SPBRs) between ccRCC samples and noncancerous samples. Metascape was utilized to perform function and pathway enrichment analyses of these DE-SPBRs. Kaplan-Meier method of overall survival (OS) was used to assess the prognostic value of DE-SPBRs in ccRCC patients. Univariate and multivariate Cox regression analyses were applied to identify candidate SPBRs, which were independently associated with overall survival of ccRCC patients. Subsequently, several internationally renowned databases were employed to conduct a comprehensive analysis of candidate SPBRs to further investigate their roles and mechanisms in ccRCC. RESULTS: A total of 33 DE-SPBRs, including 18 upregulated SPBRs and 17 downregulated SPBRs, were screened between ccRCC samples and noncancerous samples. Among them, two candidate SPBRs, KDELC1 and TRMT1, were identified. Additionally, we observed that upregulated KDELC1/TRMT1 expression in ccRCC at both gene and protein levels was significantly associated with clinicopathological features. Furthermore, we found that KDELC1/TRMT1 genetic mutation has an unfavorable influence on prognosis of patients with ccRCC. Functional enrichment analysis revealed that KDELC1/TRMT1 was closely enriched in several vital biological processes and pathways. Finally, we noticed that KDELC1/TRMT1 was remarkably associated with immune infiltrates. CONCLUSION: In summary, we screened DE-SPBRs of ccRCC, which were enriched mainly in various biological and signaling pathways with tumor progression. Furthermore, we identified two candidate DE-SPBRs (KDELC1 and TRMT1), which could serve as promising biomarkers and therapeutic targets of patients with ccRCC.