Improved Survival In Patients Research Articles

Clinical Exploration of Immunosuppressants Combined with Abiraterone in the Treatment of Metastatic Castration-Resistant Prostate Cancer

Prostate cancer is a malignant tumor with a high incidence in elderly men. In recent years, with the improvement of people’s living standards and the advancement of detection technology, the incidence of prostate cancer has been increasing year by year. Castration-resistant prostate cancer (CRPC) is a highly challenging type of advanced prostate cancer treatment, which clinically shows resistance to hormonal deprivation therapy. The overall treatment efficacy of CRPC is currently poor and further relevant therapeutic studies are needed to improve patient survival and quality of life. Immunosuppressants can play a role in combating the immune system of tumors, and abiraterone has also achieved remarkable results in prostate cancer treatment. This study will investigate the possible clinical effects and safety of immunosuppressants combined with abiraterone in the treatment of metastatic CRPC. The population-based study will provide clinicians with more effective treatment options, as well as enhance the understanding of novel combination therapy strategies to be implemented in the future for such patients.

Anti-angiogenic therapy in head and neck squamous cell carcinoma - current limitations and future directions

Angiogenesis, the formation of new blood vessels, plays a crucial role in the progression and metastasis of various cancers, including head and neck squamous cell carcinoma (HNSCC). HNSCCs are characterized by altered levels of angiogenesis-related factors, including the overexpression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), as well as the dysregulation of angiogenesis inhibitors. Together, these factors drive the formation of new blood vessels within the tumor microenvironment and are considered therapeutic targets in HNSCC. Although preclinical studies are promising, challenges have emerged in the clinical use of anti-angiogenic agents in the clinic, including treatment-related toxicities and the development of resistance to therapy. There is an unmet need for further research to elucidate the molecular pathways involved in HNSCC angiogenesis, identify novel therapeutic targets, and discover predictive biomarkers to improve patient selection.

IMG-31. DEUTERIUM METABOLIC IMAGING OF RESPONSE TO PRECISION THERAPY IN BRAF-V600E MUTANT GLIOMAS

Abstract BACKGROUND Oncogenic BRAF-V600E mutations are frequently observed in low- and high-grade gliomas in children. BRAF transduces signals from receptor tyrosine kinases to downstream effectors such as MEK1/2 and ERK, which regulate metabolism and proliferation. The combination of the BRAF-V600E inhibitor dabrafenib and the MEK1/2 inhibitor trametinib (Dab/Tra) improves patient survival. However, there is considerable variation in response durability, underscoring the need for early biomarkers of treatment response. Magnetic resonance imaging (MRI), which is the gold standard for patient management, does not reliably assess response to therapy. Since the BRAF/MEK pathway regulates metabolism, the goal of this study was to determine whether Dab/Tra induces alterations in glucose metabolism that can be leveraged for non-invasive imaging of response to therapy. METHODS We performed gene expression profiling, in vivo metabolomics, stable isotope tracing, and deuterium metabolic imaging in patient-derived and syngeneic BRAF-V600E mutant models (AM38, 2341). RESULTS Our studies indicate that Dab/Tra downregulates glucose metabolism to lactate in AM38 and 2341 cells. In vivo infusion with [U-13C]-glucose in mice bearing intracranial AM38 tumors confirmed that Dab/Tra downregulates 13C-lactate production in the tumor. Mechanistically, Dab/Tra destabilizes hypoxia inducible factor-1a and downregulates glycolytic genes, including SLC2A1, HK2, PFKFB3, and LDHA. Importantly, deuterium metabolic imaging using [6,6’-2H]-glucose, which is a clinical stage method of imaging glycolysis, shows a reduction in lactate production within 48h of treatment with Dab/Tra in AM38 tumor-bearing mice. CONCLUSIONS Our studies mechanistically link BRAF/MEK inhibition with reduced glycolysis and identify [6,6’-2H]-glucose as a novel, non-invasive agent for imaging early response to therapy. Since [6,6’-2H]-glucose is a safe, orally administered agent, our studies can be rapidly translated to the clinic, where they will provide physicians with a much-needed tool to determine whether patients are responding to therapy at an early timepoint that predicts extended survival.

