bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lactate-induced lactylation circularly regulates glucose metabolism enzymes in breast cancer.
Authors: Xu Jia-lin , Shen Hong-yu , Zhu Zhen , Tang Jinhai 
Published: June 2023

e13092 Background: Breast cancer is the most common malignant tumor in the female population worldwide and has become the disease with the highest cancer-related mortality. Among the molecular subtypes of breast cancer, triple-negative breast cancer accounts for only 15% of primary malignancies, but due to its increasing recurrence, metastasis, and mortality, we need to find new therapeutic targets to address this phenomenon. Analysis from the field of metabolism found that the level of glycolysis in triple-negative breast cancer was significantly higher than that in other cancers. Glycolysis is a common malignant phenotype of cancer, namely the famous Warburg effect. LDHA is the last metabolic enzyme in the glycolytic pathway, and its expression is increased in triple-negative breast cancer. Lactate is the final product of glycolysis, which converts pyruvate to lactate and NADH to NAD+ under the catalysis of LDHA. The acidic tumor microenvironment formed by the accumulation of lactate will not only affect the progression of tumors and the therapeutic effect of anticancer drugs, but also inhibit the function of immune cells. Lactic acid groups can bind to histones and non-histone proteins to produce a new post-translational modification, lactylation. Methods: Breast cancer cells were infected with lentivirus vectors overexpressing or knocking down LDHA, and cell proliferation and cytotoxicity assay, transwell assay and Lactic Acid Content Assay were performed. To further explore the presence of lactylation of LDHA, immunoprecipitation experiments were performed and the modification sites were mutated to examine the enzymatic activity and function of LDHA. Results: In triple negative breast cancer with strong glycolytic metabolic phenotype, altering LDHA level can affect the biological function of breast cancer cells. Secondly, RNA-seq sequencing results showed that LDHA can affect the protein and transcription levels of MEST and CSTA. Finally, the lactylation of histones was also significantly changed after LDHA dysregulated. Reduced levels of LDHA were accompanied by reduced levels of MEST, CSTA, and histone lactylation. In addition, LDHA itself also has lactic acid modification, and mutations in the modification sites can change the enzymatic activity and function of LDHA. Conclusions: The regulatory axis of LDHA-lactate-lactylation has important value and function in the occurrence and development of breast cancer. LDHA regulates the function of some genes by lactate-induced lactylation of histones. In addition, the lactylation of LDHA can alter the enzyme activity, which may be a new therapeutic target for breast cancer.
Effect of microRNA-21 blockade in human triple negative breast cancer allografts on progression and immune checkpoint proteins.
Authors: Jin Yuan-Yuan , Desai Vilas Shivaji , Castro Miguel M. , Mitchell Edith P. , Wickstrom Eric 
Published: June 2023

e13097 Background: Triple negative breast cancer (TNBC) is an orphan disease that attacks > 46,000 US women every year. TNBC recurs after standard-of-care surgery, chemotherapy and radiation, killing half its victims within 4 years. Poly(ADP-ribose) polymerase (PARP) inhibitors, topoisomerase inhibitors, immune checkpoint inhibitors, and antibody-drug conjugates extend the survival of a fraction of TNBC patients for a few months. Thus, TNBC shows a critical need for molecularly-targeted therapy. Most TNBC cells show high microRNA 21 (miR-21), identical in humans and mice, which decreases tumor suppressor proteins that keep cell growth in check. Hypothesis: Short anti-miR-21 RNA analogs conjugated to a receptor ligand will direct TNBC cell uptake and slow the growth of TNBC orthotopic allografts with immune activation and minimal toxicity. Methods: We designed an anti-miR-21 RNA analog using aminomethyl bridged nucleic acid (BNA), exhibiting low toxicity, and serum stability. We lipofected a concentration ramp of the anti-miR-21 RNA analog into human TNBC cell lines (MDA-MB-231, MDA-MB-157, MDA-MB-436, MDA-MB-468, BT-20, BT-549, HCC1806, HCC1937, HCC1806) representing a spectrum of TNBC subtypes, then measured proliferation and biochemical markers. We also conjugated a peptide analog for endocytosis by the insulin-like growth factor 1 receptor (IGF1R), overexpressed in most TNBC lesions. The peptide ligand for IGF1R provides a unique strategy for delivering the anti-miR-21 RNA analog preferentially into TNBC cells. We administered 5 mg/kg of the anti-miR-21 RNA-peptide analog in sterile saline intraperitoneally twice a week for 14 days into immunocompetent female Balb/c mice bearing syngeneic EMT6 TNBC tumors in their mammary fat pads. Results: The anti-miR-21 RNA analog slowed proliferation, increased apoptosis, elevated tumor suppressor proteins, and suppressed immune checkpoint gene expression in multiple human TNBC lines. IC50 for inhibiting cell proliferation correlated with miR-21 copies/cell in 7 TNBC cell lines, but not in the non-tumorigenic breast epithelial cell line MCF-10A. The anti-miR-21 RNA-peptide analog stopped orthotopic TNBC allograft growth in syngeneic immunocompetent female Balb/c mice during 14 days of therapy, with apparent safety. Conclusions: This strategy optimizes cancer cell-specific delivery to block proliferation and immune checkpoints. The results support further preclinical proof-of-concept studies to enable an eIND submission for the anti-miR-21 RNA-peptide analog.
