tbuckley/cabot-search huggingface dataset:
Germline polymorphisms in genes maintaining replication fork to predict the efficacy of oxaliplatin and irinotecan in metastatic colorectal cancer (mCRC) patients enrolled in MAVERICC trial.
Authors: Hiroyuki Arai, Yi Xiao, Jingyuan Wang, Francesca Battaglin, Natsuko Kawanishi, Priya Jayachandran, Shivani Soni, Zhang Wu, Christoph Mancao, Bodour Salhia, Shannon M. Mumenthaler, Joshua Millstein, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2021)

3139 Background: Protection of replication forks is critical for the survival of cancer cells. Chemotherapeutic drugs such as oxaliplatin and irinotecan can impede the progression of replication forks by inducing DNA lesions, which cause fork collapse and generate double-strand breaks. We hypothesized that functional genetic variants in genes involved in the maintenance of replication forks may predict the efficacy of cytotoxic drugs in mCRC patients. Methods: We analyzed genomic and clinical data from MAVERICC, a phase II trial which compared mFOLFOX6 and FOLFIRI in combination with bevacizumab in untreated mCRC patients. Genomic DNA extracted from blood samples was genotyped using an OncoArray (Illumina, Inc., San Diego, CA, USA). Candidate six missense single nucleotide polymorphisms (SNPs) ( SLFN11 rs9898983, SLFN11 rs12453150, RPA1 rs5030749, MCM3 rs2230240, TIMELESS rs2291739, and TIMELESS rs774047) were tested for association with progression-free survival (PFS) and overall survival (OS), using Cox proportional hazards model. To confirm the predictive value, the treatment-by-SNP interaction was tested. Results: A total of 324 patients were available for the SNP analyses (mFOLFOX6 plus bevacizumab arm [OHP arm]: n = 161; FOLFIRI plus bevacizumab arm [IRI arm]: n = 163). In the OHP arm, univariable analysis showed a significantly better PFS in patients with G/G genotype of TIMELESS rs2291739 compared to those with any A allele, and in patients with T/T genotype of TIMELESS rs774047 compared to those with any C allele. However, neither of these SNP’s associations were confirmed by multivariable analysis: TIMELESS rs2291739 (any A allele vs G/G, hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.31–1.17, p = 0.12) and TIMELESS rs774047 (any C allele vs T/T, HR = 0.74, 95% CI = 0.41–1.36, p = 0.33). In the IRI arm, univariable analysis showed a significantly worse OS in patients with G/G genotype of TIMELESS rs2291739 compared to those with any A allele, and in patients with T/T genotype of TIMELESS rs774047 compared to those with any C allele. Multivariable analysis confirmed the significant associations in these SNPs: TIMELESS rs2291739 (any A allele vs G/G, HR = 3.06, 95% CI = 1.49–6.25, p &lt; 0.01) and TIMELESS rs774047 (any C allele vs T/T, HR = 2.95, 95% CI = 1.43–6.08, p &lt; 0.01). Treatment-by-SNP interaction test confirmed the significant predictive value of both SNPs, both on PFS and OS. Conclusions: Germline polymorphisms in the TIMELESS gene involved in the protection of replication forks may predict efficacy of oxaliplatin and irinotecan in mCRC patients. Our novel findings warrant further validation studies.
