tbuckley/cabot-search huggingface dataset:
Patient-derived lung cancer organoids for the selection of therapeutic options in an <i>ALK-</i>rearranged tumor.
Authors: Beatriz Jimenez Munarriz, Zahra Dantes, Javier De Castro, Paloma Navarro, Monica Yagüe, Arantzazu Barquin, Juan Francisco Rodriguez-Moreno, Elena Sevillano, Sergio Ruiz, Anabel del Barrio, Gema García Ledo, Miriam Dorta, Ana Collazo Lorduy, Emiliano Calvo, Jesús García-Donas, Sandra Serrano, Apoorva Manjunath, Luciana Ferreira, Barbara Hefel, Jordi Remon
Journal: Journal of Clinical Oncology (2021)

e21014 Background: ALK rearrangements are key targets in non-small-cell lung cancer (NSCLC). Unfortunately, the optimal sequential strategy of ALK-tyrosine kinase inhibitors (TKI) remains to be defined. Testing drug sensitivity in patient derived organoids (PDOs) could support a rational drug selection in this setting. Methods: We designed an observational study assessing the correlation between drug sensitivity of PDOs established in Invitrocue and the clinical outcome in our institution. To date, forty cases have been included, of which nine were lung cancers. Results: PDO was sucessfully established in 7/9 cases (77%). Three patients did not receive any of the drugs tested in vitro due to clinical deterioration. One patient was deemed as sensitive to carboplatin but tumor showed to be resistant. A meaningful correlation was observed in an oncogenic addicted tumor. A 54-year-old never-smoker man who had been diagnosed with lung adenocarcinoma stage IVa (T3N1M1a). He received standard first-line therapy with platinum-based chemotherapy, immunotherapy and antiangiogenics achieving tumor progression. A next-generation sequencing (NGS) panel revealed the presence of the EML4-ALK fusion variant 3a/b. The patient started alectinib but showed progression after 12 months. A second NGS panel did not identify any new ALK resistance mutation but acquiring TP53. Treatment was switched to brigatinib with no response. Finally, fresh tumor tissue was obtained from a liver biopsy to establish PDOs and drug sensitivity to 8 compounds was tested. The In vitro results demonstrated no activity of lorlatinib but a strong response to crizotinib. The patient started Crizotinib 250mg BID achieving partial response after 8 weeks and treatment duration of 6 months. A third liver biopsy for PDOs and NGS revealed acquired ALK C1156Y and I1171T mutations that confer resistance to crizotinib but sensitive to ceritinib, respectively. Conclusions: We present clinical evidence that PDOs are an alternative tool in oncogenic addicted tumors helping to guide treatment decisions and increasing a more personalized sequential treatment approach.
Are current family-history based colorectal cancer screening guidelines adequate for early detection and potential prevention of young-onset cases?
Authors: Y. Nancy You, Miguel A. Rodriguez-Bigas, George J. Chang, Brian K. Bednarski, John Michael Skibber, Maureen E Mork, Julie B Moskowitz, Sa Thi Nguyen, Selvi Thirumurthi, Patrick M. Lynch, Scott Kopetz, Eduardo Vilar Sanchez
Journal: Journal of Clinical Oncology (2021)

3549 Background: Strategies to detect and prevent young-onset colorectal cancer (YOCRC, diagnosed under age 50) are critical. Established high-risk screening guidelines (SGs) aim to detect/prevent YOCRCs arising from hereditary syndromes. For non-hereditary YOCRCs, average-risk screening is being considered at an earlier age, but family history (FH)-based increased-risk screening has been poorly studied. We aimed to define the proportion of non-hereditary YOCRC with a FH, and to determine whether existing SGs could have detected/prevented these cases. Methods: 394 consecutive YOCRC patients presenting for surgical resection were reviewed for tumor MMR status, pedigree and genetic testing. Those with known/suspected hereditary syndrome (by phenotype, MMR status, and/or germline mutation) were excluded (N = 65). Pedigrees (N = 329) were analyzed for first- or second-degree relatives (FDR, SDR) with CRC and the ages of diagnosis. The gap between the recommended age for FH-based CRC screening and the age of YOCRC diagnosis was calculated. Results: 89 (27%) non-hereditary YOCRC patients had a FH of CRC. The median age of diagnosis was 45; the tumors were mostly from the distal colon (22%) and rectum (60%), and stage III (48%) and IV (27%). Twenty-one (24%) patients had 22 FDRs with CRCs diagnosed at age 64 (median); and 71 (80%) patients had 92 SDRs with CRCs diagnosed at age 65 (median). Thirteen (15%) had a FH of YOCRC. The existing SGs consider 39 patients (44%) at increased-risk, and the remaining, average-risk (Table). Screening would have begun prior to the YOCRC diagnoses in 28 (31% [or 46, 52%]) patients. But YOCRC diagnosis preceded the recommended screening age in the remaining 61(69% [or 43, 48%]) patients by a median of 5.3 [or 3.9] years (Table). Conclusions: FH is found in 27% of the non-hereditary YOCRC patients; 15% has a FH of YOCRC. In nearly half of the patients, YOCRC was diagnosed several years earlier than the recommended age for FH-based screening, even assuming perfect SG adoption and starting average risk screening at age 45. Refining existing FH-based SGs can potentially be impactful.[Table: see text]
Abstract 13175: Outcomes of Clostridium Difficile Infection in Patients With Heart Failure: A Nationwide Analysis
Authors: Devesh Rai, Muhammad Waqas Tahir, Amit Bansal, Qiu Tong, Mohammad Abu Sheikha, Raseen Tariq
Journal: Circulation (2019)

