tbuckley/cabot-search huggingface dataset:
Durable response with venetoclax in combination with decitabine or azacitadine in elderly patients with acute myeloid leukemia (AML).
Authors: Courtney Denton Dinardo, Keith William Pratz, Jalaja Potluri, Vinod A. Pullarkat, Brian Andrew Jonas, Andrew H. Wei, Pamela Sue Becker, Olga Frankfurt, Tu Xu, Wan-Jen Hong, Brenda Chyla, Daniel Aaron Pollyea, Anthony G. Letai
Journal: Journal of Clinical Oncology (2018)

7010 Background: Venetoclax (VEN), an oral BCL-2 inhibitor, has synergistic activity when combined with hypomethylating agents. This clinical study explores the optimal dose and efficacy of VEN in combination with decitabine (DEC) or azacitadine (AZA) in elderly AML. Methods: This is an open-label, phase 1b, dose escalation and expansion study (NCT02203773) on the safety and efficacy of VEN, with DEC or AZA, in elderly patients (≥65 years) with untreated AML. VEN was coadministered daily with 20 mg/m2 of DEC on days 1-5 or 75 mg/m2 of AZA on days 1-7, each 28 day cycle. VEN was dosed at 400, 800, or 1200 mg in the escalation phase, and 400 or 800 mg in the expansion phase. Complete remission (CR), CR with incomplete blood count recovery (CRi), overall survival (OS) and adverse events (AEs) were evaluated. Results: Data cutoff was July 7, 2017. Of 145 patients, 56% were male; the median age was 74 years (range: 65–86). Overall, 60, 74, and 11 patients received VEN at 400, 800, and 1200 mg, respectively. Key grade ≥3 AEs were febrile neutropenia (43%), thrombocytopenia (23%) and neutropenia (16%); pneumonia and bacteremia (all grades) occurred in 18% and 8% of patients, respectively. At 400mg of VEN, the rate of CR+CRi was 73% (76% with AZA and 71% with DEC); efficacy data are in the table. Minimal residual disease (MRD) assessment in marrow aspirates was performed at disease assessment in a central lab using multicolor flow cytometry assay; overall, 37% (36/97) of patients with CR/CRi had MRD levels below the 10-3 cutoff. Median follow up was 15.1 months. Conclusions: Preliminary data suggest that 400 mg of VEN has the optimal benefit-risk profile in combination with DEC or AZA, which demonstrated a tolerable safety profile with deep responses and durable outcomes in elderly patients with AML. Clinical trial information: NCT02203773.Patient subgroup n CR/CRi Duration of CR/CRi n (%) median months OS All VEN doses 145 97 (67) 11.3 17.5 Intermediate cytogenetic risk 74 55 (74) 12.9 NR Poor cytogenetic risk 71 42 (59) 6.7 9.6 Secondary AML 36 24 (67) NR NR Age ≥75 years 62 40 (65) 9.2 11.0 VEN 400 mg + AZA 29 22 (76) NR NR + DEC 31 22 (71) 12.5 15.2 VEN 800 mg + AZA 37 21 (57) 11.7 14.2 + DEC 37 27 (73) 9.2 17.5 OS, overall survival; NR, not yet reached (if applicable)
Differences between screen-detected and interval breast cancers among BRCA mutation carriers.
