tbuckley/cabot-search huggingface dataset:
A novel clinical tool to estimate risk of false negative KRAS mutation in circulating tumor DNA testing.
Authors: Stefania Napolitano, Ryan Sun, Aparna Raj Parikh, Jason Henry, Christine Megerdichian Parseghian, Jason Willis, Kanwal Pratap Singh Raghav, Van K. Morris, Arvind Dasari, Michael J. Overman, Rajyalakshmi Luthra, Ryan Bruce Corcoran, Scott Kopetz
Journal: Journal of Clinical Oncology (2021)

3594 Background: Recently, in metastatic colorectal cancer (mCRC), the detection of RAS mutations by circulating tumor (ct) DNA has recently emerged as a valid and non-invasive alternative approach, overall showing a high concordance with the standard tissue genotyping, giving information on response to EGFRi treatment and resistant mechanisms. However, RAS mutations may be missed due to low levels of any ctDNA in the blood (false-negative), and it has been difficult to distinguish this from patients without a RAS mutation in the tumor (true-negative). We propose a methodology that can be applied to multi-gene ctDNA testing panels to accurately distinguish true- and false-negative tests. Methods: 357 subjects with tissue and multi-panel ctDNA testing from MD Anderson (MDACC) were used as a training dataset and 295 subjects from Massachusetts General Hospital (MGH) dataset as the testing dataset. CtDNA panels contained between 65 and 70 genes, allowing evaluation of tumor ctDNA shedding from variant allele fraction (VAF) levels in the plasma from other genes (such as APC and TP53). Based on the relationship between KRAS and the VAFs of other gene, we established a Bayesian model providing a posterior probability of false negative in the ctDNA test, using thresholds of &lt; 5% (low), 5-15% (medium), and &gt; 15% (high). This model was validated on the MGH database. Results: Across both cohorts, 431 patients were ctDNA wild type for KRAS. Of those, 29 had tissue documenting a KRAS mutation for a false negative rate of 8%. The model provides the posterior probability that a KRAS mutation is indeed present in the tissue given the observed values of allele frequencies for other mutated genes in the plasma. In the validation cohort, a predicted low false negative had no false negatives (0/62, 95% CI 0%-5.8%), while a predicted medium false negative rate was associated with 3% false negative (1/32, 95% CI 0%-16%). In contrast, a high predicted false negative rate was associated with 5% false negative (5/100, 95% CI 1.6%-11%). The results demonstrate the ability of our tool to discriminate between subjects with true negative and false negatives, as a higher proportion of false negatives are observed at higher posterior probabilities. Conclusions: In conclusion, our approach provides increased confidence in KRAS ctDNA mutation testing in clinical practice, thereby facilitating the identification patients who will benefit from EGFR inhibition while reducing the risk of false negative tests. Extension of this methodology to NRAS and BRAF is possible, with clinical application enabled by a freely available online tool.
HGG-39. ALTERNATIVE SPLICING OF <i>NEUROFIBROMIN 1</i> IS ASSOCIATED WITH ELEVATED MAPK ACTIVITY AND POOR PROGNOSIS IN HIGH-GRADE GLIOMA
Authors: Robert Siddaway, Scott Milos, Arun Vadivel, Tara Dobson, Jyothishmathi Swaminathan, Scott Ryall, Sanja Pajovic, Javad Nazarian, Oren Becher, Michael Brudno, Arun Ramani, Vidya Gopalakrishnan, Cynthia Hawkins
Journal: Neuro-Oncology (2021)

