Metastatic Kidney Cancer: Does the Location of the Metastases Matter? Moving towards Personalized Therapy for Metastatic Renal Cell Carcinoma.

The management of renal cell carcinoma (RCC) has been revolutionized over the past two decades with several practice-changing treatments. Treatment for RCC often requires a multimodal approach: Local treatment, such as surgery or ablation, is typically recommended for patients with localized tumors, while stage IV cancers often require both local and systemic therapy. The treatment of advanced RCC heavily relies on immunotherapy and targeted therapy, which are highly contingent upon histological subtypes. Despite years of research on biomarkers for RCC, the standard of care is to choose systemic therapy based on the risk profile according to the International Metastatic RCC Database Consortium and Memorial Sloan Kettering Cancer Centre models. However, many questions still need to be answered. Should we consider metastatic sites when deciding on treatment options for metastatic RCC? How do we choose between dual immunotherapy and combinations of immunotherapy and tyrosine kinase inhibitors? This review article aims to answer these unresolved questions surrounding the concept of personalized medicine.

Tumor-to-Tumor Metastasis of Lung Cancer to Kidney Cancer: A Review of the Literature and Our Experience.

Tumor-to-tumor metastasis (TTM) is a rare phenomenon documented in patients with multiple primary cancers. This condition is defined as a metastasis between two true primary tumors. The most frequently reported recipient tumor is renal cell carcinoma (RCC), and the lung carcinomas are the most common metastatic tumor donors. Therefore, this paper attempts to address the current gap in knowledge about this rare phenomenon. The first part of this review outlines the recently proposed models and mechanisms involved in the TTM process. The second part then summarizes and analyzes previous case reports in the literature. We also present our experience with the case of lung cancer that metastasized into RCC. Given the sporadic incidence of TTM, no specific management guidelines exist. Therefore, considering TTM in patients with multiple primary tumors is important as it could potentially modify the oncological management offered.

Role of Tumor Molecular Profiling With FoundationOne®CDx in Advanced Solid Tumors: A Single-Centre Experience From Romania.

Background In the field of precision oncology, comprehensive genomic profiling tests play a very important role by providing a complex understanding of the molecular characteristics of malignant tumors. Therefore, next-generation sequencing (NGS) has become a valuable tool in various aspects of cancer care from diagnosis and monitoring to treatment selection and personalized cancer treatment. Our aim was to evaluate the role of tumor molecular profiling in tailored treatment selection. Methods In our study, we conducted a retrospective analysis to assess the practicality of utilizing NGS testing in patients with metastatic solid tumors. The genomic testing was performed on blood or tissue samples from a fresh biopsy, less than six months old, and the expression of programmed death-ligand 1 was evaluated by immunohistochemistry. Results A total of 75 tests were performed on 66 patients between 2019 and 2022, with a success rate of 80%. The most common pathologies were gastro-intestinal tract cancer (26%), breast cancer (14%), non-small cell lung cancer (11%), and pancreatic cancer (11%). There were 9% liquid biopsies and 91% tissue biopsies. From all 66 patients tested, 55 had at least one genetic alteration. The most frequent genetic alteration found was TP53 (n=32) followed by KRAS (n=15) and BRCA1/2 (n=12) mutations. There were nine patients tested (14%) that presented a high tumor mutational burden, and only one patient presented high microsatellite instability. There were 37 patients (56%) with actionable alterations found from which 14 received matched therapy and four patients were enrolled in clinical trials. The NGS testing played a significant role in determining the next therapeutic strategy in 20 out of 66 patients (30.3%). Conclusion From all the patients included in our analysis, 83% had at least one mutation that is known to be of pathogenic significance but only 23% received treatment selected by the analysis of the tumor's genome, and only 6% were included in a clinical trial. This moderate success of personalized medicine using NGS testing highlights the importance of evaluating the factors that could lead to further improvement.

Consistent effects of the genetics of happiness across the lifespan and ancestries in multiple cohorts.

