tbuckley/cabot-search huggingface dataset:
Oncotype DX DCIS use and clinical utility: A SEER population-based study.
Authors: Yao Yuan, Alison Len Van Dyke, Allison W. Kurian, Serban Negoita, Valentina I. Petkov
Journal: Journal of Clinical Oncology (2019)

e12046 Background: OncotypeDX DCIS is a 12-gene assay designed to predict the 10-year risk of local recurrence and to guide treatment decisions, specifically the benefit of radiation therapy in breast ductal carcinoma in situ (DCIS). The test became available in December 2011 and is not currently recommended by guidelines. The Surveillance, Epidemiology and End Results (SEER) program captures cancer data at the population-level and has been conducting annual linkages with Genomic Health Clinical Laboratory, the only lab performing the test, to identify patients receiving the test. Methods: SEER cases diagnosed with in situ breast cancer (DCIS or papillary in situ) between 2011-2015 were included in the analysis. SEER data on patient demographics, tumor characteristics, and treatments were combined with linkage variables for OncotypeDX DCIS tests reported by Genomic Health. Logistic regression was used to identify which patient related factors were associated with having received the test and to evaluate the relationship between test generated risk categories and treatments. Results: Of the 68,826 in situ breast cancer cases, 2,155 were linked to DCIS test data. Test utilization increased from &lt; 1% to 5.3% for patients diagnosed in 2011 vs. 2015. Patients were less likely to receive the test if they had larger and higher-grade tumors, were divorced, had Medicaid insurance, and were in the lowest socioeconomic status tertile. The majority of patients (68%) were at low risk, 17% intermediate, and 15% in the high risk group. Patients at intermediate or high risk were more likely to receive radiation (OR = 2.4, 95% CI: 1.8-3.2 and OR = 3, 95% CI: 2.3,4.1, respectively) than the low risk group. High risk patients were more likely than low risk patients to receive chemotherapy (OR = 4.3, 95% CI: 1.2, 14.4) and to undergo mastectomy than lumpectomy (OR = 1.47, 95% CI: 1.12-1.93). Conclusions: Clinical adoption of the OncotypeDX DCIS test has been slow. The association between multiple demographic factors and receiving the test indicated disparities in the US population. Clinical factors also influenced whether patients received the test. OncotypeDX DCIS results appeared to guide clinical decisions.
Effect of immunotherapy at any line of treatment on survival in Hispanic patients with advanced metastatic non-small cell lung cancer (NSCLC) compared with chemotherapy (Quijote-CLICaP).
Authors: Andres Felipe Cardona Zorrilla, Alejandro Ruiz-Patiño, Oscar Arrieta, Claudio Martin, Luis E. Raez, Zyanya Lucia Zatarain Barrón, Feliciano Barron Barron, Luisa Ricaurte, Maria Bravo, Luis Mas, Leonardo Rojas, Lorena Lupinacci, Florencia Perazzo, Carmen Puparelli, Manglio Miguel Rizzo, Christian Diego Rolfo, July Rodriguez, Diana Carolina Sotelo Rodríguez, Hernan Carranza, Rafael Rosell
Journal: Journal of Clinical Oncology (2019)

e20637 Background: To compare survival outcomes of patients with advanced or metastatic NSCLC who received immunotherapy at first, second or beyond versus matched patients receiving standard chemotherapy. Methods: A retrospective multicenter international cohort study of 296 patients with unresectable/ metastatic NSCLC treated with immunotherapy either as first, second, third or fourth line was conducted. A matched comparison with a historical cohort of first line chemotherapy was conducted. Results: Median age was 64 years (Range 34-90) and 40.2% were female patients. 91.2% of patients had an ECOG performance score ≤ 1. Immunotherapy as first line was given to 39 patients (13.7%), second line to 140 (48.8%), and as third line and beyond to 108 (37.6%). Median overall survival was 12.7 months (95% CI 9.67-14 months) and progression-free survival was 4.27 months (95% CI 3.97-5.0). Factors associated with increased survival included treatment as first-line (p &lt; 0.001), type of response (p &lt; 0.001) and PD-L1 status (p = 0.0039). Compared to the historical cohort, immunotherapy proved to be superior in terms of OS (p = 0.05) but not PFS (p = 0.2). Conclusions: Patients who receive immune checkpoint inhibitors as part of their treatment for NSCLC have better OS compared with matched patients treated with standard chemotherapy, regardless treatment line.
