Improvement In Survival Research Articles

Multiple Myeloma: Improved Outcomes Resulting from a Rapidly Expanding Number of Therapeutic Options.

Multiple myeloma (MM) is a bone-marrow-based cancer of plasma cells. Over the last 2 decades, marked treatment advances have led to improvements in the overall survival (OS) of patients with this disease. Key developments include the use of chemotherapy, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies. MM remains incurable, with outcomes influenced by many factors, including age, sex, genetics, and treatment response. This review summarizes recent studies regarding monitoring and treatment of MM, emphasizing the efficacy of new therapies, the impact of maintenance treatments, and approaches for managing relapsed or refractory MM. The role of specific drug classes used to treat MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and newer treatments such as chimeric antigen receptor T-cell therapies and bispecific antibodies are discussed. Combination therapies have significantly improved outcomes. Maintenance therapies, particularly with lenalidomide, have been effective in extending OS but lead to an increased risk of secondary cancers. Venetoclax, selinexor, and ruxolitinib have shown potential as new therapeutic options for patients with relapsed or refractory MM. Immune-based treatments, such as chimeric antigen receptor T-cell therapy and bispecific antibodies, mark a major advancement for heavily pretreated patients, although challenges remain related to cost, availability, and side effects. The treatment landscape for patients with MM has seen significant progress, with current therapies providing a longer OS and better quality of life. Future research should focus on optimizing these strategies, personalizing therapies, and exploring new therapeutic targets.

Indolent lymphoma: addressing the needs of survivors.

Over the past two decades, there has been a continuous improvement in outcome for patients with indolent lymphoma (iNHL) resulting in a gradual accumulation of survivors. While life expectancy in the current era approaches that of the lymphoma-free population, patients continue to experience lifelong complications of the disease and its treatment affecting general health, emotional, psychological and social wellbeing, relationships, employment, finances, and fitness. Contemporary care models while suited to the management of lymphoma are often lacking when it comes to identification and management of these additional needs. Given improvements in physical survival achieved over the past decades, it is timely for us to focus on other issues affecting patient wellbeing including immunodeficiency and infection, second cancers, cardiovascular disease, bone health, psychological wellbeing, and sexual health. Many of these aspects are in the domain of the primary care physician; however, there is limited guidance on how these issues should be addressed. It is now time for us to engage our patients, their caregivers, and other healthcare providers in care aspects beyond the lymphoma diagnosis, so they can anticipate a rich and full life, free from both direct and indirect consequences of the lymphoma diagnosis.

Enhanced Intracellular Delivery via a Titanium-Coated TiO2 Microstructure Device: Leveraging an Infrared Laser for Optimal Efficiency.

This study presents a novel optoporation technique using a titanium-coated TiO2 microstructure (TMS) device activated by an infrared diode laser for highly efficient intracellular delivery. The TMS device, fabricated with 120 nm titanium coating on a titanium dioxide (TiO2) microstructure containing microneedles (height ∼2 μm and width ∼4.5 μm), demonstrates enhanced biocompatibility and thermal conductivity compared to the conventional TiO2 microstructure (MS). Exposure to the TMS device with an IR diode laser (980 nm) generates heat, forming photothermal bubbles that disrupt the cell membrane and create transient pores for biomolecular delivery. Unlike traditional optoporation methods, which rely on large, vibration-sensitive lasers, the IR diode laser-assisted TMS device-based optoporation technique offers a compact, cost-effective, and portable alternative, making it suitable for clinical and research applications in resource-constrained environments. The performance of the TMS and MS devices was compared in various cancer cell lines (HeLa, L929, and N2a), with the TMS device showing superior delivery success rates for biomolecules of varying molecular sizes. Notably, the TMS device achieved a 99.30% delivery success rate for the smallest molecule, PI dye, and an 85.17% success rate for the largest studied molecule, β-galactosidase enzyme-Cy5. Furthermore, the TMS device consistently provided a higher delivery success rate at lower laser power, minimizing cellular stress and preserving cell survivability. Moreover, using Western Blot analysis, the TMS device demonstrated lower levels of apoptosis compared to the MS device, with statistically significant differences, highlighting its potential for efficient intracellular delivery while minimizing cellular stress and damage. These results highlight the potential of the TMS device as an advanced tool for large-size intracellular biomolecular delivery, offering significant improvements in stability, efficiency, and cell survivability.

