bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world outcomes of sacituzumab govitecan in breast cancer.
Authors: Singh Vaishnavi , Dhaibar Hemangini , Peddi Prakash 
Published: June 2024

e13137 Background: Sacituzumab govitecan (Trodelvy), a novel antibody-drug conjugate, has emerged as a promising treatment option, in patients with metastatic triple-negative breast cancer (mTNBC). It gained FDA approval for unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies based on ASCENT trial which demonstrated that progression-free survival (PFS) and overall survival (OS) was significantly longer with sacituzumab govitecan than with single-agent chemotherapy. Hence, here in our current study, we further explore the outcomes of patients on sacituzumab govitecan in the setting of mTNBC. Methods: A single-center retrospective analysis was conducted on 21 women (aged 30-80 years old) with mTNBC breast cancer treated with sacituzumab govitecan over a span of 4 years. Baseline characteristics, pre-sacituzumab govitecan treatment PFS correlations, PFS and OS of sacituzumab govitecan were assessed and compared with the ASCENT trial. Results: A total of 21 women, comprising 10 African American, 10 Caucasian, and 1 Asian were evaluated over a span of 4 years. In our study with an average population of 50.6 years, the overall mean (± standard error of the mean) observed was 5.00 months (SEM 1.02) for PFS and 8.33 months (SEM 1.62) for OS. Patients with brain metastasis (n=8) and without brain metastasis (n=13) exhibited a mean of 5.99 months (SEM 2.23) and 4.40 months (SEM 0.97) for PFS respectively whereas 8.34 months (SEM 2.28) and 8.33 months (SEM 2.29) for OS respectively. The average number of previous treatment exposures in this subset was 5.6, with a mean PFS of 11.33 months (SEM 3.64) for prior treatment before initiation of sacituzumab govitecan. Conclusions: Our data reflects a similar interpretation with ASCENT trial study for mean PFS, however with a lower mean OS. In our study, the mean PFS from 8 patients who had brain metastasis closely matched with the patients without brain metastasis and the median PFS of the trial, thus suggesting potential consideration of sacituzumab govitecan in patients with active brain metastasis, as the patients with brain metastasis were excluded from the primary endpoint analysis in the ASCENT trial. No correlation was observed between the mean PFS of the prior line of therapy before sacituzumab govitecan and sacituzumab govitecan’s mean PFS. Overall, sacituzumab govitecan represents a significant advancement in breast cancer treatment and offers hope for patients with mTNBC.
A phase II trial of anlotinib combined chemotherapy as second-line and above therapy in HER2-negative advanced breast cancer.
Authors: Yuan Yuan , Zhang Lili , Xu Ting , Xiong Weili , Hu Sainan , Huang Jiayuan , Dong Min , Xu Xinyu , Lou Kexin 
Published: June 2024

e13140 Background: The group of HER2-negative accounts for about 75% of breast cancer and has limited response to chemotherapy. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. In this study, we assessed the efficacy and safety of anlotinib plus chemotherapy in second-line and above treatment of HER-2 negative advanced breast cancer. Methods: This open-label, single-arm, phase II study enrolled women aged 18-75 years with HER2-negative breast cancer who underwent at least one-line chemotherapy. All patients were treated with anlotinib (12mg, qd, administered orally on Days 1-14 of each 21 day cycle) in combination with investigator-selected chemotherapy. The primary endpoint evaluated in this study was the median progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR) and safety. Results: From August 2022 to August 2023, 33 patients were enrolled in this study including 22(66.7%) HR+/HER2- patients and 11(33.3%) TNBC patients. After a median follow-up time of 11 months (95% CI, 5.8-16.2), the median PFS (mPFS) of the all patients was 8.6 months (95% CI 7.3-NA). In the HR+ and HR- populations, mPFS was 7.6 months versus 9.5 months (HR,0.376 [95%CI 0.12-1.13], p=0.072), respectively. All the patients had the confirmed best overall response assessments, no patient achieved complete response (CR); 11(33.3%) patients got partial response (PR) and 19(57.6%) patients achieved stable disease (SD). ORR was 33.3% (95% CI 18.0-51.8), DCR was 90.9% (95% CI 75.7-98.1) and CBR was 60.6% (95% CI 42.1-77.1). The most frequently observed adverse events were elevated triglycerides (78.8%), elevated blood sugar (63.6%), anemia (60.6%), elevated cholesterol (51.5%), elevated alanine aminotransferase (48.5%), and leukopenia (48.5%). Dose reductions due to adverse events occurred in 7 (21.2%) patients. Conclusions: Anlotinib combined with chemotherapy showed a promising efficacy with an acceptable safety profile for second-line and above patients with HER2-negative metastatic breast cancer. Further studies enrolling more patients are still needed.
Cryptolepine: A naturally derived alkaloid inhibits breast cancer progression by blocking cell cycle progression and inducing apoptosis.
Authors: Mir Manzoor Ahmad , Qayoom Hina 
Published: June 2024

