tbuckley/cabot-search huggingface dataset:
TDM-1 efficacy in trastuzumab-pertuzumab pre-treated HER2 positive metastatic breast cancer patients: A meta-analysis.
Authors: Claudia Omarini, Federico Piacentini, Isabella Sperduti, Krisida Cerma, Monica Barbolini, Fabio Canino, Cecilia Nasso, Massimo Dominici, Luca Moscetti
Journal: Journal of Clinical Oncology (2021)

e13010 Background: Based on the results reported in Emilia trial population, current guidelines consider TDM-1 the standard second-line therapy for HER2 positive metastatic breast cancer (MBC) patients. Despite that, there are no prospective studies supporting the efficacy of TDM-1 following trastuzumab (T) + pertuzumab (P) and taxane first-line treatment. Currently, only real-world data have investigated this sequence with controversial results Methods: We performed a meta-analysis of the available real world data to determine the efficacy of TDM-1 after first-line TP in HER2 positive MBC patients. We used a random-effect model to find differences in the rate of 1-year progression free survival (PFS) between TP pre-treated population and the phase III Emilia trial (T pre-treated population). Results: Seven studies were eligible, in three of them data were from sub-group population analysis. The meta-analysis showed a combined 1-years PFS risk difference for TDM-1 efficacy after TP in second or more lines of -0.122, with lower and upper limits of -0.253 and 0.010, respectively (p=0.07) , with low heterogeneity among studies (I 2 &lt; 0.0001, p =0.836). Considering the four studies on TDM-1 in second-line setting, 1-years PFS risk was -0.034 (95% CI -0.207 – 0,139; p=0.701) (I 2 &lt; 0.0001, p =0.91). Conclusions: Results from the meta-analysis show that the efficacy of TDM-1 after TP double-block seems to be similar to the previously reported in Emilia trial. In the second line setting, available data are not mature enough to confirm TDM-1 efficacy in TP pre-treated population. Currently, TP pretreated patients should receive TDM-1 as indicated in the guidelines.
Comparing practice patterns and outcomes for early-stage hormone receptor-positive and node-positive breast cancer patients with high-intermediate-risk Oncotype Dx scores in the National Cancer Database.
Authors: Keerthi Tamragouri, Ethan M. Ritz, Ruta D. Rao, Cristina O'Donoghue
Journal: Journal of Clinical Oncology (2021)

e12520 Background: Oncotype Dx (ODX) is a commercial diagnostic test primarily used to predict the likely benefit from chemotherapy in ER+, HER2-, and node negative breast cancer. The prognostic value (recurrence risk) has also been demonstrated to apply to early stage lymph node positive (LN+) disease in a number of retrospective and prospective studies. The ongoing RxPONDER trial aims to clarify the predictive value of RS in LN+ population. In light of the initial results, we analyzed the practice patterns and outcomes for HR+/Her2 -/node positive breast cancer patients receiving ODX testing in the years from 2010-2017 with RS 14-25 in a retrospective observational study of the NCDB. Methods: Women with HR+/Her2 -/node positive breast cancer receiving ODX testing from 2010-2017 were identified in the NCDB using TAILORx and RxPONDER patients’ inclusion criteria: ages 18-75, 6-50mm invasive tumors, N1, M0, ER+/HER2 -. The impact of ODX results in the high-intermediate range (14-25) and other clinico-pathologic variables on the receipt of chemotherapy were compared. Additionally, we examined the impact of chemotherapy on overall survival (OS). Frequencies, Kaplain-Meier analysis, and changepoint analysis using the Contal and O’Quigley method were utilized. Results: There were 109,652 T1-2 and N1 patients of whom 32,506 (29.6%) received ODX testing. 13,461 (41.4%%) women had scores in the high-intermediate (14-25) range. The majority tended to have only 1 LN involved (1LN: 77.2%, 2LNs: 17.5%, 3LNs: 5.3%), had a mean age of 57.8y, were Caucasian (86.4%), and were preferentially tested at academic or comprehensive community cancer programs (79.2%). 6,610 (49.3%) patients were recommended chemotherapy, the median ODX score for all women who were recommended chemotherapy was 20 compared to 17 for those whom chemotherapy was not recommended. 5,068 (76.7%) women had documentation of receiving chemotherapy which correlated with improved OS regardless of age. Conclusions: In the group of women with HR+/Her2 -/node positive breast cancer, clinicians appear to utilize ODX testing in less than one-third of patients, possibly finding RS to be most useful in guiding adjuvant therapy recommendations when only 1LN is involved. Both the recommendation and receipt of chemotherapy correlated linearly with increasing RS, as expected based on the current NCCN guideline recommendations. We identified an OS benefit when chemotherapy was administered, regardless of patient age. Long-term follow-up in the RxPONDER trial will likely continue to clarify the predictive value of RS &lt; 25 in the ER+/HER2-/node positive breast cancer population.
H&amp;E-like histology of unstained fresh and formalin fixed breast tissue with Photo Acoustic Remote Sensing (PARS) microscopy.
Authors: John Robert Mackey, Benjamin Ecclestone, Deepak Dinakaran, Gilbert Bigras, Parsin Haji Reza
Journal: Journal of Clinical Oncology (2021)

