Survival Of Patients Research Articles

Impact of thyrotropin levels on outcomes in T1N0M0 papillary thyroid cancer after microwave ablation

Objective To evaluate the impact of thyroid-stimulating hormone (TSH) levels on tumor progression and survival in patients with uni- and multifocal T1N0M0 papillary thyroid cancer (PTC) treated with microwave ablation (MWA). Methods This retrospective study analyzed the records of 525 patients with uni- and multifocal T1N0M0 PTC who underwent MWA from January 2015 to December 2022. Patients were stratified into uni-focal (U-PTC) and multifocal (M-PTC) groups and further categorized based on post-ablation TSH levels into low (≤1 mU/L), medium (1–2 mU/L), and high (>2 mU/L) subgroups. The tumor progression rates and progression-free survival were assessed. Results In U-PTC patients, lower TSH levels were significantly associated with higher tumor progression rates (10.1%) compared to those in the medium (2.9%) and high (2.1%) TSH groups (p = .009). Conversely, in M-PTC patients, tumor progression rates did not vary significantly across TSH levels. Progression-free survival rates in U-PTC patients were notably lower at the 5-year mark in the low TSH group (85.7%) compared to the medium TSH group (96.5%, p = .046). However, progression-free survival rates in M-PTC patients showed convergence across all TSH levels by the 5-year follow-up. Conclusion Maintaining TSH levels within the normal range post-ablation may be appropriate for managing T1N0M0 PTC treated with MWA, but randomized controlled trials are needed to confirm optimal TSH targets and their impact on outcomes.

Zanubrutinib Versus Bendamustine and Rituximab in Patients With Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Median 5-Year Follow-Up of SEQUOIA.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.2 months) and subsequent analysis (43.7 months) found superior progression-free survival (PFS; the primary end point) in patients who received zanubrutinib compared with BR. At a median follow-up of 61.2 months, median PFS was not reached in zanubrutinib-treated patients; median PFS was 44.1 months in BR-treated patients (hazard ratio [HR], 0.29; one-sided P = .0001). Prolonged PFS was seen with zanubrutinib versus BR in patients with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided P = .0003) and unmutated IGHV genes (HR, 0.21 [95% CI, 0.14 to 0.33]; one-sided P < .0001). Median overall survival (OS) was not reached in either treatment arm; estimated 60-month OS rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients, respectively. No new safety signals were detected. Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.

Rhabdomyosarcoma of the Middle Ear Case Report

Background: Rhabdomyosarcoma (RMS) is a highly malignant soft tissue tumor derived from primitive embryonal mesenchymal tissue that differentiates into striated skeletal muscle. Despite the improved outcome based on the EFS and OS using the three different treatment modalities-chemotherapy, radiotherapy and surgical treatment, the survival of patients depends on their IRS groups—pathological and surgical. On the other hand in the last thirty years a great improvement of the five-year overall survival (OS) of children with RMS have been observed based on the results of large multinational collaborative trials and successive studies dedicated to children, though prognosis is variable and dependent on several factors including histologic variant, primary sites of the tumor, extent of disease (disease resectability), and molecular-level characteristics. Case presentation: We present a clinical case of a five-year-old male with initial complains of left side peripheral facial nerve palsy and secondary cervical and retroauricular lymphadenomegaly. After an exam, surgery of the temporal bone, CT and MRI embryonal type of rhabdomyosarcoma was diagnosed, and adjuvant chemotherapy was initiated in combination with concomitant local radiotherapy. Results: The results show that in these areas surgery itself is insufficient for RMS treatment(usually it is limited to taking a biopsy only). The combination of chemotherapy and local control with radiotherapy achieved a good result in our patient. Conclusions: Middle ear Embryonal Rhabdomyosarcoma is a common solid tumor, which could mimic middle ear inflammation or mastoid inflammation in patients. The multimodal approach seemed to be the ideal management of RMS. It involves a combination of chemotherapy and local control with surgery and/or radiotherapy.

Sarcoma: Last Year's Practice Changing Papers.