e13151 Background: Triple Negative Breast cancer is an aggressive breast cancer subtype. TNBC has a more aggressive clinical course, an earlier age of beginning, a larger propensity for metastasis, and worse clinical outcomes as evidenced by a higher risk of recurrence and a shorter survival rate when compared to hormone receptor-positive or HER2-positive illness. Currently, the primary options for TNBC treatment are surgery, radiation, and chemotherapy. These treatments, however, remain ineffective due to recurrence. However, given that p53 mutations have been identified in more than 60–88% of TNBC, translating p53 into the clinical situation is particularly important in TNBC. Given the scope that some natural drugs can be used as specifically targeting prospective therapeutic in TNBC and to sensitize this aggressive malignancy while reducing side effects. In this study, we screened and evaluated the therapeutic potential of CRP in TNBC in-vitro models being an anti-malarial drug it could be repurposed as an anti-cancer therapeutic in TNBC. Moreover, the cytotoxicity activity of cryptolepine to TNBC cells and a detailed anti-tumor mechanism in mutant P53 has not been reported. Methods: MTT assays were used to examine the cytotoxicity and cell viability activity of Cryptolepine in TNBC, non-TNBC T47D and MCF-7 and non-malignant MCF10A cells. Scratch wound and clonogenic assay was used to evaluate cryptolepine’s effect on migration and colony forming ability of TNBC cells. Flow cytometry, MMP and DAPI was used to assess cell cycle arrest and cell apoptosis. The expression of proteins was detected by western blots. The differential expression of RNAs was evaluated by RT-PCR and the interaction between P53 and drug was evaluated computationally using in-silico approach and in-vitro using ChIP assay. Results: In this study, we found that cryptolepine has more preferential cytotoxicity in TNBC than non-TNBC cells. Notably, our studies revealed the mechanism that cryptolepine can induce intrinsic apoptosis and inhibit migration, colony formation ability, induce cell cycle arrest by inducing conformational change in the mutant P53 thereby increasing its DNA binding ability and also inducing its own transcriptional activation to synthesize new P53 protein and hence activating its tumor suppressing potential significantly. Conclusions: Our study revealed that CRP significantly reduced the proliferation, migration and colony forming ability of TNBC cells lines. Moreover, it was revealed that CRP induces cell cycle arrest and apoptosis by activating mutant P53 and enhancing its DNA binding ability to induce its tumor suppressing ability.
Impact of aromatase inhibitors on mortality and hospitalization costs in patients with breast cancer: A National Inpatient Sample analysis 2020.
Authors: Kasire Sripada Preetham , Mylavarapu Maneeth 
Published: June 2024

e13160 Background: Breast cancer is a significant public health concern globally, affecting millions of individuals each year. Aromatase inhibitors are a class of medications commonly used in the treatment of hormone receptor-positive breast cancer. The significance of the study lies in the impact of aromatase inhibitors on mortality and also healthcare-related costs for the treatment of breast cancer. Methods: The National Inpatient Sample database (2020) was used to identify adult patients with breast cancer using ICD-10 codes. Demographics (age, race, sex, region, and hospital size), co-morbidities, and hospitalization costs were compared between the two groups of patients: those who are on aromatase inhibitors and those who are not. The odds of mortality were analyzed. A p<0.05 was considered statistically significant. Results: Out of 166870 patients who had breast cancer, 12975(7.7%) were on aromatase inhibitors. The aromatase inhibitors group was relatively older (median age, 69.4 years vs 64 years) and predominantly white (71.50% vs 66%) compared to the non-aromatase inhibitors group. The prevalence of heart failure and osteoporosis was greater in the aromatase inhibitors group than in the non-aromatase inhibitors group. The adjusted odds ratio of mortality in the aromatase inhibitors group was 0.45, 95% CI (0.39-0.50, p<0.0001). Furthermore, the average total cost of hospitalization in the aromatase inhibitor group was $6426 less than the non-aromatase inhibitor group. Conclusions: Our study findings indicate that breast cancer patients treated with aromatase inhibitors experienced lower odds of mortality and lesser costs of hospitalization. However, the aromatase inhibitor group was found to have a higher prevalence of heart failure and osteoporosis. Hence, further research needs to be done on potential adverse effects and long-term effects of the aromatase inhibitors treatment.
Mechanisms of mammalian orthoreovirus-induced cell death and NF-kB activation in ER+ breast cancer.
Authors: Hilgendorf Syrena , Ostrander Julie , Roman Ortiz Natasha 
Published: June 2024