Abstract Despite a good understanding of the coding mutations underlying high-grade gliomas (HGG), their prognosis remains poor. We sought to characterize their transcriptional alterations and how this contributes to pathogenesis. We analyzed a large cohort of pediatric HGG (pHGG) by DNA sequencing (n=79) and RNA-Seq (n=63 plus normal brain, n=20), finding spliceosome mutations that are associated with increased splicing burden. High levels of alternative splicing were found in known cancer driver genes, with enrichment for chromatin regulators (including the SWI/SNF and NuRD complexes) and the RAS/MAPK pathway, in particular neurofibromin 1 (NF1). Both pediatric and adult HGG preferentially expressed NF1-II, a less active RAS GTPase, resulting in increased RAS/MAPK activity resulting from inclusion of exon23a into the GAP-related domain of NF1. In IDH wild-type, adult HGG, NF1-II was associated with reduced survival independently from RAS/MAPK pathway mutations. NF1 exon23a splicing was regulated by REST-mediated suppression of splicing factors controlling its inclusion. Together, our results identify a novel mechanism by which HGG can activate RAS/MAPK signaling and other oncogenic pathways to promote tumorigenesis independently from direct mutations.
The Mitral Annular Disjunction of Mitral Valve Prolapse
Authors: Benjamin Essayagh, Avi Sabbag, Clémence Antoine, Giovanni Benfari, Roberta Batista, Li-Tan Yang, Joseph Maalouf, Prabin Thapa, Samuel Asirvatham, Hector I. Michelena, Maurice Enriquez-Sarano
Journal: JACC. Cardiovascular imaging (2021)
Chromosomal instability associated with pathogenesis in adenomyosis.
Authors: Xiaopei Chao, Wendy Wu, Lei Li, Hui Li, Zhenzhen Li
Journal: Journal of Clinical Oncology (2021)

e22517 Background: Uterine adenomyosis is a benign condition in which endometrium-like epithelial and stromal tissue appear in the myometrium, but easily concurrent with uterine cancer and other diseases. To date, few investigations have explored the molecular mechanism of adenomyosis. This research is the first report that found the association between chromosomal instability and pathogenesis in adenomyosis. Methods: Whole exome (̃39Mb CDS of over 18,000 genes; WES) and RNA sequencing were conducted on a total of 57 adenomyosis patients enrolled in this study from 2018 to 2020, including 57 normal endometrium (EN), 57 adenomyosis (AM) and 11 endometrioses (EMT) samples. Genomic test results including somatic SNVs and CNVs as well as the whole genome duplication status were determined, which were all analyzed correlated with clinical factors. Results: We identified the presence of whole genome doubling event in 19 specimens from 16 adenomyosis patients (grouped as WGD, the other 41 patients grouped as noWGD), related to 7 normal endometrium (EN), 9 adenomyosis (AM) and 3 endometriosis (EMT) samples, which was significant with p value of 4.5e-12 by means of Wilcoxon rank sum test. Disease Free Survival (DFS) of WGD patients was significantly shorter than noWGD patients (Wilcoxon rank sum test: P = 2.42e-04), which indicated that WGD group has early on-set in adenomyosis. Estrogen therapy was applied to 31 patients before uterectomy (11 in WGD group and 20 in noWGD group), and the effectiveness of the treatment was significantly higher in WGD patients (Fisher’s exact test: P = 0.02). We found that one third adenomyosis performed whole genome doubling events, which leaded to the early on-set of this disease and significantly sensitive to estrogen therapy. Cellular stressors are extensive correlated with the generation of polyploid cells in a diploid organism form by cell proliferation progress. Compared with the normal and energy-intensive cell differentiation process, cell proliferation offers a “fast but cheap” solution under stress. Our results suggested that when cell differentiation in uterine could not be carried out properly, cell proliferation would have performed instead and produced more polyploid cells, shown as whole genome doubling events. While this circumstance would have been relieved when easing the metabolic stress with estrogen treatment. Conclusions: Our results explored the strong association between chromosomal instability and pathogenesis of adenomyosis and assumed that polyploidy caused by abnormal cell proliferation might be the molecular mechanism of uterine adenomyosis. More accurate verdict could be concluded through larger scale cohort study.
Heart failure drug titration, discontinuation, mortality and heart failure hospitalization risk: a multinational observational study (<scp>US</scp>, <scp>UK</scp> and Sweden)
Authors: Gianluigi Savarese, Johan Bodegard, Anna Norhammar, Peter Sartipy, Marcus Thuresson, Martin R. Cowie, Gregg C. Fonarow, Muthiah Vaduganathan, Andrew J.S. Coats
Journal: European Journal of Heart Failure (2021)