e12590 Background: Approximately 30% of breast cancer patients undergoing breast-conserving surgery (BCS) require re-excision(s) to obtain clear margins, causing delays in adjuvant treatment, poor aesthetic results, and increased infection rates, costs, and patient anxiety. Frozen section pathology assessment (FSA) reduces re-excision rates from 27% to 6%, but FSA extends operative times and has a false negative rate of 17%. Photo-Acoustic Remote Sensing (PARS) is a new laser-based light microscope that permits non-contact cellular resolution imaging of unstained tissues. Methods: We used an ultraviolet reflection-mode PARS microscope to study i) formalin-fixed, paraffin embedded (FFPE) breast tissue blocks, ii) unstained thin sections of FFPE invasive ductal carcinoma and ductal carcinoma in situ, iii) formalin fixed bulk surgical specimens of benign and malignant human breast tissue, and iv) benign and malignant fresh rodent mammary tissue without fixation, processing, or staining. Fresh tissues were imaged after a range of warm ischemic times and across a range of cold ischemic times in neutral phosphate buffered saline at 4°C. For each condition, an ultraviolet laser was used to excite DNA and other cellular components in these samples, and signals were captured using a continuous-wave detection laser. The PARS signal was false-colored to closely replicate traditional hematoxylin and eosin staining. Results: In all fixed tissues, PARS virtual histology images were of diagnostic quality, permitted margin assessment, and analogous to transmission light microscopy of standard hematoxylin and eosin-stained FFPE slides, achieved without tissue sectioning or tissue staining. Furthermore, PARS microscopy also provided cellular level virtual histology images in fresh breast tissue with warm and cold ischemic times ranging from twenty minutes to two hours; these images have no available clinical comparators as non-contact cellular level imaging of unprocessed fresh tissue has not previously been reported. In aggregate, we demonstrate the feasibility of PARS to provide diagnostic and margin assessment images across a range of tissues including formalin fixed and freshly resected, unstained, unprocessed breast tissue. Conclusions: PARS is a new microscope technology addressing the practical needs of intraoperative margin assessment during BCS: i) no requirement for tissue staining, ii) rapid acquisition of hematoxylin and eosin-like images without the requirement for tissue freezing, embedding, or sectioning, iii) diagnostic quality cellular resolution, and iv) assessment of resected bulk tissue margins. In principle, this technology may also permit label-free non-contact intraoperative margin assessment of the surgical cavity. These data support the clinical development and evaluation of PARS microscopic intraoperative assessment of BCS margins.
Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in patients with advanced pancreatobiliary cancer.
Authors: Nebojsa Skorupan, Mehwish Iqra Ahmad, Guillaume Joe Pegna, Cody J. Peer, Jane B. Trepel, Min-Jung Lee, Sunmin Lee, Shraddha Rastogi, Nahoko Sato, William Douglas Figg, Raffit Hassan, David JP FitzGerald, Ira Pastan, Christine Alewine
Journal: Journal of Clinical Oncology (2021)