Background: Clostridium diffcile infection (CDI) is the most common nosocomial infection. Patients with heart failure (HF) are frequently hospitalized due to exacerbations or with common bacterial ...
Clinical and Functional Characterization of Atypical<i>KRAS</i>/<i>NRAS</i>Mutations in Metastatic Colorectal Cancer
Authors: Jonathan M. Loree, Yucai Wang, Muddassir A. Syed, Alexey V. Sorokin, Oluwadara Coker, Joanne Xiu, Benjamin A. Weinberg, Ari M. Vanderwalde, Anteneh Tesfaye, Victoria M. Raymond, Benjamin Miron, Gabi Tarcic, Ori Zelichov, Russell R. Broaddus, Patrick Kwok Shing Ng, Kang Jin Jeong, Yiu Huen Tsang, Gordon B. Mills, Michael J. Overman, Axel Grothey, John L. Marshall, Scott Kopetz
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Mutations in KRAS/NRAS (RAS) predict lack of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). However, it is unclear if all RAS mutations have similar impact, and atypical mutations beyond those in standard guidelines exist. Experimental Design: We reviewed 7 tissue and 1 cell-free DNA cohorts of 9,485 patients to characterize atypical RAS variants. Using an in vitro cell-based assay (functional annotation for cancer treatment), Ba/F3 transformation, and in vivo xenograft models of transduced isogenic clones, we assessed signaling changes across mutations. Results: KRAS exon 2, extended RAS, and atypical RAS mutations were noted in 37.8%, 9.5%, and 1.2% of patients, respectively. Among atypical variants, KRAS L19F, Q22K, and D33E occurred at prevalence ≥0.1%, whereas no NRAS codon 117/146 and only one NRAS codon 59 mutation was noted. Atypical RAS mutations had worse overall survival than RAS/BRAF wild-type mCRC (HR, 2.90; 95% confidence interval, 1.24–6.80; P = 0.014). We functionally characterized 114 variants with the FACT assay. All KRAS exon 2 and extended RAS mutations appeared activating. Of 57 atypical RAS variants characterized, 18 (31.6%) had signaling below wild-type, 23 (40.4%) had signaling between wild-type and activating control, and 16 (28.1%) were hyperactive beyond the activating control. Ba/F3 transformation (17/18 variants) and xenograft model (7/8 variants) validation was highly concordant with FACT results, and activating atypical variants were those that occurred at highest prevalence in clinical cohorts. Conclusions: We provide best available evidence to guide treatment when atypical RAS variants are identified. KRAS L19F, Q22K, D33E, and T50I are more prevalent than many guideline-included RAS variants and functionally relevant.
Whole-exome sequencing in advanced-stage sensitizing <i>EGFR</i> mutation non-small cell lung cancer: Explore resistance biomarkers to EGFR TKI treatment.
Authors: Chanida Vinayanuwattikun, Piyada Sitthideatphaiboon, Chinachote Teerapakpinyo, Krittiya Korphaisarn, Naravat Poungvarin, Poonchavist Chantranuwatana, Shanop Shuangshoti, Chatchawit Aporntewan, Virote Sriuranpong
Journal: Journal of Clinical Oncology (2021)

