Oxaliplatin-induced Acute Neurotoxicity Recovers Between Repeat Infusion Cycles: An Axonal Excitability Repeated Multiple Measurements Study.

Background/Aim: Oxaliplatin, a platinum-based chemotherapy used in the treatment of colorectal cancer, induces acute neurotoxicity following infusion. The aim of this study was to establish whether alterations in axonal excitability develop progressively with higher cumulative doses and whether there is a recovery in motor axons after each cycle of treatment. Patients and Methods: Twenty consecutive patients with a colorectal cancer diagnosis, referred from the Oncology Department of Aretaieion Hospital of Athens, were enrolled in this study between October 2018 and May 2019. None of the participants had diabetes, alcohol abuse, known neuropathy or were previously treated with another neo-adjuvant therapy. Threshold Tracking techniques and Qtrac software were used for assessing axonal excitability in motor axons. Excitability recordings were undertaken before and immediately after the end of oxaliplatin infusion. Results: Statistically significant changes were found (p<0.01) in axonal excitability (relative refractory period, refractoriness at 2 ms and 2.5 ms, sub-excitability and super-excitability) before and after oxaliplatin infusion. No statistically significant changes (p>0.05) were found in threshold electrotonus and strength-duration parameters before and after oxaliplatin infusion. We also did not find statistically significant differences (p>0.05) between means of excitability parameters before infusion at each cycle. Conclusion: Our study confirms oxaliplatin-induced acute neurotoxicity following infusion and suggests that motor axons recover between repeat infusion cycles.

ENGOT-EN20/GOG-3083/XPORT-EC-042 - A phase III, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients with p53 wild-type, advanced, or recurrent endometrial carcinoma: rationale, methods, and trial design.

BACKGROUND: Patients with advanced/recurrent endometrial cancer have a poor prognosis and limited treatment options. Biomarkers such as tumor protein 53 (TP53) in endometrial cancer can integrate novel strategies for improved and individualized treatment that could impact patient outcomes. In an exploratory analysis of the phase III ENGOT-EN5/GOG-3055/SIENDO study of selinexor maintenance monotherapy 80 mg in advanced/recurrent endometrial cancer, a pre-specified subgroup of patients with TP53 wild type (wt) endometrial cancer showed preliminary activity at long-term follow-up with a generally manageable safety profile (median progression-free survival 27.4 months vs 5.2 months placebo, HR=0.41). PRIMARY OBJECTIVE: To evaluate the efficacy of selinexor compared with placebo as maintenance therapy in patients with advanced or recurrent TP53wt endometrial cancer. STUDY HYPOTHESIS: Selinexor administered at 60 mg weekly as maintenance therapy will show manageable safety and maintain efficacy in patients with TP53wt advanced/recurrent endometrial cancer after systemic therapy versus placebo. TRIAL DESIGN: This is a prospective, multicenter, double-blind, placebo-controlled, randomized phase III study designed to evaluate the efficacy and safety of selinexor as a maintenance therapy in patients with advanced or recurrent TP53wt endometrial cancer. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have histologically confirmed endometrial cancer, TP53wt confirmed by next-generation sequencing, completed at least 12 weeks of platinum-based therapy with or without immunotherapy, with confirmed partial response or complete response, and primary Stage IV disease or at first relapse. PRIMARY ENDPOINT: The primary endpoint is investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the intent-to-treat population. SAMPLE SIZE: A total of 220 patients will be enrolled. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual is expected to be completed in 2024 with presentation of results in 2025. TRIAL REGISTRATION: NCT05611931.

A Randomized Phase III Study of Arfolitixorin versus Leucovorin with 5-Fluorouracil, Oxaliplatin, and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer: The AGENT Trial.