Authors: Melissa Louise Pilewskie, Emily Craig Zabor, Michelle Stempel, Oriana Petruolo, Debra Mangino, Mark E. Robson, Maxine S. Jochelson
Journal: Journal of Clinical Oncology (2018)

1529 Background: BRCA mutation carriers have an elevated lifetime and interval breast cancer risk. We sought to compare BRCA mutation carriers with screen-detected versus clinically detected, interval breast cancers. Methods: Women with a known BRCA mutation prior to a breast cancer diagnosis were identified. Clinical and pathologic factors, and imaging within 18 months of diagnosis were compared among screen-detected vs clinically detected/interval cancers. Clinically detected tumors were those detected by physical exam regardless of screening history, whereas interval cancers were those detected by physical exam among women undergoing regular screening. Results: Of 115 breast cancers, 93 were screen and 22 clinically detected, of which 11 were interval cancers among regular screeners. Women with clinically detected/interval cancers were younger, had lower BMIs, and were more likely to be Black than those with screen-detected cancers (p < 0.05). Clinically detected/interval cancers were all invasive, were larger, more likely to be node positive and to have lymphovascular invasion, and were more likely to require axillary lymph node dissection and chemotherapy (p < 0.05). No significant differences were seen by BRCA mutation, mammographic density, MRI background parenchymal enhancement, tumor grade, or receptor status between cohorts. Women screened with both mammogram and MRI had significantly lower rates of clinically detected/interval cancer rates compared to women screened with only mammogram or MRI alone (p < 0.05)(Table). Conclusions: Clinically detected/interval breast cancers among BRCA mutation carriers have worse clinicopathologic features than screen-detected tumors, and require more aggressive medical and surgical therapy. Imaging with mammogram and MRI is associated with lower interval cancer development and should be utilized among this high-risk population. Imaging Screen-Detected Clinically Detected P value Screen-Detected Interval Cancers P value All Women Regular Screeners Alternating q6 Month Mammo/MRI 34 (89%) 4 (11%) 0.003 32 (91%) 3 (9%) 0.014 Synchronous Mammo/MRI 38 (90%) 4 (10%) 25 (93%) 2 (7%) Mammo Only 18 (58%) 13 (42%) 7 (58%) 5 (42%) MRI Only 3 (75%) 1 (25%) 1 (50%) 1 (50%)
Association of preoperative testosterone levels with testicular germ cell tumor histology.
Authors: Siamak Daneshmand, Cory Michael Hugen, Daneil Shin, Claire Burton, David I. Quinn, Anne K. Schuckman, Hooman Djaladat, Victoria K Cortessis
Journal: Journal of Clinical Oncology (2016)

e16045 Background: Testicular germ cell cancer incidence has increased over the past several decades. Unfortunately, epidemiologic studies have been unable to identify causative factors to explain the increasing incidence. The androgen receptor and androgen signaling are potential mechanisms that have been implicated with testicular germ cell carcinogenesis. We hypothesized that pre-orchiectomy testosterone levels may predict testicular cancer histology. Methods: An IRB approved retrospective review was performed on patients who underwent radical orchiectomy at our institution for germ cell tumors between 2009-2014. Patients were included if they had a total testosterone level measured prior to orchiectomy. Logistic regression was performed to determine if pre-orchiectomy testosterone level was associated with testicular cancer histology. Results: A total of 89 patients met inclusion criteria during the study period, of whom 51 had non-seminomatous germ cell tumors (NSGCTs) and 38 had seminomatous germ cell tumors. Median age was 30.3(range:18.8-52.0) and 26.6(range: 16.7-53.5) years for seminomatous and NSGCTs, respectively. After correcting for age, when pre-operative level of serum testosterone was tested as a continuous variable it was negatively associated with seminoma histology (OR 0.998 per unit testosterone, p = 0.045). When pre-operative testosterone was categorized by very low ( < 200ng/dL), low (200-350ng/dL), and normal ( > 350ng/dL) values, tumor histology was associated in the same direction with testosterone level, but the association did not achieve statistical significance (p = 0.319). Conclusions: Preliminary data suggest that higher pre-orchiectomy testosterone levels are negatively associated with seminomatous germ cell tumor histology. Further study is needed with a more robust patient population to determine if this association remains.
Individualized cancer vaccine to elicit tumor debulking immunity in advanced HCC.