Biological disease-modifying antirheumatic drugs may mitigate the risk of psoriatic arthritis in patients with chronic plaque psoriasis
Authors: Paolo Gisondi, Francesco Bellinato, Giovanni Targher, Luca Idolazzi, Giampiero Girolomoni
Journal: Annals of the Rheumatic Diseases (2021)

To estimate the incidence of psoriatic arthritis (PsA) in patients with psoriasis who had received a continuous treatment with biological disease-modifying antirheumatic drugs (bDMARDs) compared with phototherapy.A retrospective non-randomised study involving patients with moderate-to-severe plaque psoriasis, who were prescribed at least 5 years of bDMARDs or at least three narrow-band ultraviolet light B (nb-UVB) phototherapy courses, and did not have a diagnosis of PsA at enrolment. Development of PsA in each patient was assessed by a rheumatologist according to the Classification for Psoriatic Arthritis criteria. The annual and cumulative incidence rate of PsA was estimated by using an event per person-years analysis. Cox proportional hazards models were undertaken to assess the hazard risk (HR) of PsA after adjustment for confounders.A total of 464 psoriatic patients (bDMARDs, n=234 and nb-UVB, n=230) were followed between January 2012 and September 2020 (corresponding to 1584 and 1478 person year of follow-up for the two groups, respectively). The annual incidence rate of PsA was 1.20 cases (95% CI 0.77 to 1.89) versus 2.17 cases (95% CI 1.53 to 3.06) per 100 patients/year in the bDMARDs versus phototherapy group, respectively (HR 0.29, 0.12-0.70; p=0.006). The variables independently associated with higher risk of PsA were older age (adjusted HR 1.04, 1.02-1.07), nail psoriasis (adjusted HR 3.15, 1.63-6.06) and psoriasis duration >10 years (adjusted HR 2.02, 1.09-3.76); notably, bDMARDs treatment was associated with a lower risk of incident PsA (adjusted HR 0.27, 0.11-0.66).bDMARDs treatment may delay or reduce the risk of incident PsA in patients with moderate-to-severe chronic plaque psoriasis.
Real-world patterns of biomarker testing and targeted therapy in metastatic non-small cell lung cancer (mNSCLC) in the community oncology setting.
Authors: Eric S. Nadler, Anupama Vasudevan, Kalatu Davies, Yunfei Wang, Ravindra Gupta, Sarika Ogale
Journal: Journal of Clinical Oncology (2021)

9079 Background: National guidelines recommend biomarker testing in mNSCLC, and targeted therapy is associated with improved outcomes. The aim of this study was to understand the real-world biomarker testing and treatment patterns in the community setting. Methods: This was a retrospective study of adult patients diagnosed with de novo mNSCLC between 01-Jan-2016 and 30-Sep-2019, with follow-up through 31-Dec-2019 using The US Oncology Network structured electronic health records data. Patients who received systemic treatment for mNSCLC were included. Results: A total of 3213 patients were identified with median age 68 years (24, 90+); 52.7% were male and 10% were current smokers. ECOG score was 0-1 in 55.2%; 60% had adenocarcinoma, 16% had squamous cell carcinoma, and the rest had other/unknown histology. Since most of the biomarker-guided therapies were approved after 2016, testing patterns are described for 2017-2019 (n=2257). Overall, 23.6% were not tested for any biomarker (PD-L1 or driver mutation [DM]) at any time during the study period, and only 49% had a biomarker test result prior to 1L treatment. We observed similar patterns when assessing DM specifically; 35.8% were never tested for DM, and only 39.3% had a DM test result prior to 1L treatment. As an example, out of 42 ALK+ patients in this study population, only 5 had test results prior to 1L treatment and only 3 received an ALK inhibitor as their 1L treatment (Table). Similar patterns were observed for the other biomarkers. Conclusions: Despite availability of promising biomarker-based therapies, the lack of adequate testing in the community oncology setting means that not all eligible patients are receiving the most effective therapies upfront. Nearly 61% of patients had no DM test reported before 1L treatment in this mNSCLC cohort (all histologies), and some were determined to be DM positive at a later time, highlighting a missed opportunity to employ the most effective biomarker-directed front-line treatment. Next steps in this study will include assessing patterns by histology. Structured data, which are recorded for clinical management, might have gaps; future research with chart reviews could provide a more comprehensive assessment.[Table: see text]
Drug Eluting Stent Implantation versus Cutting Balloon Angioplasty for In-Stent Restenosis of Drug Eluting Stent
Authors: Kwak Jae-Jin, Park Keun-Ho, Kim Yong-Seok, Suh Jung-Won, Cho Young-Seok, Chae In-Ho, Choi Dong-Ju, Kim Cheol-Ho, Kim Hyo-Soo, OH Byung-Hee, Park Young-Bae, Chung Woo-Young
Journal: Circulation (2007)
Genomic landscape differences in patients with advanced non-small cell lung cancer by sex and age.
