Survival Benefit Research Articles

Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): a multi-dose, open-label, randomised, phase 2 trial

Resistance to endocrine therapies in hormone receptor-positive breast cancer is challenging. We aimed to assess the next-generation oral selective oestrogen receptor degrader (SERD) and complete oestrogen receptor antagonist, camizestrant, versus the first-approved SERD, fulvestrant, in post-menopausal women with oestrogen receptor-positive, HER2-negative, advanced breast cancer. SERENA-2 is an open-label, randomised, phase 2 trial that is being conducted at 74 study centres across Asia, Europe, the Middle East, and North America. Female patients aged 18 years or older who were post-menopausal with histologically or cytologically confirmed metastastic or locoregional oestrogen receptor-positive, HER2-negative breast cancer, an Eastern Cooperative Oncology Group or WHO performance status of 0 or 1, and disease recurrence or progression on at least one line of endocrine therapy, and no more than one previous endocrine therapy in the advanced setting. Patients were initially randomly assigned (1:1:1:1) to receive oral camizestrant once daily at 75 mg, 150 mg, or 300 mg (until the 300 mg group was closed), or fulvestrant intramuscularly at 500 mg (per label). Randomisation was managed through an interactive web-based system and stratified by previous treatment with CDK4/6 inhibitors and presence of liver and/or lung metastases. The primary objective was to determine clinical efficacy of camizestrant versus fulvestrant at each dose level using the primary endpoint of investigator-assessed progression-free survival, per Response Evaluation Criteria in Solid Tumours (version 1.1), assessed by intention to treat in all randomly assigned patients (full analysis set). No formal statistical comparison for the efficacy analysis of the camizestrant 300 mg dose versus fulvestrant was to be performed. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04214288, and is ongoing. Between May 11, 2020, and Aug 10, 2021, 240 patients were randomly assigned to receive camizestrant 75 mg (n=74), 150 mg (n=73), 300 mg (n=20), or fulvestrant (n=73), and were included in the full analysis set. All patients received at least one dose of study drug. Median follow-up was 16·6 months (IQR 12·9-19·4) for the camizestrant 75 mg group, 16·3 months (12·9-18·3) for the camizestrant 150 mg group, and 14·7 months (12·7-20·1) for the fulvestrant 500 mg group. Median progression-free survival was 7·2 months (90% CI 3·7-10·9) with camizestrant 75 mg, 7·7 months (5·5-12·9) with camizestrant 150 mg, and 3·7 months (2·0-6·0) with fulvestrant. The hazard ratio for camizestrant 75 mg versus fulvestrant was 0·59 (90% CI 0·42-0·82; p=0·017), and the hazard ratio for camizestrant 150 mg versus fulvestrant was 0·64 (0·46-0·89; p=0·0090). Treatment-related adverse events occurred in 39 (53%) of 74 patients in the camizestrant 75 mg group, 49 (67%) of 73 patients in the camizestrant 150 mg group, 14 (70%) of 20 patients in the camizestrant 300 mg group, and 13 (18%) of 73 patients in the fulvestrant group. No single grade 3 or worse treatment-emergent adverse event occurred in more than two (3%) patients in any group. Serious treatment-emergent adverse events occurred in six (8%) patients in the camizestrant 75 mg group, seven (10%) patients in the camizestrant 150 mg group, two (10%) patients in the camizestrant 300 mg group, and four (5%) patients in the fulvestrant group. No treatment-related deaths occurred. Camizestrant at 75 and 150 mg showed a significant benefit in progression-free survival versus fulvestrant. These results support further development of camizestrant for the treatment of oestrogen receptor-positive, HER2-negative breast cancer. AstraZeneca.

Development and Validation of a Predictive Nomogram for Patients With Myxopapillary Ependymoma: A Surveillance, Epidemiology, and End Results (SEER) Retrospective Cohort Analysis.

Retrospective Study. Myxopapillary ependymomas (MPEs) are a unique subgroup of spinal ependymomas originating from the filum terminale's ependymal glia. The 2021 WHO classification reclassified all MPEs as grade 2, recognizing their higher recurrence risk. Due to their rarity, our objective with this study is to understand MPEs' clinical course and optimal management through a large retrospective cohort analysis. From the years 2000 to 2020, patients with MPEs were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariable Cox proportional hazard models were run to identify variables that had a significant impact on the primary endpoint of overall survival (OS). A predictive nomogram was built to predict 5-year and 10-year survival probability. This retrospective cohort includes 1373 patients. Patients 65 years or older at diagnosis had a poorer OS (P < 0.001). Most patients received subtotal resection. Only 320 patients (23%) received gross total resection (GTR). Patients that received GTR had the best OS when compared against all other modalities of treatment (P < 0.05). Receiving radiotherapy did not affect OS in patients with MPE (P = 0.2). Nomogram includes patient age and treatment modalities, demonstrating acceptable accuracy in estimating the survival probability at 5-year and 10-year intervals, with a C-index of 0.80 (95% CI of 0.71 to 0.90). This study highlights the survival benefit of GTR in the treatment of patients with MPE. The role of adjuvant radiotherapy remains unclear as it did not seem to improve OS. The nomogram stratifies the risk of survival in patients with MPE based on age and treatment modality.

