tbuckley/cabot-search huggingface dataset:
Phase II trial (BCD-100-2/MIRACULUM) of the novel PD-1 inhibitor (BCD-100) in patients with advanced melanoma.
Authors: Sergey Fogt, Mariia Shustova, Lev V. Demidov, Vladimir Moiseyenko, Sergei Tjulandin, Tatiana Semiglazova, Svetlana Protsenko, Svetlana Odintsova, Ruslan Zukov, Sergey Lazarev, Yuliya Makarova, Marina Nechaeva, Dina Sakaeva, Aleksey Andreev, Anna Tarasova, Natalia Fadeeva, Olesya Gavrilova, Roman Ivanov
Journal: Journal of Clinical Oncology (2019)

9549 Background: MIRACULUM (NCT03269565) is a multicenter open-label parallel-arm phase II study investigating the antitumor activity of BCD-100, an IgG1 anti-PD-1 monoclonal antibody with Fc silencing “LALA” mutation, in patients with advanced melanoma. Interim analysis at 6-months is presented. Methods: Patients (pts) with unresectable or metastatic melanoma, without autoimmune disease, and no prior anti-PD-1 or anti-CTLA-4 therapy were eligible. Pts received BCD-100 1 mg/kg Q2W (arm 1) or BCD-100 3 mg/kg Q3W (arm 2) until disease progression or intolerable toxicity. Primary endpoint was ORR assessed per irRECIST by independent central radiology review. A statistical hypothesis that BCD-100 has significant anti-tumor effect (ORR more than 28% in per protocol population) was tested for each study arm with alpha 0.05 and 80% power. Results: 126 pts were treated and 114 were evaluable for the primary endpoint (9 pts dropped out before their first efficacy assessment and 3 pts had major protocol deviations). In arm 1 and arm 2, 17 (27%) and 16 (25%) pts received prior treatment for advanced disease, respectively. The study met its primary endpoint in both study arms. In arm 1, 34% ORR was achieved among 59 response-evaluable patients, including 4 CR and 16 PR, and the disease control rate (DCR) was 68%. In arm 2, 29% ORR was achieved among 55 response-evaluable pts, including 2 CR and 14 PR, and the DCR was 55%. All responses were durable; only one patient in arm 1 presented disease progression, and median PFS and OS were not reached in either study arms at 6 months follow-up. Treatment-related AEs (TRAEs) occurred in 48% of pts in each study arm, including 6% and 5% with grade 3/4 TRAEs in arm 1 and 2, respectively. Immune-related AEs (irAEs) occurred in 29% of pts in arm 1 and 30% of pts in arm 2, including 3% of pts with grade 3/4 irAEs in each arm. Conclusions: Both dosing regimens of BCD-100 (1 mg/kg Q2W and 3 mg/kg Q3W) have durable antitumor activity and a manageable safety profile in patients with advanced melanoma. Clinical trial information: NCT03269565.
Omega-3 fatty acids and ERPR(-) and HER2/neu(+/-) breast cancer prevention.
Authors: Chidimma Kalu, Sarah Woelke, Jianying Zhang, Martha Belury, Rulong Shen, Steven K. Clinton, Lisa Yee
Journal: Journal of Clinical Oncology (2019)

TPS1589 Background: The most aggressive breast cancer subtypes tend to be estrogen and progesterone receptor negative (ERPR(-)) and human epidermal growth factor receptor type 2 positive (HER2(+)). Women with these breast cancer subtypes (triple negative, ERPR(-)HER2(+)) tend to experience worse clinical outcomes and have a relatively higher risk of recurrence. Our previous research demonstrated that dietary omega-3 (n-3) fatty acids can significantly inhibit ERPR(-) HER2(+) tumorigenesis in MMTV-HER2/neu transgenic mice fed fish oil vs corn oil-based diets. The fish oil diet group developed 30% fewer breast tumors, had lower Ki67 expression, and experienced less mammary atypia relative to the corn oil diet group. Other studies involving diet, nutrition and breast cancer point to the potentially protective effect of an anti-inflammatory diet on the risk of developing ER(-) and HER2(+) breast cancer, further supporting the evidence that the ERPR(-), HER2(±) subtypes may be highly responsive to this bioactive nutrient. Methods: This is a double-blinded, randomized clinical trial of high dose (~5.4 g EPA+DHA) vs low dose (~0.9 g EPA+DHA in fatty acid mix of the typical American diet) of n-3 fatty acids in breast cancer survivors of ERPR(-), HER2(±) breast cancer. Eligible participants will take 5 capsules/day for 12 months, with cellular samples of breast epithelial and/or adipose tissue obtained by fine needle aspirations of the contralateral breast. The study aims to determine whether n-3 fatty acid supplementation will modify fatty acid metabolite content in breast adipose tissue, modulate cytomorphology and/or cell proliferation in breast epithelial cells, affect DNA methylation patterns, and modulate pro- vs anti-inflammatory gene expression patterns in breast adipose tissue. Correlative aims will evaluate possible associations between factors such as breast adipose tissue, red cell membrane fatty acid profiles, BMI, and reported dietary intake. Sample size of 40 participants per arm was calculated to provide at least 80% power to detect a statistically significant difference for each primary endpoint. This study focuses on women survivors of high risk breast cancer subtypes, specifically triple negative or ERPR(-)HER2(+) disease, who are currently without long term adjuvant options. Eligibility criteria include prior diagnosis of ERPR(-) stage 0 to III breast cancer, ≤5 years from completion of standard therapy.The study was closed to accrual in November 2018; less than 9 months of follow-up remain for active study participants. Clinical trial information: NCT02295059.