Dense stroma activates the TGF-β1/FBW7 axis to induce metabolic subtype switching in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases. Although several chemotherapy regimens have been developed over the past decades, few targeted therapies have shown a significant improvement in overall survival, partly due to the identification of PDAC as a single disease. Combining metabolomic analysis and immunohistochemistry staining with Oil Red O staining, analysis for the oxygen consumption rate and extracellular acidification rate, we stratified pancreatic cancer cells into two subtypes. The impact of transforming growth factor β (TGF-β)-1/F-box and WD repeat domain-containing 7 (FBW7) on the switch of the metabolic subtype was further validated in vitro and in vivo. Finally, cell growth was performed to identify the TGF-β1/FBW7 ratio as a molecular marker for gemcitabine resistance. PDAC was stratified into the glycolytic subtype and lipogenic subtype. Furthermore, pancreatic cancer-associated fibroblasts-derived TGF-β1 and tumor cell-derived FBW7 were demonstrated to co-determine the metabolic phenotypes in PDAC. A high TGF-β1/FBW7 ratio always represented the glycolytic PDAC with dense stroma. This subtype of PDAC exhibited mesenchymal features and was predictive of unfavorable prognoses, despite being more sensitive than the lipogenic subtype to combination treatment with gemcitabine and an inhibitor of TGF-β receptor I (TGF-βR1). The TGF-β1/FBW7 ratio could be regarded as a molecular marker of metabolic phenotypes in PDAC and may contribute to the development of effective therapeutic strategies to improve the survival of PDAC patients.

Understanding the Impact of Obesity on Liver Transplant Outcomes: A Comprehensive Analysis.

The purpose of this investigation is to assess how effective it is to exclude individuals from the liver transplant (LT) using the body mass index (BMI) as a criterion. A retrospective longitudinal analysis of patients with liver transplant outcomes from January 2001 to May 2020 was conducted using the United Network for Organ Sharing (UNOS) database. A total of 118,486 LT cases included in the study. Based on their BMI, patients were split into three groups: a BMI<35kg/m2, a 35≤BMI < 40kg/m2, and a BMI≥40kg/m2. The data analysis revealed a significant improvement in 10-year graft survival in the 2011-2020 group compared to the 2001-2010 group (mean 70% vs. 53% and P<0.001). Interestingly, a BMI above 35kg/m2 did not have a significant effect on the graft survival, and in both time frames, there was no clinically significant difference between the recipients of the different BMI spectrum. The patient's survival was also characterized by the same pattern. Primary graft failure was the most significant cause of allograft transplant failure in all the BMI spectrum, except recipients with a BMI<35kg/m2, in 2011-2020 group. The outcomes of LT in patients requiring a LT are not significantly affected using the BMI, considering the advancements in surgical techniques and postoperation improvements, and excluding obese patients based on the BMI alone would be inappropriate.

Surgical Approach and Variation in Long-Term Survival Following Colorectal Cancer Surgery Using Instrumental Variable Analysis

Objective: The study aimed to determine whether increased use of minimally invasive surgical approaches, compared with open, improves long-term survival after colon and rectal cancer resections. Background: Existing prospective and observational data comparing surgical approach for colon and rectal cancer are limited by selection bias, necessitating better approaches for causal inference to understand the relationship between surgical approach and long-term survival. Methods: We included colon and rectal cancer patients who underwent colon or rectal resection from the American College of Surgeons National Cancer Database between 2011 and 2018. Using an instrumental variable (IV) approach, we accounted for measured and unmeasured differences between patients undergoing colon or rectal cancer resection based on operative approach – robotic, laparoscopic, or open. The IV used in this study was rate of robotic-assisted colon and rectal cancer surgery within 81 different hospital regions based on US Census region and rurality during the 12 months before each patient’s operation. Proportional hazard modeling was used to estimate risk-adjusted mortality rates. Results: There were 326,406 colon and 96,979 rectal cancer patients included in this study. The risk-adjusted 5-year cumulative incidence of mortality for colon and rectal cancer was highest for patients who underwent open approaches (35.73 [95% confidence interval {CI}: 35.37–36.1] and 39.27 [95% CI: 28.44–30.13], respectively), compared with lower mortality for those undergoing laparoscopic (28.91 [95% CI: 28.55–29.27] and 22.93 [95% CI: 22.11–23.78], respectively) and robotic approaches (26.39 [95% CI: 24.51–28.42] and 19.77 [95% CI: 17.32–22.43], respectively). Growth in utilization of minimally invasive approaches outpaced improvements in long-term survival. Conclusions: Patients undergoing minimally invasive surgical approaches for colon and rectal cancer had improved long-term survival. However, long-term survival changes did not correlate with the large expansion of minimally invasive approaches, which suggests that growing these approaches is not a viable strategy to improve long-term patient outcomes.

