Survival Advantage Research Articles

Role of B7-H3 in predicting response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

Neoadjuvant platinum-based chemotherapy offers a modest survival advantage in muscle-invasive bladder cancer (MIBC) for patients with pathologic response. B7-H3 (CD276), an immune checkpoint overexpressed in various cancers, including urothelial-cell carcinoma (UCC), has been associated with chemoresistance and poor oncologic outcomes. We aimed to explore if B7H3 expression on bladder biopsy samples was a predictive biomarker for pathologic response to neoadjuvant platinum-based chemotherapy. This was a retrospective cohort study among MIBC patients receiving neoadjuvant platinum-based chemotherapy followed by radical cystectomy. All patients underwent routine preoperative biopsy of their tumour. Immunohistochemistry was used to evaluate B7-H3 expression from pre-operative specimens. The primary outcome of interest was pathologic complete response (pCR). Statistical analysis included Mann-Whitney U test, Fisher's exact test, Kaplan-Meier method, and Cox regression for survival analysis. Among 87 patients analysed, high B7-H3 expression was found in 44.8% (n = 39) of patients. The median follow-up periods were similar between the high and low B7-H3 groups (high expression; 4.29 years [SD 3.04], low expression 3.94 years [SD 3.04], p = 0.60). Only 20.5% of patients with high B7-H3 expression achieved pCR, compared to 41.7% in the low expression group (p = 0.04). Cox regression showed no significant differences in recurrence-free or cancer-specific survival between the high and low B7-H3 expression groups (p > 0.05). High B7-H3 expression is associated with a reduced likelihood of achieving pCR in MIBC patients undergoing neoadjuvant chemotherapy. This suggests B7-H3's potential as a predictive biomarker for chemotherapy response. Further research is needed to explore the role of B7-H3 on platinum-based chemotherapy response in urothelial cancer.

Updated review on pulmonary arterial hypertension: Differences between down syndrome and non-down syndrome populations

BackgroundPulmonary arterial hypertension (PAH) is a major concern in patients with Down syndrome (DS) and congenital heart disease (CHD). Understanding the unique characteristics of PAH in these populations is essential for developing tailored management strategies. This review examines differences in PAH between DS and non-DS (nDS) patients with CHD, focusing on pathophysiology, clinical presentation, hemodynamic profiles, and treatment outcomes. MethodsA retrospective analysis of 93 adults with PAH was conducted, including 18 with DS and 75 with CHD but without DS (nDS). Data on demographics, clinical presentations, comorbidities, and hemodynamic parameters were collected using echocardiography and right heart catheterization. Statistical analyses included Mann–Whitney U tests, Student's t-tests, and Kaplan–Meier survival analysis to compare the DS and nDS groups. ResultsDS patients presented with PAH at a younger age (mean age 25.06 years) compared to nDS patients (mean age 42.4 years; p < 0.001). Hypothyroidism was more prevalent in DS patients (61.1 %) than in nDS patients (29.3 %; p = 0.012). Hemodynamic assessments showed lower mean arterial pressure (MAP) in DS patients (76.24 ± 11.6 mmHg) versus nDS patients (93.95 ± 15 mmHg; p < 0.001), and a higher TAPSE/PASP ratio (0.41 vs. 0.23; p = 0.009), suggesting less severe right ventricular dysfunction. DS patients had a significant survival advantage over nDS patients (p = 0.043). ConclusionsDS patients have distinct clinical and hemodynamic profiles in PAH, requiring personalized management. Early detection and tailored treatment are crucial for improving outcomes. Further research should refine these strategies and explore new therapies.

Application of galactosylated albumin for targeted delivery of triptolide to suppress hepatocellular carcinoma progression through inhibiting de novo lipogenesis

Hepatocellular carcinoma (HCC) remains the fourth leading cause of cancer-associated death globally with a lack of efficient therapy. The pathogenesis of HCC is a complex and multistep process, highly reliant on de novo lipogenesis, from which tumor cells can incorporate fatty acids to satisfy the necessary energy demands of rapid proliferation and provide survival advantages. Triptolide (TP) is a bioactive ingredient exhibiting potent abilities of anti-proliferation and lipid metabolism regulation, but its clinical application is constrained because of its toxicity and non-specific distribution. The present study has developed galactosylated bovine serum albumin nanoparticles loaded with TP (Gal-BSA-TP NPs) to alleviate systemic toxicity and increase tumor-targeting and antitumor efficacy. Furthermore, Gal-BSA-TP NPs could inhibit de novo lipogenesis via the p53-SREBP1C-FASN pathway to deprive the fuel supply of HCC, offering a specific strategy for HCC treatment. In general, this study provided a biocompatible delivery platform for targeted therapy for HCC from the perspective of de novo lipogenesis.

