Outcomes from treatment of metastatic renal-cell carcinoma following failure of first-line anti-VEGF/VEGFR therapy: real-life evidence on the change of the treatment paradigm.

Recently approved agents for post-vascular endothelial growth factor/post-vascular endothelial growth factor receptor (VEGF/VEGFR) inhibitors treatment of metastatic renal-cell carcinomas (mRCC), such as axitinib, nivolumab, and cabozantinib were shown to improve prognosis and substituted everolimus in this setting. We studied practice patterns, efficacy, and tolerability of these agents in a real-world series of Greek patients. We included patients with mRCC who received everolimus, axitinib, or nivolumab after progression on first-line anti-VEGF/VEGFRs therapy. Patients were stratified into three groups. Group A received nivolumab with or without cabozantinib at some point in their disease. Group B received axitinib but without nivolumab or cabozantinib. Group C received only everolimus among the four approved agents. Overall, 131 patients were included in the analysis. Everolimus and nivolumab were mainly used in the second line, while axitinib and cabozantinib were mostly used in the third and fourth lines. Median overall survival (OS) from first-line initiation was 8.7 [95% confidence interval (CI), 4-not reached], 3.6 (95% CI, 2-6), and 2.1 years (95% CI, 1.4-2.6) for Group A, B, and C, respectively ( P < 0.001). Median OS from the initiation of second-line therapy was 3.5, 2.7, and 1.3 years, respectively ( P < 0.001). There was no impact of first-line agent or treatment timing on survival. International Metastatic Renal Cell Carcinoma Database Consortium risk stratification was associated with OS. Toxicities observed were within expected frequencies. Grade ≥3 events were rare. Adoption of modern standards in everyday treatment of mRCC results in prolongation of survival. Real-world datasets are the new landmarks of survival for future research.

Pembrolizumab in combination with bevacizumab and oral cyclophosphamide in heavily pre-treated platinum-resistant ovarian cancer.

OBJECTIVE: Immune checkpoint inhibitors have been widely implemented in the treatment of solid tumors. Combinations of immune checkpoint inhibitors with chemotherapy, anti-vascular endothelial growth factor (VEGF) compounds, and poly-adenosine diphosphate-ribose polymerase inhibitors (PARP) are under evaluation in ovarian cancer. We aim to explore the efficacy of pembrolizumab in combination with bevacizumab and oral cyclophosphamide in patients with recurrent epithelial ovarian cancer. METHODS: This was a retrospective study of all patients who received pembrolizumab in combination with bevacizumab and oral cyclophosphamide for recurrent platinum-resistant heavily pre-treated ovarian cancer in the Oncology Unit of Alexandra University Hospital from January 2021 to July 2022. RESULTS: Median age at diagnosis was 56 years (SD 9.2; range 37-72). All patients were diagnosed with high-grade serous ovarian carcinoma. Initial disease stage was International Federation of Gynecology and Obstetrics (FIGO) IIIC in most cases (11/15, 73%). Patients were heavily pre-treated with a median of six (range 4-9) prior lines of systemic therapy. All patients experienced disease progression on first-line platinum-based chemotherapy, and median progression-free survival on first-line treatment was 22 months (95% CI 10.6 to 33.4). Patients received a median of four cycles of pembrolizumab in combination with cyclophosphamide and bevacizumab (range 3-20). Overall response rate was 13% (2/15) and disease control rate was 33% (5/15) with two patients achieving partial response and three patients achieving stable disease. Median progression-free survival was 3.5 months (95% CI 1.3 to 5.7) and the 6-month progression-free survival rate was 20%. Treatment was well tolerated with no dose-limiting toxicities. CONCLUSION: We showed that the combination of pembrolizumab with bevacizumab and oral cyclophosphamide is an effective alternative in heavily pre-treated patients with ovarian cancer who have otherwise limited treatment options.

Lymphocytic infiltration and Chemotherapy Response Score as prognostic markers in ovarian cancer patients treated with Neoadjuvant chemotherapy.