PURPOSE: Suboptimal treatment outcomes with 5-fluorouracil (5-FU)/folate, the standard of care for metastatic colorectal cancer (mCRC), have generated interest in optimizing the folate. Arfolitixorin ([6R]-5,10-methylene-tetrahydrofolate) is an immediately active folate and may improve outcomes over the existing standard of care (leucovorin). EXPERIMENTAL DESIGN: AGENT was a randomized, phase III study (NCT03750786). Patients with mCRC were randomized to arfolitixorin (120 mg/m2 given as two intravenous bolus doses of 60 mg/m2) or leucovorin (400 mg/m2 given as a single intravenous infusion) plus 5-FU, oxaliplatin, and bevacizumab. Assessments were performed every 8 weeks. The primary endpoint was the superiority of arfolitixorin for overall response rate (ORR). RESULTS: Between February 2019 and April 2021, 490 patients were randomized (245 to each arm). After a median follow-up of 266 days, the primary endpoint of superiority for ORR was not achieved (48.2% for arfolitixorin vs. 49.4% for leucovorin, Psuperiority = 0.57). Outcomes were not achieved for median progression-free survival (PFS; 12.8 and 11.6 months, P = 0.38), median duration of response (12.2 and 12.9 months, P = 0.40), and median overall survival (23.8 and 28.0 months, P = 0.78). The proportion of patients with an adverse event of grade ≥3 severity was similar between arms (68.7% and 67.2%, respectively), as was quality of life. BRAF mutations and MTHFD2 expression were both associated with a lower PFS with arfolitixorin. CONCLUSIONS: The study failed to demonstrate clinical benefit of arfolitixorin (120 mg/m2) over leucovorin. However, it provides some useful insights from the first-line treatment setting, including the effect of gene expression on outcomes. SIGNIFICANCE: This phase III study compared arfolitixorin, a direct-acting folate, with leucovorin in FOLFOX plus bevacizumab in mCRC. Arfolitixorin (120 mg/m2) did not improve the ORR, potentially indicating a suboptimal dose.

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial.

PURPOSE: Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS: This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS: Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION: Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.

RediScore: Prospective validation of a pipeline for homologous recombination deficiency analysis.

Tumors harboring homologous recombination deficiency (HRD) are considered optimal candidates for poly(ADP-ribose) polymerase 1 (PARP) inhibitor treatment. Such deficiency can be detected by analyzing breast cancer type (BRCA)1/2 gene mutations, as well as mutations in other genes of the homologous recombination pathway. The algorithmic measurement of the HRD effect by identifying genomic instability (GI) has been used as biomarker. As compared with the direct measurement of somatic gene alterations, this approach increases the number of patients who could benefit from PARP inhibitor treatment. In the present study, the performance of the Oncoscan CNV assay, accompanied by appropriate bioinformatic algorithms, was evaluated for its performance in GI calculation and was compared with that of a validated next-generation sequencing (NGS) test (myChoice HRD test). In addition, the clinical utility of the GI score (GIS) and BRCA1/2 tumor analysis were investigated in a cohort of 444 patients with ovarian cancer. For that reason, single nucleotide polymorphism (SNP) arrays and appropriate bioinformatics algorithms were used to calculate GIS in 29 patients with ovarian cancer with known GIS status using a validated NGS test. Furthermore, BRCA1/2 analysis results were compared between the aforementioned assay and the amplicon-based Oncomine™ BRCA Research Assay. BRCA1/2 analysis was performed in 444 patients with ovarian cancer, while GIS was calculated in 175 BRCA1/2-negative cases. The bioinformatics algorithm developed for GIS calculation in combination with NGS BRCA1/2 analysis (RediScore), and the OncoscanR pipeline exhibited a high overall agreement with the validated test (93.1%). In addition, the Oncomine NGS assay had a 100% agreement with the validated test. The BRCA1/2 mutation frequency was 26.5% in the examined patients with ovarian cancer. GIS was positive in 40% of the BRCA1/2-negative cases. The RediScore bioinformatics algorithm developed for GIS calculation in combination with NGS BRCA1/2 analysis is a viable and effective approach for HRD calculation in patients with ovarian cancer, offering a positive prediction for PARP inhibitor responsiveness in 55% of the patients.

An impossibility theorem in game dynamics.