The diagnostic accuracy of 12-point core biopsy of a tumor bed compared to the study of surgically obtained breast tissue in patients with locally advanced triple-negative or HER2-positive breast cancer after neoadjuvant systemic and targeted therapy.
Authors: Petr Krivorotko, Sergey Yerechshenko, Garik Dashyan, Elena Zhiltsova, Alexander Bessonov, Tengiz Tabagua, Konstantin Zernov, Alexander Komyahov, Kirill Nikolaev, Larisa Gigolaeva, Alexander Emelyanov, Vladimir Semiglazov, Vladislav Semiglazov, Tatiana Semiglazova
Journal: Journal of Clinical Oncology (2019)

e12097 Background: Innovative advances in neoadjuvant systemic and targeted breast cancer therapy implicate surgical treatment in specific patient groups can be avoided. The core biopsy of the tumor bed and some diagnostic approaches (breast ultrasound, mammography, SPECT/CT) allow for precise evaluation of the treatment efficacy. Methods: This research started in our department in 2018, we picked two groups of 15 patients each treated for locally advanced TNBC or grade cT1-4N1-3M0 HER2-positive breast cancer: HER2+/ER+ or HER2+/ER- breast cancer. The TNBC group received 6 cycles of NACT of paclitaxel combined with doxorubicin and carboplatin AUC5. The HER2+ group received 4 cycles of АС polychemotherapy followed by 4 cycles of monochemotherapy with the docetaxel and 3-weekly trastuzumab. The HER2+ group is receiving adjuvant trastuzumab for up to one year, where ER-positive patients are also given hormone therapy with tamoxifen or aromatase inhibitors. The response to neoadjuvant treatment was assessed in all patients using standard two-dimensional mammography, ultrasound elastography, and SPECT-CT. The 12-point core biopsy of a tumor bed was performed in the operating room setting by previously marked tumor projections. Then, all patients underwent either breast-conserving surgery or mastectomy with immediate reconstruction with expander/implant. Results: After neoadjuvant therapy, in a group of 15 patients with TNBC in surgically obtained material, the pathologic complete response (pCR) was observed in 8 patients (53.33%), whereas residual disease was found in 7 (46.67%) patients. The core biopsy results showed no tumor cells in 10 (66.67%) patients, and were detected in 5 (33.33%) patients (p = 0.0011), the accuracy of the method in this group was 80%. The overall response rate in the group of 15 patients with HER2-positive breast cancer was 8 (53.33%) patients with residual disease and 7 (46.67%) patients with pCR. According to core biopsy, tumor cells were present in 3 (20%) patients and were absent in 12 (80%) patients (p = 0.0787). Conclusions: Avoiding surgical treatment through not less than 12-point core biopsy of a tumor bed in patients with complete regression after neoadjuvant therapy is a new trend in the treatment of breast cancer. Any new approach in this sphere requires a long-term elaboration, compliance with the safety principles, rethinking standard procedures and following-up patients.
Incidence of venous thromboembolic disease (VTE) in a cohort of patients with colorectal cancer (CRC) according to KRAS, NRAS and BRAF status.