The Evolution of Nadofaragene Firadenovec: A Review and the Path Forward.

The intravesical gene therapy nadofaragene firadenovec (rAd-IFNα/Syn3) was FDA approved in 2022 for non-muscle invasive bladder cancer (NMIBC) unresponsive to frontline treatment with BCG, and the first gene therapy developed for bladder cancer. This non-replicating recombinant adenovirus vector delivers a copy of the human interferon alpha-2b gene into urothelial and tumor cells, causing them to express this pleotropic cytokine with potent antitumor effects. To provide a historical overview describing how several decades of preclinical and clinical studies investigating the role of interferon in the treatment of bladder cancer ultimately led to the development of gene therapy with nadofaragene for NMIBC. We conducted a review of the literature using PubMed, Google Scholar, and ClinicalTrials.gov to summarize our knowledge of the evolution of interferon-based therapy in NMIBC. The FDA approval of this therapy represents an important landmark in urologic oncology and several decades of research dedicated to the study of interferon's direct and indirect antitumor properties in NMIBC. The data gathered from the phase 1, 2, and 3 clinical trials continue to provide additional insights into the precise mechanisms underlying both the efficacy of and resistance to nadofaragene. Nadofaragene leverages the cytotoxic, anti-angiogenic, and immune-modulatory roles of interferon to effectively treat NMIBC that is resistant to BCG. Ongoing studies of resistance mechanisms and prognostic biomarkers have been promising; these will ultimately improve patient selection and allow for the modulation of factors in the tumor or immune microenvironment to further increase therapeutic response.

Clinical characteristics and outcomes of hospitalized kidney transplant recipients with COVID-19 infection in China during the Omicron wave: a single-center cohort study.

BACKGROUND: Following the short-term outbreak of coronavirus disease 2019 (COVID-19) in December 2022 in China, clinical data on kidney transplant recipients (KTRs) with COVID-19 are lacking. METHODS: We conducted a single-center retrospective study to describe the clinical features, complications, and mortality rates of hospitalized KTRs infected with COVID-19 between Dec. 16, 2022 and Jan. 31, 2023. The patients were followed up until Mar. 31, 2023. RESULTS: A total of 324 KTRs with COVID-19 were included. The median age was 49 years. The median time between the onset of symptoms and admission was 13 d. Molnupiravir, azvudine, and nirmatrelvir/ritonavir were administered to 67 (20.7%), 11 (3.4%), and 148 (45.7%) patients, respectively. Twenty-nine (9.0%) patients were treated with more than one antiviral agent. Forty-eight (14.8%) patients were treated with tocilizumab and 53 (16.4%) patients received baricitinib therapy. The acute kidney injury (AKI) occurred in 81 (25.0%) patients and 39 (12.0%) patients were admitted to intensive care units. Fungal infections were observed in 55 (17.0%) patients. Fifty (15.4%) patients lost their graft. The 28-d mortality rate of patients was 9.0% and 42 (13.0%) patients died by the end of follow-up. Multivariate Cox regression analysis identified that cerebrovascular disease, AKI incidence, interleukin (IL)‍-6 level of >6.8 pg/mL, daily dose of corticosteroids of >50 mg, and fungal infection were all associated with an increased risk of death for hospitalized patients. CONCLUSIONS: Our findings demonstrate that hospitalized KTRs with COVID-19 are at high risk of mortality. The administration of immunomodulators or the late application of antiviral drugs does not improve patient survival, while higher doses of corticosteroids may increase the death risk.