Association between Mild Overweight and Survival: A Study of an Exceptionally Long-Lived Population in the Sardinian Blue Zone.

Background/Objectives: Overweight and obesity are generally considered risk factors for premature mortality. However, scientific evidence suggests that among older populations, mild conditions of overweight might be associated with reduced comorbidity and longer survival. This study investigates the potential association between anthropometric parameters and survival among a cohort of nonagenarians in Sardinia, Italy. Methods: This study included 200 subjects (50% females) aged 89 and older, enrolled in 2018 in the Sardinian Blue Zone-a population known for longevity-and followed for up to six years. Anthropometric variables such as body height, weight, age, sex, comorbidity, disability, and food group intake were collected using validated questionnaires and analyzed through multivariable analysis. Results: Out of 200 participants at baseline, 28 (14%) were still alive after six years of follow-up (females 10%, males 18%). Mean survival was 3.36 years (range 0.1-6.9 years) for males and 3.03 years (range 0.2-6.6 years) for females. Participants with a Body Mass Index (BMI) in the range of 25.0-27.0 kg/m2 among males and 25.0-27.2 kg/m2 among females had longer survival compared to those who were underweight (p = 0.002) or obese (p < 0.0001). The Cox proportional hazards regression model, adjusted for age, sex, and comorbidity, revealed a statistically significant association between the BMI and survival, demonstrating an inverted-U relationship. This indicates that mild overweight was associated with a survival advantage compared to both normal weight and obesity. Conclusions: Our study indicates that mild, but not severe, overweight in nonagenarians is associated with extended lifespan. Therefore, primary care physicians and geriatricians should exercise caution before recommending calorie-restricted diets for mildly overweight elderly patients.

Mitochondria and Acute Leukemia: A Clinician's Perspective.

Acute leukemia is a group of aggressive hematological malignancies, with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) being the most common types. The biology of acute leukemia involves complex genetic and epigenetic alterations that lead to uncontrolled cell proliferation and resistance to apoptosis. Mitochondrial dysfunction is a feature of acute leukemia that results in altered energy production, unregulated cell death pathways, and increased cancer cell survival. Apoptosis, particularly via the mitochondrial pathway, is crucial for cellular homeostasis and cancer prevention. In acute leukemia, disruption of apoptosis is pivotal in disease development and progression, with elevated levels of anti-apoptotic proteins conferring a survival advantage to leukemia cells and promoting resistance to conventional therapies. Targeting mitochondrial apoptosis using BH3 mimetics and anti-apoptotic protein inhibitors is a viable therapeutic strategy. Alterations in the mitochondrial membrane potential, metabolism, and dynamics also contribute to the pathogenesis of acute leukemia. Continued research is vital for developing novel therapies and enhancing survival outcomes in patients with acute leukemia while minimizing the long-term adverse effects of treatment. In this narrative review, we provide a birds-eye view of the available scientific literature on the importance of mitochondria in acute leukemia, and discuss the role of BH3 mimetics in targeting the mitochondrial internal apoptotic machinery.

Neoadjuvant therapy versus upfront surgery in resectable pancreatic cancer: reconstructed patient-level meta-analysis of randomized clinical trials.