Leveraging machine learning for preoperative prediction of supramaximal ablation in laser interstitial thermal therapy for brain tumors.

Maximizing safe resection in neuro-oncology has become paramount to improving patient survival and outcomes. Laser interstitial thermal therapy (LITT) offers similar survival benefits to traditional resection, alongside shorter hospital stays and faster recovery times. The extent of ablation (EOA) achieved using LITT is linked to patient outcomes, with greater EOA correlating with improved outcomes. However, the preoperative predictors for achieving supramaximal ablation (EOA ≥ 100%) are not well understood. By leveraging machine learning (ML) techniques, this study aimed to identify these predictors to enhance patient selection and therefore outcomes. The objective was to explore preoperative predictors for supramaximal EOA using ML in patients with glioblastoma. A retrospective study was conducted on the medical records of 254 patients undergoing LITT from 2013 to 2023 at a single tertiary center. Cohort criteria included age ≥ 18 years, diagnosis of glioblastoma, single-trajectory ablation, and a complete dataset. The study assessed preoperative clinical and radiographic factors, using EOA ≥ 100% as the endpoint. Five ML models were used: logistic regression, random forest (RF), gradient boosting, Gaussian naive Bayes, and support vector machine. Training and testing cohorts were subsequently assessed across ML models with fivefold cross-validation. Models were optimized using hyperparameter tuning. Performance was primarily quantified using the area under the curve (AUC) of the receiver operating characteristic curve. The final cohort consisted of 72 patients. Among the ML models, RF achieved the highest AUC (mean ± SD 0.94 ± 0.06). The leading models identified that lower preoperative volume, history of prior radiation therapy, history of prior craniotomy, preoperative neurological deficits, history of preoperative seizures, and distance from intracranial heat sinks were predictive of successful ablations in patients. Additionally, RF had the best mean metrics: accuracy 0.88, precision 0.87, specificity 0.87, and sensitivity 0.89. This is the first study to investigate the role of ML for optimizing ablation volumes in LITT. These ML models suggest that low preoperative volumes, previous craniotomy, previous radiation therapy, no previous neurological deficits, larger catheter-heat sink distance, and the presence of preoperative seizures are important prognostic factors for predicting successful supramaximal ablations with LITT.

Survival Benefits of Postoperative Chemotherapy in Patients With Colorectal Mucinous Adenocarcinoma: An Analysis Utilizing Propensity Score Matching From the Surveillance, Epidemiology, and End Results Database.

This study aimed to investigate the characteristics of patients with colorectal mucinous adenocarcinoma (MAC) who benefit from postoperative chemotherapy (POCT) and to develop effective postoperative survival nomograms for predicting overall survival (OS) in colorectal MAC patients. Data of colorectal MAC patients who underwent surgery from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2020 were collected. Patients were grouped based on POCT, and intergroup analysis was performed using 1:1 propensity score matching (PSM). Kaplan-Meier (K-M) curves were used to compare the prognosis between the 2 groups. Cox analysis was employed to identify factors associated with OS in patients with colorectal MAC who underwent POCT. The variance inflation factor (VIF) and bilateral stepwise regression were used to determine factors included in the model. Additionally, a nomogram was constructed to predict postoperative survival outcomes for patients. The discriminative ability of the nomograms was evaluated using the C-index and calibration curve analysis, the decision curve analysis (DCA) assessed the clinical utility of the nomogram, and the receiver operating characteristic (ROC) curve evaluated the nomograms' performance. This study encompassed 6829 patients with colorectal MAC, among whom 2258 received POCT, and 4571 did not. Whether pre or post PSM, patients in the POCT group consistently exhibited a superior median OS compared to those in the postoperative non-chemotherapy group (P < .0001). For colorectal MAC patients undergoing POCT, OS was correlated with factors such as patient age, carcinoembryonic antigen levels, tumor deposits, perineural invasion (PNI), lymph node examination count, T staging, and Grade staging. Notably, a significant chemotherapy advantage was observed in patients without perineural invasion, those with lymph node examination counts exceeding 12, and patients with moderately differentiated tumors. The overall colorectal MAC patient postoperative OS predictive nomogram demonstrated a C-index of .74, with a calibration curve near the diagonal and a DCA curve indicating positive net benefits. In comparison to TNM staging, the ROC curves of the nomogram at 1 year, 3 years, and 5 years demonstrated superior predictive capabilities (AUC: .80 vs .71, .78 vs .71, .77 vs .70). This study revealed the characteristics of colorectal MAC patients who benefit from POCT and established effective prognostic nomograms, which can aid clinicians in designing personalized treatment plans for individual patients and promote precision medicine.