Neoadjuvant Chemotherapy (NACT) followed by Interval Debulking Surgery (IDS) is an accepted frontline treatment in patients with advanced Epithelial Ovarian Cancer (EOC). Histopathologic assessment of tumor post NACT may provide a surrogate for response to treatment. The present study aims to characterize the pathological response and to examine its prognostic significance in these patients. Medical records of women with EOC treated in our institution from 2011 to 2016 were retrospectively identified. IDS specimens were reviewed by study pathologist and Chemotherapy Response Score (CRS), lymphocytic infiltration, necrosis and mitosis were assessed. 55 patients with EOC treated with NACT were identified and 48 had complete clinical and pathological data. Median age was 63 years. CRS assessed at omentum predicted PFS when adjusted for age, stage, debulking status (complete, optimal, suboptimal) and post IDS bevacizumab administration (mPFS CRS 1 vs 2 vs 3: 10.3-14-18.7 months 95% CI [7.4-15.7], [12.2-22.9], [13.5-31.3]). Presence of lymphocytic infiltration was associated with improved OS (log-rank test P = 0.015). Post IDS bevacizumab was associated with shorter PFS in patients with lymphocytic infiltration. BRCA status was known for 25 patients and presence of BRCA1/2 mutations was strongly correlated with lymphocytic infiltration (P = 0.011) but not CRS omentum (P = 0.926). Our study confirms the predictive value of CRS in EOC patients treated with NACT and IDS, but also demonstrates the prognostic significance of lymphocytic infiltration as well as its possible interaction with bevacizumab treatment.

Response of an oncology unit in the midst of the COVID-19 outbreak.

Coronavirus disease 19 (COVID-19) pandemic has caused an emergency in health systems worldwide. Apart from its apparent morbidity and mortality, COVID-19 has also imposed unique challenges in the management of cancer patients. We report here measures taken by a major oncology Unit in Greece to continue operation of the department while ensuring safety of the patients and health care professionals. The efficacy of these measures could serve as guidance for Oncology departments in view of a second wave of COVID-19 cases.

Clinical Perspectives of ERCC1 in Bladder Cancer.

ERCC1 is a key regulator of nucleotide excision repair (NER) pathway that repairs bulky DNA adducts, including intrastrand DNA adducts and interstrand crosslinks (ICLs). Overexpression of ERCC1 has been linked to increased DNA repair capacity and platinum resistance in solid tumors. Multiple single nucleotide polymorphisms (SNPs) have been detected in ERCC1 gene that may affect ERCC1 protein expression. Platinum-based treatment remains the cornerstone of urothelial cancer treatment. Given the expanding application of neoadjuvant and adjuvant chemotherapy in locally advanced bladder cancer, there is an emerging need for biomarkers that could distinguish potential responders to cisplatin treatment. Extensive research has been done regarding the prognostic and predictive role of ERCC1 gene expression and polymorphisms in bladder cancer. Moreover, novel compounds have been recently developed to target ERCC1 protein function in order to maximize sensitivity to cisplatin. We aim to review all the existing literature regarding the role of the ERCC1 gene in bladder cancer and address future perspectives for its clinical application.

The combination of bevacizumab/temsirolimus after first-line anti-VEGF therapy in advanced renal-cell carcinoma: a clinical and biomarker study.

BACKGROUND: Vascular endothelial growth factor (VEGF) targeting represents the standard first-line therapy for metastatic renal-cell carcinoma (mRCC), while blocking the mammalian target of rapamycin (mTOR) is effective in relapsed disease. Since continuing blockade of VEGF may be of value, we studied the combination of bevacizumab with temsirolimus in mRCC patients relapsing after first-line treatment. METHODS: A prospective, phase II study of the combination of bevacizumab (10 mg/kg, every 2 weeks) with temsirolimus (25 mg weekly) in patients with mRCC who failed first-line anti-VEGF treatment. 6-month progression-free survival (PFS) rate was the primary end point. The association of VEGFa, VEGFR2, fibroblast growth factor (FGF) b, platelet-derived growth factor receptor (PDGFR) a and PDGFRb with prognostic factors and outcomes were also studied. RESULTS: 39 patients were enrolled. First-line therapy included: sunitinib (n = 16), bevacizumab/interferon (n = 12), pazopanib (n = 10), sorafenib (n = 1). After a median follow-up of 37 months, 6-month PFS rate was 50.9% [95% confidence interval (CI) 33.8-65.7], median time to progression 6.8 months (95% CI 5.5-9.2) and median overall survival (OS) 18.2 months (95% CI 12.9-27.2). Objective response rate was 27%. The most common AEs were metabolic (33%), renal (8%) and gastrointestinal (GI) (7%). The most common grade 3-5 AEs were GI (18%), infections (14%) and metabolic (25%). Toxicity was the most frequent cause of treatment discontinuation (40%). FGFb levels were associated with OS. CONCLUSIONS: In concert with recent data, our study confirms the efficacy of anti-VEGF/anti-mTOR combination in mRCC relapsing after anti-VEGF therapy. Toxicity was considerable leading to high rate of treatment discontinuations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01264341.

