tbuckley/cabot-search huggingface dataset:
Oral maintenance capecitabine versus active monitoring for patients with metastatic colorectal cancer (mCRC) who are stable or responding after 16 weeks of first-line treatment: Results from the randomized FOCUS4-N trial.
Authors: Richard Adams, David Fisher, Janet Graham, Jenny F. Seligmann, Matthew Seymour, Richard S. Kaplan, Emma Yates, Susan D Richman, Philip Quirke, Rachel Butler, Ewan Brown, Stephen Falk, Fiona Jane Collinson, Richard H. Wilson, Louise C. Brown, Tim Maughan
Journal: Journal of Clinical Oncology (2021)

3504 Background: There is extensive randomised evidence supporting the use of treatment breaks in mCRC, but breaks from treatment are not universally offered to patients despite reductions in toxicity, without detriment to OS. Prior trials have shown that the combination of Cp and bevacizumab extend PFS but not OS. FOCUS4-N explores oral maintenance Cp monotherapy in patients with disease control on first line therapy. Methods: FOCUS4 was a molecularly stratified trial programme registering patients with newly diagnosed mCRC from 88 hospitals in the UK. Whilst undergoing 16 wks of first line treatment, a sample of tumour was sent for laboratory testing to stratify their disease into molecular subtypes: MSI, BRAF, PIK3CA, TP53 and RAS mutations. For some molecular groups, a targeted therapy subtrial was available but entry into the FOCUS4-N trial was offered to those in whom a targeted subtrial was unavailable. Patients were randomised 1:1 between maintenance Cp therapy or AM. The primary outcome was PFS assessed using 8-wkly RECIST reported CT scans with quality of life (using EQ5D 8 weekly) and OS as secondary outcomes. Toxicity and tolerability were assessed 4-wkly. On progression, from the nadir, patients recommenced first line treatment. Cox regression was used to assess efficacy by intention-to-treat (ITT) with adjustment for tumour location, WHO status, metastatic burden, first line treatment and biomarker subtype. Results: Between March 2014 and March 2020, 254 patients were randomised (127 to Cp and 127 to AM). Baseline characteristics were balanced between groups but event rates were higher than anticipated in the AM group and the final analysis was triggered early as a result of the COVID-19 pandemic halting recruitment. The table presents results for PFS and OS. Compliance with treatment was good with per-protocol analysis results very similar to ITT (PFS HR=0.38 (95% CI 0.28-0.51)). Toxicity from Cp v AM was as expected with G≥2 fatigue (25% v 12%), diarrhoea (23% v 13%) and hand-foot syndrome (26% v 3%). Quality of life showed no statistically significant differences between the two arms. Conclusions: Despite strong evidence of prolongation of PFS with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as a safe management alternative for patients who are stable or responding well to first line treatment for mCRC. Cp without bevacizumab may be used to extend PFS, in the interval after 16 weeks of combination therapy. Clinical trial information: ISRCTN#90061546. [Table: see text]
Long-Term Results of Brentuximab Vedotin in Relapsed and Refractory Hodgkin Lymphoma: Multi-Center Real-Life Experience
Authors: A. Burhan Ferhanoglu, Murat Özbalak, Ayse Salihoglu, Teoman Soysal, ihsan Karadoğan, Semra Paydas, Evren Ozdemir, Birol Yıldız, Nuri Karadurmuş, Leylagül Kaynar, Zeynep Arzu Yeğin, Ezgi Pınar Özbalak, Gülsan Sucak, Vildan Ozkocaman, Pervin Topçuoğlu, Muhit Ozcan, Elif Birtas, Hakan Goker
Journal: Blood (2017)
Geolocation of uterine cervical neoplasms (UCN) in the context of a prevention program in Tucumán, Argentina.