A Neuro-Fuzzy-based Approach to Detect Liver Diseases

The liver is a crucial organ in the human body and performs vital functions essential for overall health, including metabolism, immunity, digestion, detoxification, and vitamin storage. Detecting liver diseases at an early stage poses challenges due to the liver's ability to function adequately despite partial damage. Early detection is crucial as liver diseases have significant clinical and socio-economic impacts, affecting other organ systems and requiring timely intervention to improve patient survival rates. Classical diagnostic methods for liver disorders may not always produce better results, thus necessitating more advanced and accurate diagnostic systems. Intelligent systems like predictive modeling and decision support systems, have shown promising results in recent years in disease detection and are aiding medical practitioners. In this research, a neuro fuzzy-based system integrating neural networks and fuzzy logic (FL) was implemented. Based on the risk factors present in the dataset that was used to benchmark the algorithm, this system offered a classification accuracy of 97% which is comparable with existing systems in the literature. This study creates a neuro-fuzzy system for early liver disease identification, solving diagnostic issues and offering healthcare improvements. The proposed system is validated by presenting the simulation results.

The Role of Multimodality Imaging (CT & MR) as a Guide to the Management of Chronic Coronary Syndromes.

Chronic coronary syndrome (CCS) is one of the leading cardiovascular causes of morbidity, mortality, and use of medical resources. After the introduction by international guidelines of the same level of recommendation to non-invasive imaging techniques in CCS evaluation, a large debate arose about the dilemma of choosing anatomical (with coronary computed tomography angiography (CCTA)) or functional imaging (with stress echocardiography (SE), cardiovascular magnetic resonance (CMR), or nuclear imaging techniques) as a first diagnostic evaluation. The determinant role of the atherosclerotic burden in defining cardiovascular risk and prognosis more than myocardial inducible ischemia has progressively increased the use of a first anatomical evaluation with CCTA in a wide range of pre-test probability in CCS patients. Functional testing holds importance, both because the role of revascularization in symptomatic patients with proven ischemia is well defined and because functional imaging, particularly with stress cardiac magnetic resonance (s-CMR), gives further prognostic information regarding LV function, detection of myocardial viability, and tissue characterization. Emerging techniques such as stress computed tomography perfusion (s-CTP) and fractional flow reserve derived from CT (FFRCT), combining anatomical and functional evaluation, appear capable of addressing the need for a single non-invasive examination, especially in patients with high risk or previous revascularization. Furthermore, CCTA in peri-procedural planning is promising to acquire greater importance in the non-invasive planning and guiding of complex coronary revascularization procedures, both by defining the correct strategy of interventional procedure and by improving patient selection. This review explores the different roles of non-invasive imaging techniques in managing CCS patients, also providing insights into preoperative planning for percutaneous or surgical myocardial revascularization.

The effect of an improved ICU physical environment on outcomes and post-ICU recovery—a protocol

BackgroundIntensive care medicine continues to improve, with advances in technology and care provision leading to improved patient survival. However, this has not been matched by similar advances in ICU bedspace design. Environmental factors including excessive noise, suboptimal lighting, and lack of natural lights and views can adversely impact staff wellbeing and short- and long-term patient outcomes. The personal, social, and economic costs associated with this are potentially large. The ICU of the Future project was conceived to address these issues. This is a mixed-method project, aiming to improve the ICU bedspace environment and assess impact on patient outcomes. Two innovative and adaptive ICU bedspaces capable of being individualised to patients’ personal and changing needs were co-designed and implemented. The aim of this study is to evaluate the effect of an improved ICU bedspace environment on patient outcomes and operational impact.MethodsThis is a prospective multi-component, mixed methods study including a randomised controlled trial. Over a 2-year study period, the two upgraded bedspaces will serve as intervention beds, while the remaining 25 bedspaces in the study ICU function as control beds. Study components encompass (1) an objective environmental assessment; (2) a qualitative investigation of the ICU environment and its impact from the perspective of patients, families, and staff; (3) sleep investigations; (4) circadian rhythm investigations; (5) delirium measurements; (6) assessment of medium-term patient outcomes; and (7) a health economic evaluation.DiscussionDespite growing evidence of the negative impact the ICU environment can have on patient recovery, this is an area of critical care medicine that is understudied and commonly not considered when ICUs are being designed. This study will provide new information on how an improved ICU environment impact holistic patient recovery and outcomes, potentially influencing ICU design worldwide.Trial registrationACTRN12623000541606. Registered on May 22, 2023. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385845&isReview=true.

