tbuckley/cabot-search huggingface dataset:
Targeted resequencing of pediatric rhabdomyosarcoma: report from the Children’s Oncology Group, the Children’s Cancer and Leukaemia Group, The Institute of Cancer Research UK, and the National Cancer Institute.
Authors: John Frederick Shern, Rajesh Patidar, Young Song, Ashley Walton, Jun S. Wei, Xinyu Wen, Erin R. Rudzinski, Donald A. Barkauskas, David Hall, Corrine M Linardic, M. Jenney, Julia Chisholm, Rebecca Brown, Anna Kelsey, Joanna Selfe, Susanne Gatz, Stephen Skapek, Douglas S. Hawkins, Janet Shipley, Javed Khan
Journal: Journal of Clinical Oncology (2018)

10515 Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor. Genomic studies by our group and others have identified 39 genes as known or potential somatic driver mutations in RMS. We therefore performed a large-scale validation study through an international consortium to more accurately determine the incidence of driver mutations and their association with clinical outcome. Methods: Formalin fixed paraffin embedded material was collected from patients enrolled on Children’s Oncology Group trials and UK patients enrolled on MMT trials. Pathology was reviewed centrally and extracted DNA subjected to targeted capture sequencing. Mutations, indels, deletions, gene amplifications and genome-wide copy number variation was called using analysis pipelines developed at the NCI. Results: DNA from six hundred and thirty-one patients was suitable for analyses. A median of 2 variant calls were found per tumor. Mutation of a RAS isoform was found in 29% of all fusion negative cases, mutation of a RAS pathway member was seen in greater than 50% of cases, and 24% had no putative driver mutation identified. BCOR (15%), NF1 (11%) and TP53 (12%) mutations were found at a higher incidence than previously reported. Interestingly, mutations in HRAS were notable in the infant population whereas those in NRAS were enriched in adolescents. Among infants < 1 year, 71% of cases harbored a mutation in HRAS or KRAS. In contrast, mutation of MYOD1 was associated with an older age and parameningeal primary site. Finally, 29% of the evaluated tumors harbored multiple driver mutations consistent with subclonal variation and tumor heterogeneity in fusion negative RMS. Detailed analyses of the association of mutations with anatomical location, histology and outcome are currently underway. Conclusions: This is the largest genomic characterization of clinically annotated patients with RMS tumors to date and adds to the understanding of the biology of this disease.
Treatment of gynecologic cancers in HIV+ women.
Authors: Kimberly Levinson, Laureen Ojalvo, David Riedel, Ana Angarita, Amanda Nickles Fader, Anne Rositch
Journal: Journal of Clinical Oncology (2016)

e17064 Background: Widespread adoption of combination antiretroviral therapy has reduced mortality among women with human immunodeficiency virus (HIV). As life expectancy increases, incidence of gynecologic malignancies also will increase. There are no recent reports on treatment practices of HIV+ women with gynecologic malignancies. The study objective is to evaluate patterns of adherence to NCCN guidelines for this population. Methods: Cancer registry, HIV clinic records, and billing diagnostic codes were used to identify HIV+ women with gynecologic cancers from 2000-2015 at 2 institutions. Chart review was performed to extract demographic, HIV, and treatment related variables . Treatment information was evaluated to determine adherence to NCCN guidelines for each gynecological malignancy. Descriptive statistics were calculated to describe the patient population and cancer treatment related information. Results: Overall, 47 gynecologic malignancies were identified. Twenty-three patients (49%) had cervical cancer (CC), 13 (28%) vulvar/vaginal cancer (VV), 6 (11%) ovarian cancer (OV), and 5 (11%) endometrial cancer (EM). Mean age at diagnosis was 45, 89% of women were black, 60% were smokers, and 31% admitted to alcohol use. Eleven women 23% had no viral load (VL) recorded at the time of cancer diagnosis, 57% had a VL < 400 and 19% VL of > 400. Of 23 CC patients, 22 (96%) received treatment according to NCCN guidelines and 1 (stage I) received no therapy. Eleven of 13 VV patients (85%) received treatment according to NCCN guidelines, and 2 (stage I) received no treatment. Sixteen patients with CC or VV received radiation as part of treatment, and only 11/16 (62%) received radiation-sensitizing chemotherapy. All 5 women with EM were stage I and (100%) received definitive surgery according to NCCN guidelines. Of the 6 OV patients, 5/6 (83%) received care consistent with NCCN guideleines, however, only 1/5 late stage (III/IV) patient received both chemotherapy and surgery. Conclusions: Most HIV+ women with gynecologic cancers were treated according to NCCN guidelines. However, over a third of women with CC and VV did not to receive radiation sensitizing chemotherapy, and women with late stage OV also tended to be less likely to be treated with ideal therapies.
Daratumumab (DARA) in combination with carfilzomib and dexamethasone (D-Kd) in lenalidomide (Len)-refractory patients (Pts) with relapsed multiple myeloma (MM): Subgroup analysis of MMY1001.
Authors: Ajai Chari, Joaquin Martinez-Lopez, Maria-Victoria Mateos, Joan Blade, Sagar Lonial, Lotfi Benboubker, Albert Oriol Rocafiguera, Bertrand Arnulf, Jesus San-Miguel, Luis Pineiro, Andrzej J. Jakubowiak, Carla De Boer, Jianping Wang, Jordan Mark Schecter, Philippe Moreau
Journal: Journal of Clinical Oncology (2018)