Development of a murine laser interstitial thermotherapy system.

The objective of this study was to develop a murine system for the delivery of laser interstitial thermotherapy (LITT) with probe-based thermometry as a model for human glioblastoma treatment to investigate thermal diffusion in heterogeneous brain tissue. First, the tissue heating properties were characterized using a diode-pumped solid-state near-infrared laser in a homogeneous tissue model. The laser was adapted for use with a repurposed stereotactic surgery frame utilizing a micro laser probe and Hamilton syringe. The authors designed and manufactured a stereotactic frame attachment to work as a temperature probe stabilizer. Application of this novel design was used as a precise method for real-time thermometry at known distances from the thermal ablative center mass during murine LITT studies. Temperature measurements were achieved during LITT that verified the direct thermometry capability of the system without the need for MR-based thermal monitoring. Application of multiple stereotactic design iterations led to an accurately reproducible surgical laser ablation procedure. Histological staining confirmed precise thermal ablation and controllable lesion size based on time and temperature control. Treatment of a syngeneic intracranial glioma model highly resistant to conventional therapy resulted in a modest survival benefit. The authors have successfully developed a murine model system of LITT with direct in situ thermometry for investigation into the effects of thermal ablation and combinatorial treatments in murine brain tumor models.

Genetic Test Predicts Survival Benefit From Docetaxel in Prostate Cancer

Genetic Test Predicts Survival Benefit From Docetaxel in Prostate Cancer

Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma.

Genomic screening uncovered interferon-gamma (IFNγ) pathway defects in tumours refractory to immune checkpoint blockade (ICB). However, its non-mutational regulation and reversibility for therapeutic development remain less understood. We aimed to identify ICB resistance-associated druggable histone deacetylases (HDACs) and develop a readily translatable combination approach for patients with hepatocellular carcinoma (HCC). We correlated the prognostic outcomes of HCC patients from a pembrolizumab trial (NCT03419481) with tumourous cell expressions of all HDAC isoforms by single-cell RNA sequencing. We investigated the therapeutic efficacy and mechanism of action of selective HDAC inhibition in 4 ICB-resistant orthotopic and spontaneous models using immune profiling, single-cell multiomics and chromatin immunoprecipitation-sequencing and verified by genetic modulations and co-culture systems. HCC patients showing higher HDAC1/2/3 expressions exhibited deficient IFNγ signalling and poorer survival on ICB therapy. Transient treatment of a selective class-I HDAC inhibitor CXD101 resensitised HDAC1/2/3high tumours to ICB therapies, resulting in CD8+T cell-dependent antitumour and memory T cell responses. Mechanistically, CXD101 synergised with ICB to stimulate STAT1-driven antitumour immunity through enhanced chromatin accessibility and H3K27 hyperacetylation of IFNγ-responsive genes. Intratumoural recruitment of IFNγ+GZMB+cytotoxic lymphocytes further promoted cleavage of CXD101-induced Gasdermin E (GSDME) to trigger pyroptosis in a STAT1-dependent manner. Notably, deletion of GSDME mimicked STAT1 knockout in abolishing the antitumour efficacy and survival benefit of CXD101-ICB combination therapy by thwarting both pyroptotic and IFNγ responses. Our immunoepigenetic strategy harnesses IFNγ-mediated network to augment the cancer-immunity cycle, revealing a self-reinforcing STAT1-GSDME pyroptotic circuitry as the mechanistic basis for an ongoing phase-II trial to tackle ICB resistance (NCT05873244).

ASO Author Reflections: Survival Benefit of Adjuvant Systemic Therapy After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma.

ASO Author Reflections: Survival Benefit of Adjuvant Systemic Therapy After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma.