Circulating methylated-HOXA9 tumor DNA as a biomarker for mortality in recurrent breast cancer.
Authors: Hansen Torben , Bakkensen Bruun Stine Bakkensen , Andersen Rikke Fredslund , Madsen Jonna Skov , Tabor Tomasz Piotr , Bechmann Troels , Kjær Ina Mathilde 
Published: June 2023

e13106 Background: The Homeobox A9 (HOXA9) gene may act as a tumor suppressor in carcinomas and induce breast cancer progression. The clinical potential of methylated HOXA9 (meth-HOXA9) as a biomarker is unclear. Therefore, this study aims to examine the association between meth-HOXA9 in tumor tissue, meth-HOXA9 in plasma, and mortality. Additionally, the study examines the association between meth-HOXA9 in metastatic tissue and plasma at the time of recurrence. Methods: The study enrolled 51 patients with recurrent breast cancer between 2011 and 2015 recruited at the Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark. Tissue samples were obtained from the primary tumor at the time of primary surgery between 1993 and 2013. Tissue samples from the metastases and plasma samples were obtained at the time of recurrence. The study follow-up period ran until death or January 2019. All samples were analyzed for meth-HOXA9 using droplet digital PCR. The optimal cut-off for meth-HOXA9 in tissue was established at ≥7.4% using tissue specimens from independent breast cancer patients and healthy controls. In plasma samples, the detection of ≥5 meth-HOXA9-containing droplets resulted in a positive test. Using Cox regression, we estimated crude and age-adjusted hazard ratios (HR) for mortality with 95% confidence intervals (CI) comparing patients with detectable and undetectable meth-HOXA9 in both tumor tissue and plasma. Fischer’s exact test was used to compare plasma and metastasis meth-HOXA9 status. Results: Among the 50 patients with data on tumor tissue meth-HOXA9, 80% had detectable meth-HOXA9 in the primary tumor, but there was no increased mortality when comparing patients with detectable and undetectable meth-HOXA9 (HR 1.09; CI 0.47-2.52). Only 34 patients had data on plasma meth-HOXA9 and 62% of these had detectable meth-HOXA9 at the time of recurrence. Patients with detectable meth-HOXA9 in plasma had higher mortality than those without (HR 3.95; CI 1.50-10.37). Among the 20 patients with data on plasma and metastatic tissue meth-HOXA9, there was no significant association between meth-HOXA9 in plasma and metastatic tissue (p = 1.00). Conclusions: These results indicate that detectable plasma meth-HOXA9 at the time of breast cancer recurrence is associated with increased mortality. However, there is no association between tumor tissue meth-HOXA9 and mortality. Metastatic tissue and plasma meth-HOXA9 are not associated. Our data support the potential relevance of plasma meth-HOXA9 as a biomarker for prognosis and mortality in recurrent breast cancer, which calls for further investigation.
Efficacy of antibody-drug conjugates in breast cancer: A systematic review and meta-analysis of randomized clinical trials.