Authors: Pilar Garcia-Alfonso, Laura Ortega Morán, Iria Gallego Gallego, Gonzalo García González, Gabriela Torres Pérez-Solero, Iker Aguilar Caballero, María de Toro Carmena, Blanca Morón García, Victoria Tirado Anula, Natalia Gutiérrez Alonso, Marianela Bringas Beranek, Javier Soto Alsar, Carmen Sandoval García, Gema Aguado Orihuela, Íñigo Martínez Delfrade, Montserrat Blanco-Codesido, Aitana Calvo Ferrándiz, Miguel Martin, Andres J. Muñoz Martín
Journal: Journal of Clinical Oncology (2019)

e15136 Background: A recent study has suggested that KRAS mutation could increase the risk of VTE in patients with CRC. The role of others biomarkers, such as BRAF, in this setting is unknown. The aim of this study is to analyze the incidence of cancer-associated thrombosis in a cohort of patients with CRC based on KRAS, NRAS and BRAF status. Methods: We performed a retrospective review of patients with metastatic CRC and KRAS/NRAS/BRAF status known, attended in the Medical Oncology Department of the Hospital General Universitario Gregorio Marañón (Madrid, Spain) between January 2010 and January 2018. Results: 194 patients were identified and included in the analysis. The median age was 64 years (18-86). Most were metastatic at diagnosis (58.1%). Khorana’s predictive model: low-risk 67.7%, intermediate-risk 31.0%, high-risk 2.3%. The median follow-up was 35 months (2-240). 41 patients (21.1%) experienced VTE (11 pulmonary embolism, 15 lower extremity deep-vein thrombosis, 12 visceral vein thrombosis, 2 catheter-related thrombosis, 1 unknown). Most had metastatic disease at the moment of VTE (90.2%). 40% of the events occurred at the time of diagnosis or within the first 6 months. 65% were incidental events. Khorana’s predictive model in VTE patients: low-risk 63.4%, intermediate-risk 24.5%, high-risk 7.3%. According to biomarkers, the incidence was 19.1% (13/68) in KRAS/NRAS mutated patients, 28.6% (6/21) in BRAF mutated patients and 21% (22/105) in triple-wild-type patients. 6/38 patients (15.8%) developed recurrent thrombosis. In the univariate analysis, the presence of chronic kidney disease (p = 0.022), ECOG ≥ 2 (p = 0.038) and high-risk Khorana score (p = 0.011) were significantly associated with increased risk of VTE. Metastatic disease showed a trend towards the statistical significance (p = 0.053). In the multivariate model, including this variables, age, sex and biomarkers, only ECOG ≥ 2 remained independent predictor of VTE (OR 8.73; CI 95% 1.32-57.82; p = 0.025). Conclusions: The biomarkers have not been associated with the risk of VTE. We have observed a high incidence of VTE in BRAF mutated patients that should be investigated in further studies.
AB1078 RED CELL DISTRIBUTION WIDTH (RDW) – A NEW POSSIBLE DISEASE ACTIVITY PREDICTOR IN RELAPSING POLYCHONDRITIS
Authors: Bianca Balan, Roxana Ioana Gutiu, Felicia Mustățea, Ioana Felea, Ileana Filipescu, Cristina Pamfil, Liliana Bene, Simona Rednic, Laura Damian
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Relapsing polychondritis (RP) is a rare condition defined by recurrent inflammation of cartilaginous tissue and systemic manifestations. Biomarkers for RP diagnosis and assessment of disease activity, damage and prognostic in clinical practice are currently lacking. Red blood cell distribution width (RDW) is an index of erythrocyte size variation depicting anizocytosis. RDW is routinely assessed, is not influenced by infections and its standard deviation (RDW-SD) does not depend on medium corpuscular volume. Recent studies showed an increased RDW in various autoimmune diseases (systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, systemic vasculitis), correlating with inflammatory markers and disease activity. Also, the RDW seen in solid tumors and hematological cancers has prognostic value. <h3>Objectives</h3> To asses the RDW-SD in RP patients, its relation with the disease activity and with the presence of neoplasia <h3>Methods</h3> We performed a retrospective study on the patients diagnosed with RP in a tertiary Rheumatology department between January 2017 and January 2019, using the Atlasmed data management system of the institution. The concomitant diseases and the inflammation parameters were recorded. The RP activity was measured using RPDAI (relapsing polychondritis disease activity index). The correlation between variables were calculated using GraphPad Prism. <h3>Results</h3> We identified 20 patients, median age 59.04 years (range 38-81), with a male-to-female ratio of 1: 5.66. An associated autoimune disease (Sjogren syndrome, Hashimoto thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis) was found in 85% of pacients. Moreover, 40% of the pacients had various types of solid or hematologic neoplasia, including myelodysplastic syndrome. An elevated RDW-SD was seen in 90% of RP patients. The average RPDAI was 10.6 points. RDW-SD significantly correlated to RPDAI (p=0.0012). Of the inflammatory parameters, RDW-SD was not found to be related to ESR and CRP. RDW-SD increased with age, but no correlation was found between RPDAI and age. All pacients with neoplasia had abnormally high RDW-SD. Nevertheless, RDW-SD was not significantly different in RP patients with or without neoplasia (Mann-Whitney test, p=0.56). <h3>Conclusion</h3> RP was frequently associated with other autoimune diseases, but also with neoplasia.The positive correlation of RDW-SD and RPDAI in RP suggests a possible new, clinically employable, biomarker of disease activity. <h3>References</h3> [1] Arnaud L et al, Autoimmun Rev 2012; 12(2):204-9. doi:10.1016/j.autrev.2012.06.005. [2] Hu ZD, JLPM 2016, doi: 10.21037/jlpm.2016.10.02 <h3>Disclosure of Interests</h3> None declared
Targeting of survivin to overcome cisplatin resistance in esophageal adenocarcinoma.