Prognostic prediction and diagnostic role of Rspondin 1 expression in esophageal squamous cell carcinoma.

Rspondin 1 (Rspo1), a protein family member featuring secreted furin-like domains, plays a pivotal role in cancer development and exhibits a positive correlation with tumor progression. However, its expression in esophageal squamous cell carcinoma (ESCC) is still unknown. Here, we assessed the correlation between Rspo1 and clinicopathological features of ESCC patients, and further investigated the potential role of Rspo1 in ESCC development and clinical outcomes. This was a pilot study. A total of 112 paraffin-embedded tumor samples from patients with ESCC, including 68 matched adjacent normal tissues, were collected post-surgery. Subsequently, tissue microarray (TMA) and immunohistochemistry (IHC) techniques were employed to assess the protein levels of Rspo1. All statistical analyses were performed with SPSS 20.0 (SPSS, Inc., Chicago, IL). We found that Rspo1 expression was significantly higher in ESCC than in adjacent normal tissues (P < 0.0001). Moreover, Rspo1 was highly expressed in ESCC tumor specimens and showed a significant correlation with the T classification of ESCC (P < 0.05). Additionally, our findings indicate a positive relationship between Rspo1 and survival time in ESCC. Patients exhibiting moderate to high levels of Rspo1 expression demonstrated superior survival outcomes compared to those with low expression (P = 0.0002). Our investigation has demonstrated that Rspo1 is upregulated in ESCC and exhibits a positive correlation with disease progression. Furthermore, we have observed a significant association between Rspo1 overexpression and improved patient survival rates, indicating its potential as a prognostic marker and therapeutic target for ESCC treatment.

Exploring the role of trifarotene against RAR-α: an investigation of expression pattern and clinicopathological significance of RAR-α in breast cancer.

The members retinoic acid receptors (RARs) (α, β, and γ) and retinoid X receptors (RXRs) (α, β, and γ) belong to the retinoid receptor family. They regulate the biological action of classical retinoids through nuclear retinoid receptors, a transcription factor that is regulated by ligands. Through the binding of particular retinoic acid-responsive elements (RAREs) located in target gene promoters, RARs and members of the RXRs form heterodimers. By binding to its nuclear receptors and triggering the transcription of the target genes downstream, retinoic acid (RA) mediates the expression of certain genes. Retinoids so mainly control gene expression to carry out their biological actions. RARs are essential for many biological processes, such as development, immunity, reproduction, organogenesis, and homeostasis. Apart from their physiological functions, RARs are also linked to pathologies and tumors due to mutations, protein fusions, changes in expression levels, or abnormal post-translational changes that lead to aberrant functions and homeostasis breakdown. The oncogenic development of animal tissues or cultured cells is linked to altered expression of retinoid receptors. The RAR-α is over-expressed in several malignancies. Increased invasion and migration in several cancer forms, including HNSC carcinoma, pediatric low-grade gliomas, lung adenocarcinoma, and breast cancer, have been linked to its upregulated expression. Numerous approved therapeutic regimens targeting RAR-α have been developed, improving patient survival rates. This study's main objective was to identify novel RAR-α-targeting drugs and evaluate the expression patterns of RAR-α in breast cancer patients. In-silico investigation using a variety of bioinformatics tools like UALCAN, TISCH, TIMER 2.0, ENRICHR, and others were employed to examine the expression of RAR-α. Further we evaluated in-silico inhibition of RAR-α with trifarotene and also tested the cytotoxicity of trifarotene in breast cancer cells. Our research indicates that RAR-α is upregulated in several malignancies including Breast Cancer. It regulates granulocyte differentiation and has an association with the retinoic acid receptor signaling pathway and cellular response to estrogen stimulus. Furthermore, trifarotene was found as a potential synthetic compound that targets RAR-α through in silico and in-vitro study. Overall, this research indicates that elevated expression of RAR-α enhances the onset of breast cancer. Using trifarotene medication to target RAR-α will significantly boost the response of breast cancer individuals to treatment and delay the development of resistance to drugs.