In 2023 and 2024, a wide variety of new studies have been published in the field of soft tissue sarcomas, representing the enormous heterogeneity of sarcoma histotypes, anatomical location, treatment variability, and biological behavior. This article summarizes the, in our view, seven most important publications in the field that will have an impact on the surgical practice and future treatment strategies of our patients. In the last year, we gained more insight in the genetic background of patients with sarcoma from a large Australian study, which will have an impact on future counseling and screening of our patients. Also, the role of radiotherapy in retroperitoneal liposarcoma became clearer in the combined STRASS-STREXIT study. Radiotherapy for extremity sarcomas can now also be done in a 3-week, hypofractioned manner, which is a major improvement for our patients. Furthermore, more evidence has been presented regarding the improved outcome of patients with retroperitoneal sarcoma when treated in high volume centers. Landmark studies with systemic treatment include the positive trial with nirogacestat in desmoid tumors, which have finally shifted the paradigm of desmoid treatment from surgery to systemic treatment. Also, the results of 2 phase 3 randomized controlled trials recently showed 1) that the combination of doxorubicin with trabectedin significantly improved progression free survival for patients with leiomyosarcoma when compared with doxorubicin alone and 2) that the combination of neoadjuvant pembrolizumab and radiotherapy followed by 1-yr adjuvant pembrolizumab significantly improved disease free survival for patients with primary localized undifferentiated pleomorphic sarcoma/myxofibrosarcoma or dedifferentiated/pleomorphic liposarcoma of the extremities or girdles. Key papers from the last year informs us that management of soft tissues sarcoma is constantly improving, since more data became available to guide us in defining the best treatment strategies.

Therapeutic targeting of cGAS-STING pathway in lung cancer.

The presence of DNA in the cytosol triggers a protective response from the innate immune system. Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) is an essential cytosolic DNA sensor that triggers a potent innate immune response. As a result of this signaling cascade reaction, type I interferon and other immune mediators activate an immune response. The cGAS-STING pathway has great anticancer immunity-boosting potential since it produces type I interferons. The detection of double-stranded DNA (dsDNA) in response to various stimuli initiates a protective host's cGAS-STING signals. So, it is clear that a substantial relationship is expected between cancer biotherapy and the functioning of the cGAS-STING pathway. Several STING agonists with promising outcomes have been created for preclinical cancer therapy research. Notably, immunotherapy has dramatically extended patient survival and radically altered the course of lung cancer treatment, particularly in more advanced instances. However, this method is still ineffective for a large number of lung cancer patients. cGAS-STING can overcome resistance and boost anticancer immunity by stimulating the activity of many pro-inflammatory mediators, augmenting dendritic cell cross-presentation, and initiating a tumor-specific CD8+ T cell response. This review aims to present the most recent results on the functionality of the cGAS-STING pathway in cancer progression and its potential as an immunotherapy target, with a focus on lung cancer.

PCSK9 inhibitors – new era of dyslipidemia treatment - effectiveness in reducing low-density lipoprotein (LDL-C) and cardiovascular risk

Introduction: Abnormal blood cholesterol levels in patients with increased cardiovascular risk have a worse prognosis for patient survival. Treating dyslipidemia is important because it can improve patient comfort and safety. It sometimes happens that currently used drugs to lower cholesterol are not effective - patients develop tolerance or experience serious side effects. For this reason, scientists are looking for new drugs with a different mechanism of action. An example of such a group of drugs are PCSK9 inhibitors used to treat dyslipidemia. In this paper, we will look at the effectiveness of currently used PCSK9 inhibitors, but also at the potential risks associated with their use. Material and methods: We searched for materials for this work in the Pubmed and Google Scholar databases using the keywords: "dyslipidemia", "cardiovascular disease", "PCSK9 inhibitors", "statins". Then we analyzed the selected materials. Aim of the study: Evaluation of the Conclusion: PCSK9 inhibitors are drugs that are very effective in lowering low-density lipoprotein (LDL-C), while reducing cardiovascular risk and potentially having long-lasting effects. Scientists are looking for new PCSK9 inhibitors with different mechanisms of action, which will be an even more effective therapy in lowering LDL-C.