The Nash equilibrium-a combination of choices by the players of a game from which no self-interested player would deviate-is the predominant solution concept in game theory. Even though every game has a Nash equilibrium, it is not known whether there are deterministic behaviors of the players who play a game repeatedly that are guaranteed to converge to a Nash equilibrium of the game from all starting points. If one assumes that the players' behavior is a discrete-time or continuous-time rule whereby the current mixed strategy profile is mapped to the next, this question becomes a problem in the theory of dynamical systems. We apply this theory, and in particular Conley index theory, to prove a general impossibility result: There exist games, for which all game dynamics fail to converge to Nash equilibria from all starting points. The games which help prove this impossibility result are degenerate, but we conjecture that the same result holds, under computational complexity assumptions, for nondegenerate games. We also prove a stronger impossibility result for the solution concept of approximate Nash equilibria: For a set of games of positive measure, no game dynamics can converge to the set of approximate Nash equilibria for a sufficiently small yet substantial approximation bound. Our results establish that, although the notions of Nash equilibrium and its computation-inspired approximations are universally applicable in all games, they are fundamentally incomplete as predictors of long-term player behavior.

The Utility of NGS Analysis in Homologous Recombination Deficiency Tracking.

Several tumor types have been efficiently treated with PARP inhibitors (PARPis), which are now approved for the treatment of ovarian, breast, prostate, and pancreatic cancers. The BRCA1/2 genes and mutations in many additional genes involved in the HR pathway may be responsible for the HRD phenomenon. The aim of the present study was to investigate the association between genomic loss of heterozygosity (gLOH) and alterations in 513 genes with targeted and immuno-oncology therapies in 406 samples using an NGS assay. In addition, the %gLOHs of 24 samples were calculated using the Affymetrix technology in order to compare the results obtained via the two methodologies. HR variations occurred in 20.93% of the malignancies, while BRCA1/2 gene alterations occurred in 5.17% of the malignancies. The %LOH was highly correlated with alterations in the BRCA1/2 genes, since 76.19% (16/21) of the BRCA1/2 positive tumors had a high %LOH value (p = 0.007). Moreover, the LOH status was highly correlated with the TP53 and KRAS statuses, but there was no association with the TMB value. Lin's concordance correlation coefficient for the 24 samples simultaneously examined via both assays was 0.87, indicating a nearly perfect agreement. In conclusion, the addition of gLOH analysis could assist in the detection of additional patients eligible for treatment with PARPis.

Neuroscience Needs Network Science.

The brain is a complex system comprising a myriad of interacting neurons, posing significant challenges in understanding its structure, function, and dynamics. Network science has emerged as a powerful tool for studying such interconnected systems, offering a framework for integrating multiscale data and complexity. To date, network methods have significantly advanced functional imaging studies of the human brain and have facilitated the development of control theory-based applications for directing brain activity. Here, we discuss emerging frontiers for network neuroscience in the brain atlas era, addressing the challenges and opportunities in integrating multiple data streams for understanding the neural transitions from development to healthy function to disease. We underscore the importance of fostering interdisciplinary opportunities through workshops, conferences, and funding initiatives, such as supporting students and postdoctoral fellows with interests in both disciplines. By bringing together the network science and neuroscience communities, we can develop novel network-based methods tailored to neural circuits, paving the way toward a deeper understanding of the brain and its functions, as well as offering new challenges for network science.

Copy Number Variations (CNVs) Account for 10.8% of Pathogenic Variants in Patients Referred for Hereditary Cancer Testing.