Authors: ErinMarie Kimbrough, Hiba I. Dada, Leylah Drusbosky, Yujie Zhao, Rami Manochakian, Yanyan Lou
Journal: Journal of Clinical Oncology (2021)

9108 Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related death in the U.S. The median age at diagnosis is 70 years, and NSCLC is uncommon among younger individuals ( &lt; 50 years). Overall, outcomes in NSCLC have improved significantly with targeted therapy. A prior study demonstrated patients &lt; 50 are more likely to have targetable alterations including EGFR, ALK, ERBB2, and ROS1. Another study reported an increased prevalence of EGFR mutations in females and KRAS mutations in males with NSCLC. The comprehensive genomic landscape of NSCLC patients in different age groups and genders remains largely unknown. In our study, we aim to investigate the genomic alterations in patients with advanced NSCLC according to age and sex. Efforts that are focused on identifying targetable alterations in NSCLC will likely help personalize treatment and improve outcomes. Methods: We performed a retrospective review of de-identified data from the Guardant Health database from March 2018 through October 2020. We reviewed 34,237 profiles from patients with NSCLC who underwent molecular profiling using the plasma-based circulating-tumor DNA (ctDNA) Next-Generation Sequencing (NGS) assay Guardant360. Single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes were analyzed. We assessed for genomic differences among patients with advanced NSCLC by both sex and age (≥70 and &lt; 70). We conducted two-tailed tests of equality of proportions comparing males to females and ≥70 to &lt; 70. Results: Of the 34,237 profiles reviewed, somatic alterations were seen in 81.7% (n = 27,972) of the patients. The median age was 70 (range 16-102) and 55% were female. Our study demonstrated that the most common genomic alterations in both age groups and genders were TP53, EGFR, KRAS, ATM, and MET. Patients ≥70 were more likely to have ATM (21% versus 14%, p &lt; 0.0001) and MET (12% versus 10 %, p &lt; 0.0001) mutations than those &lt; 70. Patients &lt; 70 were more likely to have EGFR (30% versus 27%, p &lt; 0.0001), STK11 (14% versus 11%, p = 0.0056), and KRAS (26% versus 24%, p &lt; 0.0001) alterations. EGFR was seen more frequently in females (33% versus 26%, p &lt; 0.0001). ATM (11% versus 6%, p &lt; 0.0001) and MET (8% versus 5%, p = 0.0050) were seen more frequently in males. Conclusions: Significant differences in the distribution of targetable genomic alterations were identified among different age groups and genders in patients with advanced NSCLC. These findings highlight the importance of taking personalized approaches to diagnostic testing and treatment of advanced NSCLC.
Joint application of a new rotavirus group from reoviridae family and PD-1 inhibitor on the growth of melanoma В16/F10.
Authors: Sergey A. Kolpakov, Elena P. Kolpakova, Elena Yu. Zlatnik, Oksana G. Shulgina, Elena I. Triandafilidi, Oksana V. Bykadorova
Journal: Journal of Clinical Oncology (2021)

e21573 Background: The purpose of the study was to assess the possible synergism of strains of a new rotavirus group (Reoviridae family) and PD-1 inhibitor pembrolizumab (P) on the growth of murine transplantable melanoma В16/F10. Methods: The study was performed using a strains 228 and 100 of a new group of rotaviruses (working title «group K», RVK) ( http://jbks.ru/archive/issue-10/article-6 ). RVK is a live attenuated and apathogenic strain growing on the PEKC culture (pig embryo kidney cells) with 5·10 9 viral particles/mL. Melanoma B16/F10 was transplanted subcutaneously (2x10 6 living tumor cells/mL) to 40 female mice C57/Bl6. RVK strains (0.3 ml of a virus-containing fluid) were injected intramuscularly once a week during 5 weeks before tumor transplantation and P was administrated intramuscularly (0,04 µg once a week during the life span of the mice) after formation of the visible tumor. The 1 experimental group received RVK 228+P, the 2 – RVK 100+P, the 3 – only P, the 4 group was tumor-bearing control; n was 10 in each group. Results: 1 week after melanoma transplantation tumor was visible and palpable in all the mice except those of the 1 group; 10 days after transplantation tumor size was 0.028±0.0046 cm 3 in the 1 group, 0.14±0.055 in the 2 group, 0.24±0.05 in the 3 group, 0.21±0.042 in the control group. A week later these parameters were 0.6±0.24, 0.99±0.3, 1.3±0.25, и 2.1±0.3 сm 3 respectively, i.e. in all the experimental groups they were decreased vs control (р &lt; 0.05). 