FRI0359 KRT77 DELETIONS IN FAMILIAL INFLAMMATORY BOWEL DISEASE MAY OFFER A NOVEL LINK TO FAMILIAL SPONDYLOARTHROPATHY
Authors: Antonio Julià, Richard Cuthbert, Anton Glueck, Javier Gisbert, Eugeni Domènech, Maria Lopez Lasanta, Núria Palau, Helena Marzo-Ortega, Dennis McGonagle, Sara Marsal
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Inflammatory bowel disease, either clinical or subclinical is a cardinal pathological process that is central to the spondyloarthropathy (SpA) category of disease that also includes psoriasis, psoriatic arthritis, uveitis and ankylosing spondylitis. <h3>Objectives</h3> To look for novel genes in familial SpA in large multcase families using a whole genome sequencing approach. <h3>Methods</h3> We used Whole Genome Sequencing to screen SpA family members with different disease manifestations. We screened 5 multicase SpA families (up to 8 members) with different disease manifestations. <h3>Results</h3> We found a 1.5MB deletion of the KRT77 gene in 3 of 7 families that segregated with SpA phenotype. Given that KRT77 is a barrier protein and given that tagging SNPs from GWAS studies do not cover the region, and given that both IBD and psoriasis are associated with barrier defects, we looked for an association with KRT77 deletion in 1,000 cases of Psoriasis, 1,000 Crohn's disease (CD) and 1,001 healthy controls. Deletion genotyping was performed using TaqMan RealTime-PCR assays. The deletion genotype frequencies in controls did not deviate from Hardy-Weinberg Equilibrium (p &gt; .1). We found an association between KRT77 deletion and CD risk (p = 0.03) and also a putative association with pustular psoriasis (p &lt; 0.05). We also demonstrated that the KRT77 protein is expressed in the intestinal lumen and Peyers Patches in addition to the know skin expression. <h3>Conclusion</h3> Given the strong association between SpA and subclinical gut inflammation and barrier defects in IBD these findings suggest that KRT77 heterozygous deletions with dysregulated gut permeability may play a role in IBD and the wider SpA phenotype. <h3>Acknowledgement</h3> We would like to thank the clinical researchers and patients participating in the IMID Consortium for their collaboration <h3>Disclosure of Interests</h3> Antonio Julià: None declared, Richard Cuthbert: None declared, Anton Glueck: None declared, Javier Gisbert: None declared, Eugeni Domènech: None declared, Maria Lopez Lasanta: None declared, Núria Palau: None declared, Helena Marzo-Ortega Grant/research support from: Janssen, Novartis and Pfizer, Consultant for: AbbVie, Celgene, Janssen, Eli-Lilly, Novartis and UCB, Speakers bureau: AbbVie, Celgene, Janssen, Eli-Lilly, Novartis and UCB, Dennis McGonagle Consultant for: Lilly, Novartis UCB, Speakers bureau: Lilly, Novartis UCB, Sara Marsal: None declared
Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: Final overall survival (OS) from the phase III HERITAGE Trial.
Authors: Cornelius F. Waller, Aleksei Manikhas, Eduardo J. Pennella, Igor Bondarenko, Guzel Mukhametshina, Maria Luisa Abesanis Tiambeng, Charuwan Akewanlop, Ihor Vynnychenko, Virote Sriuranpong, Sirshendu Ray, Miguel Hernandez-Bronchud, Jay Herson, Joseph D. Parra, Joseph D. Parra, Gia Nemsadze, Unmesh Gopalakrishnan, Subramanian Loganathan, Rafael Muniz, Abhijit Barve, Hope S. Rugo
Journal: Journal of Clinical Oncology (2019)

1021 Background: The multicenter, double-blind, randomized, parallel-group, phase 3 Heritage trial (NCT02472964) evaluated efficacy and safety of trastuzumab-dkst (Ogivri), a trastuzumab biosimilar, vs trastuzumab, plus taxane as first-line therapy for patients with HER2+ metastatic breast cancer. Overall response at week (wk) 24 and progression-free survival (PFS) at wk 48 have been reported (Rugo et al, JAMA 2017; ASCO 2018). Methods: Eligible patients were randomized 1:1 to trastuzumab-dkst or trastuzumab, plus taxane. After 24 wks, patients with responding/stable disease continued monotherapy per randomization. Safety and OS during maintenance, cumulative through 36 months of follow-up from last patient on study, are described. Results: 500 patients were randomized; 343 received monotherapy after 24 wks (trastuzumab-dkst, n = 179; trastuzumab, n = 164). 