Authors: Ali Muhammad Ashar , Aiman Wajeeha , Afzal Fatima , Zahoor Hafsa , Kazmi Syeda Hafsa , Anwar Aqsa , Bajwa Ayfa Riaz , Maroules Michael , Guron Gunwant K. , Shaaban Hamid Salim 
Published: June 2023

e13113 Background: Breast cancer (BC) is the 2nd most common cause of cancer related deaths in women. Antibody-drug conjugates are monoclonal antibodies conjugated to the cytotoxic payload and are directed towards cell surface proteins specific to tumor cells. This systematic review and meta-analysis aims to assess the efficacy of ADCs in breast cancer and comparison of different ADCs. Methods: A literature search was performed on PubMed, Embase, WOS, and clinicaltrials.gov with key words “breast neoplasms,” and “immunoconjugates” from the inception of data till 6/6/2022. Cochrane and PRISMA guidelines were followed to establish guidelines registered on Prospero (CRD42022329529). Out of 4,570 articles, seven randomized clinical trials (RCTs, N=5,302) were included. R programming language software with “meta” package was used for this meta-analysis. Results: In 7 RCTs (N=5,302), 4,834 patients had HER-2 positive disease while 468 patients were triple negative BC (TNBC). 1,486 patients had residual invasive disease while 3,816 patients had metastatic breast cancer (mBC). 3,389 patients were treated with ADC (235 with sacituzumab govitecan (saci-gov), 2,339 with trastuzumab emtansine (T-DM1) and 261 trastuzumab deruxtecan (T-der)), 2,105 patients were treated with chemotherapy regimens. In 4 RCTs on HER-2 patients (N=2,825), pooled HR of PFS and OS were 0.72 (95% CI=0.61-0.84, I2=71%) and 0.73 (95% CI=0.64-0.84, I2=20%), respectively, in favor of ADC. Risk of ORR was 1.48 (95% CI=0.84-2.60, I2=91%) in favor of ADC. In RCT on TNBC (N=468), HR of PFS and OS were 0.55 (95% CI=0.51-0.61) and 0.59 (95% CI=0.54-0.66), respectively, in favor of saci-gov (ADC). In RCT on HER-2 positive residual invasive breast cancer, HR of recurrence/death was 0.61 (95% CI=0.54-0.69) in favor of T-DM1. In an RCT by Cortes et al. (N=524) comparing two ADCs in HER-2 mBC, the HR of PFS and OS were 0.28 (95% CI= 0.22-0.37) and 0.55 (95% CI=0.36-0.86), respectively, in favor of T-der as compared to T-DM1. The RR of ORR and CR were 2.33 and 1.28, respectively, in favor of T-der. Conclusions: ADCs are significantly more effective than chemotherapy in patients with HER-2 positive mBC, HER-2 positive residually invasive BC, and metastatic TNBC in terms of improving survival and response rates. Among ADCs, T-der was significantly more effective than T-DM1 in patients with HER-2 positive mBC. More double blinded multicenter RCTs are needed to confirm these results.
Treatment (Tx) patterns, efficacy and safety of eribulin for advanced and heavily pretreated breast cancer (ABC): A single-center, real-world study.
Authors: Yang Jin , Yang Jiao , Wang Guangxi , Zhang Haochen , Zhao Shidi , Zhao Xiaoai , Dong Danfeng , Wang Le 
Published: June 2023

e13118 Background: We evaluated the Tx patterns, efficacy and safety of eribulin for heavily pretreated ABC in real-world practice. Methods: Patients (pts) with ABC who had progression on anthracycline/taxane Tx and received eribulin (1.4 mg/m2 IV on Days 1 and 8 of a 21-day cycle) between April 2020 and August 2022 were enrolled. Response was evaluated using RECIST v1.1. Results: 73 pts were enrolled. Median (range) age was 54 (30–79) years; 78.1% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1, and pts had a median of 3 prior lines of chemotherapy. 69.9% of pts had Ki67 >30% and 52.1% had HR+/HER2− disease. 