Authors: Rosalie V. Douglas, Leanne Stevenson, Ralph Santos, Lauren Cairns, Niamh H McCabe, Richard D. Kennedy, Jaine K. Blayney, Richard C. Turkington
Journal: Journal of Clinical Oncology (2019)

e15535 Background: The incidence of Esophageal Adenocarcinoma (EAC) has risen in the western world but response rates to chemotherapy are low and survival is poor. Increased molecular understanding is needed to develop novel treatments. Methods: Transcriptional profiling of 274 treatment naïve EAC biopsies was performed using the Almac Diagnostics Xcel array™. All patients received platinum-based neo-adjuvant chemotherapy prior to surgical resection at four United Kingdom centers between 2004-2012. Semi-supervised clustering was performed followed by functional enrichment using DAVID. Cluster membership was assessed for independence of prognostic factors using Cox proportional hazards. Candidate targets were identified by siRNA screening in OE33 cells. Treatment with the survivin inhibitor, YM155 in EAC cell lines was also assessed. Results: Semi-supervised hierarchical clustering identified two groups with significant differences in RFS [HR = 0.54 (0.29-0.99), p = 0.05] and OS [HR = 0.52 (0.28-0.96), p = 0.04]. There were significant associations between the clusters and both nodal and TNM downstaging but not with pathological response. The PI3K-AKT, p53, tight junction and HIF-1 signaling pathways were upregulated in the poor prognostic group. Eighty-four genes were selected and taken forward in a functional genomic siRNA screen. Twenty-seven genes showed a significant reduction in viability following siRNA-mediated knockdown and further verification resulted in twelve candidate genes. Finally, target knockdown in seven EAC cell lines resulted in four interrelated hits- BIRC5, JAK1, OSMR and SLC2A1. Knock down of BIRC5 (Survivin) induced apoptosis, as evidenced by PARP cleavage, in both the parental OE33 and cisplatin-resistant OE33CDDPR cell lines. YM155, a survivin inhibitor, is shown to induce apoptosis at nanomolar concentrations across a panel of parental and cisplatin-resistant EAC cell lines and further mechanistic work is ongoing. Conclusions: We have performed clustering of a large transcriptomic dataset and defined a poor prognostic group of EAC patients. We identified Survivin (BIRC5) as a mediator of cisplatin resistance in EAC and a potential novel drug target. Further pre-clinical and clinical work to assess the benefit of survivin inhibition in EAC is warranted.
Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7)
Authors: Per Ljungman, Rafael de la Camara, Christine Robin, Roberto Crocchiolo, Hermann Einsele, Joshua A Hill, Petr Hubacek, David Navarro, Catherine Cordonnier, Katherine N Ward
Journal: The Lancet Infectious Diseases (2019)
The chick embryo chorioallantoic membrane assay: <i>In ovo</i> model for personalized assessment and evaluation of the most effective therapeutic approach in cancer therapy.