3PM-guided innovation in treatments of severe alcohol-associated hepatitis utilizing fecal microbiota transplantation

Abstract Rationale Severe alcohol-associated hepatitis (SAH) is the most critical, acute, inflammatory phenotype within the alcohol-associated liver disease (ALD) spectrum, characterized by high 30- and 90-day mortality. Since several decades, corticosteroids (CS) are the only approved pharmacotherapy offering highly limited survival benefits. Contextually, there is an evident demand for 3PM innovation in the area meeting patients’ needs and improving individual outcomes. Fecal microbiota transplantation (FMT) has emerged as one of the new potential therapeutic options. In this study, we aimed to address the crucial 3PM domains in order to assess (i) the impact of FMT on mortality in SAH patients beyond CS, (ii) to identify factors associated with the outcome to be improved (iii) the prediction of futility, (iv) prevention of suboptimal individual outcomes linked to increased mortality, and (v) personalized allocation of therapy. Methods We conducted a prospective study (NCT04758806) in adult patients with SAH who were non-responders (NR) to or non-eligible (NE) for CS between January 2018 and August 2022. The intervention consisted of five 100 ml of FMT, prepared from 30 g stool from an unrelated healthy donor and frozen at − 80 °C, administered daily to the upper gastrointestinal (GI) tract. We evaluated the impact of FMT on 30- and 90-day mortality which we compared to the control group selected by the propensity score matching and treated by the standard of care; the control group was derived from the RH7 registry of patients hospitalized at the liver unit (NCT04767945). We have also scrutinized the FMT outcome against established and potential prognostic factors for SAH — such as the model for end-stage liver disease (MELD), Maddrey Discriminant Function (MDF), acute-on-chronic liver failure (ACLF), Liver Frailty Index (LFI), hepatic venous-portal pressure gradient (HVPG) and Alcoholic Hepatitis Histologic Score (AHHS) — to see if the 3PM method assigns them a new dimension in predicting response to therapy, prevention of suboptimal individual outcomes, and personalized patient management. Results We enrolled 44 patients with SAH (NR or NE) on an intention-to-treat basis; we analyzed 33 patients per protocol for associated factors (after an additional 11 being excluded for receiving less than 5 doses of FMT), and 31 patients by propensity score matching for corresponding individual outcomes, respectively. The mean age was 49.6 years, 11 patients (33.3%) were females. The median MELD score was 29, and ACLF of any degree had 27 patients (81.8%). FMT improved 30-day mortality (p = 0.0204) and non-significantly improved 90-day mortality (p = 0.4386). Univariate analysis identified MELD ≥ 30, MDF ≥ 90, and ACLF grade &gt; 1 as significant predictors of 30-day mortality, (p = 0.031; p = 0.014; p = 0.034). Survival was not associated with baseline LFI, HVPG, or AHHS. Conclusions and recommendations in the framework of 3PM In the most difficult-to-treat sub-cohort of patients with SAH (i.e., NR/NE), FMT improved 30-day mortality. Factors associated with benefit included MELD ≤ 30, MDF ≤ 90, and ACLF &lt; 2. These results support the potential of gut microbiome as a therapeutic target in the context of 3PM research and vice versa — to use 3PM methodology as the expedient unifying template for microbiome research. The results allow for immediate impact on the innovative concepts of (i) personalized phenotyping and stratification of the disease for the clinical research and practice, (ii) multilevel predictive diagnosis related to personalized/precise treatment allocation including evidence-based (ii) prevention of futile and sub-optimally effective therapy, as well as (iii) targeted prevention of poor individual outcomes in patients with SAH. Moreover, our results add to the existing evidence with the potential to generate new research along the SAH’s pathogenetic pathways such as diverse individual susceptibility to alcohol toxicity, host-specific mitochondrial function and systemic inflammation, and the role of gut dysbiosis thereof.

Survival Outcomes of an Early Intervention Smoking Cessation Treatment After a Cancer Diagnosis