Happiness is a fundamental human affective trait, but its biological basis is not well understood. Using a novel approach, we construct LDpred-inf polygenic scores of a general happiness measure in 2 cohorts: the Adolescent Brain Cognitive Development (ABCD) cohort (N = 15,924, age range 9.23-11.8 years), the Add Health cohort (N = 9129, age range 24.5-34.7) to determine associations with several well-being and happiness measures. Additionally, we investigated associations between genetic scores for happiness and brain structure in ABCD (N = 9626, age range (8.9-11) and UK Biobank (N = 16,957, age range 45-83). We detected significant (p.FDR < 0.05) associations between higher genetic scores vs. several well-being measures (best r2 = 0.019) in children of multiple ancestries in ABCD and small yet significant correlations with a happiness measure in European participants in Add Health (r2 = 0.004). Additionally, we show significant associations between lower genetic scores for happiness with smaller structural brain phenotypes in a white British subsample of UK Biobank and a white sub-sample group of ABCD. We demonstrate that the genetic basis for general happiness level appears to have a consistent effect on happiness and wellbeing measures throughout the lifespan, across multiple ancestral backgrounds, and multiple brain structures.

An Overview of the Safety Profile and Clinical Impact of CDK4/6 Inhibitors in Breast Cancer-A Systematic Review of Randomized Phase II and III Clinical Trials.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer over the last decade. These inhibitors are currently established as first- and second-line systemic treatment choices for both endocrine-sensitive and -resistant breast cancer populations alongside endocrine therapy (ET) or monotherapy. Data on targeted therapy continue to mature, and the number of publications has been constantly rising. Although these drugs have been demonstrated to prolong overall survival (as well as progression-free survival (PFS) in breast cancer patients), changing the paradigm of all current knowledge, they also cause important adverse events (AEs). This review provides the latest summary and update on the safety profile of the three CDK4/6 inhibitors, as it appears from all major phase II and III randomized clinical trials regarding palbociclib, ribociclib, and abemaciclib, including the most relevant 15 clinical trials.

Second-Line Treatment of Metastatic Renal Cell Carcinoma in the Era of Predictive Biomarkers.

BACKGROUND: Over the past few years, significant advancements have been achieved in the front-line treatment of metastatic renal cell carcinomas (mRCCs). However, most patients will eventually encounter disease progression during this front-line treatment and require further therapeutic options. While treatment choices for mRCCs patients are determined by established risk classification models, knowledge of prognostic factors in subsequent line therapy is essential in patient care. METHODS: In this retrospective, single-center study, patients diagnosed with mRCCs who experienced progression after first-line therapy were enrolled. Fifteen factors were analyzed for their prognostic impact on survival using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: Poor International Metastatic RCCs Database Consortium (IMDC) and Memorial Sloan-Kettering Cancer Center (MSKCC) risk scores, NLR value > 3, clinical benefit < 3 months from a therapeutic line, and the presence of sarcomatoid differentiation were found to be poor independent prognostic factors for shortened overall survival. CONCLUSIONS: This study provided new insights into the identification of potential prognostic parameters for late-line treatment in mRCCs. The results indicated that good IMDC and MSKCC prognostic scores are effective in second-line therapy. Moreover, patients with NLR < 3, no sarcomatoid differentiation, and clinical benefit > 3 months experienced significantly longer overall survival.

Does the Rechallenge with Another CDK 4/6 Inhibitor in Breast Cancer Work? A Case Report and Literature Review.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and endocrine therapy are the gold standards for systemic therapy for patients with hormone-positive (HR+)/human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer. Following progression, no prospective randomized data exist to help guide second-line treatment. Moreover, there is a scarcity of data on rechallenge treatment strategies with another CDK4/6 inhibitor after prior limiting toxicity. We report a real-world experience of rechallenging with abemaciclib after the prior reaction of grade 4 liver toxicity to ribociclib, with high transaminases values of more than 27 times the upper limit of normal (ULN) and unexpected grade 3 neutropenia and diarrhea after a few months of abemaciclib. After two years of treatment, the patient had stable oncological disease, with normal complete blood count, hepatic enzymes, and a very good performance status. We believe that our clinical case, along with others gathered from all around the world, will help with the consolidation of an unmet clinical need to readjust the treatment after experiencing toxicity to CDK4/6 inhibitors.