Authors: Michael Har-Noy, Wattana Sukeepaisarnjaroen, Wirote Lausoontornsiri, Aaron Wittenberg, Miriam Bloch, Tehila Sonnenfeld, Elena Fingerut, Yael Kaminer, Anucha Ahooja, Jitraporn Wongwiwatchai, Vivian Klungboonkrong, Michael Bishop, Supaporn Suparak, Dan Jondle, Reuven Or
Journal: Journal of Clinical Oncology (2018)

e15054 Background: A bioengineered allograft (BAG) designed to elicit the same anti-tumor effects as allogeneic stem cell transplant (ASCT) without GVHD, matched donor or chemotherapy conditioning was combined with heat shock proteins (HSP) purified from lysed biopsy samples to make a personalized therapeutic vaccine. BAG activates innate and adaptive immunity and counter-regulates the suppressive tumor microenvironment. Methods: 15 subjects with advanced HCC, BCLC stage C, Child Pugh class A, ECOG < 2, 13/15 first line, 2/15 second line, 14/15 macrovascular invasion, 10/15 extrahepatic disease, 10/15 HBV+ and 2/15 HCV+. Subjects were primed with 4 intradermal (ID) injections of BAG and vaccinated with 4 ID HSP+BAG over 24d, followed on d28 by 5 monthly IV BAG+ ID HSP boosters. Longitudinal liver biopsies, CT scans and plasma were collected. Serum was analyzed for HSP70 (tumor lysis), IL-6 (HCC growth factor) and sCD163 (macrophage activation). Results: Of the 15 subjects, 11 had liver lesions evaluable at Day 56 by mRECIST. In the target liver lesions: 2/11 (18%) had CR , 2/11 (18%) PR, 4/11 (36%) SD and 3/11 (27%) PD. Later, 2 PD transformed to SD; 1 PR to CR. Liver biopsy demonstrated increased T-cell infiltration at the border of tumor nests surrounded by tumor necrosis and new fibrosis. Most liver responders exhibited progression of existing extrahepatic lesions and/or new lymphadenopathy. Currently, survival is trending favorably to historic controls with 1/15 clinically stable at 16 months, 5/15 at 6 months and 1/15 at 5 months. Historical control: 4.2 months (3.75–5.46). The ORR/DCR in liver was 4/11 (36%)/ 10/11 (90%). HSP70 increased and IL-6 decreased in most responders. Survival trended with decreased serum sCD163 expression. No DLT or AE > grade III associated with vaccine. Conclusions: Evidence from longitudinal radiology, pathology and biomarker data supports unprecedented tumor killing effects in the liver in this population. Extrahepatic disease progression possibly represents an
Frequency of <i>BRCA1</i> and <i>BRCA2</i> germline mutations in uterine serous carcinomas and uterine carcinosarcomas.
Authors: Deanna Gerber, Fanny Dao, Narciso Olvera, Nolan Piccola, Douglas A. Levine
Journal: Journal of Clinical Oncology (2018)

e13521 Background: Germline mutations in BRCA1 or BRCA2 may increase the risk of developing uterine serous carcinoma (USC). The Cancer Genome Atlas (TCGA) identified BRCA2 mutations in uterine carcinosarcomas (UCS). Published reports suggest that serous or serous-like endometrial cancers are associated with the hereditary breast and ovarian cancer (HBOC) syndrome. The purpose of our study was to determine the frequency of BRCA1 and BRCA2 germline mutations in a series of USC and UCS. Methods: We conducted a retrospective review at a single institution to identify patients with histologically confirmed USC or UCS. DNA was extracted from formalin-fixed, paraffin-embedded tissue blocks using standard laboratory methods. Targeted libraries were prepared for BRCA1 and BRCA2 using the Illumina TruSeq Custom Amplicon v2.0 protocol and sequenced on an Illumina MiniSeq system. The mean coverage for targeted regions was 3187X, with a minimum depth of 636X. Cases were anonymized prior to variant calling. Results: Targeted sequencing was successfully completed in 94 cases (43 USC; 51 UCS). The median age of patients with USC was 66 years and 70 years for UCS. Cases were evenly distributed between early and late FIGO surgical stage. Fourteen patients (15%) had a history of breast cancer, 8 (9%) reported taking tamoxifen. One UCS patient was confirmed to have a p.Ser1982Argfs frameshift mutation in BRCA2, a founder mutation in the Ashkenazi Jewish population. There were no germline frameshift mutations identified in patients with USC. This finding represents a 2% and 1% mutation rate among the UCS subtype and entire study group, respectively. Conclusions: In this series of high-risk uterine cancer patients, we identified a single UCS patient with a BRCA2 germline mutation. The data are consistent with some previously published reports that suggest USC and UCS are not necessarily components of the HBOC syndrome. Hysterectomy at the time of risk-reducing bilateral salpingo-oophorectomy among BRCA1 and BRCA2 mutation carriers remains controversial. Previously published data may suffer from bias due to breast cancer treatment and properly designed studies remain warranted.