Use and dosing of guideline-directed medical therapy (GDMT) in patients with heart failure (HF) have been shown to be suboptimal. Among new users of GDMT in HF, we followed the real-life patterns of dose titration and discontinuation of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), beta-blockers, mineralocorticoid receptor antagonists (MRA) and angiotensin receptor-neprilysin inhibitors (ARNI).New users were identified in health care databases in Sweden, UK and US between 2016-2019. Inclusion criterion was a recent HF hospitalization (HHF) triggering the initiation of GDMT. Patients were grouped by GDMT, i.e. ACEi, ARB, beta-blocker, MRA and ARNI, and stratified by initial dose. Follow-up was 12 months, until death or study end. Outcomes were dose titration within each drug class, discontinuation and first HHF or death. Dose/discontinuation follow-up was assessed daily based on the coverage length of a filled prescription and reported on day 365. New users of ACEi (n = 8426), ARB (n = 2303), beta-blockers (n = 10 476), MRA (n = 17 421), and ARNI (n = 29 546) were identified. Over 12 months, target dose achievement was 15%, 10%, 12%, 30%, and discontinuation was 55%, 33%, 24% and 27% for ACEi, ARB, beta-blockers and ARNI, respectively. MRA was rarely titrated and discontinuation rates were high (40%). Event rates for HHF or death ranged from 40.0-86.9 per 100 patient-years across the treatment groups.Despite high risk of clinical events following HHF, new initiation of GDMT was followed by consistent patterns of low up-titration and early GDMT discontinuation in three countries with different health care and economies. Our data highlight the urgent need for moving away from long sequential approach when initiating HF treatment and for improving just-in-time decision support for patients and health care providers.
A randomized trial of a clinic-based weight loss intervention in cancer survivors.
Authors: Rachel Lynn Yung, Anita Giobbie-Hurder, Laura Shockro, Keelin O'Connor, Nancy Campbell, Jocelyn Kasper, Beth Overmoyer, Erica L. Mayer, Sara M. Tolaney, Ann H. Partridge, Jennifer A. Ligibel
Journal: Journal of Clinical Oncology (2016)

167 Background: Evidence increasingly links obesity to increased risk of cancer recurrence and mortality in breast and other cancers, but few studies have evaluated weight loss interventions in cancer patients. We evaluated the impact of a group-based weight loss intervention implemented through an oncology clinic on weight and other outcomes in a mixed population of cancer survivors. Methods: Overweight and obese cancer survivors were randomized 1:1 to immediate or delayed participation in a 15-week group-based weight loss program focused on calorie restriction and increased physical activity. Weight, body composition, physical activity, fitness and quality of life were assessed at baseline and 15 weeks. Changes in measurements between baseline and 15 weeks were compared using Wilcoxon rank sum tests. The primary outcome was change in weight between baseline and 15 weeks between groups. Results: 60 participants were randomized; 30 to intervention and 30 to control. Median age was 52, average BMI was 31.8 kg/m2, 97% of participants were women, and 80% had breast cancer. Intervention participants lost 5.3% of baseline weight at 15 weeks vs 0.2% weight gain in controls (P &lt; 0.001) (Table). Improvements in fitness (6-minute walk test) and physical functioning (EORTC QLQ C30) were also observed in the intervention group vs. controls. Conclusions: We found thatparticipation in a 15-week group-based intervention resulted in weight loss and improvements in fitness and physical functioning in overweight and obese cancer survivors. More work is needed to evaluate the feasibility and sustainability of weight loss programs implemented through oncology practices. Clinical trial information: NCT01978899. [Table: see text]
Ibrutinib Restores Tumor-specific Adaptive Immunity in Chronic Lymphocytic Leukemia
Authors: Clive S. Zent
Journal: Clinical Cancer Research (2021)

Abstract Chronic lymphocytic leukemia (CLL) is characterized by early and profound immune suppression and reversal of these effects is essential to improve patient outcome. Targeted therapy with small-molecule inhibitors such as ibrutinib is highly effective and tolerable. Emerging data suggest that patients with CLL responding to ibrutinib therapy can recover anti-CLL adaptive immune cytotoxicity. See related article by Baptista et al., p. 4624
Time to review the role of intraluminal brachytherapy for dose escalation after concurrent chemoradiation in cancer esophagus: A retrospective audit.
Authors: Ankita Mehta, Piyush Kumar, Richa Gupta, Ayush Garg, Shubhi Agarwal
Journal: Journal of Clinical Oncology (2021)