Expression and prognostic significance of VEGF and mTOR pathway proteins in metastatic renal cell carcinoma patients: a prognostic immunohistochemical profile for kidney cancer patients.

PURPOSE: To identify prognostic molecular profiles in patients with mRCC treated with sunitinib, we performed immunohistochemical analysis for VEGF and PI3K/Akt/mTOR pathway components. METHODS: The immunohistochemical expression of VEGF, p85α, p110γ, PTEN, p-Akt, p-mTOR, p-4E-BP1 and p-p70S6K was studied in 79 patients with mRCC who received first-line treatment with sunitinib. Expression was correlated with clinicopathological features and survival. RESULTS: VEGF was highly expressed (median H-Score 150), while positivity for the markers of the PI3K/Akt/mTOR pathway was: p85α 43/66 (65 %), p110γ41/60 (68 %), PTEN 32/64 (50 %), p-Akt57/63 (90 %), p-mTOR48/64 (75 %), p-4E-BP1 58/64 (90 %) and p-p70S6K 60/65 (92 %). No single immunohistochemical marker was found to have prognostic significance. Instead, the combination of increased p-mTOR and low VEGF expression was adversely correlated with overall survival (OS) (3.2 vs. 16.9 months, P = 0.001). CONCLUSION: Immunohistochemistry for VEGF and p-mTOR proteins may discriminate patients refractory to first-line sunitinib with poor prognosis. Prospective validation of our findings is needed.

Two cycles of adjuvant carboplatin in stage I seminoma: 8-year experience by the Hellenic Cooperative Oncology Group (HECOG).

PURPOSE: Following the establishment of adjuvant carboplatin in stage I testicular seminoma as a standard, we adopted this treatment for all stage I seminoma patients. We report our 8-year experience and compare these results with our previous adjuvant etoposide/cisplatin (EP) strategy. PATIENTS AND METHODS: Patients with stage I seminoma, treated with adjuvant carboplatin and with a minimum follow-up of 1 year, were included. Two cycles of carboplatin [area under the curve (AUC) 6] were administered. RESULTS: A total of 138 patients with median age of 34 years, treated from September 2003 to December 2011, were selected. There were 5 relapses [5-year relapse-free rate (RFR) 96.8 % (95 % confidence interval 91.6-98.8)]: 3 relapses at retroperitoneal lymph nodes, 1 relapse at the adrenal gland, and 1 isolated brain metastasis. Four patients with relapse were cured with salvage chemotherapy. All patients with relapse had tumor diameter ≥4 cm and/or age ≤34 years. Patients with at least 1 of the above risk factors (n = 111) had a significantly higher relapse rate compared with a similar population (n = 64) treated with 2 cycles of adjuvant EP: 5-year RFR was 95 % (SE 2 %) versus 100 % (SE 0 %), (p = 0.067). CONCLUSIONS: Age and tumor diameter were associated with relapse in stage I seminoma treated with adjuvant carboplatin. Although adjuvant carboplatin in patients with age ≤34 and/or tumor diameter ≥4 cm is associated with higher relapse rates than EP, the prognosis of these patients is excellent, and therefore, the use of less toxic treatment is justified.

Novel therapies for advanced squamous cell carcinoma of the lung.

Advanced squamous non-small-cell lung carcinoma (SqCC) has traditionally been considered the 'neglected sibling' compared with lung adenocarcinoma due to lack of effective targeted treatment options. Currently, limited progress has been made in the systemic treatment of advanced disease and combination chemotherapy remains the gold standard. However, the recent completion of the molecular characterization of SqCC revealed an interestingly complex genomic profile, comprising various genetic alterations that can potentially function as molecular targets for the development of novel targeted agents. Recent encouraging results of the use of immune checkpoint inhibitors in several neoplasms has emerged as a promising novel treatment option for advanced SqCC. Future personalized studies, enrolling SqCC patients according to specific driving mutations are underway.