Metabolic dysregulation of tricarboxylic acid cycle and oxidative phosphorylation in glioblastoma.

Glioblastoma multiforme (GBM) exhibits genetic alterations that induce the deregulation of oncogenic pathways, thus promoting metabolic adaptation. The modulation of metabolic enzyme activities is necessary to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates essential for fulfilling the biosynthetic needs of glioma cells. Moreover, the TCA cycle produces intermediates that play important roles in the metabolism of glucose, fatty acids, or non-essential amino acids, and act as signaling molecules associated withthe activation of oncogenic pathways, transcriptional changes, and epigenetic modifications. In this review, we aim to explore how dysregulated metabolic enzymes from the TCA cycle and oxidative phosphorylation, along with their metabolites, modulate both catabolic and anabolic metabolic pathways, as well as pro-oncogenic signaling pathways, transcriptional changes, and epigenetic modifications in GBM cells, contributing to the formation, survival, growth, and invasion of glioma cells. Additionally, we discuss promising therapeutic strategies targeting key players in metabolic regulation. Therefore, understanding metabolic reprogramming is necessary to fully comprehend the biology of malignant gliomas and significantly improve patient survival.

Potential of MMP-2 and MMP-9 Gelatinase Blockade as a Therapeutic Strategy in Fibrosarcoma Treatment: A Decadal Review

Fibrosarcoma represents a significant challenge in oncology, characterized by high invasiveness and a poor prognosis. Gelatinases, particularly matrix metalloproteinases MMP-2 and MMP-9, play a pivotal role in the degradation of the extracellular matrix, facilitating tumor invasion and metastasis. Inhibiting these enzymes has emerged as a promising therapeutic strategy. This review evaluates the progress in the development and therapeutic potential of gelatinase inhibitors as treatments for fibrosarcoma over the last decade, highlighting molecular mechanisms and future directions. A comprehensive literature review was conducted, focusing on studies published from 2013 to 2023. Research articles and review papers relevant to gelatinase inhibition and fibrosarcoma were examined to assess the efficacy and mechanisms of gelatinase inhibitors. Gelatinase inhibitors have shown the potential to reduce tumor progression, invasion, and metastasis in fibrosarcoma. Clinical trials, although limited, have indicated that these inhibitors can be effectively integrated into existing therapeutic regimens, offering a reduction in metastatic spread and potentially improving patient survival rates. Mechanistic studies suggest that the inhibition of MMP-2 and MMP-9 disrupts critical pathways involved in tumor growth and cell invasion. Gelatinase inhibition represents a viable and promising approach to fibrosarcoma treatment. Future research should focus on developing more specific inhibitors, understanding long-term outcomes, and integrating gelatinase inhibition into multimodal treatment strategies to enhance efficacy.

Exploring the Survival Determinants in Recurrent Ovarian Cancer: The Role of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

Recurrent ovarian cancer (ROC) significantly challenges gynecological oncology due to its poor outcomes. This study assesses the impact of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) on ROC survival rates. Conducted at the Medical University of Lublin from April 2011 to November 2022, this retrospective observational study involved 71 patients with histologically confirmed ROC who underwent CRS and subsequent HIPEC. The median overall survival (OS) was 41.1 months, with 3-year and 5-year survival rates post-treatment of 0.50 and 0.33, respectively. Patients undergoing radical surgery for primary ovarian cancer had a median OS of 61.9 months. The key survival-related factors included the Peritoneal Carcinomatosis Index (PCI) score, AGO score, platinum sensitivity, and ECOG status. The key factors enhancing ROC patients' survival include radical surgery, optimal performance status, platinum sensitivity, a positive AGO score, and a lower PCI. This study highlights the predictive value of the platinum resistance and AGO score in patient outcomes, underlining their role in treatment planning. Further prospective research is needed to confirm these results and improve patient selection for this treatment approach.