Authors: Silvia Victoria Holgado, Ana Vinuales, Daniel Gustavo Goroso, William Tsutomu Watanabe, Juan Jose Zarba, Adriana Gonzalez, Natalia Bliss, Italia Vega
Journal: Journal of Clinical Oncology (2021)

e13535 Background: : UCN is one of the major public health problems in Tucumán, that must be related to the type of population to which it belongs (Rural or Urban). Geolocation allows the processing and analysis of geographic information whose results support decision-making in solving complex planning and management problems on the territory. The objective of this study is to carry out management quality controls of the PPCCUT (Programa de Prevención de Cáncer Cervical Uterino-Tucumán) to achieve adequate prevention and detection of uterine cervical lesions in the province. Methods: An observational cross-sectional study of 1343 women, (16-90 years), with a biopsy diagnosis UCN, under PPCCUT (years 2013-2020). Preanalytical work: allowed the review quality the registries and the diagnoses follow-up. Data recollection from SITAM (Online Information System for Screening), population registry database. Variables: Address: registered in SITAM, joined by information from the provincial female electoral roll 2019. Histological Diagnosis: High grade squamous intraepithelial lesion (HSIL), Invasive Squamous Carcinoma (ISC), Adenocarcinoma In situ (AIS), Invasive Adenocarcinoma (IDA). Analytical work: The conversion from address to latitude and longitude was performed by programming Google Sheet. This data was segmented by hospital center and opened in layers inside QGIS, as well as the map of Argentina. Results: Preanalytical. Register showed from 1343 patients received 1748 biopsies, were excluded 160 without address (incomplete data loading by the effectors). Lack of coordination in diagnosis area: 33 patients received first “in situ diagnosis” and in a short time later were consider “invasive lesions”. Some Patients had 2 bis 6 biopsies with same diagnosis. Analytical (geolocation): showed the influence of PPCCUT outside the province, including living abroad. It was found correlation between patients’ distribution with the population density. Conclusions: The importance of the work lays in the lack of antecedents in the application of the geolocation tool in programs of UCN in Tucumán and in other regions of Argentina. This allowed monitoring in different aspects of the programmatic management.
Effectiveness and tolerability of FOLFOXIRI regimen in the third- and subsequent lines of therapy in patients with metastatic colorectal cancer.
Authors: Kseniya Yakimovich, Mariya Alaniya, Polina Shilo, Anastasia Mochalova, Evgeny Ledin
Journal: Journal of Clinical Oncology (2021)

e15584 Background: Options of therapy are limited for patients with colorectal cancer who developed disease progression during standard 5-FU-, oxaliplatin-, and irinotecan-contained regimens. There is straight information about synergy of irinotecan (SN-38) and oxaliplatin gained from fundamental and early clinical trials. We aimed to analyze effectiveness and safety of triple drug-combination of 5-FU, oxaliplatin and irinotecan (FOLFOXIRI) in heavily pretreated patients with metastatic colorectal cancer. Methods: Patients with a metastatic colorectal cancer who received more than 2 lines of standard 5-FU-, oxaliplatin- and irinotecan-based doublet regimens with or without targeted therapy were included. Reinduction of chemotherapy in previous lines was allowed. The retrospective analysis of medical histories was done. Eligible patients had to receive number of cycles that were sufficient for response rate estimation. Disease response was evaluated according to RECIST 1.1 criteria. Survival analysis was performed using the Kaplan-Meier method. Tolerability was estimated by CTCAE v. 5.0. Results: Forty-six patients were included in retrospective per protocol analysis. The median follow-up was 19 months. The median number of previous lines of chemotherapy was 2 (2-6). Primary resistance to oxaliplatin- and irinotecan-based chemo during previous lines was noted in 20 patients (43%) and 16 patients (35%), respectively, while seven patients (15%) developed the primary resistance to both agents given in a sequential order. All patients were treated with targeted therapy during previous treatment lines. The median of FOLFOXIRI cycles was 8 (range, 2-19). Two patients (4%) were treated with FOLFOXIRI without any targeted agents. The objective response rate was 33% (n = 15). The disease stabilization was reached in 43% (n = 20). The disease control rate was 76% (n = 35). Eleven patients (24%) had the progression of disease at the first follow-up. The median progression free survival and median overall survival were 6 months and 11 months, respectively. Toxicity was evaluated in 35 patients. The most common severe adverse events (grade 3 and 4) were neutropenia (46%) and fatigue (26%). Treatment was delayed in 20 patients (57%), and 13 patients (37%) required dose reduction. One patient had to discontinue treatment due to unacceptable toxicity. Conclusions: According to our study FOLFOXIRI provides the objective response and increased life expectancy in heavily pretreated patients. The further assessment of FOLFOXIRI regimen for refractory colorectal cancer in the prospective trials is needed.