90.4% of pts had visceral metastasis. Eribulin was monotherapy in 28.8% of pts, and combined with bevacizumab, capecitabine, bevacizumab + capecitabine, and anti-HER2 agents in 28.8%, 10.9%, 4.1%, and 27.4%, respectively. The objective response rate was 24.7%; disease control rate was 75.3%. Median progression-free survival (PFS) overall was 6.0 (95% CI, [3.8–8.2]) months (mo). Univariate analysis indicated pts with HER2+ disease had longer PFS than pts with HR+/HER2− or triple-negative BC (median, 8.0, 6.0, and 3.0 mo, respectively; P = 0.049). Pts with Ki67 expression ≤30% had longer PFS than pts with Ki67 >30% (median, 8.0 vs. 4.0 mo; P = 0.024). Pts with late relapse (disease-free survival [DFS] >24 mo) had longer PFS than pts with early recurrence (DFS 6–24 mo) or de novo disease (DFS <6 mo; median PFS, 9.0, 4.5, and 3.6 mo, respectively; P = 0.026). Among 38 pts with HR+/HER2− ABC, pts who received eribulin plus capecitabine had longer PFS than pts who received eribulin monotherapy (median 11.4 vs. 4.0 mo, P = 0.021). Among the 18 pts with a partial response, median PFS was 9.5 mo. Multivariate analysis indicated line of Tx predicted PFS; pts who received eribulin as line 1–3 had longer PFS than pts who received eribulin as line >3 (HR=0.42 [95% CI, 0.19–0.93]; P = 0.034). The most common adverse events were leukopenia (43.2%), anemia (37.9%), and neutropenia (37.8%). Neurotoxicity was rare (2.7%). Conclusions: In this single-center study of pts with heavily pre-treated ABC in China, eribulin Tx resulted in favorable PFS irrespective of molecular subtype, with a manageable safety profile. In pts with a large tumor burden and a good PS, eribulin-based combinations may further improve outcomes. [Table: see text]
In-hospital outcomes of patients with breast cancer and venous thromboembolism.
Authors: Sanghvi Ankushi , Nanavaty Dhairya , Bansal Kannu , Narayan Gayatri , Shah Shailja 
Published: June 2023

e13133 Background: Breast cancer is the most common cause of cancer in women in the USA after skin cancer. About 264000 cases of breast cancer are diagnosed in women each year in the USA. 42000 women die from this cancer each year. Less is known regarding the association of venous thromboembolism (VTE) in breast cancer. We aim to study the prevalence of VTE in breast cancer and its effect on healthcare utilization using a national database. Methods: We used the National Inpatient Sample (NIS) to collect data for all adult patients >18 years with a diagnosis of breast cancer from 2017-2019 using appropriate ICD 10 codes. These patients were further classified into patients with and without DVT/PE. Multivariate regression analysis was performed to study the effect of DVT/PE in patients with breast cancer taking mortality as primary outcome and total cost and length of hospital stay as secondary outcomes. Results: There were a total of 855494 admissions with a diagnosis of breast cancer. The mean age was 63.87 years and 98.8% of them were females. Acute DVT was found in 1.87% of patients and acute PE was found in 3.01% of patients with breast cancer. A total of 7.36% of breast cancer patients who had acute DVT and 8.04% with acute PE died during the hospital stay. The odds of all-cause mortality for DVT (OR 1.58; 95% CI 1.38-1.82, p<0.001) and PE (OR 1.71, 95% CI 1.52-1.94, p<0.001) were significantly higher in patients with breast cancer than those without. The total cost of hospital stay was 26099 USD ($21814-$30383, p<0.001) higher and LOS was 2.51 days higher (2.22-2.81; P<0.001) when patients developed acute DVT however there was no significant difference in these parameters with PE hospitalizations. Conclusions: Our study concludes that patients with breast cancer who develop acute DVT or PE tend to have worse outcomes in terms of mortality. Length of hospital stay and total hospital charge are also increased in patients developing DVT. Current guidelines (2020) recommend against offering thromboprophylaxis to patients with any cancer. Given the worse outcomes, this study reflects the need to formulate risk assessment models for role of primary thromboprophylaxis in breast cancer.
Virtual nutrition services in oncology.