Smoking after a cancer diagnosis increases mortality and risk for a second cancer. To determine the association between time of entry into a smoking cessation intervention following a cancer diagnosis and survival outcomes. Using a prospective cohort study design, patients with cancer who smoked and received cessation treatment were assessed at 3 months, 6 months, and 9 months following tobacco treatment onset. Survival outcomes of tobacco treatment were measured and compared among patients at the MD Anderson Cancer Center Tobacco Research and Treatment Program. Treatment occurred between January 1, 2006, and March 3, 2022. Patients were excluded if they died before the tobacco treatment ended, received their diagnosis more than 6 months after beginning cessation treatment, or lacked staging information. The data analysis took place from September 2023 to May 2024. Cessation treatment consisted of 6 to 8 personalized counseling visits and 10 to 12 weeks of pharmacotherapy. More than 95% of visits were provided via telemedicine. The primary outcomes were survival as recorded in the MD Anderson Cancer Center tumor registry and 7-day point prevalence abstinence at each follow-up. The main analytical sample consisted of 4526 currently smoking patients diagnosed with cancer and receiving cessation treatment (2254 [49.8%] female; median [IQR] age, 55 [47-62] years). Survival over 15 years increased for those quitting smoking at 3 months (adjusted hazard ratio [aHR], 0.75 [95% CI, 0.67-0.83]), 6 months (aHR, 0.79 [95% CI, 0.71-0.88]), and 9 months (aHR, 0.85 [95% CI, 0.76-0.95]) of follow-up. The optimal survival outcomes were observed for patients who received tobacco treatment within 6 months of a cancer diagnosis. At the 75th percentile, their survival increased from 2.1 years (95% CI, 1.8-2.4 years) among continuing smokers (nonabstainers) vs 3.9 years (95% CI, 3.2-4.6 years) for patients who quit (abstainers). Similar but less pronounced outcomes were noted when tobacco treatment began within 6 months to 5 years following diagnosis, with survival at the 75th percentile of 4.8 years (95% CI, 4.3-5.3 years) for nonabstainers vs 6.0 years (95% CI, 5.1-7.2 years) for abstainers. The results of this prospective cohort study suggest that evidence-based smoking cessation treatment within 6 months following a cancer diagnosis maximizes survival benefit. This study supports smoking cessation as an important early clinical intervention for patients after being diagnosed with cancer.

Beyond hazard ratios: appropriate statistical methods for quantifying the clinical effectiveness of immune-oncology therapies – the example of the Netherlands

BackgroundThe Dutch Committee for the Evaluation of Oncological Drugs evaluates the effectiveness of new oncological treatments. The committee compares survival endpoints to the so-called PASKWIL-2023 criteria for palliative treatments, which define if treatment effects are considered clinically relevant. A positive recommendation depends on whether the median overall survival (OS) is below or above 12 months in the comparator arm. If the former applies, an OS benefit of at least 12 weeks, and a hazard ratio (HR) smaller than 0.7 are required. If the latter applies, an OS or progression free survival (PFS) benefit of at least 16 weeks, and an HR smaller than 0.7 are required. Nonetheless, the median survival time may not be reached and the proportional hazards (PH) assumption, quantified by the HR, is likely violated for immuno-oncology (IO) therapies, deeming these criteria inappropriate.MethodsWe conducted a systematic literature review to identify statistical methods used to represent the clinical effectiveness of IO therapies based on trial data. We searched MEDLINE and EMBASE databases from inception to August 31, 2022, limited to English papers. Methodological studies, randomized controlled trials, and discussion papers recognising key issues of survival data analysis of IO therapies were eligible for inclusion.ResultsA total of 1,035 unique references were identified. After full paper screening, 17 publications were included in the review. Additionally, 43 papers were identified through ‘snowballing’. We conclude that the current PASKWIL-2023 criteria are methodologically incorrect under non-PH. In that case, single summary statistics fail to capture the treatment effect and any measure should be interpreted in combination with the Kaplan-Meier curves. We recommend ’parameter-free’ measures, such as the difference in restricted mean survival time, avoiding assumptions on the underlying survival.ConclusionsThe HR is commonly used to assess treatment effectiveness, without investigating the validity of the PH assumption. This happens with the application of the PASKWIL-2023 criteria for palliative oncology treatments, which can only be valid under a PH setting. Under non-PH, alternative treatment effect measures are suggested. We propose a step-by-step approach supporting the choice of the most appropriate methods to quantify treatment effectiveness that can be used to redefine the PASKWIL-2023 criteria, or similar criteria in other clinical areas.

The Effect of PD-1/PD-L1 Inhibitor and Statin Combination Therapy on Overall Survival and Gastrointestinal Toxicity.

Immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, have been approved to treat a variety of cancers. Recently, studies have suggested that ICIs and statins are synergistic. However, the addition of statins to ICI therapy may increase the risk of gastrointestinal immune-related adverse events (irAEs). We investigated the effect of combination therapy with PD-1 and/or L1 inhibitors and statins on overall survival and gastrointestinal irAEs. We reviewed the charts of patients with select cancers who received PD-1 and/or PD-L1 inhibitors and statins. The incidence of gastrointestinal irAEs and overall survival were compared with that in a matched control group of patients who received PD-1 and/or PD-L1 inhibitors without statins. Of the 823 patients in the statin group, 707 received PD-1 inhibitors, 86 received PD-L1 inhibitors, and 30 received both. Patients taking any statins (10.8%) and those taking high-intensity statins (15.8%) had higher rates of gastrointestinal irAEs than patients not taking statins (8.7%; P=0.046 and 0.006, respectively). Compared with the nonstatin treatments, statin use was associated with improved overall survival for patients taking PD-1 inhibitors (P<0.001) and for patients with (P=0.021) and without (P<0.001) gastrointestinal irAEs. Synergism of statins with PD-1 and PD-L1 inhibitors continues to be a developing field of interest. Our data demonstrate the survival benefit of combination therapy with PD-1 and/or PD-L1 inhibitors and statins, warranting further investigation.