Neoadjuvant treatment has shown promising results in patients with borderline resectable pancreatic ductal adenocarcinoma. The potential benefits of neoadjuvant treatment on long-term overall survival in patients with resectable pancreatic ductal adenocarcinoma have not yet been established. The aim of this study was to compare long-term overall survival of patients with resectable pancreatic ductal adenocarcinoma based on whether they received neoadjuvant treatment or underwent upfront surgery. A systematic review including randomized clinical trials on the overall survival outcomes between neoadjuvant treatment and upfront surgery in patients with resectable pancreatic ductal adenocarcinoma was conducted up to 1 August 2023 from PubMed, MEDLINE and Web of Science databases. Patient-level survival data was extracted and reconstructed from available Kaplan-Meier curves. A frequentist one-stage meta-analysis was employed, using Cox-based models and a non-parametric method (restricted mean survival time), to assess the difference in overall survival between groups. A Bayesian meta-analysis was also conducted. Five randomized clinical trials comprising 625 patients were included. Among patients with resectable pancreatic ductal adenocarcinoma, neoadjuvant treatment was not significantly associated with a reduction in the hazard of death compared with upfront surgery (shared frailty HR 0.88, 95% c.i. 0.72 to 1.08, P = 0.223); this result was consistent in the non-parametric restricted mean survival time model (+2.41 months, 95% c.i. -1.22 to 6.04, P < 0.194), in the sensitivity analysis that excluded randomized clinical trials with a high risk of bias (shared frailty HR 0.91 (95% c.i. 0.72 to 1.15; P = 0.424)) and in the Bayesian analysis with a posterior shared frailty HR of 0.86 (95% c.i. 0.70 to 1.05). Neoadjuvant treatment does not demonstrate a survival advantage over upfront surgery for patients with resectable pancreatic ductal adenocarcinoma.

Aneuploidy of Specific Chromosomes is Beneficial to Cells Lacking Spindle Checkpoint Protein Bub3.

Accurate chromosome segregation is crucial for the proper development of all living organisms. Errors in chromosome segregation can lead to aneuploidy, characterized by an abnormal number of chromosomes, which generally impairs cell survival and growth. However, under certain stress conditions, such as in various cancers, cells with specific mutations and extra copies of advantageous chromosomes exhibit improved survival and proliferation. In our study, we discovered that cells lacking the spindle checkpoint protein Bub3 became aneuploid, retaining specific chromosomes. This finding was unexpected because although bub3 Δ cells have a higher rate of chromosome mis-segregation, they were not thought to maintain an aneuploid karyotype. We investigated whether the increased copy number of specific genes on these acquired chromosomes offered a benefit to Bub3-deficient cells. Our results revealed that several genes involved in chromosome segregation and cell cycle regulation prevented the gain of chromosomes upon Bub3-depletion, suggesting that these genes confer a survival advantage. Overall, our study demonstrates that cells lacking Bub3 selectively retain specific chromosomes to increase the copy number of genes that promote proper chromosome segregation.

Star wars against leukemia: attacking the clones.

Leukemia, although most likely starts as a monoclonal genetic/epigenetic anomaly, is a polyclonal disease at manifestation. This polyclonal nature results from ongoing evolutionary changes in the genome/epigenome of leukemia cells to promote their survival and proliferation advantages. We discuss here how genetic and/or epigenetic aberrations alter intracellular microenvironment in individual leukemia clones and how extracellular microenvironment selects the best fitted clones. This dynamic polyclonal composition of leukemia makes designing an effective therapy a challenging task especially because individual leukemia clones often display substantial differences in response to treatment. Here, we discuss novel therapeutic approach employing single cell multiomics to identify and eradicate all individual clones in a patient.

Does Hepatic Metastasectomy for Breast Cancer Oligo-Metastasis to the Liver Offer Survival Advantage? Systematic Review and Meta-Analysis

Abstract Background: The impact of liver resection on survival in patients with hepatic metastasis from breast cancer has remained a controversial topic, with multiple studies reporting conflicting results. Objective: We perform this meta-analysis comparing metastasectomy to systemic therapy in terms of survival outcomes in cases of hepatic oligo-metastasis from breast cancer. Materials and Methods: A systematic search of PubMed, Embase, and Cochrane Library was conducted for relevant studies. The search terms used included “Breast Neoplasms,” “Liver,” hepatic” “Metastasis” “Hepatectomy,” “Metastasectomy” “resection,” and “surgery.” The primary outcome was overall survival (OS). Only studies published in English and studies that compared OS between patients that had metastasectomy and those that received systemic therapy were included. Results: Thirteen studies were included in the meta-analysis. The one year overall survival of patients who had surgery is superior to those who received systemic therapy only, with a risk ratio (RR) of 7.59 and P value of &lt;0.00001. There is also a superior overall survival at 3 years after metastasectomy when compared with patients that received systematic therapy (RR = 2.83, P = 0.005). Five years is also superior, with RR of 2.78 and P value of 0.005. Conclusion: Hepatic metastasectomy in combination with systemic therapy is superior to systemic therapy alone in patients with breast cancer and oligo-metastasis of the liver.