Automatized self-supervised learning for skin lesion screening

Melanoma, the deadliest form of skin cancer, has seen a steady increase in incidence rates worldwide, posing a significant challenge to dermatologists. Early detection is crucial for improving patient survival rates. However, performing total body screening (TBS), i.e., identifying suspicious lesions or ugly ducklings (UDs) by visual inspection, can be challenging and often requires sound expertise in pigmented lesions. To assist users of varying expertise levels, an artificial intelligence (AI) decision support tool was developed. Our solution identifies and characterizes UDs from real-world wide-field patient images. It employs a state-of-the-art object detection algorithm to locate and isolate all skin lesions present in a patient’s total body images. These lesions are then sorted based on their level of suspiciousness using a self-supervised AI approach, tailored to the specific context of the patient under examination. A clinical validation study was conducted to evaluate the tool’s performance. The results demonstrated an average sensitivity of 95% for the top-10 AI-identified UDs on skin lesions selected by the majority of experts in pigmented skin lesions. The study also found that the tool increased dermatologists’ confidence when formulating a diagnosis, and the average majority agreement with the top-10 AI-identified UDs reached 100% when assisted by our tool. With the development of this AI-based decision support tool, we aim to address the shortage of specialists, enable faster consultation times for patients, and demonstrate the impact and usability of AI-assisted screening. Future developments will include expanding the dataset to include histologically confirmed melanoma and validating the tool for additional body regions.

Clinical efficacy and safety analysis of immune checkpoint inhibitors combined with concurrent chemoradiotherapy for stage IIIC1-IVA cervical cancer: A prospective cohort study.

e17505 Background: Stage IIIC1 with larger/more short lymph node diameters and IIIC2-IVA cervical cancer patients had a particularly poor prognosis. Clinical practices have found that stage IIIC1-IVA patients diagnosed with pelvic lymph node short diameter ≥ 1.5cm/number of positive lymph nodes ≥ 3, or paraaortic lymph node metastasis, had a higher recurrence rate and lower overall survival rate. The overall survival rate is approximately 29% -52%. Sequential systemic chemotherapy after concurrent chemoradiotherapy (CCRT) can not improve survival in such patients. However, the current research results on the combination of CCRT with immune checkpoint inhibitors for cervical cancer are not ideal, which may be due to the lack of stratified analysis. This study compared the efficacy and safety of CCRT and combined use of immune checkpoint inhibitors (non sequential) for stage IIIC1-IVA cervical cancer through the cohort analysis, and analyzed the prognostic factors. Methods: Patients diagnosed with stage IIIC1-IVA cervical cancer who underwent concurrent chemoradiotherapy from October 2019 to October 2022 were enrolled. Patients were divided into the study group (35 cases) receiving Sintilimab concurrently with chemoradiotherapy and the control group (35 cases) receiving standard treatment. The primary endpoints were the assessment of one-year progression-free survival (PFS), objective response rate (ORR), and associated influencing factors. Secondary endpoints included treatment-related adverse events (TRAEs). Results: The one-year PFS rates were 88.6% in the study group and 62.9% in the control group, showing a significant difference (χ2=6.293, P=0.012). The median PFS was not reached. The ORR for tumor response was 74.30% in the study group, significantly higher than the 51.43% in the control group (P=0.048). Univariate analysis identified tumor maximum diameter (p = 0.01) and concurrent use of ICIs (p = 0.039) as prognostic factors for PFS. Multivariate Cox analysis also revealed tumor maximum diameter (p = 0.0121) and concurrent use of ICIs (p=0.049) as independent predictors of PFS. The most common TRAEs in both groups included leukopenia, decreased appetite, nausea/vomiting, and fatigue, with no significant differences in incidence (P&gt;0.050). Grade ≥3 TRAEs were most frequently leukopenia (47.5%) and thrombocytopenia (17.1%) in the study group and leukopenia (51.4%) in the control group. All adverse reactions were alleviated after symptomatic treatment, dose reduction, or discontinuation, and no TRAE-related deaths occurred. Conclusions: In patients with stage IIIC1-IVA cervical cancer undergoing definitive concurrent chemoradiotherapy, the addition of ICIs may improve patient survival with manageable safety.