Irreversible Electroporation and β-Glucan Induced Trained Innate Immunity for the Treatment of Pancreatic Ductal Adenocarcinoma: A Phase II Study.

Irreversible electroporation(IRE) has augmented the effects of certain immunotherapies in pancreatic cancer(PDA). Yeast-derived particulate beta-glucan induces trained innate immunity and has successfully reduces murine PC tumor burden. This is a Phase II study to test the hypothesis that IRE may augment beta-glucan induced trained immunity in patients with PDA. Phase II clinical trial (NCT03080974), surgical ablative IRE was performed on clinical stage-III PDA followed by oral beta-Glucan administration for 12-months or until disease recurrence. Peripheral blood was taken pre-op, 14-days, and every 3-months and was evaluated by mass cytometry and compared to patients who received IRE alone. Thirty consecutive patients with pre-operative clinical stage-III PDA were treated with IRE and then initiated on oral beta-glucan post-operatively was compared to 20 patients treated with IRE alone. There were no dose limiting toxicities with oral beta-glucan and compliance with therapy was 96% in all patients. Seven(23%) patients developed grade 3/4 treatment related adverse events(AEs) at 90-days; none required a dose modification of oral beta-glucan. Median disease-free interval of 18 months (range 6-48), with a median overall survival of 32.5 months(range 4-53). At 12-months post IRE, immunophenotyping was demonstrated a significant effect with improvement in the IRE-Beta-Glucan treated group. This also resulted in a significant decrease on naïve CD4 and CD8 T cells with increased CD4 and CD8 terminal effector cells in the IRE-Beta glucan treated group, which correlated with a significant improvement in disease free interval (DFI) and overall survival (OS)(P=0.001). Combined beta-glucan with IRE ablated PDA tumor cells elicited a potent trained response and augmented anti-tumor functionality at 12 months post IRE, which translated into an improved DFI and OS.

Role of the androgen receptor in melanoma aggressiveness

Malignant melanoma represents the fifth most common cancer in the world and its incidence is rising. Novel therapies targeting receptor tyrosine kinases, kinases and immune checkpoints have been employed with a significant improvement of the overall survival and long-term disease containment. Nevertheless, the disease often progresses and becomes resistant to the therapies. As such, the discovery of new targets and drugs for advanced melanoma still remains a difficult task. Gender disparities, with a female advantage in melanoma incidence and outcome, have been reported. Although emerging studies support the pro-tumorigenic role of androgen/androgen receptor axis in melanoma, the molecular bases of such evidence are still under intense investigation. We now report that ligand activation of the androgen receptor drives melanoma invasiveness and its escape from natural killer-mediated cytotoxic effect. By combining different experimental approaches, we observe that melanoma escape is mediated by the androgen-triggered shedding of the surface molecule MICA. Specific blockade of ADAM10 or androgen receptor impairs the androgen-induced MICA shedding and melanoma immune-escape. Further, the increase in MICA serum levels correlates with a poor outcome in melanoma patients treated with the anti-PD-1 monoclonal antibody, pembrolizumab. At last, melanoma cells depleted of the androgen receptor become more responsive to the most commonly used immunocheckpoint inhibitors, suggesting that the receptor dampens the immunotherapy efficacy. Taken together, our findings identify the androgen receptor as a diagnostic guidance in melanoma and support the repositioning of AR blockers in clinical management of patients.

A randomized controlled trial comparing embryo vitrification with slush nitrogen to liquid nitrogen in women undergoing frozen embryo transfer: embryology and clinical outcomes.