TCT-476 New Onset Atrial Fibrillation in Patients Undergoing Transfemoral Transcatheter Aortic Valve Replacement - Risk Factors and Outcome
Authors: Felix Woitek, Norman Mangner, Stephan Haussig, Lisa Crusius, Florian Schlotter, Georg Stachel, Philipp Kiefer, David Holzhey, Sergey Leontyev, Holger Thiele, Michael Borger, Axel Linke
Journal: Journal of the American College of Cardiology (2018)
P01.044 Impact of the addition of vinorelbine to temozolomide in the first-line treatment of pediatric high grade gliomas
Authors: M Guidi, M Lucchesi, A Buccoliero, S Scoccianti, S Farina, C Fonte, C Caporalini, C Moscheo, L Genitori, I Sardi
Journal: Neuro-Oncology (2018)

Pediatric high-grade gliomas (HGGs) are comprised primarily of anaplastic astrocytomas (AA, WHO-grade III) and glioblastomas (GBM, WHO-grade IV). Despite advances in treatment for other childhood tumors, their outcomes are comparable to adults, with 5-year survival rates less than 20%. Primary treatment includes surgery, followed by radiotherapy and chemotherapy with temozolomide. Consolidated studies demonstrated that adjuvant treatment remains important for improving outcome. We considered 19 HGG patients admitted to the Neuro-Oncology Unit in Florence between September 2008 and January 2018. Patients were enrolled in a temozolomide-vinorelbine chemotherapy protocol developed on the basis of EORTC-COG experiences. The children were subjected to resection and to radiotherapy with concomitant chemotherapy (6 weeks) with vinorelbine (20 mg/sqm i.v weekly), temozolomide (75 mg/sqm i.o daily). The adjuvant phase consisted in 12 months of treatment with exclusive chemotherapy with vinorelbine 30 mg/sqm i.v. days 1, 14 every 28, temozolomide 150 mg/sqm i.o. days 1–5 every 28. The median age of 19 treated patients was 10 years (range 6–25). Six patients (31,6%) had GBM and thirteen patients (68,4%) had an AA. According the localization, 16 tumors (84,2%) were sovratentorial and 3 (15,8%) infratentorial tumors. Radical surgery was performed in seven patients. The median of follow-up was 50 months. At time of analysis, 12 patients were still alive and more than 50% of the patients have not yet relapsed. Five patients (26,3%) had a disease progression during the adjuvant phase. One patient died after radiotherapy. The patients who received the highest dose of radiotherapy (59–60 Gy vs 54 Gy) showed better survival (not reached vs 38,8 months). Patients who experienced disease progression during the maintenance treatment had a significant worst survival (11,3 months vs NR p< 0.0001). Adjuvant chemotherapy is crucial for a better outcome of malignant gliomas. In pediatric HGGs, the combination of vinorelbine to temozolomide seems to be safely, without significant adverse events. At 50 months of follow-up (beyond the median OS described in the literature) more than 50% of patients have not yet experienced recurrence. Our analysis confirms that disease progression during the treatment represents a negative prognostic factor for survival. This may identify a subgroup of patients with a marked chemoresistance.