Cutaneous Toxicities of Advanced Treatment for Cutaneous Melanoma: A Prospective Study from a Single-Center Institution

Background/Objectives: The landscape of advanced melanoma treatments has shifted dramatically in recent years. Target therapy and immunotherapy have changed the management of patients with both metastatic (stage IV according to AJCC 8th ed.) and nodal (stage IIB/C and III) disease. As the use of novel agents has increased, so have the cutaneous toxicities associated with these medications. While most skin reactions are low-grade and can be managed conservatively with topical therapies, high-grade or life-threatening drug reactions can arise during therapy, requiring prompt dermatologic recognition and treatment. Given the survival benefit attributed to these new agents, treating skin toxicity and maintaining a patient’s quality of life is of paramount importance. Methods: We undertook a prospective, monocentric, and descriptive study in Bologna, Italy, including patients referred to the Oncologic Dermatology Unit of IRCCS AOU of Bologna who developed biopsy-proven cutaneous adverse events (AE) under treatment with immunotherapy for cutaneous melanoma with nodal (stage IIB/C, III) and metastatic (stage IV) disease from January 2016 to April 2024. Results: In 202 identified patients, 75 (37.5%) developed skin AEs. Ipilimumab was causal for 48.1% of skin AEs, followed by nivolumab (37%) and pembrolizumab (31.4%). Recorded types of skin AEs included erythematous rash, vitiligo, alopecia, lichenoid, maculopapular, acneiform, urticarial, psoriasiform, granulomatous, eczematous, and severe cutaneous AEs, such as Erythema multiforme/Stevens-Johnson syndrome and bullous autoimmune dermatoses. Most AEs were low-grade [CTCAE 1–2] (97%) and typically occurred after 10 weeks of treatment. Conclusions: This study comprehensively describes skin AEs occurring during systemic treatment with ICIs for cutaneous melanoma at a single center.

Reverse epidemiology of obesity paradox: Fact or fiction?

Obesity paradox refers to the clinical observation that when acute cardiovascular decompensation occurs, patients with obesity may have a survival benefit. This apparently runs counter to the epidemiology of obesity, which may increase the risk for non-communicable diseases (NCDs). The scientific community is split on obesity paradox, with some supporting it, while others call it BMI paradox. This review: (a) defines the obesity paradox, and its proposed role in overall mortality in NCDs; (b) delineates evidence for and against obesity paradox; (c) presents the importance of using different indices of body mass to assess the risk in NCDs; (d) examines the role of metabolically healthy obesity in obesity paradox, and emerging importance of cardio-respiratory fitness (CRF) as an independent predictor of CVD risk and all-cause mortality in patients with/without obesity. Evidence suggests that the development of obesity and insulin resistance are influenced by genetic (or ethnic) make up and dietary habits (culture) of the individuals. Hence, this review presents lean diabetes, which has higher total CVD and non-CVD mortality as compared to diabetics with obesity and the possibility of maternal factors programming cardiometabolic risk during fetal development, which may lead to a paradigm shift in our understanding of obesity.

Predicting survival benefits of immune checkpoint inhibitor therapy in lung cancer patients: a machine learning approach using real-world data.

Due to the heterogeneity in the effectiveness of immunotherapy for lung cancer, identifying predictors is crucial. This study aimed to develop a machine learning model to identify predictors of overall survival in lung cancer patients treated with immune checkpoint inhibitors (ICIs). A retrospective analysis was performed on data from 1314 lung cancer patients at the Chongqing University Cancer Hospital from September 2018 to September 2022. We used the random survival forest (RSF) model to identify survival-influencing factors, using backward elimination for variable selection. A Cox proportional hazards (CPH) model was constructed using the most significant predictors. We assessed model performance and generalizability using time-dependent receiver operating characteristics (ROC) and predictive error curves. The RSF model demonstrated better predictive accuracy than the CPH (IBS 0.17 vs. 0.17; C-index 0.91 vs. 0.68), with better discrimination and prediction performance. The influential variables identified included D-dimer, Karnofsky performance status, albumin, surgery, TNM stage, platelet count, and age. The RSF model, which incorporated these variables, achieved area under the curve (AUC) scores of 0.95, 0.94, and 0.98 for 1-, 3-, and 5-year survival predictions, respectively, in the training set. The validation set showed AUCs of 0.94, 0.90, and 0.95, respectively, exceeding the performance of the CPH model. The study successfully developed a machine learning model that accurately predicted the survival benefits of ICI therapy in lung cancer patients, supporting clinical decision-making in lung cancer treatment.