Effectiveness of hyperthermic intraperitoneal chemotherapy during primary curative resection for colorectal carcinoma

PurposePeritoneal metastasis (PM) is the life-threatening cause of colorectal cancer patients (CRC). Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) plus cytoreductive surgery exhibited promising effects in preventing recurrence and increasing the survival of CRC patients. However, the outcomes of HIPEC on treating advanced CRC with risk of PM are still controversial. Here, we retrospectively examined the impact of HIPEC on preventing PM and its overall effects on patients with locally advanced CRC who underwent primary curative resection at our center.MethodsWe retrospectively analyzed 45 patients diagnosed with locally advanced colorectal cancer (CRC) who underwent primary curative laparoscopic surgery with proactive hyperthermic intraperitoneal chemotherapy (HIPEC), in conjunction with adjuvant systemic chemotherapy at our center between 2019 and 2022. An additional 55 patients with locally advanced CRC who underwent similar surgery and received adjuvant systemic chemotherapy but did not undergo HIPEC during the same period were selected as the control group. Disease-free survival (DFS), overall survival (OS), and PM incidence were compared between patients with and without HIPEC.Results and conclusionsThe cumulative PM incidence was 2.2% in the HIPEC group and 14.5% in the control group(P = 0.0347). No significant adverse effects were observed in the HIPEC group. Furthermore, Kaplan–Meier survival analysis showed that the HIPEC correlated to better DFS [hazard ratio (HR) 0.4670, 95% confidence interval (CI) 0.2305–0.9462; P = 0.0345] and extended the overall survival of CRC patients [hazard ratio (HR) 0.3978, 95% confidence interval (CI) 0.1684–0.9395; P = 0.0355]. Therefore, our data supports that adjuvant HIPEC can prevent peritoneal failure in CRC patients and improve both PFS and OS survival following primary curative resection.

Impact of neck dissection in cN0 patients undergoing primary or salvage total laryngectomy.

It is debatable whether neck dissection is necessary in patients with advanced laryngeal carcinoma who are clinically node-negative (cN0). We assessed the effect of neck dissection on overall survival in patients with cN0 undergoing primary or salvage laryngectomy. A retrospective evaluation of cN0 patients who underwent primary or salvage total/pharyngolaryngectomy at a French tertiary facility in 2008-2018, with or without neck dissection, was carried out. Patients were divided into two groups: primary (n = 65) and salvage (n = 84). Comparing subglottic (HR = 3.978; p = 0.023) and hypopharyngeal (HR = 2.958; p = 0.018) malignancies to other tumor subsites, the mortality rates were greater. The primary group had a greater rate of occult metastases (23.07% vs. 14.28%; p = 0.089) than the salvage. The average lymph node ratio was significantly different between the treatment groups (0.05 ± 0.04 vs. 0.17 ± 0.33; p = 0.004). If LNR > 0.05, we found poor survival rates (p < 0.001). Although performing a neck dissection during the primary treatment increased the 5-year OS rate (Yes 89.5% vs. No 83.3%; p = 0.062), there was no discernible difference in the salvage group (Yes 80.3% vs. No 78.6%; p = 0.806; Log-rank p > 0.05). For the predicted survival variables, no significant relationships were detected in the Cox regression analysis (all p-values > 0.05). Although the primary group had a greater frequency of occult metastases, neither the primary group's survival outcomes nor those of the salvage laryngectomy cases were significantly affected by neck dissection. LNR and the location of the tumor were important variables that could affect survival and the choice to do a neck dissection.

A Phase II Study of Acalabrutinib, Venetoclax, and Obinutuzumab (AVO) in a Treatment-Naive CLL Population Enriched for High-Risk Disease.