First-in-human, first-in-class phase I study of MTL-CEBPA, a small activating RNA (saRNA) targeting the transcription factor C/EBP-α in patients with advanced liver cancer.
Authors: Debashis Sarker, Elizabeth R. Plummer, Bristi Basu, Tim Meyer, Kai-Wen Huang, T.R. Jeffry Evans, Duncan Spalding, Yuk Ting Ma, Daniel H. Palmer, Cheng Ean Chee, Han Chong Toh, Nagy A Habib
Journal: Journal of Clinical Oncology (2017)

TPS2612 Background: saRNAs are small oligonucleotide drugs designed to selectively upregulate therapeutic proteins by recruiting endogenous transcriptional complexes to a target gene, leading to increased expression of naturally processed mRNA. Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) is a leucine zipper protein which acts as a master regulator of liver homeostasis and multiple oncogenic processes including cell cycle control, proliferation and angiogenesis. MTL-CEBPA comprises a double stranded RNA payload formulated inside a SMARTICLES liposomal nanoparticle to specifically target the CEBPA gene and has been shown to improve liver function and inhibit hepatocellular cancer (HCC) tumor growth in preclinical models (Reebye et al, Hepatology, 2014). MTL-CEBPA is the first saRNA and the first drug targeting C/EBP-α to enter clinical trials. Methods: Pts with advanced HCC (Child-Pugh A or B7 only) or secondary liver cancer refractory to or ineligible for standard treatment, ECOG PS 0-1, acceptable haematologic, liver and renal function, are currently being enrolled in a standard 3+3 dose escalation study. Once the RP2D is defined, 12-15 patients with advanced HCC will be evaluated further in a dose expansion cohort. MTL-CEBPA is administered as a 1-hr IV infusion on Day 1, 8 and 15 of a 28-day cycle. RECIST tumor response is assessed after every 2 cycles. The primary objective is to determine safety and tolerability; secondary objectives include PK, liver function improvement and anti-tumor activity. Correlative studies include C/EBP-α mRNA levels in PBMCs and optional tumor tissue, evaluation of C/EBP-α downstream target genes (e.g.TGFβ) and distal target engagement in white blood cells (e.g.IL-6, NF-κB, IFN-γ). Recruitment to cohort 2 is shortly to be completed, with no DLTs reported to date. Clinical trial information: NCT02716012.
Toxicity disparities between Hispanics and non-Hispanics enrolled in clinical trials in south Texas.
Authors: Ojas Harihar Vyas, Marcela Mazo- Canola, Juan Francisco Garza, Ruchi Hamal, Lashandra Royster, Ellen Johnson, Leyla Bohanini, Virginia G. Kaklamani
Journal: Journal of Clinical Oncology (2017)

e18089 Background: The U.S. Hispanic (H) population is estimated to increase from 55 million in 2014 to 119 million in 2060, growing from 17% to 29% of the total population. H are underrepresented in cancer trials. A review of practice-changing oncology trials showed only 3.9% of included patients were H. Disparities have been identified in time to diagnosis, treatment and outcomes in H patients, including those on clinical trials, despite uniform stage, treatment, and follow-up. Given our institution’s history of strong H accrual, we aimed to look at the rate of enrollment and toxicity in our early phase cancer trials of H compared with non-Hispanic whites (NHW). Methods: We retrospectively reviewed charts of patients enrolled in Phase I trials at UTHSCSA to assess rates of selected toxicities, death, hospitalizations and reasons for withdrawal from phase 1 trials. The following toxicities were recorded: anemia, neutropenia, neuropathy, nausea, vomiting, and fatigue. All H patients were compared to randomly selected statistical controls. Patients who were on multiple trials were excluded. Results: Of the 520 patients reviewed, 376 (72.3%) self-identified as H, 123(23.7%) as NHW, and 448 (86.2%) of patients had a solid tumor diagnosis. H and NHW with solid tumors are compared in the Table. They were similarly matched for sex, but H were noted to be older and more likely to receive cytotoxic therapy. Rates of patients experiencing any grade 3/4 toxicity or hospitalization were similar as shown. H were more likely to withdraw from trial due to disease progression. Conclusions: This retrospective analysis shows H patients did not experience significantly more toxicities in early phase clinical trials at an academic center in a minority-majority community. Prospective data collection is needed to provide more detailed information in the disparities that exist in toxicity and outcomes in H compared with NHW in cancer trials. [Table: see text]
The influence of yoga on mediational relationships between sleep and cancer-related fatigue: A URCC NCORP RCT in 321 cancer patients.