Does the use of slush nitrogen (SN) for embryo vitrification improve embryo transfer outcomes compared to liquid nitrogen (LN)? SN is a safe method for embryo preservation and significantly improves post-warming survival rates during repeated vitrification-warming cycles; however, after a single freeze-thaw cycle, pregnancy outcomes are not improved when embryos are vitrified with SN compared to LN. SN is a combination of solid and LN, with a temperature lower than regular LN, and it is an alternative to conventional LN in achieving a faster cooling speed. Studies have shown that SN improves survival in non-human embryos and human oocytes. However, it is unknown whether the use of SN reduces blastocyst damage in humans during vitrification-as indicated by increased survival across multiple vitrification-warming cycles-or whether it enhances pregnancy outcomes in a single vitrification-warming cycle. Following the pre-clinical trial assessing embryo survival after repeated freeze-thaw cycles using SN and LN on 50 donated embryos per group, a randomized controlled trial was performed, where 253 patients were enrolled between September 2020 and January 2022, and 245 underwent an IVF stimulation, which resulted in at least one blastocyst for cryopreservation. Of those, 121 were allocated to the SN (study), and 124 were allocated to the LN (control) group. Randomization occurred on the day of blastocyst biopsy using a computer-generated block schema. Groups were assigned via opaque envelopes, opened by the embryologist on vitrification day. The patient, physician, and clinical team were blinded to the intervention. All couples with female aged between 18 and 42 years old undergoing IVF stimulation at one university-affiliated infertility center, with plan for preimplantation genetic testing for aneuploidy and subsequent single, frozen embryo transfer (FET) were eligible for inclusion in this study. The pre-clinical trial demonstrated significant improvements in blastocyst survival, with the SN group achieving a mean of 7.5 survived vitrification-warming cycles (range: 3-22), significantly surpassing the mean of 3.0 cycles (range: 0-10) in the LN group (P < 0.0001). Following the pre-clinical trial, 223 patients randomized to SN or LN underwent single FET. Baseline characteristics were similar between groups, as were embryology outcomes, including the number of oocytes retrieved, mature oocytes, fertilization rate, and total blastocysts biopsied. No significant differences were observed between the two groups in pregnancy rate, clinical pregnancy rate, sustained implantation rate, or miscarriage rate (P = 0.16, 0.80, 0.49, and 0.74, respectively, using Student's t-test). A futility analysis indicated no value in continuing recruitment and therefore the study was closed. Neonatal or birth outcomes were not assessed. Termination of the study based on futility analysis precludes a conclusion of equivalence between SN and LN. This study demonstrates that SN is a safe alternative to traditional LN for vitrification; however, it did not demonstrate improvements in the reproductive potential of vitrified embryos. The project was funded by the Foundation for Embryonic Competence. NCT04496284. 3 August 2020. 5 September 2020.

The fluoroquinolone compounds potentiate the antifungal activity of the echinocandins against Aspergillus fumigatus.

The antifungal drugs of the echinocandin family show high efficacy against Aspergillus fumigatus. However, their paradoxical effect, which restores fungal growth at high drug concentrations, and the emergence of resistant strains necessitate improvements. We identified 13 fluoroquinolone compounds from a chemical library containing 10,000 compounds that potentiate the antifungal activity of caspofungin. Among them, NE-E07 significantly enhanced the efficacy of echinocandins against A. fumigatus, including resistant strains, without potentiating other antifungal families like voriconazole or amphotericin B. Specifically, NE-E07 demonstrated a unique ability to potentiate caspofungin's activity against the echinocandin-resistant strain USHM-M0051 isolated from patients. Our experiments revealed that NE-E07, in combination with caspofungin, affected ergosterol biosynthesis in a manner consistent with azole drugs. Docking tests suggest NE-E07 has a high binding affinity with CYP51, which affects ergosterol biosynthesis similarly to azole drugs. Interestingly, known fluoroquinolones like ciprofloxacin, nalidixic acid, and norfloxacin did not show this potentiating effect, suggesting that NE-E07's unique structure is critical for its activity. Moreover, NE-E07 did not enhance echinocandin activity against Candida albicans or Cryptococcus neoformans, highlighting its specific action against A. fumigatus. In vivo studies demonstrated that co-treatment with NE-E07 and caspofungin increased the survival rate of mice infected with A. fumigatus. This significant improvement in survival underscores the potential clinical relevance of NE-E07 as a co-administered drug with echinocandins for treating fungal infections, particularly those resistant to echinocandins.

Protocol of a decisional intervention for older adults with newly diagnosed acute myeloid leukemia and their caregivers: UR-GOAL 3.