Cardiovascular complications of ribociclib in breast cancer patients.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have unprecedentedly advanced hormone-dependent breast cancer treatment paradigm. In the metastatic setting, ribociclib has consistently demonstrated survival benefit in pre-, peri-, and postmenopausal patients, conjugating efficacy with health-related quality of life preservation. Accordingly, the emergence of cardiac and/or vascular adverse events related to this novel targeted agent is gaining significant interest. This narrative review provides an overview of the incidence and spectrum of cardiovascular toxicity, in both clinical trial framework and real-world evidence. The potential pathogenetic mechanism, along with the available diagnostic parameters including biomarkers, and proper management, are also summarized.

Predictive tissue markers in testicular germ cell tumors: Immunohistochemical expression of MLH1 and REV-7 proteins.

PURPOSE: Testicular Germ Cell Tumors (TGCTs) are the most frequent solid malignancies in young adult men. Regardless of differences in their cell of origin, all TGCTs are considered highly curable malignancies. However, approximately 3-5% of all TGCTs do not respond to platinum-based chemotherapies. The purpose of our paper is to investigate whether immunohistochemical expression of MLH1 and REV-7 can be used as predictive tissue markers for TGCTs. MATERIAL AND METHODS: The main demographic and clinicopathological characteristics of 64 male patients with TGCTs who underwent orchiectomy from 2007 to 2022 were retrospectively obtained from two large Oncology Clinics in Greece. Both patients with chemosensitive and chemoresistant disease were included. Immunohistochemical staining for MLH1 and REV-7 proteins was applied in specimens of these patients. RESULTS: 31 seminomas and 33 non-seminomas were included. 48 patients had chemosensitive disease, while 16 had chemoresistant disease. 53 specimens showed preserved MLH1 expression, while 11 specimens had lost MLH1 expression. Expression of MLH1 was only significantly associated with patients' age. 16 specimens showed positive REV-7 expression, while 48 specimens were REV-7 negative. Interestingly, 50% of patients with chemoresistant disease and 16,7% of patients with chemosensitive disease were REV-7 positive. This difference was statistically significant. Moreover, REV-7 positivity was significantly associated with chemoresistance, various clinicopathological parameters and patients' prognosis and survival. CONCLUSION: Loss of MLH1 expression was only found to be significantly associated with lower patients' age. Positive immunohistochemical REV-7 expression was significantly associated with various clinicopathological parameters, while it was also associated with significantly lower survival and greater hazard. REV-7 positive percentages were significantly higher in patients with chemoresistant disease. Our findings imply that immunohistochemical staining for REV-7 could potentially be used as a predictive tissue marker for TGCT tumors. Moreover, targeting of REV-7 protein, could represent a potential therapeutic strategy for chemoresistant TGCT cases. The implementation of well-designed studies on a larger scale is of utmost importance, in order to draw safer conclusions. Additional studies are needed so as to draw safer conclusions.

Intravenous rituximab and oral cyclophosphamide for the treatment of cancer­associated retinopathy in a patient with epithelial ovarian cancer: A case report.

Cancer-associated retinopathy (CAR) is a rare paraneoplastic disorder mediated by auto-antibodies that cross-react with retinal antigens leading to gradual visual defects. Early diagnosis and initiation of treatment is crucial to avoid permanent visual loss. Although most patients with CAR respond to intravenous steroids and intravenous immunoglobulin (IVIG), there are some cases refractory to the aforementioned treatment strategies. The present study describes a case of CAR in a patient with ovarian cancer that was initially resistant to most treatment regimens (chemotherapy, steroids, IVIG). Treatment with rituximab at 375 mg/m2 and oral cyclophosphamide was administered and the patient showed marked improvement of visual acuity. Electroretinogram showed a 40 and 10% improvement in scotopic and photopic vision, respectively. Notably, at the most recent follow up, the patient was still in remission. In conclusion, treatment with intravenous rituximab and oral cyclophosphamide is a promising treatment option for those cases of CAR that do not respond to steroids, immunomodulatory agents and IVIG.

Optimal Time Interval between Neoadjuvant Platinum-Based Chemotherapy and Interval Debulking Surgery in High-Grade Serous Ovarian Cancer.