e16054 Background: Intraluminal brachytherapy (ILBT) for dose escalation after concurrent chemoradiation (CRT) in cancer esophagus is not routinely practiced. This is particularly attributable to radiotherapy toxicity in terms of strictures and fistulas. Cancer esophagus has poor locoregional control and overall survival rates in comparison to head and neck cancers. Dose escalation may be an option to counteract the high failure rates. Methods: A retrospective analysis was conducted for esophageal cancer patients treated between 2008 to 2016 planned for radical CRT to a minimum dose of 59.4 Gy in 33 fractions along with concurrent cisplatin 35 mg/m 2 and 5 FU 375 mg/m 2 on weekly basis. Further, the patients who received dose escalation after external beam radiotherapy (EBRT) completion by ILBT to a dose of 6 Gy in a single fraction to the pre EBRT volume were also analysed. The patient, tumor, treatment characteristics along with response rates, survival outcomes, and toxicities were evaluated and compared between the two groups - the patients who received ILBT and those who did not. Statistical significance between variables was analysed with the Chi-Square or Fischer’s exact test and t-test. Survival analysis was done by Log-Rank test. The analysis was done on a worst-case scenario basis where the patients lost to follow-up were considered dead. Results: The total number of patients treated by CRT was 69, out of which 13 patients received ILBT for dose escalation. The median age was 60 years (Range - 40 to 80 years) and the male: female ratio was 1.09, mean tumor length was 6.4 ± 2.4 cms (Range-1.5-12 cms). The commonest tumor site was the middle third observed in 58% patients. The median EBRT dose was 59.4 Gy (Range- 9 to 63 Gy). The median concurrent chemotherapy cycles were 5. The median follow-up period was 15 months (range 1-100 months). In terms of complete response rates, there was a trend towards significant improvement in patients receiving ILBT compared to those receiving EBRT alone (84.61% versus 57.49%, p=0.07). Also, the overall survival (OS) was significantly higher in the ILBT group (45.31 months versus 19.20 months; p = 0.005). The other patient, tumor, and treatment characteristics analyzed showed no significant impact on OS. There was no significant difference in the incidence of strictures (p=0.206) and severity (p=0.764) of strictures amongst both the groups. Grade ≥3 late toxicity was reported in 10 patients (17.85%) receiving EBRT alone and in 3 patients (23.07%) receiving ILBT. None of the patients receiving ILBT developed a fistula. Conclusions: The present study reveals a dramatic increase in OS by dose escalation with ILBT. The limitations of the present study were a small sample size and a lesser number of patients in the ILBT group. Recapitulating the concept of ILBT to increase the local tumoricidal dose may improve the survival rates.
The BURAN study of buparlisib (AN2025) in combination with paclitaxel compared to paclitaxel alone, in patients with recurrent or metastatic head and neck squamous cell carcinoma.
Authors: Denis Soulieres, Sandrine J. Faivre, Kevin Dreyer, Lisa F. Licitra
Journal: Journal of Clinical Oncology (2021)