e13171 Background: Estrogen receptor positive (ER+) breast cancer is one of the most commonly diagnosed types of breast cancer in the United States. Although the five-year survival rate of ER+ breast cancer is 90% or higher, ER+ breast cancer can recur and metastasize 10-20+ years after initial diagnosis. Novel therapeutic strategies are needed to prevent and treat breast cancer recurrence and metastasis. A possible solution is mammalian orthoreovirus (MRV), a replication-competent natural oncolytic virus. The strain T3D (Reolysin) is in current clinical trials to treat metastatic breast cancer; however, the mechanisms of MRV-induced death are not well elucidated. Furthermore, other MRV strains have not been well studied for their oncolytic potential in ER+ breast cancer. Our studies aim to explore the different cell death pathways elicited by MRV. Prior studies have reported that MRV induces cell death in L929 cells (murine fibroblasts, permissive to MRV infection) by activating apoptosis, necroptosis, and inhibiting the NFκB pathway to enhance viral replication. Methods: Our goal is to compare the effects of MRV in L929 cells and ER+ breast cancer cell line MCF7 using chemical inhibitors of necroptosis, apoptosis, and the NFκB pathway. Results: Our results indicate that necroptosis inhibitors do not impact cell viability in response to MRV infection, but apoptosis inhibitors increase cell viability, suggesting that MRV-induces apoptotic cell death in ER+ breast cancer cells. Previous work has shown that the NFκB pathway may be activated or inhibited by MRV. Our cell viability studies in MCF7 cells with the IKK inhibitor BAY-11-7082 indicate that several MRV strains likely activate the NFκB pathway to potentially enhance viral replication. Conclusions: Future studies are aimed at further defining mechanisms of MRV-induced cell death in ER+ breast cancer. We anticipate future studies will lead to an improved MRV virotherapeutic that may be combined with clinically relevant treatments, such as CDK4/6 inhibitors and anti-estrogens, to prevent and treat therapy-resistant ER+ breast cancer.
Characteristics of hospital admission during checkpoint-inhibition therapy.
Authors: Fröhlich Tabea Constanze , Wiegmann Jonas Paul , Möhn Nora , Mahjoub Susann , Duzzi Laura , Narte Emily , Aurich Johanna , Berliner Dominik , Wirth Thomas , Golpon Heiko , von Wasielewski Imke , Heidel Florian , Skripuletz Thomas , Gutzmer Ralf , Beutel Gernot , Ivanyi Philipp 
Published: June 2024

e14510 Background: Immune checkpoint inhibitors (ICI) have enriched the therapeutic armamentarium in outpatient oncology care; however, data on necessity of hospitalizations associated with immune-related adverse event (irAEs) are scarce. Here, we retrospectively characterize hospitalizations of patients (pts) undergoing ICI. Methods: Between 12/2019 and 06/2022, 237 pts were included. Clinical data and characteristics of ICI were collected during a 6-month observation period after the initiation of therapy. Descriptive Statistics and Kaplan-Meier statistics were administered. Results: 30 out of 237 pts were hospitalized (HA+). Most common underlying tumor entities in the overall cohort were malignant melanoma (59.5%), renal cell carcinoma (13.1%), and non-small cell lung carcinoma (12.7%). Hospitalized pts exhibited an increased rate of pulmonary and cerebral metastases. We observed a significantly higher hospitalization rate during dual ICI with Nivolumab and Ipilimumab. The predominant irAEs for hospitalization were colitis (26.7), followed by hypophysitis (13.3%), leading to a median hospitalization of 7 days (range 1-34). Most pts were treated on the general ward (76.7%). Interdisciplinary consultations were frequent, especially to gastroenterology (46.7%) and neurology (26.7%). Although a trend towards an overall survival in the HA+ subgroup was identified, no statistically significant difference was found among the subgroups. Conclusions: The hospitalization rate of 12.6% is comparable to the literature. There was a disproportionate admission of patients with immune-related colitis and hypophysitis compared to the prevalence described under ICI. We observed a high need for interdisciplinary consults in line with the heterogeneity of immune-mediated side effects. When compared to non-hospitalized pts, there was no survival disadvantage in the cohort of hospitalized patients.
Example of a simple and scalable manufacturing process for immunomodulatory alpha neutrophils, a specifically designed immuno-cell therapy with direct and indirect anti-cancer activity for solid tumour indications.
Authors: Patel Durva , Florence Samuel , McGinley Aoife , Lich Jakub , Thacker Urvi , Blyth Alex , Willis Andrew , Quintas-Cardama Alfonso , Polyakova Oxana 
Published: June 2024