Transcriptomic analysis reveals transcription factors implicated in radon-induced lung carcinogenesis.

Radon, a potent carcinogen, is a significant catalyst for lung cancer development. However, the molecular mechanisms triggering radon-induced lung cancer remain elusive. Utilizing a radon exposure concentration of 20,000Bq/m3 for 20min/session, malignant transformation was induced in human bronchial epithelial cells (BEAS-2B). Radon-exposed cells derived from passage 25 (BEAS-2B-Rn) exhibited enhanced proliferation and increased colony formation. Analysis of differential gene expression (DEG) through transcription factors revealed 663 up-regulated and 894 down-regulated genes in radon-exposed cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed significant alterations in the malignant transformation pathway of cells, including those related to cancer and the PI3K/AKT signaling pathway. A PPI network analysis indicated a significant association of oncogenes, such as CCND1, KIT, and GATA3, with lung cancer among differentially expressed genes. In addition, the stability of the housekeeping gene was determined through RT-qPCR analysis, which also confirmed the results of transcriptome analysis. The results suggest that transcription factors may play a pivotal role in conferring a survival advantage to radon-exposed cells. This is achieved by malignant transformation of human bronchial epithelial cells into lung carcinogenesis cell phenotypes.

785. MANAGEMENT OF ESOPHAGEAL CANCER WITH CONCURRENT CERVICAL NODE METASTASIS: A NATIONWIDE POPULATION-BASED COHORT STUDY

Abstract Background In the Netherlands, the standard treatment of locally advanced, resectable esophageal cancer without metastasis is neoadjuvant chemoradiotherapy followed by esophagectomy. There is a small subset of patients that present with concurrent cervical lymph node metastasis (LNM). Historically this was seen as distant metastasis and surgical intervention has usually not been an option for these patients. The contemporary TNM classification now categorizes these lymph node stations as locoregional disease. Our current study aims to describe current treatment paradigms in the Netherlands for patients presenting with esophageal cancer and concurrent cervical LNM. Methods This population-based cohort study utilized data from the Netherlands Cancer Registry (NCR), encompassing patients with locally advanced thoracic esophageal or gastroesophageal junction cancer and concurrent cervical lymph node metastasis. Treatment modalities were categorized into five options: neoadjuvant therapy followed by surgery (Neo + S), definitive chemoradiotherapy (dCRT), chemotherapy with or without radiotherapy &amp;lt; 30 Gray (CT), radiotherapy (RT), and best supportive care (BSC). Overall survival (OS) was assessed using the Kaplan-Meier method and compared via the log-rank test. Hazard rates were computed using Cox proportional hazards regression, with adjustment for confounding achieved through inverse probability of treatment weighting (IPTW). Results Between 2015 and 2021, a cohort of 412 patients was identified from the NCR database. Median survival durations were observed as follows: 24.2 months for Neo + S, 18.0 months for dCRT, 14.5 months for CT, 7.0 months for RT, and 3.2 months for BSC (Figure). A comparison between the Neo + S group and dCRT demonstrated a significant improvement in survival (p=0.02). Further subdivision of the surgical group into neoadjuvant CRT or chemotherapy did not reveal a significant difference in survival (p=0.6). Utilizing IPTW to adjust for confounding factors, Neo + S maintained its survival advantage. Conclusion The retrospective cohort findings suggest that neoadjuvant therapy followed by surgery may represent the optimal approach for managing esophageal cancer patients with cervical LNMs Yet, it's vital to recognize the influence of confounding by indication, which statistical adjustments may not entirely rectify. Furthermore, immortal time bias notably skews results favorably toward surgery. Nevertheless, the results emphasize the importance of considering surgery as a viable option for these patients. These limitations underscore the critical need for a prospective study, prompting the launch of the NODE-II trial.

Post-Transcriptional Regulation of Rab7a in Lysosomal Positioning and Drug Resistance in Nutrient-Limited Cancer Cells.