HGG-23. IN VITRO AND IN VIVO PRECLINICAL DRUG SCREENING OF PROMISING THERAPEUTICS FOR DIFFUSE MIDLINE GLIOMA (DMG)
Authors: Chiara Cianciolo Cosentino, Sandra Laternser, Justyna M Przystal, Sridevi Yadavilli, Jie Zhang, Timothy Müller, Bettina Kritzer, Sabine Müller, Javad Nazarian
Journal: Neuro-Oncology (2021)

Abstract Introduction Diffuse midline gliomas (DMGs) are amongst the most unforgiving pediatric brain tumors, characterized by an intrinsic resistance to therapy. Despite major advances in understanding of tumor biology, the prognosis remains exceedingly poor, and treatment options are limited. New therapeutics are being evaluated at a fast rate by different laboratories. In order to prioritize effective drug candidates for DMG treatment, we comprehensively characterized a panel of promising therapeutic agents in in vitro and in different vivo systems. Methods We determined the sensitivity of primary DMG cell lines to a panel of small molecule inhibitors targeting known DMG targets and pathways. Dose response curves were generated for more than 20 different compounds and possible synergistic effects were investigated by SynergieFinder. In an effort to highlight potential toxicities and associated mechanisms at a large scale, we performed a preclinical toxicity evaluation in zebrafish larvae, with a slightly modified version of the official Fish Embryo Acute Toxicity (FET) test. Drug toxicity was tested by continuous exposure of zebrafish larvae to increasing concentrations of the different compounds. Survival curves, morphological analyses and behavioral tests were performed at a maximum tolerated dose (MTD). To confirm the findings obtained in zebrafish, we further performed in vivo studies in mice for promising candidates. Results Among the tested drugs in vitro we found 10 drugs showing promising dose- dependent reduction in cell viability with IC50 in nM to µM range. These were further evaluated for toxicity in zebrafish. The zebrafish larvae toxicities observations strongly correlated with the findings in murine in vivo studies, reinforcing the importance of zebrafish as an accurate investigative toxicology model to assess acute toxicity of molecules in preclinical studies. Conclusions By testing a wide range of drugs, targeting different pathways on DMG cells and in different in vivo systems we identified promising drug candidates for clinical management of children diagnosed with DMG.
Serial plasma and CSF cell-free tumor DNA (cf-tDNA) tracking in diffuse midline glioma patients undergoing treatment with ONC201.
Authors: Evan Cantor, Kyle Wierzbicki, Rohinton Tarapore, Chase Thomas, Rodrigo Cartaxo, Viveka Nand Yadav, Ramya Ravindran, Amy Bruzek, Andrea Franson, Rajen Mody, Hugh Garton, Yazmin Odia, Cassie Kline, Nicholas A Vitanza, Soumen Khatua, Sabine Mueller, Joshua E. Allen, Sharon L. Gardner, Carl Johannes Koschmann
Journal: Journal of Clinical Oncology (2021)

2012 Background: Diffuse midline glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. There are few available means of monitoring the disease beyond serial MRI scans, making clinical decision making slow, difficult, and often reactive. Methods: We conducted a multi-site phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n=24) underwent serial lumbar puncture (baseline, 2 and 6 months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. CSF collection was feasible in this cohort, with no procedural complications. We collected a total of 96 plasma samples and 53 CSF samples from 29 patients, including those with H3F3A (H3.3) (n=13), HIST13HB (H3.1) (n= 4), and unknown H3 status/not biopsied (n=12) [range of 0-8 CSF samples and 0-10 plasma samples]. We performed digital droplet polymerase chain reaction (ddPCR) analysis and/or amplicon-based electronic sequencing (Oxford Nanopore) of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Results: Preliminary analysis of samples (n=58) demonstrates a correlation between changes in tumor size and H3K27M cf-tDNA VAF, when removing samples with concurrent bevacizumab. Analysis of remaining CSF and plasma samples is ongoing, including analysis of novel biomarkers of response. In multiple cases, early reduction in CSF cf-tDNA predicts long-term clinical response (&gt;1 year) to ONC201 and does not increase in cases of later-defined pseudo-progression (radiation necrosis). For example, a now 9-year old patient with thalamic H3K27M-mutant DMG underwent treatment with ONC201 after initial radiation and developed an increase in tumor size at 4 months post-radiation (124% baseline) of unclear etiology at the time. Meanwhile, her ddPCR declined from baseline 6.76% VAF to &lt;1%, which has persisted, with now near complete response (85% tumor reduction) at 30 months on treatment from diagnosis. Conclusions: In summary, we present the feasibility and utility of serial CSF/plasma monitoring of a promising experimental therapy for DMG.