The AMPLIFY trial recently established fixed-duration acalabrutinib, venetoclax, and obinutuzumab (AVO) as a new standard of care option for patients with previously untreated chronic lymphocytic leukemia (CLL) with wildtype TP53; however, due to the chemoimmunotherapy control arm, AMPLIFY excluded patients with the high-risk TP53 aberration, for whom current standards of care are continuous Bruton tyrosine kinase inhibitor therapy or alternatively fixed-duration venetoclax-based doublets. AVO has not previously been evaluated in patients with CLL with TP53 aberration. This investigator-sponsored, multicenter, phase 2 study enrolled patients with treatment-naïve CLL enriched for high-risk CLL, defined by TP53 aberration (NCT03580928). Patients received acalabrutinib, obinutuzumab, and then venetoclax, with each treatment introduced sequentially and in combination, with the duration guided by measurable residual disease (MRD). Patients who achieved undetectable MRD (uMRD) after either fifteen or twenty-four cycles could discontinue treatment. The primary endpoint was complete response (CR) with bone marrow uMRD (BM-uMRD) at the start of cycle 16. Seventy-two patients were accrued, including 45 patients with TP53 aberration. The CR with BM-uMRD rates at the start of cycle 16 were 42% in patients with TP53 aberration and 42% in all-comers, and the BM-uMRD rates were 71% and 78%, respectively. Hematologic toxicities were mainly low-grade, and cardiovascular toxicities and bleeding complications were infrequent. After a median follow-up of 55.2 months, ten patients had progressed, including 4 with transformation, and three patients died. Four-year progression-free and overall survival for patients with or without TP53 aberration were 70%/96% and 88%/100%, respectively. AVO was highly active and well-tolerated in patients with previously untreated CLL with high-risk CLL, supporting its use as a new standard of care treatment option.

Post-diagnosis statin use and survival among head and neck cancer patients: a cohort study in a universal health care system.

Little research has been conducted on the relationship between statin use and the survival of head and neck cancer patients. This study assessed whether statin use after head and neck cancer diagnosis is associated with overall survival among patients in the U.S. military health system (MHS) that provides universal health care to its beneficiaries. The study included 1842 patients with head and neck squamous cell carcinoma (HNSCC) from MHS. Statin use was extracted from the pharmacy database of the Military Health System Data Repository (MDR). Time-dependent multivariate Cox proportional hazards models were used to assess the relationship between post-diagnosis statin use and overall survival with the adjustment for potential confounders. Compared to non-users, increased post-diagnosis cumulative use of statins (per one-year of use) conferred a significant improved survival with adjusted hazard ratio (HR) of 0.70 (95% Confidence Interval, CI = 0.55 to 0.90). When analysis was stratified by status of statin use prior to HNSCC diagnosis, the HRs were 0.31 (95% CI = 0.15-0.65) and 0.81 (95% CI = 0.59-1.11) for post-diagnosis users who also used it before HNSCC diagnosis and those who only used it after the diagnosis, respectively. Prolonged statin use was associated with improved survival among HNSCC patients in MHS.

Evaluating the impact of cardiac substructure dosimetric parameters on survival in lung cancer patients undergoing postoperative radiotherapy.

The association of cardiac dosimetric parameters with survival in lung cancer patients is well established. However, most research has concentrated on patients undergoing definitive treatment. This study aims to investigate the relationship between cardiac dosimetric parameters and survival in patients receiving postoperative radiotherapy (PORT). Sixty patients who received PORT between 2011 and 2021 were retrospectively evaluated. The substructures of the heart were delineated on the simulation computed tomography scans of the patients. Univariate and multivariate Cox regression analyses were conducted to investigate the correlation between dosimetric parameters and overall survival. The Statistical Package for the Social Sciences (SPSS) version 23.0 (IBM Corp., Armonk, NY, USA) was utilized for statistical analyses. Right atrium (RA) maximum dose (Dmax) was the only variable that was significantly associated with ashorter OS. Further receiver operating characteristic (ROC) analysis revealed that the optimum cut-off value for RA Dmax was 43.6 Gy, with asensitivity of 69% and aspecificity of 62%. In addition, inclusion of the upper right paratracheal (2R), lower right paratracheal (4R), left pulmonary ligament (9L), and right hilus (10R) lymphatic stations in the treatment field led to an increase in RA Dmax. The results of this retrospective study show that RA Dmax appears to have an impact on overall survival in patients undergoing PORT. Limiting the RA Dmax dose to below 43.6 Gy and avoiding elective nodal irradiation might potentially enhance survival in this patient cohort.