BACKGROUND/AIM: Germline copy number variation (CNV) is a type of genetic variant that predisposes significantly to inherited cancers. Today, next-generation sequencing (NGS) technologies have contributed to multi gene panel analysis in clinical practice. MATERIALS AND METHODS: A total of 2,163 patients were screened for cancer susceptibility, using a solution-based capture method. A panel of 52 genes was used for targeted NGS. The capture-based approach enables computational analysis of CNVs from NGS data. We studied the performance of the CNV module of the commercial software suite SeqPilot (JSI Medical Systems) and of the non-commercial tool panelcn.MOPS. Additionally, we tested the performance of digital multiplex ligation-dependent probe amplification (digitalMLPA). RESULTS: Pathogenic/likely pathogenic variants (P/LP) were identified in 464 samples (21.5%). CNV accounts for 10.8% (50/464) of pathogenic variants, referring to deletion/duplication of one or more exons of a gene. In patients with breast and ovarian cancer, CNVs accounted for 10.2% and 6.8% of pathogenic variants, respectively. In colorectal cancer patients, CNV accounted for 28.6% of pathogenic/likely pathogenic variants. CONCLUSION: In silico CNV detection tools provide a viable and cost-effective method to identify CNVs from NGS experiments. CNVs constitute a substantial percentage of P/LP variants, since they represent up to one of every ten P/LP findings identified by NGS multigene analysis; therefore, their evaluation is highly recommended to improve the diagnostic yield of hereditary cancer analysis.

Fallopian tube cytology as a diagnostic tool for adnexal malignancy: the CytoSaLPs score.

INTRODUCTION: During the past decade, the theory that high-grade extrauterine pelvic tumors originate from the fallopian tube has been strongly suggested. Our study aims to illuminate the possible role of tubal cytology as an accessory identification tool for gynecologic extrauterine malignancies, allowing in the long term the implementation of population-level cytologic tube evaluation during all benign gynecologic surgeries that do not result in salpingectomy. MATERIALS AND METHODS: We ex vivo collect salpingeal epithelial cells from the fibria directly from fresh fallopian tube specimens from women undergoing salpingectomy for any indication. The cytomorphologic characteristics of the salpingeal cells are subsequently evaluated and categorized into malignant and non-malignant. Finally, the ipsilateral adnexa are examined with the SEE-FIM (Sectioning and Extensively Examining the FIMbriated End) protocol and the pathology reports are corelated with the cytologic findings. Our research protocol is ongoing and is designed to include a total of 300 patients in order to confirm the sensitivity and specificity of salpingeal cytology as a method in the early diagnosis of extrauterine gynecologic malignancies. RESULTS: So far, we have obtained 343 salpingeal brushings from a total of 214 patients. The sensitivity of cytology regarding distinguishing malignant from non-malignant tumors is 69.64% (95% CI: 55.90%-81.22%), and its specificity 75.96% (95% CI: 70.59%-80.79%). Cytology's positive predictive value (PPV) is 16.33% (95% CI: 12.57%-20.67%), while the negative predictive value (NPP) reached 92.77% (95% CI: 89.56%-95.04%). In general, the diagnostic accuracy of the cytologic evaluation reaches 74.93% (95% CI: 66.99%-79.43%). CONCLUSIONS: Salpingeal cytomorphologic evaluation appears to be a promising method for early detection of adnexal cancer.

Anti-Tumor Immunity and Preoperative Radiovaccination: Emerging New Concepts in the Treatment of Breast Cancer.

Neoadjuvant chemotherapy (NACT) for certain breast cancer (BC) subtypes confers significant tumor regression rates and a survival benefit for patients with a complete pathologic response. Clinical and preclinical studies have demonstrated that immune-related factors are responsible for better treatment outcomes, and thus, neoadjuvant immunotherapy (IO) has emerged as a means to further improve patient survival rates. Innate immunological "coldness", however, of specific BC subtypes, especially of the luminal ones, due to their immunosuppressive tumor microenvironment, hinders the efficacy of immune checkpoint inhibitors. Treatment policies aiming to reverse this immunological inertia are, therefore, needed. Moreover, radiotherapy (RT) has been proven to have a significant interplay with the immune system and promote anti-tumor immunity. This "radiovaccination" effect could be exploited in the neoadjuvant setting of BC and significantly enhance the effects of the already established clinical practice. Modern stereotactic irradiation techniques directed to the primary tumor and involved lymph nodes may prove important for the RT-NACT-IO combination. In this review, we provide an overview and critically discuss the biological rationale, clinical experience, and ongoing research underlying the interplay between neoadjuvant chemotherapy, anti-tumor immune response, and the emerging role of RT as a preoperative adjunct with immunological therapeutic implications in BC.