3 weeks after transplantation the melanoma size became equal in the 3 and 4 groups (2.0±0.38 и 2.43±0.38 сm 3 respectively) while in mice of the 1 group it remained decreased (1.17±0.26 сm 3 ; р &lt; 0.05). 1 month after transplantation the minimal tumor size was observed in mice of the 2 group (1.9±0.6 cm 3 ), in the 1 group it was 2.6±0.17 сm 3 . By this time only 1 mouse survived in control group while 5 mice survived in the 3 and 1 groups, 6 mice in the 2 group. So in both of the groups vaccinated with RVK before P tumor burden was less than in controls and in mice with only P. The life span of all the experimental groups was similar and significantly higher than in controls. Conclusions: Application of RVK strains №228 and №100 in vaccination mode enhanced the antitumor effect of PD-1 inhibitor pembrolizumab on B16/F10 growth; this defines a solid rationale for their joint use. Strain 228 demonstrates the result in early and strain 100 – in later term of tumor growth.
HGG-35. IDENTIFICATION OF G PROTEIN-COUPLED RECEPTOR 17 (GPR17) UP-REGULATION IN PAEDIATRIC H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA AND EXAMINATION OF ITS ROLE IN DIFFUSE MIDLINE GLIOMA CELL LINES
Authors: Katie Loveson, Helen Fillmore
Journal: Neuro-Oncology (2021)

Abstract Paediatric H3 K27M-mutant diffuse midline glioma (pDMG) is an incurable, aggressive childhood brain malignancy, that arises in a region- and age-specific nature. The underlying pathophysiology suggests dysregulation of postnatal neurodevelopmental processes causing aborted cell differentiation. The cell of origin is unclear, but data suggests an oligodendrocytic lineage (OPC), supported by the over-expression of transcription factors such as Olig1 and Olig2 in 80% of DIPG cases. In-depth bioinformatics and principal component analyses (PCA) of genes involved in brain development and pDMG support reports of OPC gene dysregulation and led to the identification of the G-protein coupled receptor 17 (GPR17) and its association with pDMG. GPR17, a rhodopsin-like orphan GPCR (unknown ligand), has the typical features of the GPCR superfamily, seven transmembrane domains (TM1-TM7), eight amphipathic helices, an extracellular N-terminal domain, and an intracellular C-terminus. GPR17 has been implicated in several normal physiological and pathological processes, such as oligodendrocyte differentiation, spinal cord injury and brain injury. GPR17 mRNA and protein expression was confirmed in all pDMG cell lines tested. Using a well-characterised agonist (MDL 299,51) and antagonist (HAMI3379) to modulate GPR17 function in pDMG cell lines resulted in phenotypic and genomic changes as well as in cell growth and migration. HAMI3379, a GPR17 specific antagonist resulted in a significant reduction in GPR17 mRNA and protein expression (p&amp;lt;0.006) and a significant reduction in migration (p&amp;lt;0.0025). When pDMG cells were pretreated with HAMI3379 in combination with known cytotoxic agents (Bleomycin, a radiation mimic, Panobinostat or Vincristine), there was a decrease in cell viability compare to cytotoxic agent alone. There are no current effective therapies for pDMG patients and the ability of blocking GPR17 function to enhance sensitivity to standard therapies is appealing and warrants further investigation.
A population-based study of acute panmyelosis with myelofibrosis in the United States: 2004 to 2015.