Limited nutrient availability in the tumor microenvironment can cause the rewiring of signaling and metabolic networks to confer cancer cells with survival advantages. We show here that the limitation of glucose, glutamine and serum from the culture medium resulted in the survival of a population of cancer cells with high viability and capacity to form tumors in vivo. These cells also displayed a remarkable increase in the abundance and size of lysosomes. Moreover, lysosomes were located mainly in the perinuclear region in nutrient-limited cells; this translocation was mediated by a rapid post-transcriptional increase in the key endolysosomal trafficking protein Rab7a. The acidic lysosomes in nutrient-limited cells could trap weakly basic drugs such as doxorubicin, mediating resistance of the cells to the drug, which could be partially reversed with the lysosomal inhibitor bafilomycin A1. An in vivo chorioallantoic membrane (CAM) assay indicated a remarkable decrease in microtumor volume when nutrient-limited cells were treated with 5-Fluorouracil (5-FU) and bafilomycin A1 compared to cells treated with either agent alone. Overall, our data indicate the activation of complementary pathways with nutrient limitation that can enable cancer cells to survive, proliferate and acquire drug resistance.

325.1: Comparison of survival advantage of simultaneous kidney-pancreas vs kidney transplant in patients with diabetes who received mate kidneys.

325.1: Comparison of survival advantage of simultaneous kidney-pancreas vs kidney transplant in patients with diabetes who received mate kidneys.

Sex-related disparities in aortic stenosis from disease awareness to treatment: a state-of-the-art review.

This state-of-the-art review aimed to synthesize evidence from various sex-stratified studies on aortic stenosis (AS), focusing on the difference in clinical presentation, anatomical characteristics, pathophysiology, and management of AS. In comparison to men, women with AS are present at later stages, are older, more symptomatic, frailer, and exhibit higher operative risk [Society of Thoracic Surgeons (STS) score]. Women tend to have smaller aortic valve (AV) areas and left ventricular (LV) outflow tract, leading to lower stroke volumes (SVs) than men and have a higher prevalence of paradoxical, low-flow, low-gradient AS. In women, chronic pressure overload due to AS results in concentric LV remodelling and hypertrophy, characterized by reduced LV cavities, higher filling pressures, lower wall stress, and more diastolic dysfunction. Conversely, men exhibit more dilated eccentric LV remodelling and hypertrophy. AVs in women are less calcified but more fibrotic. Moreover, women are often underdiagnosed, have severity underestimated, and experience delays or receive fewer referrals for AV replacement (AVR). However, women tend to benefit from transcatheter AVR (TAVR) with a long-term survival advantage over men, although the incidence of vascular complications and bleeding events in 30 days after TAVR is higher in women. Surgical AVR (SAVR) in women has high operative risk, is technically demanding and has poorer outcomes with increased mortality at 30 days compared to men. According to the STS score and EuroSCORE, the female sex itself is considered a risk factor for SAVR. Therefore, addressing sex-related disparities in AS and increasing awareness among physicians promises improved diagnosis and treatment, facilitating equitable care and the development of sex-specific personalized medicine.

494. DO WE NEED GENDER SPECIFIC GUIDELINES FOR ESOPHAGEAL CANCER MANAGEMENT?

Abstract Background The incidence of esophageal cancer is disproportionately greater in males, but trials of treatments are not gender stratified. It is unclear whether the response or outcome following neoadjuvant chemoradiotherapy (NCR) is gender specific. This study compared the presentation, response to NCR and outcome of female with male patients. (48) Methods A prospectively maintained database of 205 esophageal carcinoma patients treated with curative intent between 1998 and 2019 was interrogated for the impact of gender on presentation, response to NCR treatment and survival. (32 words) Results Of 205 patients, 59 (29%) females were significantly older than males [mean (SD) age 66.1 (10.8) v. 61.6 (11.2) (p=0.008)]. Sixty-six percent of females had squamous cell carcinoma (SCC) while 116 (79.5%) males had adenocarcinoma (AC) (&amp;lt;0.001). Females with SCC had a mean age 66.7 years versus 58.9 years for males (p=0.006). Seventy-eight percent of females had a clinical complete response (cCR), versus 43.8% of males (P&amp;lt;0.001). Sixty-nine percent of females with AC had a cCR versus 39% of males (p=0.04). Controlling for age, diagnostic stage and treatment type, females survived significantly longer than males [HR 0.71 CI 0.52-0.98 (p=0.035)]. (100 words) Conclusion This study found that females were on average a decade older with a significantly greater cCR rate, and a superior survival advantage compared to males. This suggests that randomized trials should stratify for gender. (35 words)