The Role of EMT-Related lncRNAs in Ovarian Cancer.

Ovarian cancer (OC) is one of the deadliest cancers worldwide; late diagnosis and drug resistance are two major factors often responsible for high morbidity and treatment failure. Epithelial-to-mesenchymal transition (EMT) is a dynamic process that has been closely linked with cancer. Long non-coding RNAs (lncRNAs) have been also associated with several cancer-related mechanisms, including EMT. We conducted a literature search in the PubMed database in order to sum up and discuss the role of lncRNAs in regulating OC-related EMT and their underlying mechanisms. Seventy (70) original research articles were identified, as of 23 April 2023. Our review concluded that the dysregulation of lncRNAs is highly associated with EMT-mediated OC progression. A comprehensive understanding of lncRNAs' mechanisms in OC will help in identifying novel and sensitive biomarkers and therapeutic targets for this malignancy.

Neuroscience needs Network Science.

The brain is a complex system comprising a myriad of interacting elements, posing significant challenges in understanding its structure, function, and dynamics. Network science has emerged as a powerful tool for studying such intricate systems, offering a framework for integrating multiscale data and complexity. Here, we discuss the application of network science in the study of the brain, addressing topics such as network models and metrics, the connectome, and the role of dynamics in neural networks. We explore the challenges and opportunities in integrating multiple data streams for understanding the neural transitions from development to healthy function to disease, and discuss the potential for collaboration between network science and neuroscience communities. We underscore the importance of fostering interdisciplinary opportunities through funding initiatives, workshops, and conferences, as well as supporting students and postdoctoral fellows with interests in both disciplines. By uniting the network science and neuroscience communities, we can develop novel network-based methods tailored to neural circuits, paving the way towards a deeper understanding of the brain and its functions.

The Utility of Fallopian Tube Cytology in the Early Detection of Extrauterine Serous Gynecological Malignancies: A Narrative Literature Review.

INTRODUCTION: The aim of the study was to analyze the published evidence for the use of fallopian tube brush cytology for the early detection of extrauterine serous gynecological cancer. METHODS: We systematically searched the literature and, additionally, cross-checked on the bibliographies of selected articles. The inclusion criteria involved studies assessing the utility of fallopian tube brush cytology and its applications in the diagnosis, screening, or follow-up of extrauterine serous gynecological cancer. RESULTS: The search strategy resulted in 21 abstracts or full-text articles, 5 of which met the inclusion criteria. The year of publication ranged from 2016 to 2022, and a total of 193 fallopian tube samples were investigated. Cytobrush, Tubebrush©, and Cytuity™ were used to obtain salpingeal samples for liquid-based cytology evaluation. CONCLUSIONS: Our findings indicate that, at present, there is a lack of satisfying evidence-based data in the literature which would support the implementation of fallopian tube brush cytology as an adjunctive tool for early detection of extrauterine serous gynecological cancer. Thus, we believe that there is need for well-designed clinical studies to assess the effectiveness and diagnostic accuracy of the method as well as to validate the cytological criteria for the diagnosis and prediction of gynecological malignancies.

Twenty-Four-Month Efficacy of Ureteroureterostomy Combined With Unilateral Nephrostomy Following Radical Cystectomy.