3051 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting a modified Pseudomonas exotoxin A payload to tumors. Previous clinical trials demonstrated that almost all patients formed anti-drug-antibodies (ADAs) to LMB-100 that made administration beyond cycle 2 ineffective. Tofacitinib is an oral JAK inhibitor that prevented formation of ADAs against a closely related immunotoxin in pre-clinical studies. The primary objective of the dose escalation cohort was assessment of safety and tolerability of LMB-100 given with tofacitinib to patients with mesothelin-expressing solid tumors. The primary objective of the expansion cohort was to determine whether co-administration of tofacitinib delays formation of neutralizing LMB-100 ADAs. Methods: Patients (n = 13) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; cholangiocarcinoma, appendix, cystadenocarcinoma) were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 mcg/kg) and co-treated with oral tofacitinib for the first 10 days of the cycle (10 mg BID). Results: Dose level 1 of LMB-100 was started at 100 mcg/kg one dose level below the single agent MTD. Dose escalation to 140 mcg/kg (dose level 2) resulted in DLTs in 2 of the 3 patients treated: grade 3 cardiac toxicity and grade 4 hyponatremia, both attributed to capillary leak syndrome. Ultimately, 7 patients were treated at dose level 1 without DLTs and 100 mcg/kg was chosen as the LMB-100 dose for the expansion cohort. The last of 6 patients treated in the expansion cohort developed grade 4 pericardial effusion leading to early closure of the study for toxicity. No objective responses were seen. Of the 8 patients who received two cycles of treatment at MTD, 4 met prespecified criteria for ADA prevention, and 2 patients who went on to receive cycle 3 had detectable LMB-100 plasma drug levels after administration. Conclusions: LMB-100 was unable to be co-administered safely with tofacitinib. ADA formation was prevented in 2 patients through 3 cycles, a rare occurrence. Clinical trial information: NCT04034238.
Results of NC-6300 (nanoparticle epirubicin) in an expansion cohort of patients with angiosarcoma.
Authors: Richard F. Riedel, Victoria S. Chua, Ted Kim, Jonathan Dang, Kitty Zheng, Ania Moradkhani, Atsushi Osada, Sant P. Chawla
Journal: Journal of Clinical Oncology (2021)

11543 Background: NC-6300 is a polymeric micelle exhibiting increased tumor accumulation compared to small-molecule epirubicin through enhanced pharmacokinetics and controlled release within the tumor through a pH-sensitive linker conjugated to epirubicin. In a phase 1b trial, which accrued twenty-nine patients with various types of sarcoma as well as solid tumors, observed dose-limiting toxicities included thrombocytopenia, stomatitis, lung infection, and febrile neutropenia. The maximum tolerated dose and the recommended phase 2 dose were determined to be 185 mg/m 2 and 150 mg/m 2 , respectively. The objective response rate (ORR) in soft tissue sarcoma subset (n = 17) was 18% with both angiosarcoma patients achieving partial response. To further evaluate the anti-tumor activity of NC-6300 in angiosarcoma, we conducted an expansion cohort of 10 additional angiosarcoma patients. Methods: Eligible patients, at least age 18 years old, with histologically confirmed angiosarcoma, including cutaneous and non-cutaneous variants, not amenable to curative treatment with surgery or radiotherapy were included. No more than two lines of prior systemic therapy were allowed. NC-6300 was administered at the dose of 150 mg/m 2 intravenously on Day 1 of a 21-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Disease assessment was performed every 6 weeks using RECIST v1.1. The primary endpoint was median progression-free survival (mPFS). Results: Ten patients (cutaneous: 2 pts; non-cutaneous: 8 pts) were enrolled and deemed evaluable. Median line of prior systemic treatment in the advanced disease setting was 1.0 and seven patients (70%) received prior anthracycline therapy. Objective response rate (ORR) was 30% (cutaneous: 1 pt, non-cutaneous: 2 pts) and mPFS was 5.4 months (95% CI: 1.2-NA). Across all angiosarcoma patients included in the phase 1 portion and expansion cohort (phase 1b portion: 2 pts, expansion cohort: 10 pts), ORR and mPFS was 42% and 7.3 months (95%CI: 3.3-NA), respectively. All patients enrolled in the expansion cohort experienced grade 3/4 AEs and no treatment related death was observed. Most frequent grade 3/4 AEs were neutropenia without fever (80%), thrombocytopenia (40%), anemia (20%) and leukopenia (20%). AEs led to NC-6300 dose reduction and medication withdrawal were seen in 70% and 10% of patients, respectively. Conclusions: Promising anti-tumor activity was observed in this cohort of patients with cutaneous and non-cutaneous angiosarcoma. The safety profile of this expansion cohort was consistent with previous clinical study results of NC-6300. Our study results warrant further development of NC-6300 for angoisarcoma. Clinical trial information: NCT03168061.
An enamel-inspired bioactive material with multiscale structure and antibacterial adhesion property
Authors: Hai Ming Wong, Yu Yuan Zhang, Quan Li Li
Journal: Bioactive Materials (2021)