9039 Background: Despite the development of predictive biomarkers to shape treatment paradigms and outcomes, 10-20% of de novo EGFR TKI resistance advanced non-small cell lung cancer (NSCLC) in the presence of EGFR mutation remains the issue of concern. Methods: We explored clinical factors in 332 advanced NSCLC who received EGFR TKI and molecular characteristics through 65 whole exome sequencing of various EGFR TKI responses including; de novo (progression within 3 months), intermediate response (IRs) and long-term response (LTRs) (durability &gt; 2 year). Results: Uncommon EGFR mutation subtype was a significant variable in de novo resistance vs. IRs and LTRs with odd ratios of 6.83 ([95% CI 2.36 – 19.80], p-value &lt; 0.001) and 16.84 ([95%CI 1.66 – 171.45, p-value 0.02), respectively. The remaining sensitizing EGFR mutation subtype (exon 19 del and L858R) accounted for 75% of de novo resistance. Genomic landscape analysis was conducted, focusing in 10 frequent oncogenic signaling pathways with functional contributions; cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGF-β, p53 and β-catenin/Wnt signaling. Cell cycle pathway was the only significant alteration pathway among groups with the FDR p-value of 6×10 -4 . We found only significant q-values of &lt; 0.05 in 7 gene alterations; CDK6, CCNE1, CDK4, CCND3, MET, FGFR4 and HRAS which enrich in de novo resistance [range 36-73%] compared to IRs/LTRs [range 4-22%]. Amplification of CDK4/6 was significant in de novo resistance, contrary to IRs and LTRs (91%, 27.9% and 0%, respectively). The presence of co-occurrence CDK4 /6 amplification correlated with poor disease outcome with HR of progression-free survival of 3.63 [95% CI 1.80-7.31, p-value &lt; 0.001]. Conclusions: The presence of CDK4 /6 amplification in pretreatment specimen serve as a predictive biomarker for de novo resistance in sensitizing EGFR mutation.
Use of High-Sensitivity Cardiac Troponin in Patients With Kidney Impairment
Authors: Peter J. Gallacher, Eve Miller-Hodges, Anoop S.V. Shah, Atul Anand, Neeraj Dhaun, Nicholas L. Mills, Nicholas L Mills, Fiona E Strachan, Christopher Tuck, Anoop SV Shah, Atul Anand, Tariq Farrar, Nynke Halbesma, James Blackmur, Andrew R Chapman, Amy V Ferry, Kuan Ken Lee, Dennis Sandeman, Philip D Adamson, Catherine L Stables, Catalina A Vallejos, Athanasios Tsanas, Lucy Marshall, Stacey D Stewart, Takeshi Fujisawa, Mischa Hautvast, Jean McPherson, Lynn McKinlay, David E Newby, Keith AA Fox, Colin Berry, Simon Walker, Christopher J Weir, Alasdair Gray, Paul O Collinson, Fred S Apple, Alan Reid, Anne Cruikshank, Iain Findlay, David A McAllister, Donogh Maguire, Jack PM Andrews, Alastair Moss, Mohamed S Anwar, John Hung, Jonathan Malo, Colin Fischbacher, Bernard L Croal, Stephen J Leslie, Catriona Keerie, Richard A Parker, Allan Walker, Ronnie Harkess, Tony Wackett, Roma Armstrong, Laura Stirling, Claire MacDonald, Imran Sadat, Frank Finlay, Heather Charles, Pamela Linksted, Stephen Young, Bill Alexander, Chris Duncan
Journal: JAMA Internal Medicine (2021)

High-sensitivity cardiac troponin (hs-cTn) assays have improved the diagnosis of myocardial infarction in patients with healthy kidney function and are now widely used in clinical practice. 1However, in patients with kidney impairment, long-term elevations in troponin levels are common, and interpretation can be more challenging. 2 As such, the effect of implementing hs-cTn testing on the diagnosis and outcomes of patients with kidney impairment is uncertain.Methods | High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome (High-STEACS) was a stepped-wedge, cluster-randomized clinical trial that evaluated the use of a hs-cTnI assay in consecutive patients with suspected acute coronary syndrome across 10 hospitals (NCT01852123) (Supplement 1; eAppendix in Supplement 2). 3 The trial was conducted in accordance with the Declaration of Helsinki and with the approval of the Scotland Research Ethics Committee, the Public Benefit and Privacy Panel for Health and Social Care, and each National Health Service Health Board.As randomization was at the hospital level, individual patient consent was not sought.Throughout the trial, cTnI was measured using contemporary and high-sensitivity assays (ARCHITECT STAT ; Abbott Laboratories).Before use, results from the hs-cTnI assay were suppressed, and the contemporary assay (single threshold based on the coefficient of variation) guided care.
Prognostic Implications of Minimal Residual Disease Detection in Acute Myeloid Leukemia (AML) with Cytarabine Based Therapy of Differing Dose Intensities
Authors: Prajwal Boddu, Mahesh Swaminathan, Farhad Ravandi, Guillermo Garcia-Manero, Gautam Borthakur, Elias J. Jabbour, Courtney D. DiNardo, Naval Daver, Nitin Jain, Naveen Pemmaraju, Jeffrey L. Jorgensen, Sa A. Wang, Michael Andreeff, Jorge E. Cortes, Hagop M. Kantarjian, Tapan Kadia
Journal: Blood (2017)
Helen Salisbury: Should GPs break the law on data privacy?
Authors: Helen Salisbury
Journal: BMJ (2021)