128 patients discontinued monotherapy (trastuzumab-dkst, n = 63; trastuzumab, n = 65); mean time to discontinuation was 19 months in both groups. Treatment-emergent adverse events (TEAEs) during monotherapy were similar for trastuzumab-dkst (69%) and trastuzumab (73%); most were low grade and serious TEAE rates were 6% in both groups. Cumulative rates of TEAEs of special interest were similar for hypersensitivity, pulmonary, and cardiac events (trastuzumab-dkst, 23%, 16%, and 5%; trastuzumab, 24%, 13%, and 5%). Incidences of left ventricular ejection fraction (LVEF) &lt; 50% ≥1 time postbaseline (trastuzumab-dkst, 5%; trastuzumab, 3%) and LVEF &lt; 50% postbaseline and ≥10% reduction (trastuzumab-dkst, 4%; trastuzumab, 3%) were low. At 36 months, 169 patients had received further lines of therapy, with similar distribution of HER2 treatments, endocrine therapies, and chemotherapies. Final median PFS was 11.1 months in both groups. Median duration of response was 9.9 and 9.8 months and median OS was 35.0 and 30.2 months for trastuzumab-dkst and trastuzumab, respectively: unstratified hazard ratio, 0.9 (95% CI, 0.70-1.17). Conclusions: Long-term safety data with similar median OS compared with originator trastuzumab further support the safety and efficacy profile of trastuzumab-dkst. Clinical trial information: NCT02472964.
A randomized phase II study of pembrolizumab with or without radiation in patients with recurrent or metastatic adenoid cystic carcinoma.
Authors: Jonathan Daniel Schoenfeld, Umair Mahmood, Yu-Hui Chen, Raymond H. Mak, Jochen H. Lorch, Glenn J. Hanna, Vishwajith Sridharan, Andrew Bang, Paul Martin Busse, Henning Willers, Harvey J. Mamon, Hyung-Jin Yoo, Sara I. Pai, Lori J. Wirth, Robert I. Haddad, Nicole Grace Chau
Journal: Journal of Clinical Oncology (2019)

6082 Background: Adenoid cystic carcinoma (ACC) is a salivary gland malignancy characterized by a high rate of distant recurrence. Systemic therapy has generally failed to produce durable benefit. Radiation (RT) is used for localized disease and as directed treatment for metastases. Here, we report the safety and efficacy of pembrolizumab (pembro) administered with or without hypofractionated RT in a phase II randomized study. Methods: Eligible patients (pts) had recurrent or metastatic ACC with evidence of progressive disease (PD) within the last 12 mos and &gt;=1 measurable non-CNS lesion, along with 1-5 additional lesions deemed appropriate for RT to 30 Gy in 5 fractions. Pts were randomized to pembro alone (200 mg IV q3 weeks) or in combination with RT given within 7 days of cycle 1, day 1. The primary endpoint was objective response rate (ORR) outside the RT field by RECIST 1.1. Using a parallel two-stage design, if &gt;=1 response out of 10 was observed in either arm, 10 more pts would be enrolled to that arm. If &gt;=3 responded, the null hypothesis (ORR=5%) would be rejected in favor of a 25% ORR. Predefined secondary endpoints included progression free survival (PFS) and toxicity. Analyses of tumor growth rate (TGR) excluding RT lesions and immune biomarkers were exploratory. Results: Ten pts per arm were randomized into the trial’s first stage with median age 65 (45-79). No objective responses were seen. Stable disease (SD) was observed in 13 pts; 6 had PD as best response, 1 was unevaluable. Median PFS was 7 mos 95% CI (3 - 13 mos), with 9 pts without progression at 6 mos. 3 pts remain on study treatment (range 8-11 mos). In pts with SD, TGR decreased by &gt;25% in 7 of 12 pts and by &gt;75% in 4 pts. There was no difference in likelihood of SD or PFS between arms. Treatment related AEs (TRAEs) occurred in 18 pts but there were no G3-5 TRAEs. Among 8 biopsies analyzed, PD-L1+ tumor/immune cells ranged from 12-52%. Conclusions: Pembro alone or with hypofractionated RT was well tolerated. We observed no objective responses, but 65% of pts with PD prior to study entry achieved SD, the majority with decreased TGR, and 15% had prolonged SD. Additional strategies are needed to further delay progression and effect response. Clinical trial information: NCT03087019.
High DNA damage levels to predict hematologic toxicity in testicular germ cell tumor (TGCT) patients treated with first-line chemotherapy.