Mechanisms of Resistance to CDK4/6 Inhibitors and Predictive Biomarkers of Response in HR+/HER2-Metastatic Breast Cancer-A Review of the Literature.

The latest and newest discoveries for advanced and metastatic hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer are the three cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) in association with endocrine therapy (ET). However, even if this treatment revolutionized the world and continued to be the first-line treatment choice for these patients, it also has its limitations, caused by de novo or acquired drug resistance which leads to inevitable progression after some time. Thus, an understanding of the overview of the targeted therapy which represents the gold therapy for this subtype of cancer is essential. The full potential of CDK4/6i is yet to be known, with many trials ongoing to expand their utility to other breast cancer subtypes, such as early breast cancer, and even to other cancers. Our research establishes the important idea that resistance to combined therapy (CDK4/6i + ET) can be due to resistance to endocrine therapy, to treatment with CDK4/6i, or to both. Individuals' responses to treatment are based mostly on genetic features and molecular markers, as well as the tumor's hallmarks; therefore, a future perspective is represented by personalized treatment based on the development of new biomarkers, and strategies to overcome drug resistance to combinations of ET and CDK4/6 inhibitors. The aim of our study was to centralize the mechanisms of resistance, and we believe that our work will have utility for everyone in the medical field who wants to deepen their knowledge about ET + CDK4/6 inhibitors resistance.

The Prognostic Value of Neutrophil-to-Lymphocyte Ratio in Patients with Metastatic Renal Cell Carcinoma.

BACKGROUND: Metastatic renal cell carcinoma (mRCC) is an aggressive cancer characterised by an increased recurrence rate and an inadequate response to treatment. This study aimed to investigate the importance of the neutrophil-to-lymphocyte ratio (NLR) as a prognostic marker for long-term survival in patients with mRCC. METHODS: We retrospectively analysed data from 74 patients with mRCC treated at our medical centre with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). We evaluated the predictive value of NLR for overall survival (OS) in these patients. RESULTS: The median OS was 5.1 months in the higher NLR group (≥3) and 13.3 months in the lower NLR group (<3) (p < 0.0001). There was no significant difference in the OS between the TKI and ICI therapies in the low NLR group (12.9 vs. 13.6 months, p = 0.411) or in the high NLR group (4.7 vs. 5.5 months, p = 0.32). Both univariate and multivariate analyses revealed that a higher NLR was an independent prognostic factor of long-term survival in patients with mRCC treated with first-line therapy. CONCLUSIONS: This retrospective study showed that adding NLR to other Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) variables might improve the prognostic and predictive power of these models.

Prognostic Models for Renal Cell Carcinoma in the Era of Immune Checkpoint Therapy.

With recent advances in oncology, immune checkpoint inhibitors (ICIs) have become a milestone in immuno-oncology. Unfortunately, although ICIs have demonstrated improved clinical efficacy in a broad spectrum of cancers, many patients do not respond to this newer therapy. As a result, it is crucial to identify predictive factors of response to immunotherapy in patients with kidney cancer. This review discusses the research investigating potential biomarkers of response to ICIs in renal cell carcinoma.

Associations of rheumatoid arthritis and rheumatoid factor with mental health, sleep and cognition characteristics in the UK Biobank.