BACKGROUND: There is limited data on the optimal time interval between the last dose of neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) in high-grade serous ovarian carcinoma (HGSC). METHODS: We retrospectively identified patients with stage IIIC/IV HGSC who received NACT followed by IDS during a 15-year period (January 2003-December 2018) in our Institution. RESULTS: Overall, 115 patients with stage IIIC/IV HGSC were included. The median age of diagnosis was 62.7 years (IQR: 14.0). A total of 76.5% (88/115) of patients were diagnosed with IIIC HGSC and 23.5% (27/115) with IV HGSC. Median PFS was 15.7 months (95% CI: 13.0-18.5), and median OS was 44.7 months (95% CI: 38.8-50.5). Patients were categorized in groups according to the time interval from NACT to IDS: <4 weeks (group A); 4-5 weeks (group B); 5-6 weeks (group C); >6 weeks (group D). Patients with a time interval IDS to NACT ≥4 weeks had significantly shorter PFS (p = 0.004) and OS (p = 0.002). Median PFS was 26.6 months (95% CI: 24-29.2) for patients undergoing IDS <4 weeks after NACT vs. 14.4 months (95% CI: 12.6-16.2) for those undergoing IDS later (p = 0.004). Accordingly, median OS was 66.3 months (95% CI: 39.1-93.4) vs. 39.4 months (95% CI: 31.8-47.0) in the <4 week vs. >4 week time interval NACT to IDS groups (p = 0.002). On multivariate analysis, the short time interval (<4 weeks) from NACT to IDS was an independent factor of PFS (p = 0.004) and OS (p = 0.003). CONCLUSION: We have demonstrated that performing IDS within four weeks after NACT may be associated with better survival outcomes. Multidisciplinary coordination among ovarian cancer patients is required to avoid any unnecessary delays.

Digging into the NGS Information from a Large-Scale South European Population with Metastatic/Unresectable Pancreatic Ductal Adenocarcinoma: A Real-World Genomic Depiction.

Despite ongoing oncological advances, pancreatic ductal adenocarcinoma (PDAC) continues to have an extremely poor prognosis with limited targeted and immunotherapeutic options. Its genomic background has not been fully characterized yet in large-scale populations all over the world. Methods: Replicating a recent study from China, we collected tissue samples from consecutive Greek patients with pathologically-confirmed metastatic/unresectable PDAC and retrospectively investigated their genomic landscape using next generation sequencing (NGS). Findings: From a cohort of 409 patients, NGS analysis was successfully achieved in 400 cases (56.50% males, median age: 61.8 years). Consistent with a previous study, KRAS was the most frequently mutated gene in 81.50% of tested samples, followed by TP53 (50.75%), CDKN2 (8%), and SMAD4 (7.50%). BRCA1/2 variants with on-label indications were detected in 2%, and 87.50% carried a variant associated with off-label treatment (KRAS, ERBB2, STK11, or HRR-genes), while 3.5% of the alterations had unknown/preliminary-studied actionability (TP53/CDKN2A). Most of HRR-alterations were in intermediate- and low-risk genes (CHEK2, RAD50, RAD51, ATM, FANCA, FANCL, FANCC, BAP1), with controversial actionability: 8% harbored a somatic non-BRCA1/2 alteration, 6 cases had a high-risk alteration (PALB2, RAD51C), and one co-presented a PALB2/BRCA2 alteration. Elevated LOH was associated with HRR-mutated status and TP53 mutations while lowered LOH was associated with KRAS alterations. Including TMB/MSI data, the potential benefit from an NGS-oriented treatment was increased from 1.91% to 13.74% (high-MSI: 0.3%, TMB > 10 muts/MB: 12.78%). TMB was slightly increased in females (4.75 vs. 4.46 muts/MB) and in individuals with age > 60 (4.77 vs. 4.40 muts/MB). About 28.41% showed PD-L1 > 1% either in tumor or immune cells, 15.75% expressed PD-L1 ≥ 10%, and only 1.18% had PD-L1 ≥ 50%. This is the largest depiction of real-world genomic characteristics of European patients with PDAC, which offers some useful clinical and research insights.

Oncological Patients With Endocrine Complications After Immunotherapy With Checkpoint Inhibitors Present Longer Progression-Free and Overall Survival.