Changes in physical activity and all-cause mortality among individuals with dementia: a cohort study using the National Health Insurance Service Database in Korea.

To examine associations between the amount and changes in regular physical activity (PA) before and after diagnosis of dementia and all-cause mortality risk, and whether these associations differ by PA intensity (light, moderate or vigorous). This retrospective cohort study used data from the Korean National Health Insurance Service Database, including 60 252 individuals newly diagnosed with dementia between 2010 and 2016 who underwent health examinations both before and after diagnosis. PA was assessed using the International Physical Activity Questionnaire-Short Form. Multivariable Cox proportional hazards regression models were used to analyse the associations between PA (amount and changes) and all-cause mortality risk. During a mean follow-up of 3.7 years, 16 431 (27.3%) deaths occurred. Higher PA levels after dementia diagnosis were associated with a dose-dependent decrease in mortality risk (p for trend <0.001). Maintaining regular PA, compared with remaining inactive, was associated with the lowest mortality risk (HR=0.71, 95% CI 0.65 to 0.79). Sustained engagement in PA of any intensity was associated with decreased mortality risk: light (HR=0.70, 95% CI 0.67 to 0.75), moderate (HR=0.74, 95% CI 0.64 to 0.86) and vigorous PA (HR=0.70, 95% CI 0.61 to 0.79). Initiating any PA intensity after dementia diagnosis was associated with at least 20% reduced mortality risk. These associations were consistent in Alzheimer's disease. Maintaining or initiating regular PA, regardless of intensity, after dementia diagnosis was associated with a reduced risk of all-cause mortality. Lifestyle modifications promoting PA might offer survival benefits for individuals with dementia.

IGSF1: a biomarker for predicting prognosis, immunotherapy response, and drug candidates in COVID-19 combined hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with poor prognosis and a common cause of cancer-related death worldwide, and despite ongoing therapeutic breakthroughs, patient survival benefits are limited. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19) and poses a major threat to humanity worldwide. As the epidemic continues to develop, more and more people are infected with SARS-CoV-2, including patients with HCC. However, the relationship between COVID-19 and HCC has not yet been fully elucidated. Our study aimed to identify the shared genetic characteristics and molecular mechanisms between COVID-19 and HCC. The data involved in this study come from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression(GTEx), and Cancer Cell Line Encyclopedia(CCLE) databases. We used differentially expressed genes to perform enrichment analysis to reveal the biological landscape of COVID-19 combined with HCC. In addition, weighted gene co-expression network analysis (WGCNA) was used to study the co-expression network related to COVID-19 and HCC. We then combined the validation datasets to screen out immunoglobulin superfamily member 1 (IGSF1) as the most important core gene. Finally, we extensively studied the functional expression of IGSF1 in tumor samples, normal tissues, and cancer cell lines. The molecular mechanisms related to COVID-19 and HCC are rarely studied. Our study identifies IGSF1 as a potential therapeutic target and immune-related biomarker for patients with COVID-19 and HCC.

Survival benefit added by adjuvant chemotherapy in adenoid cystic carcinoma of salivary gland

The aim of this study was to investigate the potential survival advantages associated with chemoradiotherapy (CRT) compared to radiotherapy (RT) as standalone modalities in the treatment of adenoid cystic carcinoma (ACC) of the salivary glands. Patients diagnosed with resected salivary gland ACC were retrospectively enrolled and categorized into two groups based on the type of adjuvant therapy received. The overall survival outcomes between the CRT and RT cohorts were evaluated using a multivariable Cox model. Post propensity score-matching, a total of 114 patients (57 in each treatment group) were included in the analysis. In the general patient population, CRT did not confer an additional survival benefit compared to RT alone. High-grade tumors, positive surgical margins, and the presence of five or more positive lymph nodes were identified as independent prognostic factors associated with poorer overall survival. Specifically, for patients with positive surgical margins, CRT was significantly associated with improved overall survival relative to RT, displaying a hazard ratio of 0.93 (95% CI: 0.81–0.99). Furthermore, in patients with more than four metastatic lymph nodes, CRT significantly reduced the risk of mortality by 6% (95% CI: 1-24%) when compared to RT alone. Conversely, in patients with high-grade tumors, the addition of adjuvant chemotherapy to RT did not yield significant alterations in survival outcomes compared to RT alone (p = 0.437, HR: 0.95, 95% CI: 0.75–2.07). CRT may offer an overall survival benefit for patients with salivary gland ACC, particularly those characterized by positive margin or the presence of five or more metastatic lymph nodes.