Optimal Shunt Type for Norwood Procedure: Predicted Adverse Impact of Discordant Surgical Approach

BackgroundThe Single Ventricle Reconstruction (SVR) trial compared survival after Norwood procedure with either modified Blalock Taussig shunt (MBTS) or right ventricle pulmonary artery shunt (RVPAS). MethodsData from all 549 participants in the SVR trial were used to develop the MBTS TFSA algorithms, which predict the transplantation-free survival advantage (TFSA) after MBTS vs RVPAS at 1 and 6 years after Norwood procedure. Linear regression analysis of the MBTS TFSA values was performed to identify factors related to more optimal outcomes with MBTS at each timepoint. The impact of discordant management (ie, predicted shunt type did not equal the one actually received) on outcomes and the extent of inconsistencies between predictions were evaluated. ResultsThe MBTS TFSA algorithm favored MBTS over RVPAS for only 6.2% of participants at 1 year and for 27.0% at 6 years. In terms of both 1- and 6-year outcomes, MBTS was favored with younger age at Norwood procedure and pre-Norwood intubation, while RVPAS was favored with younger gestational age and metrics indicating larger right ventricle size in the parasternal echocardiographic views. Other predictors were timepoint-specific. MBTS TFSA based allocation could have led to an absolute risk reduction in heart transplantation and mortality of 8.0% at 1 year and 16.8% at 6 years, mostly by preventing discordant MBTS management. Notably, separate predictions from the 1-year and 6-year algorithms produced discordant predictions for 136 participants (24.8%). ConclusionsThe incorporation of data-derived patient-specific factors for selection of shunt type for the Norwood procedure may produce more optimal transplantation free survival. These precision medicine algorithms require prospective validation.

Potential Impact of Direct Versus Indirect Central Venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO) Cannulation in Refractory Postcardiotomy Cardiogenic Shock.

Background Central venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a commonly employed strategy to support patients in refractory postcardiotomy cardiogenic shock (RPCS). This support can be provided using either indirect central ECMO (icECMO) with a closed thorax or direct central ECMO (dcECMO) with an open thorax. Methods This single-center retrospective analysis included 60 patients undergoing central VA-ECMO for RPCS from January 2019 to December 2020. The primary endpoint of this study is to compare 30-day survival outcomes between the icECMO and dcECMO approaches in RPCS patients. Secondary endpoints include the evaluation of adverse events and the identification of predictors that influence 30-day mortality. Results The study included 60 patients, 25 received icECMO and 35 treated with dcECMO due to RPCS. The icECMO group demonstrated significantly better 30-day survival rates (icECMO; 10 [40%] vs. dcECMO; 5 [14.3%], log-rank test; p=0.042). Despite comparable ECMO flow rate and ECMO RPM (rotations per minute) in the first day between the study groups ([icECMO; 4.5 l/min vs. dcECMO; 4.6 l/min, p=0.124], [icECMO; 3510 rpm vs. dcECMO; 3800 rpm, p=0.115], respectively), lactate levels were significantly higher in the dcECMO group on the 1st and 3rd post-extracorporeal life support (ECLS) days (p=0.006 and p=0.008, respectively). Gastrointestinal ischemia was more common in the dcECMO group (p=0.036). Successful ECMO weaning was more frequent in the icECMO group (56% vs. 22.9%, p=0.014). Multivariable logistic regression identified arterial lactate on the first day with a cutoff 4 mmol/las an independent risk factor for 30-day mortality with Exp(B) of 8.9 (p=0.007). Conclusions Our findings suggest a potential survival advantage with the icECMO technique in patients undergoing central ECMO cannulation after RPCS. However, larger prospective studies are essential to confirm this observation.

P53 Abnormal (Copy Number High) Endometrioid Endometrial Carcinoma Has a Prognosis Indistinguishable From Serous Carcinoma.