Authors: Nicole McLaughlin, Gordon Ruan, Courtney N. Day, William S. Harmsen, Caleb J. Smith, Moritz Binder, Naseema Gangat, Ronald S. Go, Ayalew Tefferi, Mithun Vinod Shah
Journal: Journal of Clinical Oncology (2021)

e19003 Background: Acute panmyelosis with myelofibrosis (APMF) is a rare subtype of acute myeloid leukemia characterized by acute panmyeloid proliferation with increased blasts, cytopenias with bone marrow fibrosis, and absence of splenomegaly. There is a paucity of population-based studies of APMF. Methods: We queried the United States Surveillance, Epidemiology, and End Results (SEER) database and National Cancer Database (NCDB) using the ICD-O-3 code 9931/3. The SEER 17 registries (2004-2015) were used to find data on incidence. For NCDB data, comorbid disease burden was calculated using the Charlson-Deyo Score (CDS). Hazard ratios (HR) with confidence intervals (CI) were calculated using a Cox proportional hazards model. Overall survival (OS) was estimated with the Kaplan-Meier method. Variables significant in univariable analysis were included in a multivariable analysis. Results: We identified 260 APMF patients using the SEER database. Incidence was 0.3 cases/million individuals and did not change significantly from 2004-2015. With a median follow up of 6.9 years (95% CI 6.1-7.8), the median OS was 2.3 years (95% CI 1.7-2.8). We identified 530 APMF patients using the NCDB. The median age at diagnosis was 67 years (range 22-90) and 311 (59%) were male. With a median follow up of 5.0 years (95% CI 3.0-7.6), the median OS was 2.3 years (95% CI: 0.8-6.5). OS was 69%, 31%, and 18% at 1-, 5-, and 10- years, respectively. Patients diagnosed in 2012-2015 had a significantly improved OS compared to those diagnosed in 2004-2007 (HR 0.65, 95% CI 0.49-0.85; p=0.002). 271 patients (53%) patients received chemotherapy. The OS for those that received chemotherapy was 70% at 1 year and 30% at 5 years versus 70% and 32% at 1- and 5- years for those who did not ( p=0.99). The median time to chemotherapy from time of diagnosis was 25 days (range 0-532 days). 52 patients (10%) underwent transplantation and the OS of those patients was 90% at 1 year and 45% at 5 years versus 67% and 29% at 1- and 5- years for those who did not (HR: 1.7 (95% CI: 1.2-2.6), p=0.006). In univariable analysis, factors predicting inferior OS were age ≥ 65 years old at diagnosis (HR 1.8, 95% CI 1.5-2.3; p&lt;0.001), male sex (HR 1.5, 95% CI 1.2-1.8; p&lt;0.001), CDS ≥ 1 (HR: 1.5 (95% CI: 1.2-2.0), p&lt;0.001), government insurance (HR 1.8, 95% CI 1.4-2.3; p&lt;0.001), diagnosis at a non-academic facility (HR 1.6, 95% CI 1.2-2.0, p&lt;0.001), and not receiving a hematologic transplant (HR 1.7, 95% CI 1.2-2.6; p=0.006). Multivariable-adjusted analysis is shown in the Table. Conclusions: The overall incidence of APMF has not changed between 2004 and 2015, but OS for 2012-2015 was improved compared to 2004-2007. Age ≥ 65 years old, male sex, CDS ≥ 1, and diagnosis at a nonacademic facility predicted inferior OS. Multivariable-adjusted analysis.[Table: see text]
肥大型心筋症(HCM)患者における心磁図上の左室伝導異常は致死的不整脈イベントを予測する
Authors: Sakane Kazushi, Takaki Hiroshi, Hashimoto Shuji, Nakajima Ikutarou, Miyamoto Kouji, Yamada Yuko, Okamura Hideo, Noda Takashi, Satomi Kazuhiro, Aiba Takeshi, Shimizu Wataru, Kamakura Shirou, Yasuda Satoshi, Sugimachi Masaru
Journal: Circulation (2013)
De-escalation of five years adjuvant endocrine therapy duration in patients with ER-low positive (immunohistochemical 1% to 10%) early-stage breast cancer: A propensity-matched analysis from the prospectively maintained database.