TPS6090 Background: Buparlisib (AN2025) is a 2,6-dimorpholino pyrimidine derivative oral pan-class I PI3K inhibitor. The PI3K signaling pathway is one of the most frequently altered pathways in HNSCC. A previous randomized, double-blind, placebo-controlled phase II study (BERIL-1) assessed patients with recurrent/metastatic HNSCC after PD on or after platinum-based chemotherapy in the metastatic setting. Patients assigned 1:1 to receive second-line oral buparlisib or placebo, plus intravenous weekly paclitaxel in 28-day cycles. Median PFS 4.6 months buparlisib arm, 3.5 months placebo arm (hazard ratio 0.65 [95% CI: 0.45–0.95], nominal one-sided p=0.011). Median OS 10.4 months buparlisib arm, 6.5 months placebo arm (hazard ratio 0.72 [95% CI: 0.49-1.04], nominal one-sided p=0.041). Best ORR buparlisib arm 39%, placebo arm 14%. Safety in buparlisib arm was manageable and comparable to placebo arm. (Soulieres, Lancet Oncology). Results suggest that buparlisib in combination with paclitaxel could be effective treatment following failure of platinum-based chemotherapy. Methods: The treatment algorithm for HNSCC was recently modified with inclusion of anti-PD-1/PD-L1 agents that provide a survival advantage, defining an unmet need after their use. The BURAN study is initiated as a confirmatory study to define activity in this setting. Methods: A multicenter, randomized, open-label phase III trial evaluating efficacy and safety of daily buparlisib (100 mg) in combination with weekly paclitaxel (80 mg/m 2 ), compared to weekly paclitaxel alone, in patients with refractory, recurrent, or metastatic HNSCC, progressing after prior anti PD-1/anti PDL-1 therapy either as monotherapy or with a platinum-based regimen (in combination or sequence), and no more than two prior lines of treatment. 483 patients will be randomized 2:1, to receive either buparlisib in combination with paclitaxel or paclitaxel alone, stratified according to historical HPV status. Primary Objective: OS of buparlisib in combination with paclitaxel compared to paclitaxel alone. Secondary Objectives: Comparative PFS, ORR, and DoR, by Investigator and Independent Radiological Review Committee. Efficacy in subgroups of patients by randomization strata. Effect on symptoms and health related QOL. Efficacy related to biomarkers, microbiome analysis. Pharmacokinetics (PK) of buparlisib in combination with paclitaxel. Safety Objective: Comparative safety and tolerability. Primary analysis is OS in the ITT population, once 383 events have occurred, to demonstrate a 20% reduction in risk of death. Survival follow-up is to a maximum of five years. Trial opened December 12, 2020; X patients currently enrolled. Clinical Trial registry number: NCT04338399. Clinical trial information: NCT04338399.
ENVASARC: A pivotal trial of envafolimab, and envafolimab in combination with ipilimumab, in patients with advanced or metastatic undifferentiated pleomorphic sarcoma or myxofibrosarcoma who have progressed on prior chemotherapy.
Authors: Sandra P. D'Angelo, Steven Ian Robinson, Joelle Lam, Bonne J. Adams, James L. Freddo, Charles P. Theuer, Robert G Maki
Journal: Journal of Clinical Oncology (2021)

TPS11581 Background: Metastatic undifferentiated Pleomorphic Sarcoma (UPS) and the genetically related myxofibrosarcoma (MFS) are soft tissue sarcoma (STS) subtypes with poor prognoses. While responses to front line chemotherapy can approach 20%, efficacy remains limited in the 2 nd line setting and beyond. Pazopanib, the only approved treatment in the refractory setting, has demonstrated an objective response rate (ORR) of 4%. Envafolimab is a single domain PD-L1 antibody administered rapidly by subcutaneous (SQ) injection that is being studied in two additional pivotal trials: microsatellite instability-high (MSI-H) cancer and biliary tract cancer. The activity of envafolimab appears to be similar to other PD-1 antibodies administered i.v. Envafolimab demonstrated a 32% objective response rate (ORR) in MSI-H colorectal cancer patients who failed three approved chemotherapeutics, similar to the ORR of 28% and 33% with nivolumab and pembrolizumab in these patient populations, respectively. The rationale for the ENVASARC trial is based on the previously reported activity of checkpoint inhibition in UPS/MFS. Single agent pembrolizumab demonstrated a 23% ORR, while the combination of nivolumab and ipilimumab demonstrated a 29% ORR in refractory UPS/MFS. Methods: ENVASARC (NCT 04480502) is a pivotal multicenter (at ̃25 U.S. centers) open-label, randomized, non-comparative, parallel cohort study of treatment with envafolimab 300 mg every 3 weeks by SQ injection (cohort A; n = 80) or envafolimab 300 mg every 3 weeks by SQ injection combined with ipilimumab 1 mg/kg every 3 weeks i.v. for four doses (cohort B; n = 80) in patients with locally advanced, unresectable or metastatic UPS/MFS who have progressed on one or two lines of prior therapy. The primary objective of each of parallel cohort is to demonstrate an ORR with a lower limit of the 95% confidence interval that excludes 5.0% in each cohort. If ≥ 9 responders are observed of the 80 patients enrolled in each cohort, then the lower bound of the 95% confidence interval will exclude 5.0%. Secondary endpoints include duration of response (DOR), PFS and OS. Key inclusion criteria: ≤ 2 prior lines of therapy (neoadjuvant and adjuvant therapy excluded), ECOG ≤ 1. Clinical trial information: NCT 04480502.