Authors: Po-Ju Lin, Ian Kleckner, Calvin Cole, Michelle Christine Janelsins, Luke Joseph Peppone, Anita Roselyn Peoples, Eva Culakova, Charles E. Heckler, Rakesh Gaur, Jeffrey K. Giguere, Michael J. Messino, Janet C. Ruzich, Karen Michelle Mustian
Journal: Journal of Clinical Oncology (2017)

10007 Background: Cancer-related fatigue (CRF) is one of the most incapacitating adverse effects of cancer and its treatments. CRF co-occurs with impaired sleep quality in cancer survivors, increasing morbidity and mortality. We have previously shown that yoga significantly lowers CRF and improves sleep quality in survivors. However, it is not clear if the effect of yoga on CRF is mediated by improvements in sleep quality. This study assessed the mediating effects of changes in sleep quality stemming from YOCAS yoga on improvements in CRF. Methods: We conducted a secondary analysis on data collected from a multicenter phase III randomized controlled clinical trial with 2 arms (standard care and standard care + a 4-week YOCAS yoga intervention). 321 cancer patients (96% female; mean age, 54 years; 77% had breast cancer) reported both sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI), and CRF, evaluated by Multidimensional Fatigue Scale Inventory (MFSI). Causal mediation analyses were used to estimate effects of the changes in global PSQI scores and in each PSQI subscale on the relationship between yoga and CRF. Results: Yoga significantly improved both CRF (p &lt; 0.01) and sleep quality (p &lt; 0.01), compared to standard care, with total reduction in CRF by 6.5 points. Sleep quality significantly mediated the changes in CRF by 1.4 points (p &lt; 0.01) in addition to the direct effect of yoga on CRF reduction (by 5.1 points; p &lt; 0.01), suggesting that 22% (95% CI: 7%-54%) of the reduction in CRF was mediated through improving sleep quality. Among the PSQI subscales, daytime dysfunction had the most mediating effect of yoga on CRF. In this model, yoga directly improved CRF by 4.1 points (p = 0.01) and the mediating effect of yoga on CRF via daytime dysfunction was 2.4 points (p &lt; 0.01), suggesting that 37% (95% CI: 23%-81%) of the improvements in CRF was mediated through decreasing daytime dysfunction. Conclusions: Between 22 and 37% of the improvements in CRF from yoga are due to improvements in sleep quality and reductions in daytime dysfunction. Clinicians should consider prescribing yoga for survivors experiencing CRF in combination with sleep disorders. Funding: NCI UGCA189961, R25 CA102618. Clinical trial information: NCT00397930.
TCT-835 Validation of PARIS Risk Scores in Patients Treated With Everolimus-Eluting Stents for Left Main Coronary Artery Disease: Analysis From the EXCEL Trial
Authors: Sabato Sorrentino, Bimmer Claessen, Roxana Mehran, David Kandzari, Marie-Claude Morice, Martin Leon, Bernard Gersh, Ori Ben-Yehuda, Bjorn Redfors, Ovidiu Dressler, Stuart Pocock, A. Pieter Kappetein, Joseph Sabik, Patrick Serruys, Gregg Stone
Journal: Journal of the American College of Cardiology (2018)