Authors: Lammersfeld Carolyn , Sonntag Kara , Dahlk Sadie , Schober Nathan , Morgiewicz Kayla , Gupta Digant , Markman Maurie 
Published: June 2023

e13504 Background: In 2016, the National Academy of Sciences, Engineering and Medicine convened a workshop to examine challenges patients experience accessing specialized nutrition care in outpatient cancer treatment settings. Inadequate Registered Dietitian Nutritionist (RDN) staffing and reimbursement were identified as barriers to timely care. Staffing challenges at our three destination community cancer centers led to a backlogged queue of nutrition consults resulting in a ≥ 4-week wait time for an appointment. A quality improvement project to address delays in care for patients at risk for malnutrition, resulted in implementation of a hybrid model utilizing remote RDNs to provide virtual Medical Nutrition Therapy (MNT) to supplement onsite RDNs. Methods: After approved in June 2022, two remote RDNs were hired to provide virtual patient care. Nationwide recruitment allowed for hiring rare talent. A project team was created to assure we followed all regulatory guidelines related to licensing and billing. RDNs were individually licensed in 14 states to cover where ≥ 70% of our patients reside. System-wide criteria and licensure alerts for appointments were established between scheduling and nutrition leaders. The first patients were seen virtually on October 14, 2022, with units of service (uos) logged in 15-minute increments. Results: Appointments were tracked from October 14, 2022, through February 3, 2023. 69.2% of 302 scheduled appointments were successfully delivered virtually via telehealth platform with a mean of 1.7 uos. The main reasons for nonuse of the platform were no shows (52.7%) and the need to convert to a phone call (32.3%). The mean uos was significantly higher in new patients compared to returning patients (2.23 versus 1.53; p<0.001). Conclusions: A hybrid model of onsite and virtual care RDNs has potential to improve access to nutrition care. New patient appointments averaged > 30 minutes, and follow-ups averaged < 30 minutes. This may help inform future scheduling of virtual MNT appointments. This model may allow for recruitment from a wider pool of RDNs. It may also help avoid delays in care for patients at risk for malnutrition and gaps in their cancer treatment. [Table: see text]
Implementation of an early-stage lung cancer survivorship clinic in a comprehensive cancer center.
Authors: Wentworth Stacy , Willis Alana , Hensley Amy E. , Hyson Jill , Sohl Stephanie Jean , D'Agostino Ralph , de Hoyos Alberto , Petty William J. , Blackstock A. William 
Published: June 2023

e13515 Background: Early-stage lung cancer survivors are a growing population. A comprehensive plan to address needs relevant to longer survival (e.g., psychological distress, persistent symptoms, physical function) and clinic capacity is necessary. How to deliver comprehensive survivorship care that meets national standards and results in improved patient outcomes is a challenge. Survivorship clinics staffed by advanced practice providers (APP) are an option to address these needs. Methods: In June 2019, Atrium Health Wake Forest Baptist Comprehensive Cancer Center (AHWFB-CCC) opened a dedicated survivorship clinic. Stakeholders from the lung cancer disease-oriented team developed a standard referral pathway for patients to survivorship. A standard workflow was developed in the electronic medical record (EPIC). Eligible lung cancer survivors were referred to the Lung Cancer Survivorship Clinic for a survivorship orientation visit (SOV) with a lung cancer specific APP. Prior to the SOV, a welcome video, disease-specific questionnaire, and electronic patient reported outcome (ePRO) tools (i.e., PROMIS-29 and Distress Thermometer) were sent to the patients’ electronic chart. At the SOV, the ePRO responses and survivorship care plan were reviewed. Analysis of survivor demographic and clinical characteristics (i.e., age, gender, race, residence according to rural-urban commuting area (RUCA) codes, treatment modality, and method used to complete ePROs) and ePRO responses was performed using several regression methods. Patients were offered a post visit survey. Results: From January 2020 to December 2022, 285 lung cancer patients completed a SOV. Most patients were able to complete the pre-visit questions via the electronic chart. AHWFB-CCC survivors reported improved PROMIS-29 T-Scores compared to the average United States (US) early-stage lung cancer survivor, with meaningfully better scores (≥ 3 pts) in five of the seven health-related domains measured. We found no significant interactions between T-Scores and a survivor’s demographic or clinical characteristic, except for gender (p < .001). Most notably, we found a lack of interaction between PROMIS-29 T-Scores and treatment modality (p=.27). Most patients found the SOV helpful and expressed better understanding of their cancer treatment and side effects after the SOV. Conclusions: Our model of an optimized electronic medical record pathway paired with an APP led survivorship visit is feasible and can address current challenges in providing survivorship care to early-stage lung cancer survivors. Survivors had similar ePRO regardless of treatment modality, indicating their survivorship care could be consolidated. Future evaluation is needed to establish if this care model improves outcomes over subsequent visits, minimizes the effect of health disparities, or enhances care capacity.