8002 Background: Len-refractory pts have poor outcomes, highlighting an unmet medical need. In the phase 1b MMY1001 study (NCT01998971), D-Kd induced deep responses and was well tolerated in pts with relapsed MM. We examined the safety and efficacy of D-Kd in len-refractory pts. Methods: In total, 85 carfilzomib (carf)-naïve pts with 1-3 prior lines of therapy were enrolled. Pts received carf (20 mg/m2 on Cycle 1 Day 1 [C1D1] and 70 mg/m2 on C1D8+) on days 1, 8, and 15 of 28-day cycles and dexamethasone 40 mg QW. DARA was given QW C1-C2, Q2W C3-C6, and Q4W thereafter; 10 pts received a standard first dose of DARA (16 mg/kg) on C1D1, and 75 pts received a split first dose of DARA (8 mg/kg on C1D1 and C1D2). Refractoriness was defined as progression ≤60 days of completion of last line of therapy. Results: Among len-refractory pts (n = 51) in the MMY1001 D-Kd arm, median age was 66 yrs (range 38-85 yrs). Pts had received a median of 2 (range 1-4) prior lines of therapy; 98% had received bortezomib (bort), 18% had received pomalidomide (pom), 43% were refractory to bort, and 18% were refractory to pom. In total, 20 pts (39%) discontinued due to progressive disease (26%), adverse events (AEs; 6%), pt withdrawal (6%), or physician decision (2%). The most common hematologic grade 3/4 treatment-emergent AEs (TEAEs; ≥10%) were thrombocytopenia (37%), anemia (29%), neutropenia (28%), and lymphopenia (26%). Infusion-related reactions were observed in 37% of pts (43% for standard first DARA dose; 36% for split first DARA dose); none were grade 3/4. With 8.3 months of median follow up, median PFS was 14.1 months (95% CI 9.4-not estimable); the 12-month PFS rate was 69% (95% CI 49-82). ORR and MRD-negative rates are summarized in the Table. Median time to MRD negativity (10–5) was 5.1 months. Conclusions: The combination of DARA and weekly Kd was well tolerated and demonstrated promising efficacy in len-refractory pts. Updated data will be presented. Clinical trial information: NCT01998971.% Len refractory All Overall response rate (ORR)a 81 86 sCR 8 6 CR 4 14 VGPR 56 53 PR 13 14 MRD-negative rate 10–4 6 9 10–5 2 5 10–6 0 2 aAmong response-evaluable pts who received > 2 cycles or discontinued treatment.
A Step Forward in the Treatment of Influenza
Authors: Timothy M. Uyeki
Journal: New England Journal of Medicine (2018)

For many years, antiviral treatment of influenza has consisted of monotherapy with a neuraminidase inhibitor. The Food and Drug Administration (FDA) approved the neuraminidase inhibitors oseltamivir (oral administration) and zanamivir (oral inhalation) in 1999 and peramivir (intravenous administration) in late 2014. These drugs work by binding to the viral neuraminidase protein and interfering with the release of influenza virus particles from infected respiratory tract cells. Neuraminidase inhibitors are FDA-approved for the treatment of uncomplicated influenza within 2 days after onset in outpatients, on the basis of randomized, controlled trials, but they are also recommended for the treatment of patients with . . .
A prognostic gene-signature based identification of high-risk thin melanomas.
Authors: Peter Koelblinger, Mitchell P. Levesque, Corina Kaufmann, Heiko Sülberg, Axel Hinke, Marie-Christine Hoffmann, Georg Brunner, Reinhard Dummer
Journal: Journal of Clinical Oncology (2018)