Explainable machine learning for predicting recurrence-free survival in endometrial carcinosarcoma patients

ObjectivesEndometrial carcinosarcoma is a rare, aggressive high-grade endometrial cancer, accounting for about 5% of all uterine cancers and 15% of deaths from uterine cancers. The treatment can be complex, and the prognosis is poor. Its increasing incidence underscores the urgent requirement for personalized approaches in managing such challenging diseases.MethodIn this work, we designed an explainable machine learning approach to predict recurrence-free survival in patients affected by endometrial carcinosarcoma. For this purpose, we exploited the predictive power of clinical and histopathological data, as well as chemotherapy and surgical information collected for a cohort of 80 patients monitored over time. Among these patients, 32.5% have experienced the appearance of a recurrence.ResultsThe designed model was able to well describe the observed sequence of events, providing a reliable ranking of the survival times based on the individual risk scores, and achieving a C-index equals to 70.00% (95% CI, 59.38–84.74).ConclusionAccordingly, machine learning methods could support clinicians in discriminating between endometrial carcinosarcoma patients at low-risk or high-risk of recurrence, in a non-invasive and inexpensive way. To the best of our knowledge, this is the first study proposing a preliminary approach addressing this task.

Effects of Tobacco Smoking on Post-Liver-Transplant Outcomes

Background/Objectives: Our study examined 5-year patient and graft survival outcomes among non-smokers, former smokers, and active smokers at the time of liver transplantation (LT) and immediate post-operative complications and short-term outcomes following LT. Methods: This was a retrospective study that examined all liver transplants occurring at Cleveland Clinic Main Campus between January 2015–October 2022. Kaplan–Meier curves examined survival outcomes, and Cox’s multivariate regression analysis was performed. Results: Over the 5-year period, patient survival did not differ statistically between patient groups (all p-values &gt;0.05). However, graft survival was significantly lower in active smokers (p = 0.012). In the multivariate analysis, age (HR = 1.03, 95% CI 1.01–1.05, p = 0.002) and admission to the ICU (HR 1.68, 95% CI 1.13–2.50, p = 0.01) were positively associated with overall mortality. Immediate and short-term complications did not differ statistically between patient groups. Cardiovascular disease (22.5%) was the most common cause of death among all patients. Conclusions: Though our study did not show decreased patient survival outcomes, our findings are in line with previous studies that have shown that pre-transplant smoking is associated with overall reduced graft survival. Combined with the risk for de novo malignancy and cardiovascular events post transplant, smoking cessation before LT should be encouraged to ensure graft longevity.

Acute myeloid leukemia treatment outcomes with isocitrate dehydrogenase mutations: A systematic review and meta-analysis.

Isocitrate dehydrogenase (IDH) gene alterations and acute myeloid leukemia (AML) treatment results remain controversial. This study reviews the literature on IDH mutations in AML to determine the foundation of individualized therapy and improve effectiveness, survival time, and recurrence rate. Seven English and 2 Chinese databases were searched for literature on IDH mutations and AML outcomes. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Twenty studies were included in this analysis. For the prognostic influence of IDH mutation on AML patients, the pooled HRs of overall survival in AML patients were 0.76 (95% CI, 0.63-0.93); the pooled HRs of event-free survival were 1.34 (95% CI, 1.15-1.57; heterogeneity: I2 = 52.2%, P = .027 < 0.05); the pooled HRs of recurrence free survival were 0.79 (95% CI, 0.61-1.02). The pooled HRs of overall survival in AML patients with mutant IDH1 were 1.62 (95% CI, 1.42-1.86) and of mutant IDH2 were 1.07 (95% CI, 0.89-1.29). The pooled HRs for event-free survival in AML patients with mutant IDH1 were 1.71 (95% CI, 1.40-2.08) and of mutant IDH2 were 0.93 (95% CI, 0.65-1.34). No evidence of publication bias was observed. Different subtypes of IDH mutations may lead to different AML prognoses, suggesting the feasibility of personalized treatment for AML patients.