Trop-2 inactivates E-cadherin and drives colon cancer metastasis.
Authors: Saverio Alberti, Emanuela Guerra, Donato F. Altomare, Raffaella Depalo, Marco Trerotola
Journal: Journal of Clinical Oncology (2021)

e15576 Background: Metastatic diffusion is the biggest hurdle for colon cancer (CRC) cure and the identification of decisive drivers of CRC metastasis is an urgent need in CRC care. Methods: The expression of target molecules in primary tumors and metastases was systematically assessed by DNA array and IHC analysis. Cell-cell adhesion capacity was quantified in 2D cell cultures and in HCT116 CRC cell spheroids. Pro-metastatic impact of wtTrop-2 and activated, tail-less Trop-2 (Δcyto) was assessed in vivo in orthotopic diffusion models of KM12SM CRC cells. Primary CRC and metastasis transcriptomes were analyzed for differential induction of EMT determinants. Kaplan–Meier plots were used to illustrate survival and metastatic relapse in independent case series of CRC patients. Results: Trop-2 was identified as uniquely upregulated in CRC models by transcriptome analysis. wtTrop-2 and ΔcytoTrop-2 were shown to induce cell migration, wound-healing and resistance to apoptosis induction . wtTrop-2 increased the metastatic capacity of KM12SM cells, raising metastasis diffusion from 45% for control cells to 90% for wtTrop-2 transfectants. The constitutively-active ΔcytoTrop-2 further boosted metastatic spreading, with metastatic livers reaching up to four times their normal size. Constitutive high expression of E-cadherin was revealed in cancer metastases. No evidence was obtained for transcriptional down-regulation of epithelial differentiation biomarkers. No induction of EMT transcription factors was observed in Trop-2-activated cells. Trop-2 tightly bound E-cadherin and caused its release from the cytoskeleton, for loss of cell-cell adhesion and activation of β-catenin. The Trop-2/E-cadherin/β-catenin-driven pro-metastatic program was recapitulated in CRC patients and was shown to impact on CRC metastatic relapse and overall patient survival. Conclusions: We identify Trop-2-driven functional inactivation of E-cadherin as a key driver of metastatic diffusion in CRC. These findings may pave the way for novel multi-marker personalized diagnostics and anti-cancer therapies. [Table: see text]
Improved transfusion independence rates for momelotinib versus ruxolitinib in anemic JAKi naïve myelofibrosis patients independent of baseline platelet or transfusion status.