Conventional dental materials lack of the hierarchical architecture of enamel that exhibits excellent intrinsic-extrinsic mechanical properties. Moreover, restorative failures frequently occur due to physical and chemical mismatch between artificial materials and native dental hard tissue followed by recurrent caries which is caused by sugar-fermenting, acidogenic bacteria invasion of the defective cite. In order to resolve the limitations of the conventional dental materials, the aim of this study was to establish a non-cell-based biomimetic strategy to fabricate a novel bioactive material with enamel-like structure and antibacterial adhesion property. The evaporation-based, bottom-up and self-assembly method with layer-by-layer technique were used to form a large-area fluorapatite crystal layer containing antibacterial components. The multilayered structure was constructed by hydrothermal growth of the fluorapatite crystal layer and highly conformal adsorption to the crystal surface of a polyelectrolyte matrix film. Characterization and mechanical assessment demonstrated that the synthesized bioactive material resembled the native enamel in chemical components, mechanical properties and crystallographic structure. Antibacterial and cytocompatibility evaluation demonstrated that this material had the antibacterial adhesion property and biocompatibility. In combination with the molecular dynamics simulations to reveal the effects of variables on the crystallization mechanism, this study brings new prospects for the synthesis of enamel-inspired materials.
BOS172738, a highly potent and selective RET inhibitor, for the treatment of <i>RET</i>-altered tumors including <i>RET</i>-fusion+ NSCLC and <i>RET</i>-mutant MTC: Phase 1 study results.
Authors: Patrick Schoffski, Byoung Chul Cho, Antoine Italiano, Herbert H. F. Loong, Christophe Massard, Laura Medina Rodriguez, Jin-Yuan Shih, Vivek Subbiah, Loic Verlingue, Karen Andreas, Craig T. Basson, Alicia Clawson, Peter T.C. Ho, Shelley Knight, Anita Scheuber, Mitchell Keegan
Journal: Journal of Clinical Oncology (2021)

3008 Background: RET (REarranged during Transfection) gene alterations (mutations and fusions) leading to constitutive kinase activity are identified as drivers of disease progression in multiple tumor types, including non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC). BOS172738 is an investigational, potent, selective oral RET kinase inhibitor. This next-generation inhibitor was designed with nanomolar potency against RET and &gt;300-fold selectivity against vascular endothelial growth factor receptor 2, to maximize the potential therapeutic window. Methods: NCT03780517 is a phase 1 study consisting of a dose-escalation and dose-expansion phase. During the escalation, 67 patients with RET-altered advanced solid tumors received once-daily oral doses of BOS172738 (10-150 mg). Intra-patient dose escalation was allowed as was over-accrual to dose levels deemed to be safe. Study endpoints were safety (CTCAE v. 4.03), tolerability and confirmed overall response rate (ORR; RECIST 1.1). The data cutoff was Dec. 11, 2020. Results: BOS172738 exhibited a favorable safety profile (n=67) for long-term administration with most treatment-emergent adverse events (TEAEs) classified as grade ≤2 and deemed unrelated to drug. The most common TEAEs were creatinine phosphokinase (CPK) increase (54%), dyspnea (34%), facial edema, aspartate aminotransferase elevation, anemia (25% each), neutropenia, diarrhea (22% each), fatigue (21%), and constipation (20%). BOS172738 was not associated with hypertension or significant hepatoxicity. BOS172738 demonstrated broad anti-tumor activity with an investigator-assessed ORR of 33% (n=18/54), a NSCLC ORR of 33% (n=10/30), MTC ORR of 44% (n=7/16, including 1 complete response) and one patient with RET fusion+ pancreatic cancer reported a partial response. Responders included patients with brain metastases with one patient whose brain lesion decreased by 43%. The median duration of response has not been reached. Many patients remain on study, including the longest of 659 days, at data cutoff. BOS172738 exhibited dose-dependent exposure (AUC, C max ), rapid absorption (median T max 1 to 4.5 h), and an extended half-life (approximately 65 hours) maximizing target coverage. Conclusions: BOS172738 is a highly potent and selective RET inhibitor with a differentiated safety profile and clinical activity against RET-altered tumors, including patients with brain metastases. BOS172738 continues to be evaluated in patients with NSCLC, MTC, and in patients previously treated with other selective RET inhibitors. Clinical trial information: NCT03780517.
Mandatory SARS-CoV-2 Vaccinations in K-12 Schools, Colleges/Universities, and Businesses
Authors: Lawrence O. Gostin, Jana Shaw, Daniel A. Salmon
Journal: JAMA (2021)