Introduction The purpose of this study was to evaluate the 24-month outcomes of ureteroureterostomy combined with unilateral nephrostomy following radical cystectomy in patients with muscle-invasive bladder cancer (BC). Materials and methods This single-center study with prospectively collected data with retrospective data analysis was carried out between December 2018 and November 2021 and enrolled 36 patients, who underwent radical cystectomy combined with ureteroureterostomy and unilateral nephrostomy. Regular renal function assessment was carried out using serum creatinine and estimated glomerular filtration rate (eGFR), and postoperative complications, endoscopic, ultrasound, and other radiological study findings were evaluated. The follow-up of the patients was carried out over a period of 24 months. Results After completion of the 24-month follow-up, the renal function proved to be slightly improved (mean serum creatinine and eGFR values of 1.38±0.72 mg/dL and 55.9±21.87 mL/min) compared to the first-year results (1.41±0.54 mg/dL and 52.10±19.64 mL/min). However, this improvement is statistically not significant (p=0.44, p=0.30). The 24-month follow-up imaging findings remained stable in 97.22% of patients compared to the first-year results, with preservation of bilateral ureteric dilatation and grade 1 dilatation of the non-drained kidney. No case of acute pyelonephritis was recorded after the completion of the second year of follow-up, in comparison to the eight patients (22.22%) of the 12-month follow-up, who suffered acute pyelonephritis. After completing of the 24-month follow-up, one patient was excluded from further analysis, due to the placement of a second permanent percutaneous nephrostomy in the non-drained kidney, due to ureteroureterostomy stenosis with consecutive hydronephrosis in the contralateral kidney and acute renal failure. No case of anastomotic leak was observed. Conclusions The function of the ureteroureterostomy combined with unilateral nephrostomy is proven to be a safe method of urinary diversion (UD) at 24 months, with minimal and easily manageable complications. Only one case of stenosis of the ureteroureterostomy with consecutive acute renal failure due to hydronephrosis in the non-drained kidney was observed. The renal function remained stable.

Is anti-PD-1 immunotherapy a means for post-irradiation tumor clearance in head and neck cancer?

Chemo-radiotherapy is the standard treatment for locally advanced head-neck cancer (LA-HNC). However, about 30% of tumors do not respond or even progress shortly after the completion of radiotherapy. We investigated whether anti-PD1 immunotherapy can eradicate the irradiated tumor and reverse the ominous prognosis of these patients. We retrospectively analyzed a small series of 9 patients with LA-HNC who did not respond (6/9) or showed local disease progression (3/9) during chemo-radiotherapy and were treated with nivolumab anti-PD1 immunotherapy. Immunotherapy started 1.5 months after the end of radiotherapy. Out of 9 patients, 3 (33.3%) had a complete response and 3 (33.3%) partial response at 6 months after the onset of immunotherapy. Two patients are alive with no evidence of disease at 36 months. One more patient with partial response and without disease progression survived 16 months after therapy when he died from intercurrent disease. Immunotherapy showed an excellent tolerance profile. One patient developed an extensive skin rash on the 16th cycle. Anti-PD-1 immunotherapy after radiotherapy can lead to clearance of the remnant tumor and ameliorate the prognosis of patients. Randomized trials are necessary to establish post-irradiation immunotherapy as a standard of care in this ill-fated subgroup of HNC patients.

Uretero-Ureterostomy Combined With Unilateral Nephrostomy as a Method of Urinary Diversion Following Radical Cystectomy.

Introduction Uretero-ureterostomy combined with unilateral nephrostomy is a rarely performed urinary diversion following radical cystectomy for muscle-invasive bladder cancer. The aim of this study is to assess the efficacy and safety of the procedure. Materials and methods Patients with muscle-invasive bladder cancer and poor performance status were enrolled in this retrospective, observational, single-centre study, carried out between December 2018 and November 2020. The patient's renal function was regularly assessed with serum creatinine and estimated glomerular filtration rate (eGFR). Evaluation of peri- and postoperative complications was performed based on clinical, laboratory, endoscopic, ultrasound and other radiological studies findings. The patient's status was assessed for 12 months. Results Thirty-six patients with a mean age of 77.4±8.6 years were enrolled in the study. 86.11% of patients had an American Society of Anesthesiologists Score ≥3 and 91.66% had an age-adjusted Charlson comorbidity index of ≥6. Slight deterioration of renal function, although not statistically significant, was observed. 36.11% of the patients developed permanent unilateral pelvic dilatation. Acute pyelonephritis, urosepsis, pyonephrosis and anastomotic leak were observed in 22.22%, 8.33%, 5.55% and 5.55% of patients, respectively; all were treated either conservatively and/or with minimally invasive procedures (nephrostomy, JJ-stent insertion) without any need for open surgical revision. Conclusions Ureteroureterostomy combined with unilateral nephrostomy is a safe and effective method of urinary diversion following radical cystectomy for muscle-invasive bladder cancer with easily manageable complications.