While previous rheumatoid arthritis (RA) studies have focussed on cardiometabolic and lifestyle factors, less research has focussed on psychological variables including mood and cognitive health, and sleep. Cross-sectional analyses tested for associations between RA and RF+ (positive rheumatoid factor) vs. mental health (depression, anxiety, neuroticism), sleep variables and cognition scores in UK Biobank (total n = 484,064). Those RF+ were more likely to report longer sleep duration (ß = 0.01, SE = 0.004, p < 0.01) and less likely to get up in the morning easily (OR 0.95, 95% CI 0.92-0.99, p = 0.01). Those reporting RA were more likely to score higher for neuroticism (ß = 0.05, SE = 0.01, p < 0.001), to nap during the day (OR 1.10, 95% CI 1.06-1.14, p < 0.001), have insomnia (OR 1.28, 95% CI 1.22-1.35, p < 0.001), have slower reaction times (ß = 0.02, SE = 0.008, p < 0.005) and score less for fluid intelligence (ß = - 0.03, SE = 0.01, p < 0.05) and less likely to get up easily (OR 0.61, 95% CI 0.58-0.64, p < 0.001). The current study suggests that prevalent RA, and RF+ status are associated with differences in mental health, sleep, and cognition, highlighting the importance of addressing these aspects in clinical settings and future research.

Use of Immune Checkpoint Inhibitors in Elderly Patients With Chronic Kidney Disease and Renal Cell Carcinoma Metastasis of the Parotid Gland: Case Report and Review of the Literature.

Renal cell carcinoma metastasis of the parotid gland is extremely rare, and the present literature review found only 23 cases reported in the last two decades. We present a case of a 75-year-old woman with a colon cancer history who had parotid gland metastasis as the first manifestation of second primary kidney cancer. The presence of multiple comorbidities affected medical decision-making. Therefore the patient was treated primarily with immunotherapy. After four cycles of dual immune checkpoint blockade, this advanced patient still benefited and was changed to nivolumab monotherapy as maintenance therapy.

Salivary Enzymatic Activity and Carious Experience in Children: A Cross-Sectional Study.

Salivary biomolecules are considered important modulators of the oral microflora, with a potential subsequent impact on dental health. The present study aimed to investigate the relationship between salivary enzymatic activity and carious experience in children. The carious experience of a sample of 22 school children was evaluated by calculating dmf/DMF indices, following WHO recommendations. Unstimulated whole saliva was collected, and salivary alpha-amylase levels, total protease activity, and matrix metalloproteinase levels (MMP-8 and MMP-9) were measured. The data were analyzed using parametric and nonparametric tests. Our findings revealed no significant relationship between the investigated salivary parameters and the carious experience in permanent teeth (DMFT/DMFS scores). Carious indices scores for primary teeth (dmft and dmfs) were positively associated with MMP-8 levels (r = 0.62, p = 0.004 and rs = 0.61, p = 0.006, respectively) and MMP-9 levels (r = 0.45, p = 0.05 and rs = 0.48, p = 0.039, respectively) and negatively associated with alpha-amylase levels (rs = -0.54, p = 0.017 and rs = -0.59, p = 0.006, respectively). Although with a marginal significance, PEK-054 levels positively correlated with dental caries, while for PFU-089, a negative correlation was observed. These results suggest that salivary alpha-amylase and MMP-8 and MMP-9 levels may be considered potential indicators of carious experience in children. Further studies with a prospective design are needed in order to elucidate the role of these biomolecules in caries development.

Congenitally missing second permanent molars in non-syndromic patients (Review).