Therapeutic advances have allowed more adults aged ≥60years with acute myeloid leukemia (AML) to receive life-prolonging treatments, with improvement in overall survival. In contrast to other cancers, the onset of AML is often sudden, high-risk treatment decisions must be made quickly, and survival is often compromised due to aging-related conditions (e.g., functional impairments). Studies have demonstrated that up to 78% of older adults with AML and their caregivers experience significant psychological distress. Distress is associated with poor quality of life, increased healthcare utilization, and increased mortality. Shared decision making (SDM) can reduce patient and caregiver distress and is essential to achieve goal-concordant care. Therefore, interventions to alleviate distress and optimize SDM in older adults with AML and their caregivers are needed. We will conduct a multicenter randomized controlled trial to evaluate the efficacy of University of Rochester-Geriatric Oncology assessment for Acute myeloid Leukemia (UR-GOAL) compared to an attention control for reducing patient distress and improving observed SDM, patient-perceived SDM, and decisional conflict. We will recruit 300 patients aged ≥60years with newly diagnosed AML, their caregivers (one caregiver per patient when available), and up to 40 oncologists from four institutions: (1) Patients will view an educational video about AML diagnosis, treatment, and prognosis; complete the Best Worst Scaling values clarification process; and review a summary report of their values with tailored question prompts and resources; (2) Caregivers will view the same educational video and receive the same summary report as patients; and (3) Oncologists will review a summary report of the patient's aging-related conditions, perception of prognosis, and values. Patients, caregivers, and oncologists will then meet during clinical visits to discuss aging-related conditions, prognosis, and patient values, and reach a treatment decision. The primary outcome measure is distress (Distress Thermometer). Secondary outcome measures include observed SDM, patient perceived SDM, and decisional conflict. This study will address significant knowledge gaps related to reducing distress and decisional conflict and improving SDM in older adults with AML. If successful, this research will inform future decisional interventions for a broader group of patients.

Mortality after cancer diagnosis among children with congenital heart disease in Denmark and Sweden.

Recent decades have witnessed tangible improvements in childhood cancer survival. However, the prognosis for children with congenital heart disease (CHD), the most prevalent birth defect, remains unclear. Due to improved survival of CHD and childhood cancer, evaluating outcomes within this intersection is important for clinical practice. We aimed to assess mortality post-cancer diagnosis among children with CHD. We conducted a study on the population of Denmark and Sweden, born 1970-2014, with a cancer diagnosis before age 20 in the national cancer registers (end of follow-up 2015; n = 20,665). CHD diagnoses (n = 397) and recorded deaths were retrieved from national health registers. We evaluated the effect of CHD on five-year mortality post-cancer diagnosis fitting Cox proportional hazards regression. When excluding children with Down syndrome, children with CHD had a higher five-year mortality post-cancer diagnosis compared to children without (HR 1.48, 95% CI 1.18-1.86). This was particularly notable in children with lymphoma (HR 2.17, 95% CI 1.11-4.25) and neuroblastoma (HR 2.39, 95% CI 1.11-5.15). In more recent decades (post-1990), children with CHD had similar five-year mortality as their counterparts without, except for children diagnosed with lymphoma, where mortality remained elevated (HR 3.37, 95% CI 1.65-6.89). In this large, register-based cohort study, children with CHD fared worse post-cancer diagnosis-particularly lymphoma and neuroblastoma. While a more positive trend emerged in recent years, lymphoma-related mortality remained disproportionately high among children with CHD, underscoring the need for continued research and interventions to improve outcomes for this vulnerable group.

Dietary rosemary oil with/without zymogen forte improves water quality, growth hormones, immune-physiological response, stress resilience, and health status of Chelon ramada grown in groundwater

With freshwater resources becoming scarce worldwide, mariculture is a promising avenue to sustain aquaculture development, especially by incorporating brackish and saline groundwater (GW) use into fish farming. A 75-day rearing trial was conducted to evaluate fish growth, immune response, overall health, and water quality of Chelon ramada cultured in brackish GW and fed on a basal diet (BD) augmented with rosemary oil (RO) or RO + zymogen forte™ (ZF) as an anti-flatulent. Five treatments were administrated in triplicate: T1: fish-fed BD without additives (control group); T2: fish-fed BD + 0.5 g RO /kg diet; T3: fish-fed BD + 0.5 g RO and 1 g ZF /kg diet; T4: fish-fed BD + 1 g RO /kg diet; T5: fish-fed BD + 1 g RO and 1 g ZF /kg diet. Three hundred fish (8.51 ± 0.01 g/fish) were housed in 15 fiberglass tanks (1500-L tank). The results revealed significant improvements (P < 0.05) in growth performance, survival, growth hormone, and insulin-like growth factor-1. Additionally, there were decreases in the feed conversion ratio (FCR) and the levels of nitrogen by-products (NH4, NH3, and NO2) and pathogenic bacterial counts in the rearing water when fish were fed diets supplemented with RO and RO + ZF. Furthermore, significant reductions in the levels of plasma stress indicators (cortisol, creatinine, and glucose) were detected. In addition, there were significant enhancements observed in the levels of innate immune markers, such as white blood cells, total protein, albumin, and immunoglobulin. The complement system, specifically complement 3 and complement 4, also showed considerable improvements. Furthermore, there were increases in plasma heat shock proteins HSP70 and HSP90, as well as enhanced antioxidant activity. These gains were associated with healthier liver and intestines. The investigation demonstrated that adding 0.5–1 g RO / kg diet or RO + ZF to a C. ramada diet has many benefits, including reducing the levels of nitrogen by-product chemicals and pathogenic bacterial load in GW used in growth tanks. Furthermore, significant improvements were observed in the rates of growth and associated hormones, efficiency of feed utilization, blood indicators, immune function, condition of internal organs (namely the intestine and liver), and overall health of the fish.