The integrin adhesome and control of anti-tumour immunity.

It is widely regarded that the anti-tumour immune response drives clearance of tumours and leads to prolonged survival in patients. However, tumours are adept at reprogramming the surrounding microenvironment to an immunosuppressive milieu to prevent successful immune directed killing. Adhesion of cells to the extracellular matrix is essential for regulating cellular processes such as survival, proliferation and migration. This adhesion is largely conducted via integrins and their related intracellular signalling networks. Adhesion proteins such as focal adhesion kinase (FAK) are expressed in both tumour cells and cells of the surrounding microenvironment, and are often dysregulated in cancers. Recent work has demonstrated that adhesion proteins are contributing to regulation of the immunosuppressive microenvironment within tumours, and could provide a new avenue to target in combination with immunotherapies. Here, we provide an overview of the effort being made to elucidate the roles adhesion proteins play in modulating anti-tumour responses within a variety of cancer settings. In particular we focus on the multifaceted role of FAK within the tumour immune microenvironment. Finally, we summarise the data in clinical trials, where targeting FAK is being exploited to prime the tumour microenvironment and create potent responses when combined with immunotherapies.

Mass-forming intrahepatic cholangiocarcinoma: treatment outcomes after curative-intent resection in an Australian tertiary referral hospital.

Mass-forming intrahepatic cholangiocarcinoma (MF-ICC) is the second most common primary liver cancer and liver resection offers the best chance of possible cure. This study aimed to assess treatment outcomes and prognostic factors for long-term survival in patients who underwent curative-intent liver resection. A retrospective analysis was conducted on prospectively collected data from patients with MF-ICC managed at the Royal North Shore/North Shore Private Hospital from January 1998 to October 2023. Baseline, peri-operative and long-term outcomes have been analysed, including an overall survival (OS) and disease-free survival (DFS) analysis. During the 25-year study period, 47 patients underwent curative-intent liver resection for primary MF-ICC at a median age of 70 years. The median OS was 36 months, with a 5-year OS of 33%. Multiple liver tumours (HR = 2.84; 95% CI = 1.24-6.48; P = 0.013) and a positive resection margin (HR = 2.46; 95% CI = 1.10-5.52; P = 0.029) were identified as independent predictors of poor long-term OS. Recurrence occurred in 62% of patients after a median DFS of 16 months, with poor tumour differentiation (HR = 3.93; 95% CI = 1.62-9.54; P = 0.002) and elevated tumour markers (HR = 3.47; 95% CI = 1.53-7.87; P = 0.003) as independent predictors of poor DFS. Liver resection can offer a significant chance for prolonged survival in a highly selected population of patients with MF-ICC. However, the surgical challenges inherent in treating this rare disease are evident, emphasizing the need for a multimodal approach and continued exploration of additional therapies to enhance personalized treatment strategies.

Nomogram for predicting post-progression-free survival in patients with recurrent pancreatic ductal adenocarcinoma after radical surgery: a retrospective analysis

Nomogram for predicting post-progression-free survival in patients with recurrent pancreatic ductal adenocarcinoma after radical surgery: a retrospective analysis

DAB2IP loss in luminal a breast cancer leads to NF-κB-associated aggressive oncogenic phenotypes.