Hypodontia (tooth agenesis) is regarded as the most common congenital dental anomaly. The present review discusses the epidemiological characteristics of congenitally missing second permanent molars (CMSPMs) within a systematic review of the literature. The review was based on Pubmed library associated with the search of various scientific databases or academic resources, improved by hand search of reference lists. The terms 'hypodontia' or 'anodontia' in combination with 'prevalence' or 'epidemiology' were searched in the data sources for studies published between January 2001 and December 2020. Abstracts of non-English papers were also analyzed. The inclusion criteria were as follows: i) Study provided precise data about CMSPMs, even if no second permanent molar was reportedly missing; ii) the number of CMSPMs distributed by jaw was provided and iii) studies on subjects >3 years were used. The exclusion criteria were as follows: i) Studies on patients with history of trauma of the maxilla or the mandible, any type of syndrome affecting bone metabolism, metabolic disorders, previous extraction or tooth loss due to dental caries, cleft lip and palate; ii) studies performed on cohorts of patients with hypodontia and iii) studies reporting data including third molars, except for those that presented sufficient data to perform correct calculations. A total of 79 studies were selected, accumulating a population of 281,968 people, with an average sample size of 3,524.60±11,255.25. The prevalence of CMSPMs (IpHSPM) was 2.79±3.16% among all missing teeth (1.03±1.59% for upper CMSPMs and 1.76±2.32% for lower CMSPMs; P=0.011). There were no significant differences (P=0.250) in IpHSPM between men (1.59±1.52%) and women (2.13±1.67%). However, significant differences were recorded between continents. Furthermore, lower CMSPMs were found more frequently in orthodontic samples (P=0.033). The prevalence of CMSPMs is low compared with the overall prevalence of CM teeth. Despite the rarity of these anomalies, early detection is important to enable practitioners to plan and start treatment at the best time for optimal results.

Research algorithm for the detection of genetic patterns and phenotypic variety of non-syndromic dental agenesis.

INTRODUCTION: Dental agenesis (DA), brings together the anodontia, oligodontia, hypodontia, characterized by a deficit in the development of a variable number of teeth. The objectives of the study were to illustrate the phenotypic variability of non-syndromic DA, to identify cases of DA with hereditary genetic transmission, and establish the mode of DA genetic pattern in these cases, together with the determination of DA prevalence in the population group study. PATIENTS, MATERIALS AND METHODS: The cross-sectional observational study was performed on a mixed population group, consisting of 861 Caucasian patients, between January 2018-December 2019. The clinical evaluation protocol of patients with DA, used to illustrate their phenotype, included the following stages: oral examination, photographic examination, and radiological examination. The evaluation protocol specific to the family genetic study of patients with DA, involved the following three stages: family survey, construction of the family tree and analysis of the pedigree structure. RESULTS: The prevalence of DA in the population group was 2.78%. Regarding the phenotype, DA mainly affected the upper arch (50% of cases); bilateral DA had a significantly increased incidence (83.33% of cases) compared to unilateral form; in most cases (75%), a patient lacked one to two teeth, the lack of two teeth being the most common form (83.33% of cases); the upper lateral incisors were the teeth most frequently involved in DA (31.11% of the total missing teeth). Regarding the family genetic study, hereditary DA with autosomal dominant inheritance was present in 37.50% of cases. In the other cases (62.50%), isolated, sporadic forms of DA were registered, suggesting a spontaneous de novo mutation or a disorder of odontogenesis of a non-genetic nature. CONCLUSIONS: We consider that this study is of interest for current scientific research with applicability in dental medicine, by bringing actual information on the prevalence of non-syndromic DA in South-East Romania, the variety of phenotypic spectrum of DA for this geographic area, and the role of heredity in the DA genetic determinism in the studied population.

Increased cognitive demands boost the spatial interference effect in bimanual pointing.

It is beyond controversy that in bimanual coordination tasks, parameter planning related to the movements of one hand influences the planning and execution of movements simultaneously performed with the other hand. A well-researched example of such bimanual interference is the finding that reaction times tend to be longer when preparing bimanual pointing movements with different amplitudes than for equal amplitude movements. Interestingly, these reaction time costs were found to increase when movement targets were cued symbolically (e.g., using letters) as compared to spatially. Therefore, it was suggested that interference may be primarily related to cue translation and response selection processes rather than resulting from cross-talk at the motor programming level. Here, we argue that spatial interference effects do not necessarily depend on the type of cues used but instead depend on the general task demands (difficulty). In two experiments we show that bimanual interference effects can (1) be abolished in symbolic cueing conditions when highly compatible cues placing minimal demands on response selection processes are used and (2) occur in direct/spatial cueing conditions when a secondary cognitively demanding, but movement-unrelated task is performed. Thus, our findings suggest that whether or not interference effects emerge during movement planning depends on the overall task difficulty and hence the resources available during movement preparation.