Iterative Intraperitoneal Chemotherapy in Gastric Cancer Peritoneal Carcinomatosis.

Background/objectives: Despite the incremental improvement of survival with systemic therapy in metastatic gastric cancer (GC), the outcomes of patients with peritoneal carcinomatosis (PC) remain poor. The limited effectiveness of systemic therapy is attributed to the blood-peritoneal barrier and anarchic intra-tumoral circulation, which reduce the penetration of systemic therapy. Approaches that incorporate intraperitoneal (IP) chemotherapy, in addition to systemic therapies, may be a viable alternate strategy. Therefore, we provide a review of biology of gastric cancer peritoneal metastasis and evidence for bidirectional iterative IP chemotherapy in GCPC. Methods: A comprehensive search in PubMed, Scopus, Embase, Web of Science, Google Scholar, and ClinicalTrials.gov was performed to find the relevant articles and ongoing phase II/III clinical trials in iterative IP chemotherapy in GCPC. Results: Intraperitoneal (IP) chemotherapy leverages the blood-peritoneal barrier to allow for the administration of high concentrations of chemotherapy directly to the peritoneal metastases, with a significant reduction in the systemic toxicity and enhanced drug efficacy against peritoneal metastasis. This pharmacokinetic advantage of IP chemotherapy can be further enhanced by additional measures such as heat or aerosolization. There are three IP chemotherapy approaches, namely, heated intraperitoneal chemotherapy (HIPEC), pressurized intraperitoneal aerosolized chemotherapy (PIPAC), and normothermic intraperitoneal chemotherapy (NIPEC). Recent evidence suggests that iterative IP chemotherapy combined with systemic therapy may offer significant survival benefits for patients with peritoneal metastasis. Furthermore, bidirectional treatment approaches may also increase the chances of surgical resection and survival. Conclusions: IP chemotherapy plays a pivotal role in the management of gastric carcinomatosis, particularly in combination with cytoreduction in highly selected patients. The combination of systemic and regional control may increase the chances of surgical resection and may ultimately lead to significant survival benefits.

Early Dynamics of Portal Pressure Gradient After TIPS Insertion Predict Mortality.

Transjugular intrahepatic portosystemic shunt (TIPS) placement leads to a reduction in portal pressure and an improvement in survival in patients with recurrent and refractory ascites and variceal haemorrhage. Prediction of post-TIPS survival is primarily determined by factors identified before the TIPS procedure, as data collected during or after TIPS implantation are limited. The aim of the study was to evaluate the influence of early hemodynamic changes after TIPS placement on survival, in order to refine post TIPS management. In this prospective bicentric study, consecutive patients (n = 105) undergoing TIPS placement for ascites or variceal haemorrhage underwent measurement of portal pressure gradient (PPG) immediately at TIPS insertion (PPG0) and 24 h later (PPG24h) and the ΔPPG was calculated from PPG24h and PPG0 (ΔPPG = PPG24h-PPG0). Kaplan-Meier survival analysis and uni- and multivariable regression analyses were conducted to identify survival predictors. Patients with lack of increased ΔPPG exhibited poorer 90-day and 1-year survival compared to patients with increased ΔPPG. This worse survival was independent of The Model for End-Stage Liver Disease (MELD) score, Child-Pugh score, bilirubin levels, creatinine and the Freiburg index of post-TIPS survival (FIPS) > 0.92. Among these patients with poorer outcome, elevated bilirubin (> 25 μmol/L) further distinguished survivors from non-survivors. Lack of increased ΔPPG post-TIPS insertion identifies a high-risk patient group with worse survival. We propose incorporating this second PPG measurement and determining ΔPPG into clinical practice to identify these patients early and tailor post-TIPS patient care.

The Landmark Series: The Future of Pancreatic Cancer Clinical Trials.