Real-world Effectiveness of Fecal Microbiota Transplantation for First or Second Clostridioides difficile Infection

Background and aimsClostridioides difficile infection (CDI) is associated with high mortality. Fecal microbiota transplantation (FMT) is an established treatment for recurrent CDI, but its use for first or second CDI remains experimental. We aimed to investigate the effectiveness of FMT for first or second CDI in a real-world clinical setting. MethodsThis multi-site Danish cohort study included patients with first or second CDI treated with FMT from June 2019 to February 2023. The primary outcome was cure of C. difficile-associated diarrhea (CDAD) eight weeks after the last FMT treatment. Secondary outcomes included CDAD cure one and eight weeks after the first FMT treatment and 90-day mortality following positive C. difficile test. ResultsWe included 467 patients, with 187 (40%) having their first CDI. The median patient age was 73 years (interquartile range (IQR) 58-82 years). Notably, 167 (36%) had antibiotic-refractory CDI, 262 (56%) had severe CDI, and 89 (19%) suffered from fulminant CDI. Following the first FMT treatment, cure of CDAD was achieved in 353 patients (76%, 95% confidence interval (CI) 71-79%) at week one. At week eight, 255 patients (55%, 95% CI 50-59%) maintained sustained effect. In patients without initial effect, repeated FMT treatments led to an overall cure of CDAD in 367 patients (79%, 95% CI 75-82%). The 90-day mortality was 10% (95% CI 8-14%). ConclusionRepeated FMT treatments demonstrate high effectiveness in managing patients with first or second CDI. Forwarding FMT in CDI treatment guidelines could improve patient survival.

Impact of insomnia on ovarian cancer risk and survival: a Mendelian randomization study

Insomnia is the most common sleep disorder in patients with epithelial ovarian cancer (EOC). We investigated the causal association between genetically predicted insomnia and EOC risk and survival through a two-sample Mendelian randomization (MR) study. Insomnia was proxied using genetic variants identified in a genome-wide association study (GWAS) meta-analysis of UK Biobank and 23andMe. Using genetic associations with EOC risk and overall survival from the Ovarian Cancer Association Consortium (OCAC) GWAS in 66,450 women (over 11,000 cases with clinical follow-up), we performed Iterative Mendelian Randomization and Pleiotropy (IMRP) analysis followed by a set of sensitivity analyses. Genetic associations with survival and response to treatment in ovarian cancer study of The Cancer Genome Atlas (TCGA) were estimated controlling for chemotherapy and clinical factors. Insomnia was associated with higher risk of endometrioid EOC (OR=1.60, 95% CI 1.05-2.45) and lower risk of high-grade serous EOC (HGSOC) and clear cell EOC (OR=0.79 and 0.48, 95% CI 0.63-1.00 and 0.27-0.86, respectively). In survival analysis, insomnia was associated with shorter survival of invasive EOC (OR=1.45, 95% CI 1.13-1.87) and HGSOC (OR=1.4, 95% CI 1.04-1.89), which was attenuated after adjustment for body mass index and reproductive age. Insomnia was associated with reduced survival in TCGA HGSOC cases who received standard chemotherapy (OR=2.48, 95% CI 1.13-5.42), but was attenuated after adjustment for clinical factors. This study supports the impact of insomnia on EOC risk and survival, suggesting treatments targeting insomnia could be pivotal for prevention and improving patient survival. National Institutes of Health, National Cancer Institute. Full funding details are provided in acknowledgments.