Authors: Michal Mego, Nikola Hapakova, Zuzana Sestakova, Andrea Holickova, Vera Miskovska, Michal Chovanec, Katarina Rejlekova, Daniela Svetlovska, Katarina Kalavska, Jana Obertova, Patrik Palacka, Valentina De Angelis, Zuzana Sycova, Jozef Mardiak, Miroslav Chovanec
Journal: Journal of Clinical Oncology (2019)

e16055 Background: TGCTs are an excellent example of chemosensitive disease. However, cisplatin-based chemotherapy has significant side effects, including myelosuppression. Previously, we found endogenous DNA damage level in peripheral blood mononuclear cells (PBMCs) to be an independent prognostic marker. We tested the hypothesis that patients with high endogenous DNA damage levels in PBMCs have an increased risk of developing hematologic toxicity. Methods: 120 chemotherapy-naïve patients with TGCTs treated in the National Cancer Institute and the St. Elisabeth Cancer Institute in Bratislava, Slovakia, from 2012 to 2018 were enrolled. All patients received platinum-based chemotherapy with G-CSF support. On the day of starting treatment, we measured the endogenous DNA damage levels in PBMCs using the Comet assay. We used a cut-off level of 5.25, a value previously found to stratify patients based on their prognosis. We monitored hematologic toxicity during the 1 st cycle of chemotherapy. The mean and SEM were calculated for all variables. Results: Patients with high DNA damage levels ( &gt; 5.25) had more significant hematologic toxicity with significantly lower nadir white blood cell count (6.0±1.1×10 9 /L vs 9.8±1.0×10 9 /L p = 0.001), absolute neutrophil count (4.1±1.0×10 9 /L vs 7.0±0.9×10 9 /L p = 0.013) and absolute lymphocyte count (ALC, 1.1±0.1×10 9 /L vs 1.5±0.1×10 9 /L p &lt; 0.001). ALCs on day 0 (1.5±0.1×10 9 /L vs 1.8±0.1×10 9 /L p = 0.005) and day 22 (2.0±0.1×10 9 /L vs 2.4±0.1×10 9 /L p = 0.046) were also significantly lower in patients with high DNA damage levels. There were no significant differences in hemoglobin levels or platelet counts between the two groups. Neutrophil to lymphocyte ratio and systemic immune-inflammation index were lower at nadir in patients with high DNA damage levels, however, these differences were not statistically significant (p = 0.08 and p = 0.10, respectively). Conclusions: This study shows that higher endogenous DNA damage levels correlate with an increased risk of hematologic toxicity. The Comet assay data can be used to select patients for closer monitoring due to a higher risk of acute chemotherapy-related complications.
Associations Between Age at Arterial Switch Operation, Brain Growth, and Development in Infants With Transposition of the Great Arteries
Authors: Jessie Mei Lim, Prashob Porayette, Davide Marini, Vann Chau, Stephanie H. Au-Young, Amandeep Saini, Linh G. Ly, Susan Blaser, Manohar Shroff, Helen M. Branson, Renee Sananes, Edward J. Hickey, J. William Gaynor, Glen Van Arsdell, Steven P. Miller, Mike Seed
Journal: Circulation (2019)

Background: Brain injury, impaired brain growth, and long-term neurodevelopmental problems are common in children with transposition of the great arteries. We sought to identify clinical risk factors for brain injury and poor brain growth in infants with transposition of the great arteries undergoing the arterial switch operation, and to examine their relationship with neurodevelopmental outcome. Methods: The brains of 45 infants with transposition of the great arteries undergoing surgical repair were imaged pre- and postoperatively using magnetic resonance imaging. Brain weight z scores were calculated based on brain volume and autopsy reference data. Brain injury scores were determined as previously described. Neurodevelopment was assessed at 18 months using the Bayley-III scores of infant development. The relationships between clinical variables, brain injury, perioperative brain growth, and 18-month Bayley-III scores were analyzed. Results: On preoperative imaging, moderate or severe white matter injury was present in 10 of 45 patients, whereas stroke was seen in 4 of 45. A similar prevalence of injury was seen on postoperative imaging, and we were unable to identify any clinical risk factors for brain injury. Brain weight z scores decreased perioperatively in 35 of 45 patients. The presence of a ventricular septal defect ( P =0.009) and older age at surgery ( P =0.007) were associated with impaired perioperative brain growth. When patients were divided into those undergoing surgery during the first 2 weeks of life (32/45) versus those being repaired later (13/45), infants repaired later had significantly worse perioperative brain growth (late repair postoperative brain weight z = –1.0±0.90 versus early repair z = –0.33±0.64; P =0.008). Bayley-III testing scores fell within the normal range for all patients, although age at repair ( P =0.03) and days of open chest ( P =0.03) were associated with a lower composite language score, and length of stay was associated with a lower composite cognitive score ( P =0.02). Conclusions: Surgery beyond 2 weeks of age is associated with impaired brain growth and slower language development in infants with transposition of the great arteries cared for at our center. Although the mechanisms underlying this association are still unclear, extended periods of cyanosis and pulmonary overcirculation may adversely impact brain growth and subsequent neurodevelopment.
