tbuckley/cabot-search huggingface dataset:
Predictors of endocrine immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICI) in routine clinical practice.
Authors: Alexander Kozhevnikov, Ashot Mkrtumyan, Polina Serrgeevna Feoktistova, Daria Filonenko, Natalya Polshina, Ekaterina Volkova, Katerina Grechukhina, Irina Bykonya, Lyudmila Zhukova
Journal: Journal of Clinical Oncology (2024)

e14713 Background: Endocrine irAEs have been reported in association with various ICI and are characterized by their correlation with improved survival outcomes. A growing clinical comprehension of endocrine irAEs has facilitated the development of effective treatment strategies involving hormone replacement, which has been shown to enhance patients' quality of life. This study aims to evaluate outcomes in patients (pts) experiencing endocrine irAEs and identify predictive factors for their occurrence. Methods: This retrospective cohort study comprised 214 adult pts with solid malignant tumors who underwent ICI, either as monotherapy or in combination with other chemotherapeutic agents, at the SBIH Moscow Clinical Scientific and Practical Center named after A.S. Loginov of DHM. Results: Between June 2016 and January 2023, 214 pts were included in the study (46.3% female, 53.7% male). The median age was 62.6 years (range 32–91). At the data cut-off (1 February 2024) the median overall survival (OS) for the analyzed population was 34,5 months (95%CI 21,15-43,91). No significant difference in median OS was observed between pts with overall endocrine irAEs and those exhibiting specific manifestations, such as hypocortisolism and destructive diabetes mellitus. However, thyroid irAEs were associated with improved median OS: 27.5 months compared to 22.6 months in those without (p=0.037); RR=1.39 (95%CI 1.025-1.89; p=0.036). The grade of endocrine irAEs did not impact the survival benefit. A significant association was observed between age group and endocrine irAEs (Pearson’s χ2=9.92, p=0.019), with a left-skewed age distribution due to a higher proportion of participants aged 32–44 years among those developing endocrine irAEs. Pts with nodular goiter had a 2.91 times higher risk of developing thyroiditis (95%CI 1.03–8.25), although this did not reach statistical significance (p=0.067). Calcium channel blockers were associated with an increased risk of developing thyroid irAEs (RR=1.54, 95%CI 1.09–2.19; p=0.036). Antihistamine use was a robust predictor of hypothyroidism with a RR=1.68 (95%CI 1.05–2.7, p=0.04). Initial derived neutrophil-to-lymphocyte ratio (dNLR) ≥3 predict the development of endocrine irAEs (Pearson χ2=4.02; p=0.045) as well as dNLR&gt;2.2 (Pearson χ2=4.22, p=0.04). Conclusions: Thyroid irAEs are correlated with improved OS. Predictors of endocrine irAEs may include young age (32-44 years), calcium channel blocker or antihistamine use, dNLR ≥3, or dNLR &gt;2.2. Prospective trials are warranted to validate these findings.
Sex inequalities in cardiovascular risk prediction
Authors: Joshua Elliott, Barbara Bodinier, Matthew Whitaker, Rin Wada, Graham Cooke, Helen Ward, Ioanna Tzoulaki, Paul Elliott, Marc Chadeau-Hyam
Journal: Cardiovascular Research (2024)

Evaluate sex differences in cardiovascular disease (CVD) risk prediction, including use of (i) optimal sex-specific risk predictors and (ii) sex-specific risk thresholds.
Phase III Randomized, Placebo-Controlled Trial of Endocrine Therapy ± 1 Year of Everolimus in Patients With High-Risk, Hormone Receptor–Positive, Early-Stage Breast Cancer
Authors: Mariana Chavez-MacGregor, Jieling Miao, Lajos Pusztai, Matthew P. Goetz, Priya Rastogi, Patricia A. Ganz, Eleftherios P. Mamounas, Soonmyung Paik, Hanna Bandos, Wajeeha Razaq, Anne O'Dea, Virginia Kaklamani, Andrea L.M. Silber, Lisa E. Flaum, Eleni Andreopoulou, Albert G. Wendt, Jennifer F. Carney, Priyanka Sharma, Julie R. Gralow, Danika L. Lew, William E. Barlow, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2024)

Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor-positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy.
Letter to the editor “Pharmacologic prevention and therapy of postoperative paralytic ileus after gastrointestinal cancer surgery – systematic review and meta-analysis”
Authors: Xinya Zhao, Biao Zhang, Xufeng Tao, Deshi Dong
Journal: International Journal of Surgery (2024)

aDepartment of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China bCollege of Pharmacy, Dalian Medical University, Dalian, 116044, China cPancreas & Biliary Center, Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning, China Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding Author Address: Pancreas & Biliary Center, Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning, China. E-Mail: [email protected] (B. Zhang). *Corresponding Author Address: Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning, China. E-Mail: [email protected] (X. Tao). *Corresponding Author Address: Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning, China. E-Mail: [email protected] (D. Dong). This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/
Phase 1 study of ZV0203, a first in class pertuzumab ADC, in patients with HER2 positive advanced solid tumors.
Authors: Zhenwei Miao, Fengjuan Lin, Xi Rao, Yong Huang, Feng Wang, Yao LU, Xiuying Huang, Yunsheng Huang
Journal: Journal of Clinical Oncology (2024)

e15004 Background: ZV0203, a first in class (FIC) pertuzumab antibody-drug conjugate (ADC), targets HER2 positive tumor cells with tubulin inhibitor DUO5 as its payload via a stable and protease-cleavable valine-citrulline linker. In preclinical studies, ZV0203 demonstrated superior antitumor activity compared to Kadcyla in multiple tumor cell line xenograft models with no noticeable toxicity. GLP toxicity studies indicated that ZV0203 was well tolerated with an estimated therapeutic index of 35. Methods: This was an open-label, multicenter, phase 1, dose-escalation study in patients (pts) with HER2+ advanced solid tumors. Primary objectives were safety, tolerability and RP2D. Secondary objectives included PK, immunogenicity and preliminary clinical efficacy. ZV0203 was administered intravenously Q3W on a 21-day cycle. An accelerated titration design was used for the 0.3 and 0.6 mg/kg doses, followed by a 3+3 design for 1.2, 1.8, 2.7 and 3.6 mg/kg dose levels. Results: As of January 18, 2024, 15 pts with solid tumors (breast [11], colorectal [2], gastric [1], lung [1]) were enrolled across doses of 0.3-3.6 mg/kg with a median age of 52 years old (range 35-65), of which 9 pts received prior HER2-targeted therapy (trastuzumab ± pertuzumab) and 14 pts completed 21-day DLT assessment (0.3 mg/kg and 0.6 mg/kg [1 each], 1.2 mg/kg, 1.8 mg/kg, 2.7 mg/kg and 3.6mg/kg [3 each]) with no DLT incidence. Treatment-related adverse events (TRAE) occurred in 14 (93.3%) pts. The most frequent TRAEs were corneal epitheliopathy [9], elevated liver enzymes [6], dry eyes [6], neutropenia [4], anemia [4], leukopenia [3], and proteinuria [3], and most were grade 1-2 in severity. 5 pts experienced grade 3 TRAEs: lymphocytopenia (1.8mg/kg [1]) , corneal epitheliopathy (3.6 mg/kg [1]) and blurred vision (2.7 mg/kg [2], 3.6 mg/kg [1]), which were manageable during treatment. No unexpected safety signals were reported. TRAEs led to 13.3% (2/15) treatment discontinuation. Among 14 pts evaluated, 5 pts achieved a best tumor response of PR; 4 pts had SD; 1 pt had Non-CR/Non-PD per RECIST v1.1. Thus, disease control rate was 71.4% (10/14). PK results demonstrated that the PK profile of total antibody was similar to that of ZV0203 ADC, whose systematic exposure increased in a dose-dependent manner and remained stable after repeated administration. Concentration of DUO5 remained scarce, suggesting good stability of ZV0203. Conclusions: ZV0203 was well tolerated and showed clinically encouraging anti-tumor activity in heavily pretreated pts with HER2 positive cancer. Clinical trial information: NCT05423977 .
Development of novel MUC1-C targeting antibody-drug conjugate for pancreatic cancer treatment.
Authors: Rehan Ahmad, Govind Panchamoorthy, Deepak Raina, Brian Lawney, Surender Kharbanda, Ravi Jasuja
Journal: Journal of Clinical Oncology (2024)