NHS Digital plans to extract all data coded in GP held medical records in England, unless patients opt out first. These data include all physical and mental health diagnoses, physiological measurements, test results, and medications. The data will be pseudonymised, meaning that identifiers such as name, NHS number, date of birth, and the second part of the postcode will be hidden—but NHS Digital has a key to re-identify records, which it will do “where there is a legal reason.”

The stated aim of the dataset is to assist research and planning. The list of organisations NHS Digital may share data with includes other government departments, universities, …
Phase I/II trial of intratumoral administration of hu14.18-IL2, with local radiation, nivolumab, and ipilimumab in subjects with advanced melanoma.
Authors: Mark R. Albertini, Zachary Scott Morris, Jacquelyn A Hank, Erik Ranheim, Cindy L Zuleger, Kimberly McDowell, Renae M Quale, Molly Monson, Erin Clements, Tamara Koehn, Heather B. Neuman, Sharon M. Weber, Jennifer Racz, Mary Beth Henry, Emily Reinstad, KyungMann Kim, Stephen D. Gillies, Paul M. Sondel
Journal: Journal of Clinical Oncology (2021)

TPS9591 Background: We are studying an intratumoral (IT) in situ vaccine strategy using the GD2-reactive hu14.18-IL2 immunocytokine (hu-IC) to convert the injected tumor into a site of enhanced tumor antigen presentation, as has been shown in mice. Hu-IC is a humanized monoclonal antibody (mAb) covalently linked to two molecules of IL-2 at the Fc region. The hu14.18 mAb recognizes GD2, a disialoganglioside found in tumors of neuroectodermal origin. We previously studied intravenous (IV) hu-IC and reported immune activation and reversible toxicities (1). Surgery to resect recurrent stage III or stage IV melanoma combined with 3 courses of IV hu-IC resulted in prolonged tumor-free survival in some patients (2). Murine GD2+ tumor models showed enhanced antitumor activity and recruitment of T cells using hu-IC IT versus IV (3). In these models, the combination of radiation therapy (RT) followed by IT hu-IC dramatically potentiates the antitumor response and enhanced response to immune checkpoint blockade (4). Biological samples (blood and tumor) will be interrogated to identify biological mechanisms and develop biomarkers for future testing. Methods: This outpatient phase I/II trial uses a 3 + 3 design to determine maximum tolerated or maximum administered dose of IT hu-IC (planned dose level: 2 mg/m 2 /day; de-escalation dose level: 1 mg/m 2 /day) when given alone (Phase 1A: 3-12 patients), after RT (Phase 1B: 6-12 patients), after RT and in combination with nivolumab (Phase 1C: 6-12 patients), and after RT and in combination with nivolumab and ipilimumab (Phase 1D: 31-34 patients). The trial will evaluate safety, antitumor activity, and immunologic endpoints and includes an expanded Phase II cohort (Phase 1D). The IT injections (once daily x 3 days) are delivered every 21 days for 4 cycles and can then continue every 28 days for up to 13 cycles if there is response/stable disease and residual injectable tumor. Key inclusion criteria: 1) histologically proven, malignant melanoma that is advanced (Stage IV) or surgically incurable; 2) at least 1 (preferably 2) sites of disease amenable to safe repeated IT injections; and 3) must have received or declined at least one FDA approved therapy, either in the adjuvant setting or for metastatic disease, with an impact on survival. Two subjects have been accrued into Phase IA as of 2-4-2021. References: (1)King DM, et al. J Clin Oncol 22:4463-4473, 2004. (2)Albertini MR, et al. Can Imm Imm 67(10):1647-1658, 2018. (3)Yang RK, et al. J of Imm 189:2656-2664, 2012. (4)Morris ZS et al. Can Res 76:3929-3941, 2016. Clinical trial information: NCT03958383.
Addressing gaps in care for patients with rare cancers and blood disorders: The impact of a collaborative digital education initiative.
Authors: Wendy Turell, Tariqa Ackbarali, Elizabeth L. del Nido, Kathryn Pucci, Randi O'Hara, Katie Kowalski, John Hopper, Jim Palma
Journal: Journal of Clinical Oncology (2021)