Resistance to CDK4/6 inhibition: Mechanisms and strategies to overcome a therapeutic problem in the treatment of hormone receptor-positive metastatic breast cancer.

Selective CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, have been approved in combination with hormone therapy for the treatment of patients with HR+, HER2-negative advanced or metastatic breast cancer (mBC). Despite their promising activity, approximately 10 % of patients have de novo resistance, while the rest of them will develop acquired resistance after 24-28 months when used as first-line therapy and after a shorter period when used as second-line therapy. Various mechanisms of resistance to CDK4/6 inhibitors have been described, including cell cycle-related mechanisms, such as RB loss, p16 amplification, CDK6 or CDK4 amplification, and cyclin E-CDK2 amplification. Other bypass mechanisms involve the activation of FGFR or PI3K/AKT/mTOR pathways. Identifying the different mechanisms by which resistance to CDK4/6 inhibitors occurs may help to design new treatment strategies to improve patient outcomes. This review presents the currently available knowledge on the mechanisms of resistance to CDK4/6 inhibitors, explores possible treatment strategies that could overcome this therapeutic problem, and summarizes relevant recent clinical trials.

Neoadjuvant treatment in ovarian cancer: New perspectives, new challenges.

Ovarian cancer remains the leading cause of death from gynecological cancer. Survival is significantly related to the stage of the disease at diagnosis. Of quite importance is primary cytoreductive surgery, having as a goal to remove all visible tumor tissue, and is the standard primary treatment in combination with platinum-based chemotherapy for patients with advanced ovarian carcinoma. Neo-adjuvant chemotherapy (NACT) has been implemented mostly in treating advanced disease, with studies performed having numerous limitations. Data extrapolated from these studies have not shown inferiority survival of NACT, compared to primary debulking surgery. The role of NACT is of particular interest because of the intrinsic mechanisms that are involved in the process, which can be proven as therapeutic approaches with enormous potential. NACT increases immune infiltration and programmed death ligand-1 (PDL-1) expression, induces local immune activation, and can potentiate the immunogenicity of immune-exclude high grade serous ovarian tumors, while the combination of NACT with bevacizumab, PARP inhibitors or immunotherapy remains to be evaluated. This article summarizes all available data on studies implementing NACT in the treatment of ovarian cancer, focusing on clinical outcomes and study limitations. High mortality rates observed among ovarian cancer patients necessitates the identification of more effective treatments, along with biomarkers that will aid treatment individualization.

Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: final long-term results of the Hellenic Cooperative Oncology Group Phase III HE10/05 Trial.

BACKGROUND: Dose-dense sequential chemotherapy with anthracyclines and taxanes achieved an 18% reduction of recurrence risk in early breast cancer (BC). The optimal chemotherapy schedule and interval between cycles remain under investigation. METHODS: Overall, 990 patients were randomised to receive either three cycles of epirubicin (E, 110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by three cycles of intensified CMF (Control Arm A, E-T-CMF) that was previously used in BC or three cycles of epirubicin followed by three cycles of CMF followed by nine consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Arm B, E-CMF-wD) or nine consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Arm C, E-CMF-wT). Trastuzumab was administered for HER2-positive disease. RESULTS: At a median follow-up of 13.3 years, 330 disease-free survival (DFS) events (33.3%) were reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus arm A either in the entire cohort (HR = 0.90, P = 0.38 and HR = 0.85, P = 0.20) or among trastuzumab-treated patients (HR = 0.69, P = 0.13 and HR = 0.67, P = 0.13). Thirty-four patients (3.4%) developed secondary neoplasms. CONCLUSIONS: Overall, no significant differences in survival were found amongst the studied regimens after a long-term observational period. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000151033.