Aim: The aim of this study was to investigate the association of endocrine complications after ICI immunotherapy with progression-free survival (PFS) and overall survival (OS) in a large single-center oncological cohort. Patients and Methods: In total, 351 patients were included in the analysis, 248 men (70.7%) and 103 women (29.3%). The median age was 66 years. Patients had a variety of cancer types, namely, bladder cancer (131, 37.3%), renal cancer (89, 25.4%), lung cancer (74, 21.1%), ovarian cancer (22, 6.3%), and other types of cancer (35, 10%). The majority (314, 89.4%) were classified as stage IV, while 10.6% (37) were classified as stage III. Most of the patients received immunotherapy with anti-PD1 agents (262, 74.6%) and the rest with anti-PD-L1 agents (89, 25.4%). Kaplan-Meier estimates were used to describe and visualize the effect of categorical variables on OS and PFS. Survival analysis was performed by Kaplan-Meier curves, and survival differences between groups were estimated using the log-rank test. The estimation of the prognostic value of several variables with patients' survival was made by Cox regression models. Results: In total, 68 (19.4%) of patients presented an endocrine complication after immunotherapy with ICIs. Specifically, 66 (18.8%) had thyroid dysfunction, 1 patient presented hypophysitis (0.3%), and 1 patient had a combination of thyroid dysfunction and hypophysitis (0.3%). Patients with an endocrine complication had mPFS of 15 months (95% CI 11.0-18.9 months), while in those without endocrine complication mPFS was 7 months (95% CI 6.1-7.9 months, p < 0.001). Similarly, median OS (mOS) was statistically significant lower in the patients' group without endocrine complication. In fact, mOS was 51 months (95% CI 39.3-62.7 months) for these patients. The presence of endocrine complications after immunotherapy with ICIs retained its significance in terms of longer PFS (HR 0.57, 95% CI 0.39-0.81) and OS (HR 0.53, 95% CI 0.32-0.90) after multivariate analysis. Conclusions: ICI endocrinopathies may be a positive predictor of immunotherapy response.

Germline and somatic variants in ovarian carcinoma: A next-generation sequencing (NGS) analysis.

Background: Germline BRCA1/2 mutations are identified in 13-15% of ovarian cancers, while an additional 5-7% of ovarian cancers harbor somatic BRCA1/2 mutations. Beyond these mutations, germline or somatic aberrations in genes of the homologous recombination (HR) pathway such as RAD51B/C/D, PALB2, ATM, BRIP1 may confer an HR deficiency in up to 50% of ovarian tumors. Next-generation sequencing (NGS) is a high-throughput massive parallel sequencing method that enables the simultaneous detection of several mutations in entire genomes. Methods: We performed NGS analysis in 86 patients with ovarian cancer treated in the Oncology Department of Alexandra University Hospital in order to identify the molecular landscape of germline and somatic mutations in ovarian cancer. Results: The genes with the highest number of pathogenic somatic mutations in high grade serous carcinoma (HGSC) patients were TP53 [68%; 34/50] and BRCA1 [22%; 11/50] followed by somatic mutations in RB1 [2%; 1/50], NF1 [2%; 1/50], BRCA2 [2%; 1/50], AKT1 [2%; 1/50], RAD50 [2%; 1/50], PIK3CA [2%; 1/50] genes. Of note, the most common TP53 genetic polymorphism was c.524G>A p.Arg175His in exon 5. Variants of unknown significance (VUS) detected in HGSC included ROS1 [26%; 13/50], RAD50 [6%; 3/50], BRCA2 [6%; 3/50], NOTCH1 [6%; 3/50], TP53 [6%; 3/50], AR [6%; 3/50]. As for germline mutations, BRCA1 [8/30; 27%] and BRCA2 [4/30; 13%] were the most common genes bearing pathogenic alterations in HGSC, while VUS germline mutations commonly affected HRR-related genes, including ATM (c.7816A>G), BRIP (c.2327 C>A), CHEK2 (c.320-5T>A). Conclusion: Overall, genetic testing should be offered in most patients with ovarian cancer to identify mutations in HRR genes and determine the population that would be susceptible to poly ADP ribose polymerase (PARP) inhibitors.

SARS-CoV-2 Neutralizing Antibodies Kinetics Postvaccination in Cancer Patients under Treatment with Immune Checkpoint Inhibition.