e15025 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of cancers, which is usually diagnosed in advanced stages and presents an abysmal 5-year survival rate of 3-10%. With late detection of metastasized/advanced disease, curative surgery is not an option for most patients. Accordingly, there is an urgent unmet need for development of therapeutics targeting the pancreatic cancer cells. MUC1 is one such cell surface antigen that is aberrantly overexpressed in most solid tumors including pancreatic cancer. In this study we report preclinical efficacy of pharmacological inhibition of MUC1 signaling by GO-203 and targeted delivery of toxin conjugated to novel MUC1-C antibodies (7B8 and 3D1) binding to the extra cellular domain (ECD) to the PDAC xenografts. Methods: Subjects from TCGA-PAAD were stratified into high (75 th percentile) and low (25 th percentile) MUC1-expressing cohorts. Differential expression was performed using DESeq2, followed by GSEA, and signaling network analysis using partial correlation networks, ARACNE, and BC3NET. Anti-MUC1 antibody-drug conjugates (ADCs) were generated by coupling monomethyl auristatin E (3D1-MMAE, 7B8-MMAE) via V-C-PAB linker and characterized for anti-tumor activity against pancreatic cancer cells including MIA PaCa-1, CAPAN2 and HAPF-II. Paired-end RNA-seq (50bp) was aligned and quantified to the Human Ensembl GRC38 reference using STAR aligner. Subcutaneous xenografts were obtained in nude mice by injecting 5X10 6 HPAF-II tumor cells. Results: Differential expression, pathway, and network analyses revealed consistent dysregulation of cancer survival-related processes, and P53-related pathways in the cohort with increased MUC1 expression. The ADCs (DAR of ~3.5) exhibited efficient internalization in cancer cells and associated apoptotic cell death (Kds = 2 - 5nM). Pharmacological inhibition of MUC1 signaling by GO-203 demonstrated reduction in canonical pathways including P53 and EMT. Treatment with 3D1-MMAE compared to both vehicle and GO-203 showed dysregulation of cellular metabolism pathways (cholesterol homeostasis, glycolysis) and exhibited several strong indicators of cellular stress including activation of unfolded protein response processes and mTorc1 signaling. Excellent tumor-suppressive effects of ADCs were observed in HPAF-II xenografts in nude mice. The 7.5 mg/kg (i.v., q7dx3), treatment showed complete tumor regression from 14th day (end of treatment) till the date of termination (Day 50). Doses up to 40 mg/kg were well tolerated by the mice and this anti-tumor efficacy was observed without any appreciable loss in body weight or adverse effects on tissues. Conclusions: Targeted delivery of MMAE toxin to the pancreatic cancer cells presents an exciting opportunity for a novel therapeutic intervention for the treatment of pancreatic cancer patients with MUC1 over expression in tumors.
Effect of circulating tumor cells in clinically stable patients on the conundrum of recurrence with cellular residual disease.
Authors: Jayant Khandare, Aarthi Ramesh, Gourishankar Aland, Prathamesh Patil, Tanvi Deshpande, Ganesh Khutale, Sreeja Jayant, Ashish Joshi, Kshitij Chandrakant Joshi, Bhuvan Chugh, Vaibhav Choudhary, Nirmal Vivek Raut, Sachin Almel, Vashishth Maniar, Vinay Deshmane, Atul Bharde, Gowhar Shafi, Aravindan Vasudevan
Journal: Journal of Clinical Oncology (2024)

e15040 Background: Despite no evidence of disease by radiological imaging, up to 30% breast cancer cases are known to relapse after treatment with a curative intent. The presence of CTCs in stage I-II cancer patients signals the activation of extravasation and invasion process leading to micro-metastasis and may lead to poor outcome. CTCs in blood circulation at any stage of cancer indicate detectable Minimal Cellular Disease (MCD). Thus the longitudinal investigation of patients with such biomarker remains highly implicative to predict the recurrence, therapy escalations, and dose modifications. The expression of Program Death - Ligand 1 (PD-L1) on CTCs is a dynamic biomarker and they may escape the elimination by immune system, indicative of progression of metastatic signature. Methods: Retrospectively, ina cohort of 20 cancer patients (e.g. lung, colon-rectal, breast, stomach, etc.) who recently underwent treatment were investigated for the presence of CTCs using CDSCO approved OncoDiscover platform having multi-components conjugated with anti EpCam antibody on magnetic nanoparticles. All patients represented clinically stable disease from previous radiological findings. CTCs enumeration assay was performed using CD45, EpCAM+, and CK18 and over-expression of PD-L1 in1.5 ml of peripheral blood using automated motorized Zeiss fluorescence microscopy. Results: In spite of 'no radiological' findings with clinically stable disease, out of 20 selected patients, 75% (n=15) showed at least 1 CTC. While, 55% (n=11) patients were detected with 1 CTC, 5% patients (n=1) with 2 CTCs, and 15% patients (n=3) were identified with 3 CTCs. In addition, 50% (n=10) of patients demonstrated with PD-L1 expression on CTCs; 1 patient exhibited a CTC cluster. Conclusions: Patients showed CRD in spite of a stable disease, which is an indication of progression of localized disease transforming from primary to secondary. The longitudinal monitoring of patients for CTCs with PD-L1 expression may reveal ‘real time’ residual disease, progression, regression, and actual response to the treatment. CRD monitoring can improve the curative intent by improving PFS and OS in solid cancers.
Comparison of efficacy of antibody drug conjugate (ADCs) between younger and older patients: A meta-analysis of phase 3 studies.
Authors: Thierry Landre, Capucine Baldini, Michael Bringuier, Maxime Frelaut, Laurent H. Zelek, Cherifa Taleb
Journal: Journal of Clinical Oncology (2024)