Authors: Shiran Shapira, Oren Bogin, Dina Kazanov, Faina Bedny, Dov Hershkovizh, Ayelet Izhaki, Eli Brazowski, Ezra Bernstein, Ido Wolf, Nadir Arber
Journal: Journal of Clinical Oncology (2019)

e14634 Background: "Personalized medicine,” is the tailoring of medical treatment to a single person aiming to maximize efficacy and minimize toxicity. Currently there is no good prediction for response to therapy. The Chick Chorioallantoic Membrane (CAM) is naturally immuno-deficient and rich in vascularity therefore an ideal system, allowing generate 3D cancerous “organoids” in a very efficient, reproducible and cost-effective manner and translates basic research to the clinic. Aims: Generate a “personalized” HTP system for a quick, reliable and effective evaluation of different therapeutic options using 3D tumors in a "humanized egg" instead of mouse PDX model. Methods: Fertilized eggs were incubated until day 3 (37°C, 75-90% humidity). Then, 2ml of albumin was pulled out to separate the CAM from the eggshell and a small window in the eggshell has been made. To destroy the chicken immune system development, the eggs were irradiated at day 5 and human immune cells were then inoculated onto the CAM. On day 7, single cells suspension or tissues, derived from cancer patients, were transplanted onto the CAM and visible tumors were performed ("CAM-PDX"). Drugs, mAbs and chemotherapy, were applied via the yolk sac. Tumor growth was measured, weighted and monitored by caliper and IVIS fluorescent imaging platform. IHC was performed and confirmed the response of the particular specimens to the tested regiment. Results: Histology and IHC analysis confirmed that the established tumors retained their characteristics. Positive Ki-67 staining confirmed that cancer cells proliferate while the treated tumors showed reduced staining. Anti-CD24 mAb, FOLFOX, cetuximab, Foflorinox and Gemcitabine, given as single agent or combinations, successfully inhibited CR and pancreatic tumors (by 70-75%). Detection of active caspase 3 confirmed those results. Biopsies from human specimens, were successfully established and expanded by serial passages allows generation of bio-bank. The stimulated human PBMCs demonstrated enhanced proliferation in vitro and in ovo, even after 5 days in the egg. Irradiated eggs showed no functional immune system even after 2 weeks of development. Conclusions: The CAM is an ideal, effective, economical and powerful avatar-based precision medicine approach to predict the best protocol for cancer therapy.
Patient-reported outcomes (PROs) in NRG oncology/NSABP B-39/RTOG 0413: A randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) in stage 0, I, or II breast cancer.
Authors: Patricia A. Ganz, Reena S. Cecchini, Julia R. White, Frank Vicini, Thomas B. Julian, Douglas W Arthur, Rachel Rabinovitch, Robert R. Kuske, David S. Parda, Michael Scheier, Kathryn A. Winter, Soonmyung Paik, Henry Mark Kuerer, Laura Vallow, Lori J. Pierce, Eleftherios P. Mamounas, Joseph P. Costantino, Beryl McCormick, Walter John Curran, Norman Wolmark
Journal: Journal of Clinical Oncology (2019)

508 Background: PBI is an alternative to WBI, with potentially greater therapy (tx) compliance, and better integration with chemotherapy (CTX). NSABP B-39/RTOG 0413 clinical outcome results from 2018 did not show equivalence of PBI to WBI in local tumor control; PBI was statistically inferior, but with clinically small differences. PBI may be an acceptable alternative to WBI for some women. Understanding cosmesis and quality of life (QOL) treatment outcomes is important. Methods: B-39/0413 included a prospective QOL substudy with PRO evaluation of breast cancer treatment outcomes (cosmesis, function, pain) and fatigue using BCTOS and SF-36 vitality scales. Secondary QOL parameters included treatment related symptoms, perceived convenience of care, and the BPI pain scale. The study sample was stratified by CTX or not, as CTX is given before WBI but after PBI. PRO assessments occurred before randomization, the last day of adjuvant tx [CTX or radiation], 4 wks later, and 6, 12, 24, and 36 mo later. Primary aims included comparisons of change in fatigue from baseline to end of tx and equivalency of change in cosmesis from baseline to 36 mo for PBI v WBI. Separate analyses were done for CTX and non-CTX pts, controlling for axillary dissection. Each comparison used α=0.0125. Planned sample size was 964. Results: From 3-23-05 to 5-27-09, 975 pts were enrolled in the PRO study; 950 had follow-up data. 504 did not receive CTX and 446 received CTX. In non-CTX pts, PBI had less fatigue (p=0.011) and did not meet criteria for cosmesis equivalence (97.5% CI, -0.02 to 0.22; ∆=0.20). In CTX pts, PBI had worse fatigue (p=0.011) and equivalent cosmesis to WBI (97.5% CI, -0.09 to 0.21; ∆=0.24). In both groups, PBI pts reported less pain at end of tx. In non-CTX pts, PBI had more pain at 36 mo but in CTX pts, there was no difference. Convenience of care and treatment related symptom outcomes will be presented. Conclusions: In non-CTX pts, PBI is more convenient with less fatigue and slightly poorer cosmesis at 36 mo. Cosmesis was equivalent at 36 mo in CTX pts. Support: U10CA180868, -180822, UG1CA189867. Clinical trial information: NCT00103181.