Pancreatic cancer has a poor prognosis despite ongoing advances in systemic and multimodal therapies. This review analyzes recent progress and future directions in pancreatic cancer clinical trials, emphasizing the evolution from traditional approaches to a more personalized and biologically-driven treatment paradigm. While improvements in overall survival have been achieved through perioperative therapies, gaps remain in our understanding of optimal treatment strategies. Key questions include selection of specific chemotherapeutic agents, duration of preoperative therapy, the role of radiotherapy, and accurate and real-time assessment of response to therapy. Historically, pancreatic cancer clinical trials have been designed based on anatomic criteria, failing to account for the inherent biologic heterogeneity of this disease. The field is now moving towards a precision oncology approach, leveraging genomic and transcriptomic data to identify predictive biomarkers and personalize treatment selection. Novel clinical trial designs, such as platform and basket trials, are accelerating the evaluation of new therapeutic strategies and facilitating efficient patient selection, particularly in the context of new emerging targeted therapies such as KRAS inhibitors. Furthermore, implementation of dynamic response assessment techniques, such as circulating tumor DNA and radiomics, may inform treatment decision-making and improve prediction of long-term outcomes. By integrating these evolving strategies, the emerging clinical trial landscape has the potential to transform the treatment of pancreatic cancer and yield meaningful improvements in patient outcomes.

The Immune-Genomics of Cholangiocarcinoma: A Biological Footprint to Develop Novel Immunotherapies.

Cholangiocarcinoma (CCA) represents approximately 3% of all gastrointestinal cancers and is a highly heterogeneous and aggressive malignancy originating from the epithelial cells of the biliary tree. CCA is classified by anatomical location into intrahepatic (iCCA), extrahepatic (eCCA), gallbladder cancer (GBC), and ampullary cancers. Although considered a rare tumor, CCA incidence has risen globally, particularly due to the increased diagnosis of iCCA. Genomic and immune profiling studies have revealed significant heterogeneity within CCA, leading to the identification of molecular subtypes and actionable genetic alterations in 40-60% of cases, particularly in iCCA. Among these, FGFR2 rearrangements or fusions (7-15%) and IDH1 mutations (10-20%) are common in iCCA, while HER2 amplifications/overexpression are more frequent in eCCA and GBC. The tumor-immune microenvironment (TIME) of CCAs plays an active role in the pathogenesis and progression of the disease, creating a complex and plastic environment dominated by immune-suppressive populations. Among these, cancer-associated fibroblasts (CAFs) are a key component of the TIME and are associated with worse survival due to their role in maintaining a poorly immunogenic landscape through the deposition of stiff extracellular matrix and release of pro-tumor soluble factors. Improved understanding of CCA tumor biology has driven the development of novel treatments. Combination therapies of cisplatin and gemcitabine with immune checkpoint inhibitors (ICIs) have replaced the decade-long standard doublet chemotherapy, becoming the new standard of care in patients with advanced CCA. However, the survival improvements remain modest prompting research into more effective ways to target the TIME of CCAs. As key mechanisms of immune evasion in CCA are uncovered, novel immune molecules emerge as potential therapeutic targets. Current studies are exploring strategies targeting multiple immune checkpoints, angiogenesis, and tumor-specific antigens that contribute to immune escape. Additionally, the success of ICIs in advanced CCA has led to interest in their application in earlier stages of the disease, such as in adjuvant and neoadjuvant settings. This review offers a comprehensive overview of the immune biology of CCAs and examines how this knowledge has guided clinical drug development, with a focus on both approved and emergent treatment strategies.

IL-6 and PD-1 antibody blockade combination therapy regulate inflammation and T lymphocyte apoptosis in murine model of sepsis

BackgroundInterleukin-6 (IL-6) plays a central role in sepsis-induced cytokine storm involving immune hyperactivation and early neutrophil activation. Programmed death protein-1 (PD-1) is associated with sepsis-induced immunosuppression and lymphocyte apoptosis. However, the effects of simultaneous blockade of IL-6 and PD-1 in a murine sepsis model are not well understood.ResultsIn this study, sepsis was induced in male C57BL/6 mice through cecal ligation and puncture (CLP). IL-6 blockade, PD-1 blockade, or combination of both was administered 24 h after CLP. Peripheral blood count, cytokine level, lymphocyte apoptosis in the spleen, neutrophil infiltration in the lungs and liver, and survival rate were measured. The mortality rate of the IL-6/PD-1 group was lower, though not statistically significant (p = 0.164), than that of CLP mice (75.0% vs. 91.7%). The IL-6/PD-1 group had lower neutrophil percentage and platelet count compared with the CLP group; no significant difference was observed in other cytokine levels. The IL-6/PD-1 group also showed reduced T lymphocyte apoptosis in the spleen and decreased neutrophil infiltration in the liver and lungs.ConclusionsIL-6/PD-1 dual blockade reduces neutrophil infiltration, lymphocyte apoptosis, and bacterial burden while preserving tissue integrity in sepsis. Although the improvement in survival was not statistically significant, these findings highlight its potential as a therapeutic approach in sepsis.