Beyond secondary prevention drugs: added benefit in survival and events of a healthy lifestyle in patients after an acute coronary syndrome

Abstract Background Despite advances in drug treatment and secondary prevention programs, cardiovascular disease remains the leading cause of death. The full extent and independent benefit of a healthy lifestyle, particularly after optimal medical therapy in secondary prevention, has not been widely reported. Purpose To quantify the added benefit on survival and events of a healthy lifestyle following an acute coronary syndrome (ACS). Our study seeks to answer the question: Is adherence to medical therapy sufficient or a healthy lifestyle provides additional improvement?. Methods This a prospective observational multi-center study of 685 patients included during admission for ACS. At 6 months patients were asked about their post-ACS lifestyle and were given a score (range: 0-7) with the following items: Intake of ≥3 fruits and vegetables/day, ≥2 fish servings/week, ≤7 alcohol beverages/week, feeling stress RESULTS: After adjusting for demographic variables, cardiovascular risk factors, characteristics of the index event, high-sensitivity C-reactive protein (hs-CRP), and drug therapy, multivariate Cox regression showed that the lifestyle SCORE was independently and inversely associated with both the incidence of the primary outcome (ischemic events [any ACS, stroke, or Transient Ischemic Attack] or death) (HR 0.65 (CI95% 0.44-0.96); p=0.029) and death (HR 0.41 [95%CI 0.18-0.91]; p=0.029). Statin therapy was also independently and inversely associated with both the incidence of the primary outcome. Kaplan-Meier curves showed a higher event-free survival for both outcomes in patients with SCORE≥4 than in those with SCORE&amp;lt;4 (p=0.03 and p&amp;lt;0.001, respectively). Additionally, patients with a SCORE≥4 had a significantly greater decrease of total cholesterol (-52 [-16.5, -79] vs -38 [-7.5, -68] mg/dl; p=0.040) and hs-CRP (-1.1 [-0.1, 2.5] vs -0.5 [0.7, -1.9] mg/L; p=0.001) at six months. Conclusions Among patients with ACS and similar medical therapy, a healthy lifestyle is an independent and added marker of a lower incidence of ischemic events and death. It is also associated with a better lipid profile and lower inflammation.

Long-term clinical outcomes and patterns of follow-up after cardiogenic shock: insights from an advanced heart failure referral center registry

Abstract Background Inpatient mortality of patients with cardiogenic (CS) has been reported as high as 50%. Those who present in CS are at high risk of having recurrent admissions to hospital or requiring advanced heart failure (HF) therapies. The Toronto General Hospital (TGH) is a quaternary cardiac center, providing mechanical circulatory support (MCS) and heart transplantation (HT), serving as a regional CS transfer hub for a population of over 8 million people. While inpatient management of CS patients has been studied extensively, there is little data on where or how these patients are followed after their discharge. We aimed to determine the long-term clinical outcomes and nature of follow up after a CS admission. Methods This was a retrospective cohort study of CS patients admitted to TGH between 2014 and 2023. We collected data regarding survival to discharge and the type of follow up patients received after their index CS admission. Survival was compared using Kaplan-Meier methods. Results 1582 patients were admitted during the study. The mean age was 59.9 + 16.1 years, including 474 (30.0%) females and 335 (21.2%) patients with acute myocardial infarction CS. In-hospital mortality was 32.4%, with a further 17 (1.8%) patients transferred to palliative care during their index CS admission. After excluding patients who underwent heart transplantation (HT) or durable MCS implant, 679 patients were discharged alive, with median follow-up of the 307 (range 0 – 3436) days. Overall mortality was 57.0%. Among discharged patients, 396 (56.8%) were followed at the regional hub hospital. A further 54 (8.0%) patients were followed by a cardiology provider at a referring community center. A total of 202 (29.7%) patients did not have outpatient follow up arranged at the time of their discharge and no details of further care were available. Median survival during follow-up was higher among patients with confirmed follow-up at the time of their discharge, but not statistically significant (1798 vs 1775 days, p=0.067). There was a significant survival benefit among CS patients followed at a heart function clinic compared with those who were not, (1821 vs. 1775 days, p= 0.020). In terms of candidacy for advanced therapies, having outpatient follow up was associated with receiving durable MCS or HT (6.3% vs. 0.5%, p=0.003). Conclusion Despite advances in the management of CS, overall mortality remains high at 57.0%. Follow-up after CS admission is of essential importance- both in improvement of long-term outcomes, and access to advanced heart failure therapies. There was a survival benefit among patients who were followed in a specialized heart function clinic. Additionally, having outpatient follow up was significantly associated with receiving advanced therapies. Further research is needed to identify the barriers to accessing post discharge follow-up care.