Despite proven therapy options for estrogen receptor-positive (ER+) breast tumors, a substantial number of patients with ER+ breast cancer exhibit relapse with associated metastasis. Loss of expression of RasGAPs leads to poor outcomes in several cancers, including breast cancer. Mining the The Cancer Genome Atlas (TCGA) breast cancer RNA-Seq dataset revealed that low expression of the RasGAP DAB2IP was associated with a significant decrease in relapse-free survival in patients with Luminal A breast cancer. Immunostaining demonstrated that DAB2IP loss occurred in grade 2 tumors and higher. Consistent with this, genes upregulated in DAB2IP-low Luminal A tumors were shared with more aggressive tumor subtypes and were associated with proliferation, metastasis, and altered ER signaling. Low DAB2IP expression in ER+ breast cancer cells was associated with increased proliferation, enhanced stemness phenotypes, and activation of IKK, the upstream regulator of the transcription factor NF-κB. Integrating cell-based ChIP-Seq with motif analysis and TCGA RNA-Seq data, we identified a set of candidate NF-κB target genes upregulated with loss of DAB2IP linked with several oncogenic phenotypes, including altered RNA processing. This study provides insight into mechanisms associated with aggressiveness and recurrence within a subset of the typically less aggressive Luminal A breast cancer intrinsic subtype.

KDM1A epigenetically enhances RAD51 expression to suppress the STING-associated anti-tumor immunity in esophageal squamous cell carcinoma

Histone lysine demethylase LSD1, also known as KDM1A, has been found to regulate multiple cancer hallmarks since it was first identified in 2004. Recently, it has emerged as a promising target for stimulating anti-tumor immunity, specifically boosting T cell activity. However, it remains unclear whether and how it remodels the tumor microenvironment to drive oncogenic processes in esophageal squamous cell carcinoma (ESCC). In this study, protein levels in ESCC tissues were evaluated by immunostaining of tissue microarrays. Cell growth was assessed by colony formation assays in vitro and subcutaneous xenograft models in vivo. High-throughput transcriptomics and spatial immune proteomics were performed using bulk RNA sequencing and digital spatial profiling techniques, respectively. Epigenetic regulation of RAD51 by methylated histone proteins was analyzed using chromatin immunoprecipitated quantitative PCR assays. Finally, our clinical data indicate that KDM1A precisely predicts the overall survival of patients with early-stage ESCC. Inhibition of KDM1A blocked the growth of ESCC cells in vitro and in vivo. Mechanistically, our transcriptomics and spatial immune proteomics data, together with rescue assays, demonstrated that KDM1A specifically removes methyl residues from the histone protein H3K9me2, a transcription repressive marker, thus reducing its enrichment at the promoter of RAD51 to epigenetically reactivate its transcription. Additionally, it significantly inhibits the expression of NF-κB signaling-dependent proinflammatory genes IL-6 and IL-1B through RAD51, thus blocking the STING-associated anti-tumor immunity in stromal tumor-infiltrating lymphocytes (sTIL). Overall, our findings not only indicate that KDM1A is a promising target for ESCC patients at early stages but also provide novel mechanistic insights into its spatial regulation of STING-associated anti-tumor immunity in sTILs to drive the oncogenic processes in ESCC. The translation of these findings will ultimately guide more appropriate combinations of spatial immunotherapies with KDM1A inhibitors to improve the overall survival of specific subgroups in ESCC.

Intratumoral delivery of lipid nanoparticle-formulated mRNA encoding IL-21, IL-7, and 4-1BBL induces systemic anti-tumor immunity

Local delivery of mRNA-based immunotherapy offers a promising avenue as it enables the production of specific immunomodulatory proteins that can stimulate the immune system to recognize and eliminate cancer cells while limiting systemic exposure and toxicities. Here, we develop and employ lipid-based nanoparticles (LNPs) to intratumorally deliver an mRNA mixture encoding the cytokines interleukin (IL)−21 and IL-7 and the immunostimulatory molecule 4-1BB ligand (Triplet LNP). IL-21 synergy with IL-7 and 4-1BBL leads to a profound increase in the frequency of tumor-infiltrating CD8+ T cells and their capacity to produce granzyme B and IFN-γ, leading to tumor eradication and the development of long-term immunological memory. Mechanistically, the efficacy of the Triplet LNP depends on tumor-draining lymph nodes to tumor CD8+ T-cell trafficking. Moreover, we highlight the therapeutic potential of the Triplet LNP in multiple tumor models in female mice and its superior therapeutic efficacy to immune checkpoint blockade. Ultimately, the expression of these immunomodulators is associated with better overall survival in patients with cancer.