e23005 Background: Clinicians are uniquely challenged to manage patients with rare cancers and blood disorders due to a lack of knowledge of diagnosis and management guidelines for these conditions. These conditions comprise a larger proportion of diagnosed cancers in minority populations, among whom a worse 5-year survival is realized in adults versus adolescents and children. Patients often experience delayed diagnoses, have limited treatment options, access to specialists, and limited clinical trials. Education surrounding rare cancers and blood disorders, diagnostic criteria, approved agents, and emerging novel agents is essential to improve treatment outcomes for patients with these rare malignancies. Methods: A 2-part CE and American Board of Internal Medicine (ABIM) Maintenance of Certification activity was launched live-online in October and November, 2020, and remains on-demand through November, 2021 at OMedLive.com, comprising 9 hours of virtual education. This first annual activity was launched in partnership with National Organization for Rare Disorders (NORD), and featured key opinion leaders with extensive expertise in rare cancers and blood disorders. Session components included case presentations, downloadable resources, live polling, and audience real-time Q&amp;A. Knowledge and competence questions were administered pre- and immediate post-activity. Patient and clinical practice impact questions were also asked at 2-month follow-up. Data from these questions were analyzed to determine engagement, remaining gaps, and the unique challenges of managing rare cancers and blood disorders. Results: 996 clinicians have participated in the activity to date. All 28 CE test questions reflected improvements in knowledge and competence regarding symptom recognition, diagnosis, clinical trial data, guidelines, treatment options, and adverse event management. At 2-mos. follow up, 71% reported improvements in clinical practice and 67% reported improvements in patient impact (n = 66). Almost half (48%) indicated diagnosis as their most significant challenge, with other noted barriers including: limited access to molecular testing (29%) and limited knowledge of tests to order (17%). The top 3 reported treatment challenges were: a lack of clinical evidence (24%), limited treatment options (22%), and high treatment cost (16%). Updated and expanded data will be shared. Conclusions: Following the targeted collaborative educational initiative, clinicians demonstrated clear knowledge and competency improvements in critical areas such as recognition, diagnosis, and management, and reported significant improvements in patient outcomes and clinical practice. The results of the two-month impact survey demonstrated a need for further tailored education on diagnostic testing and clinical evidence on treatment options for rare malignancies.
Diabetes Risk Reduction Diet and Survival after Breast Cancer Diagnosis
Authors: Tengteng Wang, Maryam S. Farvid, Jae H. Kang, Michelle D. Holmes, Bernard A. Rosner, Rulla M. Tamimi, Walter C. Willett, A. Heather Eliassen
Journal: Cancer Research (2021)

Type II diabetes is associated with poor breast cancer prognosis. To study the association between a diabetes risk reduction diet (DRRD) and survival following breast cancer, we followed 8,482 women with breast cancer from two large cohort studies. Information on diet and other factors was repeatedly measured in validated questionnaires every two to four years. The DRRD includes 9 components: higher intakes of cereal fiber, coffee, nuts, whole fruits and polyunsaturated/saturated fat ratio; and lower glycemic index, trans fat, sugar-sweetened beverages, and red meat. Cumulative average DRRD score was calculated using repeated measures of postdiagnostic diet. Deaths were assessed by family members or via National Death Index. Multivariable-adjusted HRs and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. During a median of 14 years of follow-up since diagnosis, 2,600 deaths occurred among participants, 1,042 of which were due to breast cancer. Women with higher postdiagnostic DRRD score had a 20% lower risk of breast cancer-specific mortality (top vs. bottom quintile HR = 0.80; 95% CI = 0.65-0.97; Ptrend = 0.02) and 34% lower risk of all-cause mortality (HR = 0.66; 95% CI = 0.58-0.76; Ptrend < 0.0001). Compared with women who consistently had lower score (≤median) before and after diagnosis, those whose score improved from low to high had a lower risk of breast cancer-specific mortality (HR = 0.77; 95% CI = 0.62-0.95) and overall mortality (HR = 0.85; 95% CI = 0.74-0.97). These findings demonstrate that greater adherence to DRRD was associated with better survival, suggesting postdiagnosis dietary modification consistent with type II diabetes prevention may be important for breast cancer survivors. SIGNIFICANCE: This study suggests that greater adherence to the diabetes risk reduction diet after diagnosis associates with improved survival outcomes among a large number of breast cancer survivors.