Considering that COVID-19 could adversely affect cancer patients, several countries have prioritized this highly susceptible population for vaccination. Thus, rapidly generating evidence on the efficacy of SARS-CoV-2 vaccination in the subset of patients with cancer under active therapy is of paramount importance. From this perspective, we launched the present prospective observational study to comprehensively address the longitudinal dynamics of immunogenicity of both messenger RNA (mRNA) and viral vector-based vaccines in 85 patients treated with immune checkpoint inhibitors (ICIs) for a broad range of solid tumors. Despite the relatively poor humoral responses following the priming vaccine inoculum, the seroconversion rates significantly increased after the second dose. Waning vaccine-based immunity was observed over the following six months, yet the administration of a third booster dose remarkably optimized antibody responses. Larger cohort studies providing real-world data with regard to vaccines effectiveness and durability of their protection among cancer patients receiving immunotherapy are an increasing priority.

Treatment with abiraterone or enzalutamide does not impair immunological response to COVID-19 vaccination in prostate cancer patients.

Data regarding the safety and efficacy of COVID-10 vaccines among cancer patients are lacking. Factors such as age, underlying disease and antineoplastic treatment confer negatively to the immune response due to vaccination. The degree of immunosuppression though may be lessen by targeted treatments like the androgen receptor-targeted agents (ARTA) that are commonly used in patients with metastatic prostate cancer. Herein, we report our data on 25 patients with prostate cancer under treatment with ARTA who were vaccinated for COVID-19. Our data suggest that these patients develop neutralizing antibodies against SARS-CoV-2 similarly to healthy volunteers. No safety issues were noted.

Assessment of Postvaccination Neutralizing Antibodies Response against SARS-CoV-2 in Cancer Patients under Treatment with Targeted Agents.

The administration of a third dose of a vaccine against SARS-CoV-2 has increased protection against disease transmission and severity. However, the kinetics of neutralizing antibodies against the virus has been poorly studied in cancer patients under targeted therapies. Baseline characteristics and levels of neutralizing antibodies at specific timepoints after vaccination were compared between patients suffering from breast, ovarian or prostate cancer and healthy individuals. Breast cancer patients were treated with cyclin D kinase 4/6 inhibitors and hormonal therapy, ovarian cancer patients were treated with poly (ADP-ribose) polymerase inhibitors and prostate cancer patients were treated with an androgen receptor targeted agent. Levels of neutralizing antibodies were significantly lower in cancer patients compared to healthy individuals at all timepoints. Antibodies' titers declined over time in both groups but remained above protective levels (>50%) at 6 months after the administration of the second dose. The administration of a third dose increased neutralizing antibodies' levels in both groups. The titers of protective against SARS-CoV-2 antibodies wane over time and increase after a third dose in cancer patients under treatment.

Risk for Arterial Thromboembolic Events (ATEs) in Patients with Advanced Urinary Tract Cancer (aUTC) Treated with First-Line Chemotherapy: Single-Center, Observational Study.

Arterial thromboembolism has been associated with cancer or its treatment. Unlike venous thromboembolism, the incidence and risk factors have not been extensively studied. Here, we investigated the incidence of arterial thromboembolic events (ATEs) in an institutional series of advanced urinary tract cancer (aUTC) treated with cytotoxic chemotherapy. The ATE definition included peripheral arterial embolism/thrombosis, ischemic stroke and coronary events. A total of 354 aUTC patients were analyzed. Most patients (95.2%) received platinum-based chemotherapy. A total of 12 patients (3.4%) suffered an ATE within a median time of 3.6 months from the start of chemotherapy. The most frequent ATE was ischemic stroke (n = 7). Two ATEs were fatal. The 6-month and 24-month incidence were 2.1% (95% confidence interval [CI]: 0.9-4.1) and 3.6% (95% CI: 1.9-6.2), respectively. Perioperative chemotherapy increased the risk for ATE by 5.55-fold. Tumors other than UTC and pure non-transitional cell carcinoma histology were also independent risk factors. No association with the type of chemotherapy was found. Overall, ATEs occur in 4.6% of aUTC patients treated with chemotherapy and represent a clinically relevant manifestation. Perioperative chemotherapy significantly increases the risk for ATE. The role of prophylaxis in high-risk groups should be prospectively studied.