e14512 Background: Recent findings have demonstrated neutrophils play a key role in tumour control and in facilitating successful responses to cancer immunotherapy. At LIfT Biosciences we have developed the first-in-class, allogeneic, off-the-shelf, stem cell-derived immuno-cell therapy with anti-cancer neutrophil properties. Immunomodulatory Alpha Neutrophils (IMANs) exert their anti-cancer activity via multiple direct and indirect mechanisms, ensuring direct antigen-independent tumour cell killing, as well as impacting anti-cancer function of other direct acting cells such as NK and gamma delta T cells, and further immunomodulation of the environment to boost adaptive immune responses ensuring maximal T cell activity can be achieved. IMANs have the potential to provide major clinical benefits in the treatment of multiple solid tumours. Methods: We present a patent-pending, GMP-compliant manufacturing process starting with CD34+ cells isolated from mobilized peripheral blood of healthy donors. Extensive characterisation of starting material in combination with in-process and raw material controls results in a simple, consistent, scalable manufacturing process using known and established manufacturing platforms. IMANs are granulopoietic myeloid progenitors derived from the expansion of CD34+ cells followed by differentiation in proprietary media compositions, composed of critical priming agents which are known to promote anti-cancer neutrophil phenotype and function. Neutrophil functional heterogeneity is becoming increasingly appreciated and we have designed our manufacturing process to produce activated, committed, persistent IMANs with multimodal mechanisms of action. IMANs are composed of distinct neutrophil progenitor populations. IMANs are cytotoxic towards numerous solid tumour cell lines, expressing tumour-ablating Neutrophil elastase. Furthermore, IMANs exert immunomodulatory properties through cytokine and chemokine secretion, and expression of ligands for T and NK cell co-stimulatory receptors. Results: The manufacturing process has been optimised with vast expansion capacity, showing up to 1000-fold increase from starting cell populations and efficient cryopreservation with exceptional post-thaw recovery. Conclusions: Cryopreserved IMANs offer a cost-effective and globally accessible cell therapy with the potential for long term clinical benefit.
Immunomodulatory alpha neutrophils: The first-in-class neutrophil progenitor-based allogeneic immuno-cell therapy with cytotoxic and immunomodulatory functionality for the treatment of solid tumours.
Authors: McGinley Aoife , Florence Samuel , Woodward Martin James , Patel Durva , Willis Andrew , Blyth Alex , Quintas-Cardama Alfonso , Polyakova Oxana 
Published: June 2024