Authors: Keda Yu, Yuwen Cai, Zhiming Shao
Journal: Journal of Clinical Oncology (2021)

538 Background: There are limited data on endocrine therapy benefits for patients with estrogen receptor (ER)-low positive breast cancer (staining 1% to 10% of tumor nuclei by immunohistology). We aimed to compare the effect of short-term 2-3 years versus standard 5 years of adjuvant endocrine therapy on survival outcomes in patients with ER-low positive early breast cancer. Methods: We used data from the prospectively maintained Breast Surgery Database of Fudan University Shanghai Cancer Center for this propensity-matched analysis. Women with ER-low positive, operable, and unilateral early-stage invasive ductal breast cancer were enrolled in this study. Patients with advanced disease, having received neoadjuvant chemotherapy or ovarian function suppression, or with unknown duration or longer than 5 years of adjuvant endocrine therapy were excluded. Enrolled patients were divided into three groups: received no endocrine therapy; received 2-3 years of endocrine therapy; and received approximately 5 years of endocrine therapy. The primary endpoint was disease-free survival (DFS). Multivariate Cox regression analysis and propensity score matching were performed to minimize bias. Hazard ratios (HR) with 95% CIs were calculated. Results: From 2012 to 2017, 634 patients with ER-low positive breast cancer in the database met the inclusion criteria. At a median follow-up of 60 months (interquartile range, 46-74), the 5-year DFS of the whole cohort was 84.9%, with 77.6% for patients who received no endocrine therapy (N = 89), 83.7% for patients who received 2-3 years endocrine treatment (N = 185), and 87.5% for patients who received 5 years endocrine therapy (N = 360). When compared with those receiving no endocrine therapy, patients receiving 5 years treatment was associated with a significantly improved DFS (HR, 0.55; 95% CI 0.32-0.95; P = 0.03); however, there was no significant difference in DFS between patients receiving 2-3 years and 5 years endocrine therapy (HR, 0.79; 95% CI, 0.48-1.28; P = 0.33). In the multivariate Cox regression analysis of the propensity score-matched samples of 360 patients, the DFS was not significantly better for patients who received 5 years of endocrine therapy than 2-3 years treatment (HR, 0.74; 95% CI 0.41-1.34; P = 0.32). An exploratory analysis of re-biopsy of the recurrence lesions indicated more than half of relapsed disease displayed ER-negative, and less than 5% lesions were proved to be ER ≥10% positive. Conclusions: Our data did not support the necessity of 5 years duration of endocrine therapy for patients with ER-low positive breast cancer. Short-term 2-3 years duration might be an alternative option. Further translational research on identifying endocrine-sensitive cases within ER-low positive patients is needed.
Finding Hybrid Incompatibilities Using Genome Sequences from Hybrid Populations
Authors: Alexandre Blanckaert, Bret A Payseur
Journal: Molecular Biology and Evolution (2021)

Natural hybrid zones offer a powerful framework for understanding the genetic basis of speciation in progress because ongoing hybridization continually creates unfavorable gene combinations. Evidence indicates that postzygotic reproductive isolation is often caused by epistatic interactions between mutations in different genes that evolved independently of one another (hybrid incompatibilities). We examined the potential to detect epistatic selection against incompatibilities from genome sequence data using the site frequency spectrum (SFS) of polymorphisms by conducting individual-based simulations in SLiM. We found that the genome-wide SFS in hybrid populations assumes a diagnostic shape, with the continual input of fixed differences between source populations via migration inducing a mass at intermediate allele frequency. Epistatic selection locally distorts the SFS as non-incompatibility alleles rise in frequency in a manner analogous to a selective sweep. Building on these results, we present a statistical method to identify genomic regions containing incompatibility loci that locates departures in the local SFS compared with the genome-wide SFS. Cross-validation studies demonstrate that our method detects recessive and codominant incompatibilities across a range of scenarios varying in the strength of epistatic selection, migration rate, and hybrid zone age. Our approach takes advantage of whole genome sequence data, does not require knowledge of demographic history, and can be applied to any pair of nascent species that forms a hybrid zone.