e15002 Background: Antibody-Drug-Conjugates (ADCs) are one of the new cornerstone of cancer treatments. New approvals are coming every year in various tumor types and settings. However, older adults remain underrepresented in clinical trials and consequently, few data is available for this population. Therefore, we performed a meta-analysis to compare the efficacy of ADCs between younger and older patients. Methods: PubMed and the ASCO or ESMO databases were searched up to December 2023. We included randomized controlled trials (RCTs) of ADCs (datopotamab deruxtecan, Enfortumab vedotin, mirvetuximab soravtansine, sacituzumab govitecan and trastuzumab deruxtecan) reporting subgroup comparison of overall survival (OS) and/or progression-free survival (PFS) based on age cutoffs. The summary hazard ratio (HR) and 95% confidence interval (CI) were calculated. Results: A total of 4654 patients from nine RCTs (ASCENT; DESTINY-Breast02, -Breast04, -Gastric01; EV-301, EV-302/KEYNOTE-A39; MIRASOL; TROPiCS-02 and TROPION-Lung01) were included. When patients are dichotomized into younger (N=2796) and older (N=1858) groups with an age cut-off of 65 years, ADCs improved OS in both younger (HR, 0.64; 95% CI, 0.52-0.80) and older (HR, 0.56; 95% CI, 0.44-0.71) groups. An improvement in PFS was observed in younger (HR, 0.55; 95% CI, 0.46-0.66) and older (HR, 0.52; 95% CI, 0.41-0.67) patients. Subgroup analyses according to ADCs and tumor type showed a consistent survival benefit in both younger and older groups. Conclusions: A benefit in OS with ADCs was significant in both younger and older patients with a cut-off age of 65 years. Prospective real life cohort study would be of interest to confirm those results with a description of geriatric parameters to better define the population.
Hemay181: A novel SDC (sugar linked drug conjugate) for solid tumors targeting tumor microenvironment.
Authors: Richard Jones, Jingjing Lv, Wei Fu, Guanghuai Zeng, Hesheng Zhang
Journal: Journal of Clinical Oncology (2024)

e15006 Background: Hemay181 is a novel broad-spectrum conjugated cytotoxic drug for treating advanced solid tumours. The drug exerts its inhibitory effect on tumour growth by releasing cytotoxic drug SN-38 in tumour tissues via β-glucuronidase (βGU) metabolism to inhibit the activity of topoisomerase I (TOP1). The water solubility of Hemay181 is increased &gt; 5000-fold compared to SN-38. Hemay181 also binds to plasma albumin to form a macromolecular drug transporter, significantly improving the drug's pharmacokinetics. In addition, βGU has low activity in normal tissues, localised to the lysosomes, but is highly expressed in the hypoxic tumour microenvironment. Methods: In vitro and In Vivo studies showed Hemay181 inhibited growth in 29 human tumour cell lines and 16 human tumor Xenograft models, including colorectal cancer, gastric cancer, triple-negative breast cancer, head and neck cancer, pancreatic cancer, lung cancer, prostate cancer and melanoma. Results: In the absence of βGU, Hemay181 showed significantly weaker inhibitory activity than Hemay181+βGU or no significant inhibitory activity. In these In vitro studies with the addition of βGU, the activity was similar to SN-38, ranging from 3.9 nM to 159 nM. Hemay181 showed tumor selectivity with low activity against two normal human cell lines. The IC 50 values of Hemay181 against Chang liver (normal liver cells) and MRC 5 (embryonic lung cells) were 318 nM and 14566 nM under non-enzymatic digestion conditions. In vivo, Hemay181 had significant inhibitory effects on the growth of human colorectal cancer, pancreatic cancer, head and neck cancer, triple-negative breast cancer, lung cancer, liver cancer, ovarian cancer and gastric cancer tumour models. The lowest effective dose of Hemay181 was 1.875mg/kg in the human colon cancer HCT116 model. Within the dose range of 3.75~60 mg/kg, the highest inhibitory rate of the above different tumour models could reach more than 90%. Hemay181 significantly reduced tumour volume compared to irinotecan, which only slowed the tumour growth rates. There was no significant decrease in the body weight of Hemay181 in these studies. In the colon cancer PDX model (CR0029) (30mg/kg), the tumour inhibition rate (TGI) was 78%. At 60mg/kg, in triple-negative breast cancer (BR1458) and non-small cell lung cancer (LU3075) PDX models, a TGI was 97% and 98%, respectively. At 60mg/kg, there was a significant tumour suppressive effect on larger tumours treated with irinotecan, with a reduction of tumour volume. In vitro , 1 μM Hemay181 is stable in CD1 mouse and SD rat plasma, with a minor degree of metabolism in beagle dog, cynomolgus monkey and human plasma. Conclusions: In summary, the novel broad-spectrum anti-tumour drug Hemay181 has the characteristics of high water solubility, tumour-targeting ability, low toxicity and side effects on normal tissues. It is under evaluation in ongoing clinical studies.
Antitumor activity of <i>nab</i>-sirolimus versus mTOR inhibitors temsirolimus, sirolimus, and everolimus in A549 NSCLC xenografts.
Authors: Shihe Hou, Maria Zalath, Andrew Kwon, Edward Spindler
Journal: Journal of Clinical Oncology (2024)