This Viewpoint examines the epidemiologic, public health, and legal considerations for mandatory SARS-CoV-2 vaccinations in primary and secondary schools, colleges/universities, and businesses in the US.
Mendelian Randomization Analysis as a Tool to Gain Insights into Causes of Diseases: A Primer
Authors: Adrienne Tin, Anna Köttgen
Journal: Journal of the American Society of Nephrology (2021)

Many Mendelian randomization (MR) studies have been published recently, with inferences on the causal relationships between risk factors and diseases that have potential implications for clinical research. In nephrology, MR methods have been applied to investigate potential causal relationships of traditional risk factors, lifestyle factors, and biomarkers from omics technologies with kidney function or CKD. This primer summarizes the basic concepts of MR studies, highlighting methods used in recent applications, and emphasizes key elements in conducting and reporting of MR studies that are important for interpreting the results.
Sudden Cardiac Death and Myocardial Fibrosis, Determined by Autopsy, in Persons with HIV
Authors: Zian H. Tseng, Ellen Moffatt, Anthony Kim, Eric Vittinghoff, Phil Ursell, Andrew Connolly, Jeffrey E. Olgin, Joseph K. Wong, Priscilla Y. Hsue
Journal: New England Journal of Medicine (2021)

The incidence of sudden cardiac death and sudden death caused by arrhythmia, as determined by autopsy, in persons with human immunodeficiency virus (HIV) infection has not been clearly established.
Efficacy and biomarker analysis of neoadjuvant carrizumab plus apatinib in patients with local advanced biliary tract cancers.
Authors: Jian-hua Rao, Chen Wu, Hui Zhang, Xuehao Wang, Ling Lu, Feng Cheng, Dongsheng Chen
Journal: Journal of Clinical Oncology (2021)

e16126 Background: Camrelizumab (anti-PD-1 antibody) plus apatinib (VEGFR2 inhibitor) as combination therapy is highly effective in advanced osteosarcoma, hepatocellular carcinoma and extensive-stage SCLC. This study aimed to access the efficacy, safety and explore predictive biomarkers of neoadjuvant carrizumab plus apatinib in local advanced biliary tract cancers (BTCs) (ChiCTR2000034283). Methods: This single-arm, phase II trial enrolled patients with local advanced BTCs. Patients received camrelizumab 200 mg every 2 weeks plus apatinib 250 mg once per day for two cycles, clinical response was then evaluated. Gene expression profiling (GEP), using the 289-gene immune-related RNA panel sequencing, was performed on baseline tumor samples. Differential gene expression analysis was performed between responder (partial response and complete response) and non-responder (stable disease and progressive disease) using Wilcoxon rank-sum test. Results: Across these patients with local advanced BTCs, neoadjuvant camrelizumab plus apatinib demonstrated antitumor activity. Seventeen (n = 13 gallbladder carcinoma; n = 4 cholangiocarcinoma) response-evaluable patients received two cycles of combination therapy, of whom 12 (70.5%) patients achieved objective response, including 2 (11.7%) with complete response, and the DCR was 76.4%. To further assess the impact of the tumor microenvironment on the combination therapy response, we sequenced baseline tumor samples performed biomarker analyses using the 289-gene immune-related RNA panel. Of all enrolled patients with evaluable responses, 16 (94.1%) patients had available GEP data. Baseline tumor samples on differential genes revealed a significantly higher S100A8 (P = 0.004), IL1B (P = 0.002), KIR2DL3 (P = 0.007) expression in non-responders compared with responders. Extensive analyses on immune cell types were also performed. ECMES positive exhausted CD8 T cells (P = 0.009) and SIGLEC5 positive neutrophils (P = 0.0014) were significantly increased in baseline non-responders. In contrast, no significant differences of CD8 positive T cells, B-cells, cytotoxic cells, dendritic cells, macrophages cells or NK cells were found at baseline between groups. Meanwhile, signature scores were calculated using the Gene Set Variation Analysis package with publicly available gene signatures between responder and non-responder groups, and no noteworthy differences were found in TILs score, Cytolytic activity score, IFN-γ signature and Teff score. Conclusions: Neoadjuvant camrelizumab plus apatinib exhibited promising antitumor activity in patients with local advanced biliary tract cancers. Elevated S100A8, IL1B, KIR2DL3 expression levels may indicate resistance in clinical response. Increased ECMES positive exhausted CD8 T cells and SIGLEC5 positive neutrophils were predictive of response in non-responder tumors.