Authors: Jean-Jacques Kiladjian, Uwe Platzbecker, Jiří Mayer, Árpád Illés, Witold Prejzner, Tomasz Woźny, Nikolay Tzvetkov, Alessandro M. Vannucchi, Ilya Kirgner, Zsolt Nagy, Sebastian Grosicki, Åsa Derolf, Mihaela Cornelia Lazaroiu, Sung-Soo Yoon, Yeow Tee Goh, Nikolas von Bubnoff, Srdan Verstovsek, Barbara J. Klencke, Rafe Donahue, Ruben A. Mesa
Journal: Journal of Clinical Oncology (2021)

e19039 Background: Momelotinib (MMB) is a potent JAK1, JAK2 and ACVR1 inhibitor with clinical activity against the hallmark features of myelofibrosis (MF), namely anemia, constitutional symptoms and splenomegaly, across the continuum of JAKi naïve or previously JAKi treated intermediate/high risk MF patients as demonstrated in the previously conducted Phase 3 SIMPLIFY-1 &amp; -2 clinical trials (S1, S2). S1 was conducted in JAKi-naïve patients with MF (n = 432) double-blind randomized 1:1 to MMB or ruxolitinib (RUX). MMB demonstrated a statistically non-inferior splenic response rate (SRR) to RUX at the W24 landmark analysis in S1 but did not meet significance for total symptom score (TSS) response. Low SRR and TSS response was observed for RUX in patients with low platelets, while MMB elicited consistent SRR and TSS response across the platelet subsets, comparable to the response in the ITT. Transfusion independence (TI) at W24 was higher for MMB vs RUX patients across all PLT strata. Methods: Progressive anemia is a common occurrence in MF with nearly all MF patients requiring transfusions as their disease advances. Given the prognostic importance of Hgb and transfusion status in MF patients including evidence that achieving or maintaining transfusion independence by Week 24 with momelotinib is associated with improved OS in S1 and S2, we expanded the previously reported retrospective platelet subset analysis to explore the W24 TI response rates for MMB and RUX randomized patients in S1 by baseline Hgb and PLT levels and transfusion status. Results: The data presented here suggest that the prognostically-important W24 TI rate was substantively higher in anemic patients receiving MMB versus RUX, irrespective of the degree of anemia. MMB is also more effective relative to RUX in achieving or maintaining TI in JAKi naïve patients irrespective of baseline PLT count or baseline transfusion status. Conclusions: Together with data suggesting that TI response at W24 with momelotinib is associated with a survival advantage, these data further support the potential TI benefits of inhibiting ACVR1 in addition to JAK1 and JAK2 with MMB in MF patients. Clinical trial information: NCT01969838, NCT02101268. [Table: see text]
COVID-19 communication to English- and Spanish-speaking cancer patients: A website analysis of seven healthcare systems in north Texas.
Authors: Robin T. Higashi, John W. Sweetenham, Aimee D. Israel, Jasmin A. Tiro
Journal: Journal of Clinical Oncology (2021)

e18515 Background: The COVID-19 pandemic created an urgent need for timely and accurate public health information. This is especially true for those with cancer because they face higher morbidity and mortality from COVID-19. At the same time, the disproportionate impact of the pandemic on Latinx populations underscores the need for information to reach Spanish-speakers. Given the large proportion of Spanish-speakers in the U.S., healthcare institutions have a professional and moral obligation to meet this critical need. Methods: We conducted a multi-modal, mixed method document review study to evaluate the equity of online information about COVID and cancer available to English- and Spanish-speakers from seven north Texas healthcare institutions. We sampled 50 websites (33 English, 17 Spanish) over a one-week period in May 2020. Websites included 27 healthcare institutions and 23 external organizations (e.g. CDC). Thematic content was analyzed using a coding conversion process; literacy level was measured using Readability software; accessibility was measured using the Patient Education and Materials Assessment Tool (PEMAT); and video and diversity content were defined and counted. Results: Content on Spanish websites was sub-optimal compared to English. We observed significant differences in thematic content, poor linkage to external Spanish content, and errors in translation. Whether differences were intentional was unclear. Across all sites, content specifically about COVID and cancer was more prevalent in English than Spanish (58% vs. 43%). Three institutions’ websites contained no information about COVID specifically for cancer patients, and three institutions included only a banner link to COVID updates or information from their main oncology page. Only one institution’s website included comprehensive COVID-related information specifically for cancer patients, such as postponing treatment, oral cancer treatments, and extra assurances taken for protection during in-person care; however, this website was available in English only. Spanish websites scored on average at a lower literacy level than English (11 th vs. 13 th grade). Using the PEMAT, healthcare institutions’ average accessibility of Spanish pages (n = 7) was slightly lower than that of English pages (n = 19) (77% vs. 81%, respectively), due mostly to discrepancies in English-only videos and visual aids; conversely, among external organizations’ websites, the average accessibility score of Spanish pages (n = 10) was higher than that of English pages (n = 13) (86% vs. 83%, respectively). Conclusions: In one region, Spanish-speakers lack equitable access to information about COVID-19 and cancer compared with English-speakers, leaving an already vulnerable patient population at greater risk for poor health outcomes. We offer recommendations for enhancing equity of access to information.