e15096 Background: The mTORC1 pathway, often activated by mutations in genes like TSC1, TSC2, PIK3CA, PTEN, STK11, and KEAP1, plays a pivotal role in cancer progression; in some settings, alterations in STK11 and KEAP1 may be associated with treatment resistance and poor prognosis. Despite the broad importance of the mTORC1 pathway in cancer cell growth and survival, mTOR inhibitors (mTORis) temsirolimus (TEM), sirolimus (SIRO), and everolimus (EVE) have limited clinical application in the cancer setting. nab-Sirolimus, an injectable form of albumin-bound SIRO that leverages unique transport properties of albumin known to increase tumor drug accumulation, is approved for treatment of malignant PEComa. Here, we report the antitumor activity of nab-sirolimus in comparison to other mTORis in A549 NSCLC ( KRAS G12S, STK11 Q37*, and KEAP1 G333C) xenografts, and the correlation of antitumor activity, tumor PK profile, and mTOR pathway suppression. Methods: Athymic mice bearing subcutaneous A549 NSCLC xenografts were treated with either saline or equal weekly doses of nab-sirolimus (administered intravenously [IV]; 5 or 15 mg/kg/week), TEM (IV; 5 mg/kg/week), or SIRO or EVE (both oral; 15 mg/kg/week). Tumors were harvested at different time points after mTORi treatment and analyzed for tumor drug levels (LC-MS/MS) and mTOR pathway biomarkers (pS6 and p4EBP1) via western blot (WB). Results: In A549 xenografts, nab-sirolimus (IV) treatment resulted in significantly greater suppression of tumor growth compared with TEM (IV), SIRO (oral), and EVE (oral) (Table). Average intratumoral drug concentrations 24 hours after IV mTORi treatment were significantly higher with nab-sirolimus (420-539 ng/g) compared with TEM (TEM [parent] 34.9 ng/g; SIRO [active metabolite measured from TEM] 13.2 ng/g) and compared with 7-day steady-state concentrations for oral SIRO (17 ng/g) and EVE (10 ng/g). WB confirmed that nab-sirolimus consistently inhibited mTOR targets pS6 and p4EBP1, whereas TEM, SIRO, and EVE were less effective. Conclusions: nab-Sirolimus resulted in significantly higher intratumoral drug concentration, stronger inhibition of mTOR targets, and greater antitumor activity compared to other IV and oral mTORis in a KRAS/STK11/KEAP1 mutated NSCLC xenograft model. These results support further clinical evaluation of nab-sirolimus as a single agent or in combination with other therapeutic agents in oncology. [Table: see text]
Comparison of laparoscopic and open surgery for colorectal malignancy in obese patients: a propensity score-weighted cohort study
Authors: Yu-Jen Hsu, Yen-Lin Yu, Jing-Rong Jhuang, Jeng-Fu You, Chun-Kai Liao, Wen-Sy Tsai, Yi-Ping Pan, Yih-Jong Chern
Journal: International Journal of Surgery (2024)

Insufficient evidence exists to ascertain the long-term prognosis in patients with obesity undergoing laparoscopic surgery versus open surgery for colorectal cancer.