Medicaid Expansion and Survival Outcomes Among Men With Prostate Cancer.

Prostate cancer stands as one of the most diagnosed malignancies among men worldwide. With the recent expansion of Medicaid under the Affordable Care Act (ACA), millions more Americans now have health insurance coverage, potentially influencing healthcare access and subsequent outcomes for various illnesses, including prostate cancer. Yet, the direct correlation between Medicaid expansion and cancer-specific survival among individuals with prostate cancer remains an area warranting comprehensive exploration. This study aims to determine the impact of the implementation of Medicaid expansion on survival outcomes among men with prostate cancer. We utilized data from the Surveillance, Epidemiology, and End Results (SEER) registry to determine the causal impact of the implementation of the ACA on outcomes among men with prostate cancer. The study covered the years 2003-2021, divided into pre-ACA (2003-2009) and post-ACA (2015-2021) periods, with a one-year washout (2014-2015) since Medicaid expansion was implemented in 2014 in Kentucky.Using a difference-in-differences (DID) approach, we compared survival among men with prostate cancers from Kentucky to Georgia. We adjusted for patient demographics, income, metropolitan status, disease stage, and treatment modalities. We analyzed a cohort of 68,222 men with prostate cancer during the study period. Of these, 37,810 (55.4%) were diagnosed in the pre-ACA period, with 70.8% from Georgia and 29.2% from Kentucky. The remaining 30,412 (44.6%) were diagnosed in the post-ACA period, with 72.3% from Georgia and 27.7% from Kentucky. Medicaid expansion in Kentucky was associated with a 16.8% reduction in the hazard of overall death, indicating improved overall survival among eligible individuals. This trend was consistent across different racial and ethnic groups. Specifically, non-Hispanic White men experienced a 16.2% reduction (DID=-16.2%; 95% CI: -31.5% to -0.8%), non-Hispanic Black men had a 17.9% reduction (DID=-17.9%; 95% CI: -34.8% to -0.9%), and Hispanic men saw a 15.9% reduction (DID=-15.9%; 95% CI: -31.3% to -0.5%) in hazard of death among low-income individuals. Medicaid expansion was associated with a substantive improvement in overall survival among men with prostate cancerin Kentucky compared to non-expansion Georgia.

Outcomes of Broader Genomic Profiling in Metastatic Colorectal Cancer: A Portuguese Cohort Study

Background: Colorectal cancer (CRC) is the third most diagnosed cancer globally and the second leading cause of cancer-related deaths. Despite advancements, metastatic CRC (mCRC) has a five-year survival rate below 20%. Next-generation sequencing (NGS) is recommended nowadays to guide mCRC treatment; however, its clinical utility when compared with traditional molecular testing in mCRC is debated due to limited survival improvement and cost-effectiveness concerns. Methods: This retrospective study included mCRC patients (≥18 years) treated at a single oncology centre who underwent NGS during treatment planning. Tumour samples were analysed using either a 52-gene Oncomine™ Focus Assay or a 500+-gene Oncomine™ Comprehensive Assay Plus. Variants were classified by clinical significance (ESMO ESCAT) and potential benefit (ESMO-MCBS and OncoKBTM). The Mann–Whitney and Chi square tests were used to compare characteristics of different groups, with significance at p &lt; 0.05. Results: Eighty-six metastatic colorectal cancer (mCRC) patients were analysed, all being MMR proficient. Most cases (73.3%) underwent sequencing at diagnosis of metastatic disease, using primary tumour samples (74.4%) and a focused NGS assay (75.6%). A total of 206 somatic variants were detected in 86.0% of patients, 31.1% of which were classified as clinically significant, predominantly KRAS mutations (76.6%), with G12D and G12V variants as the most frequent. Among 33.7% RAS/BRAF wild-type patients, 65.5% received anti-EGFR therapies. Eleven patients (12.8%) had other actionable variants which were ESCAT level I-II, including four identified as TMB-high, four KRAS G12C, two BRAF V600E, and one HER2 amplification. Four received therapies classified as OncoKbTM level 1–2 and ESMO-MCBS score 4, leading to disease control in three cases. Conclusions: NGS enables the detection of rare variants, supports personalised treatments, and expands therapeutic options. As new drugs emerge and genomic data integration improves, NGS is poised to enhance real-world mCRC management.