Effect of Treatment of Residual Disease After Immunotherapy-Based Combinations on Complete Response Rate of Patients With Metastatic Renal Cell Carcinomas

IntroductionImmune checkpoint inhibitor (ICI)-based combinations have revolutionized the management of first-line metastatic renal cell carcinoma (mRCC) by improving patient survival. Large phase 3 randomized trials assessing ICI-based combinations have reported complete response (CR) rates of 10% to 18% in the first-line setting. However, there is a scarcity of data about the effect of treatment of residual disease regarding CR rates improvement. Materials and MethodsWe included retrospectively all consecutive mRCC patients treated in first-line setting at the Institut de Cancérologie Strasbourg Europe with an ICI-based combination involving ICI or TKI, either alone or with added local treatment of residual disease. Patients were characterized according to IMDC risk. Radiologic response was defined according to RECIST v1.1. ResultsWe enrolled 80 mRCC patients treated with ICI-based combinations between May 2015 and May 2022. The median age was 63 years. Regarding IMDC risk, there were 12 favourable (15%), 50 intermediate (63%), and 18 poor-risk (22%) patients. Forty-seven patients (59%) received ICI + ICI, 24 (30%) received ICI + TKI, and 9 (11%) received another ICI-based therapy. In total, 8 achieved CR (10%), 36 patients (45%) achieved partial response, 23 (29%) achieved stable disease and 12 achieved progressive disease (15%) as the best response with systemic therapy alone. By adding local treatment of residual disease, 11 additional patients (14%) achieved radiological NED. Residual disease resected sites included kidney (n = 6), lymph nodes (n = 5), lung metastases (n = 2) and liver metastases (n = 1). ConclusionsThe resection of residual disease after first-line ICI-based therapy is associated with improved CR rate (CR + NED) in patients with mRCC. These results need to be validated in prospective trial. Patient SummaryIn recent years, the advent of immunotherapy has radically changed the management of patients with metastatic kidney cancer. Approximately 10% to 18% of these patients using immune checkpoint inhibitor (ICI)-based combinations no longer have detectable disease on CT scans (complete response). There are currently few data on the use of treatment of residual disease to increase the number of patients in complete response. In this retrospective study, the complete response rate with ICI-based treatment was 10%. When local treatment was added, the number of patients with a complete response increased to 24%. This strategy could increase the number of patients with a prolonged complete response in the future.

Rearranging the furniture: A blueprint for reappropriating fixed resources to create an emergency department resuscitative care unit.

Emergency department (ED) care teams face challenges in providing timely, high-quality care to critically ill patients because of competing patient care priorities and a multitude of system strains, including patient boarding. Patients who are boarding in the ED experience increased morbidity and mortality, and this is particularly true for those who are critically ill. Geography-based models for critical care delivery in the ED range from resuscitation bays to full-fledged ED intensive care units. Studies have shown that such models can improve patient survival without affecting cost. Here, we describe how we reappropriated limited fixed resources to create a critical care resuscitation unit in a busy, urban, academic ED. Our objective is to provide a blueprint for similar models, paying particular attention to operations, clinical care, education, and financial stability.

Воспроизведенная комбинация модуляторов белка CFTR — ивакафтора и лумакафтора. Этические и фармакокинетические аспекты

The lack of effective and affordable therapies for rare diseases is an important ethical issue. One example is cystic fibrosis (CF), a chronic, progressive disease characterized by an impaired function of all exocrine glands. The combination of ivacaftor and lumacaftor (CFTR potentiator and corrector) should lead to a sufficient level of protein on the cell surface and to an increase in its activity, thereby correcting the impaired function. Development of a generic drug containing ivacaftor and lumacaftor as active pharmaceutical substances will increase the availability of this medication and improve patient survival. To study comparative pharmacokinetics and bioequivalence of drugs containing ivacaftor and lumacaftor in healthy volunteers. It was conducted as an open-label, randomized, crossover bioequivalence study involving a single intake of the drug during each period under fed condition in healthy male and female volunteers. The conclusion about bioequivalence was made if 90% confidence interval for primary pharmacokinetic parameters (Cmax, AUC0-t) fell within the accepted bioequivalence limits of 80–125%. According to the results of the study, it was shown that the values of 90% CI of the geometric mean of the main pharmacokinetic parameters for ivacaftor and lumacaftor fall within the acceptance limits for bioequivalence. According to the applied criteria, the drugs are bioequivalent, which makes it possible to recommend the investigational drug to the Ministry of Health of the Russian Federation for obtaining the registration status.