Haploidentical hematopoietic cell and kidney transplantation for hematological malignancies and end-stage renal failure
Authors: Yi-Bin Chen, Nahel Elias, Eliot Heher, Jeannine S. McCune, Kerry Collier, Shuli Li, Candice Del Rio, Areej El-Jawahri, Winfred Williams, Nina Tolkoff-Rubin, Jay A. Fishman, Steven McAfee, Bimalangshu R. Dey, Zachariah DeFilipp, Paul V. O’Donnell, A. Benedict Cosimi, David Sachs, Tatsuo Kawai, Thomas R. Spitzer
Journal: Blood (2019)
Exosomes derived miR-454-3P to promote the progression of colorectal cancer via MIER1-mediated Notch signaling activation.
Authors: Dawei Li, Senglin Zhao, Ye Xu, Xinxiang Li, Sanjun Cai
Journal: Journal of Clinical Oncology (2019)

e15108 Background: Mesoderm induction early response 1 (MIER1) was downregulated and predicted poor prognosis in CRC patients. However, the mechanisms of the down regulation of MIER1 in CRC remained unclear. Increasing evidence indicates that dysregulation of microRNAs promotes the progression of cancer through the repression of tumour suppressors.Here, we identified exosomes derived miR-454-3p as a novel regulator of MIER1 in CRC. Methods: The effect of miR-454-3p expression on cancer proliferation and metastasis was assessed in cells by altering the expression of miR-454-3p in vitro and in vivo. Mechanistic investigation was carried out by using cell and molecular biology approaches. Results: Functionally, ectopic expression or silencing of exosomes derived miR-454-3P, respectively, promoted or inhibited CRC cell proliferation, colony formation and cell cycle transition, as well as enhanced or prevented the invasion, metastasis of CRC cells and epithelial to mesenchymal transition of CRC cells in vitro and in vivo. Molecularly, exosomes derived miR-454-3P functioned as an onco-miRNA by activating the MIER1-regulated NOTCH pathway. Overexpression or silencing of MIER1 could partially reverse the effects of the overexpression or repression of exosomes derived miR-454-3P on CRC progress caused by activation of the NOTCH pathway in vitro and in vivo. Clinically, high miR-454-3P expression predicted poor survival in CRC patients, especially combined with low MIER1 expression. Conclusions: Collectively, we identified exosomes derived miR- 454-3p as an onco-miRNA, which acts by directly repressing MIER1 in CRC.
Economic analysis of ceritinib used as second-line versus third-line treatment for patients with ALK-rearranged non-small-cell lung cancer.
Authors: Bin Wu, Hongchao Li
Journal: Journal of Clinical Oncology (2019)

e18355 Background: Targeted therapy with ceritinib notably improves survival in patients with advanced non–small-cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) rearrangement tumors after the failure of chemotherapy and crizotinib. However, the economic outcome of ceritinib used as the second-line versus third-line treatment is still unclear. Methods: A mathematical model was constructed to project 21-day patient transitions. The clinical data were primarily extracted from the ASCEND-5 trial. The health resource consumption data were estimated from the perspective of the Chinese health care system. The cost, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) was measured in a 10-year time horizon. Sensitivity analyses were conducted to test the impact of uncertainties. Results: Comparing with the 3rd-line strategy, ceritinib 2nd-line strategy achieved the comparable life years and additional 0.06 QALYs with the less cost of $6,694 (Table), which suggested that ceritinib used as 2nd-line treatment is a dominant strategy. The utility of disease-free survival and the cost of ceritinib were the factors that had the considerable impact on the model outcomes. Conclusions: These results indicate that ceritinib used in 2nd-line setting is a more favorable treatment option than in the 3rd-line setting. [Table: see text]