Among the 4 molecular subgroups of endometrial carcinoma, the p53 abnormal (copy number high) subgroup has the worst prognosis; however, the histologic characteristics of this subgroup are not well established. Also, it is not well established whether low-grade tumors can belong to the p53 abnormal molecular subgroup and if so, what is the prognostic significance of the p53-mutated molecular subgroup in low-grade tumors. In the current study, we included 146 p53-mutated endometrial carcinomas and performed molecular subgrouping either based on a combination of immunohistochemical studies for p53 and MMR protein expression and POLE mutation testing (81 cases) or based on array-based and sequencing-based technologies (65 cases). We excluded cases that belonged to the POLE mutant or MSI molecular subgroups and only studied p53 abnormal (molecular subgroup) endometrial carcinomas (125 cases). In 71 cases, the molecular subgroup was determined by a combination of immunohistochemical studies and POLE mutation testing, and in 54 cases by array-based and sequencing-based methods. We reviewed 1 to 2 representative digital slides from each case and recorded the morphologic characteristics as well as clinical, treatment, and survival follow-up data. Overall, 47 cases were classified as endometrioid carcinoma, 55 serous carcinoma, and 23 other histotypes. Eight cases were FIGO 1, 21 were FIGO 2, and 91 were FIGO 3. A significant proportion of the cases (24.2%) were histologically classified as low-grade (FIGO 1 or 2) endometrioid carcinoma. There was no morphologic characteristic that showed prognostic implication. There was no significant difference in survival among different histotypes (P=0.60). There was no significant difference in survival among low-grade endometrioid (FIGO 1 or 2) versus high-grade (FIGO 3) tumors (P=0.98). Early-stage (stage I), low-grade tumors showed no significant survival advantage over early-stage, high-grade tumors (P=0.16) and this was more evident in FIGO 2 tumors. Although not statistically significant, the FIGO 2 tumors showed a trend toward worse survival than FIGO 3 tumors. Among the cases with available treatment data, more patients with early-stage high-grade tumors received adjuvant treatment, compared to patients with early-stage low-grade tumors, possibly explaining this trend (P=0.03). In conclusion, the findings of our study suggest that low-grade p53 abnormal endometrioid endometrial carcinomas (especially FIGO 2 tumors) have an aggressive course, with a prognosis similar to high-grade tumors. Furthermore, our study suggests that patients who had early-stage low-grade p53 abnormal disease might have been undertreated because of the "low-grade" histotype.

Understanding Metabolic Pathway Rewiring by Oncogenic Gamma Herpesvirus.

Gamma herpesviruses, including Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), are key contributors to the development of various cancers through their ability to manipulate host cellular pathways. This review explores the intricate ways these viruses rewire host metabolic pathways to sustain viral persistence and promote tumorigenesis. We look into how EBV and KSHV induce glycolytic reprogramming, alter mitochondrial function, and remodel nucleotide and amino acid metabolism, highlighting the crucial role of lipid metabolism in these oncogenic processes. By understanding these metabolic alterations, which confer proliferative and survival advantages to the virus-infected cells, we can identify potential therapeutic targets and develop innovative treatment strategies for gamma herpesvirus-associated malignancies. Ultimately, this review underscores the critical role of metabolic reprogramming in gamma herpesvirus oncogenesis and its implications for precision medicine in combating virus-driven cancers.

Evidence for Radiation Therapy in Stage III Locoregionally Advanced Cutaneous Melanoma in the Post-Immunotherapy Era: A Literature Review.

In the landscape of Stage III locoregionally advanced cutaneous melanoma treatment, the post-immunotherapy era has sparked a number of questions on the management of the nodal basin. However, much of the available literature is not focused on radiation therapy as an adjuvant therapy. This literature review aims to illuminate the evidence surrounding radiation therapy's potential to mitigate regional recurrences in the adjuvant setting for melanoma. Additionally, it seeks to identify adjunct systemic therapy options and explore the synergy between systemic therapy and radiation. Despite strides in surgical techniques and systemic therapies, controlling regional Stage III melanoma remains a formidable clinical hurdle. While historical data strongly suggest the efficacy of adjuvant radiation therapy in reducing regional recurrence risk, its evaluation predates the advent of MAPK pathway inhibitors and robust immunotherapy options. Notably, clinical trials have yet to definitively demonstrate a survival advantage with adjuvant radiation therapy. Additional research should focus on refining the definition of high risk for regional recurrence through gene expression profiling or tumor immune profiling scores and elucidate the optimal role of adjuvant radiation therapy in patients treated with neoadjuvant systemic therapy.