e14523 Background: Adoptive cell therapy for the treatment of cancer has largely focused on the administration of autologous engineered αβ T cells. Although successful in some haematological malignancies, the solid tumour microenvironment (TME) poses significant challenges to the efficacy of CAR-T cells, including physical barriers, heterogeneous antigen expression or antigen escape and immunosuppressive mediators. Remodeling the immunosuppressive solid TME is pivotal to the success of immunotherapies. Recent studies have highlighted key roles for neutrophils in tumour control and in facilitating successful responses to cancer immunotherapy, with neutrophil functional heterogeneity within the TME becoming increasingly appreciated. Methods: At LIfT Biosciences we have developed the first-in-class, stem cell-derived immuno-cell therapy with anti-cancer neutrophil properties called Immunomodulatory Alpha Neutrophils (IMANs). IMANs are derived from CD34+ stem cells expanded and differentiated in proprietary media compositions in a simple and scalable GMP-compliant manufacturing process. IMANs are designed to recapitulate those neutrophil states that are both cytotoxic and capable of immunomodulating the solid TME for long-lasting tumour control. Off-the-shelf, allogeneic, innate IMANs have the potential to provide major clinical benefits in the treatment of multiple solid tumours. Results: IMANs multimodal mechanisms of action (MoA) have been demonstrated in different state-of-the-art solid tumour models, including co-culture with patient-derived xenograft organoids (PDX-O) and with 3D ex vivo patient tissues (tumour-on-a-chip). Direct antigen-independent cytotoxicity towards PDX-O from a range of solid tumour indications has been demonstrated. Additionally, and fundamental to IMANs MoA is their ability to migrate to the solid TME and recruit and activate recipients’ anti-tumour immune responses. We have demonstrated IMANs ability to rapidly migrate into the solid TME and promote recruitment of patients’ immune cells leading to enhanced tumour cell death using tumour-on-a-chip technology accompanied by daily live cell imaging. Mechanistically, co-culture with IMANs enhanced expression of co-stimulatory receptors on T and NK cells, such as OX40 and 4-1BB, as well as promoting secretion of TME-modulating factors, such as CXCL10. Furthermore, co-culture with IMANs enhanced secretion of IFN-γ by activated tumour-infiltrating lymphocytes. Conclusions: These cytotoxic and immunomodulatory functions enable IMANs to remodel the TME, leaving the solid tumour more susceptible to host immune responses.
Influence of gender on acute kidney injury among patients undergoing chimeric antigen receptor T-cell (CAR-T cell) therapy: Insights from National Inpatient Sample.
Authors: Zakhour Joud , Akkawi Abdul Rahman , Alqam Anas , Karam Wissam , Shah Raj N , Mattar Bassam Ibrahim 
Published: June 2024

e14524 Background: Chimeric antigen receptor T-cell (CAR-T Cell) immunotherapy has shown promising results in patients with B-cell leukemia and lymphoma and multiple myeloma. The side effect profile is still being studied and acute kidney injury (AKI) following treatment has been a commonly reported outcome in the context of cytokine release syndrome. In most cases, the kidney injury is reversible with adequate hydration and treatment of the underlying cytokine release syndrome when needed. This study aimed to investigate the outcomes of gender in patients undergoing CAR-T cell therapy along with the protective variables and independent predictors of AKI in this patient population. Methods: This was a retrospective analysis of data the National Inpatient Sample (NIS) between January 2019 and December 2020 to identify patients who underwent CAR-T cell therapy. We stratified the data based on gender and studied the incidence of AKI in patient admitted to the hospital primarily for CAR-T cell treatment. The primary endpoint was in-hospital mortality, AKI, average age, length of stay (LOS), and total charge by hospital. Additionally, we explored independent predictors and protective variables for AKI in patients receiving the treatment. Results: A total of 4010 patients underwent CAR-T Cell therapy from January 2019 to December 2020. Among these patients, females comprised 41.1% (n=1650). The mean age at the time of CAR-T cell treatment for males was 57.5 and for females 56.9. The inpatient mortality rates for both groups were 3% (p=0.97). The total incidence of AKI in patients undergoing CAR-T cell therapy was 14.9%, with rates of 19% in males and 9% in females (p<0.01). LOS for males and females was 19 days, and 20 days respectively (p=0.4). Average total hospital charge for males was 958,345 and 1,017,685 for females (p=0.3642). Interestingly, there was no difference between genders in relation to the incidence of cytokine release syndrome (p=0.3). Notably, CKD, obesity, liver disease, and electrolyte imbalances were independent predictors of AKI with an adjusted odds ratio of 4.26 (p<0.01; 95% confidence interval [CI]: 1.7-10.6), 2.7 (p=0.015; 95% CI: 1.2-6.06), 2.7 (p=0.045; 95% CI: 1.02-7.23), 2.5 (p<0.01; 95% CI: 1.67-3.81). Importantly, gender was a protective variable for females when it came to AKI after CAR-T cell therapy with an adjusted odds ratio of 0.38 (p<0.01; 95% CI: 0.23-0.63). Conclusions: AKI has been documented as a common side effect in patients undergoing CAR-T cell therapy. In most cases the kidney injury is reversible with adequate hydration and CRS treatment when necessary. Our study highlights CKD, obesity, liver disease, and electrolyte imbalance as independent predictors of AKI after CAR-T cell therapy and female gender as a predictive variable against developing AKI.