e21575 Background: While prognosis of thin primary cutaneous melanoma (TCM) is good, 25% of melanoma-specific mortality occurs with primary tumors ≤ 1 mm in thickness. A prognostic gene expression profile (GEP)-based risk score was previously developed to identify high-risk primary CMs. The aim of this retrospective, double-blind, case-control study was to validate the prognostic value of the GEP score specifically in TCMs. Methods: Formalin-fixed paraffin-embedded (FFPE) TCMs (≤ 1mm in thickness) were retrospectively identified and blinded for gene expression analysis. The study cohort (n = 88 TCMs; sentinel node (SLN) biopsy, n = 18/88) comprised 22 high-risk TCMs (relapse and/or melanoma-specific death, 9/22; SLN negative, 5/22, or no SLN biopsy, 17/22) and 66 control TCMs (no relapse). Median follow-up was 44 months, and median thickness was 0.8 mm (high-risk TCMs) and 0.6 mm (control TCMs). Tumor samples were independently analyzed, blinded to clinical outcome, by real-time RT-PCR to determine a GEP risk score. Based on previous analyses (n = 114 TCMs; median follow-up, 95 months; n = 12 progression-free survival [PFS] events), a pre-specified GEP score cut-off of 0.35 was applied to identify high-risk TCMs. Results: A GEP-score based analysis determined 7/22 relapse-free survival (RFS) and 4/9 melanoma-specific survival (MSS) events. The sensitivity was higher for eventually fatal TCMs (Tab. 1). A combined analysis of our data, including this study and previous GEP data of TCMs (Tab. 1), suggest a clinically relevant range of sensitivity (38-42%) and specificity (66%). Conclusions: The GEP risk score identified a significant proportion of high-risk TCMs that was undetectable by conventional staging. Although sensitivity was below 50%, this is still superior to any other available method for assessing recurrence risk of TCMs. The detection of high-risk TCMs by the GEP score is being validated in a larger, ongoing multi-center trial. Table 1. Validation study (n = 88) Combined analysis of validation and previous data (n = 202) GEP sensitivity GEP specificity (≥ 5 yrs follow-up) GEP sensitivity GEP specificity (≥ 5 yrs follow-up) MSS, long-term 44.4% 76.7% MSS, long-term 42.1% 65.6% RFS, long-term 31.8% 77.3% PFS, long-term 38.2% 66.1%
Impact of proton pump inhibitors (PPIs) on sunitinib (SU) pharmacokinetics (PK) and activity in GIST patients (pts).
Authors: Olivier Mir, Romain Coriat, Angelo Paci, Charles Honoré, Matthieu Faron, Sarah Naomie Dumont, Philippe Terrier, Julien Adam, Axel Le Cesne
Journal: Journal of Clinical Oncology (2018)

11538 Background: PPIs alter the PK of several oral drugs, either through a decrease in absorption due to higher GI tract pH, or the induction of efflux pumps such as ABCB1. The PK of SU is well correlated with its activity in GIST. Previous works have suggested a deleterious impact of PPI intake on SU activity in mRCC, but sunitinib PK was unchanged in pts with previous gastrectomy. Overall, the impact of PPI intake on SU PK and activity in GIST remains to define. Methods: Steady-state plasma concentrations of SU were determined in 57 GIST pts treated in the 2nd line setting over 10 years (2008-2017), at the dose of 50 mg/day 4 weeks/6, or 37.5 mg daily, according to their performance status (PS) and co-morbidities, at the discretion of the treating physician. PK data were analyzed with a nonlinear mixed-effect modeling approach, using the Monolix software. For the population PK model, covariates included lean body mass (LBM, estimated using CT-scan) and PPI intake. PFS was analyzed using the Kaplan-Meier method. Results: 18 pts (32%) received PPIs troughout SU treatment. SU PK was satisfactorily described by a one-compartment model with a zero-order absorption. SU CL/F and V/F were increased by a 1.55 factor when co-administered with PPI, resulting from a decreased relative bioavailability. Covariate modeling showed that PPI intake decreased the fraction of dose absorbed by ~40%, and LBM was better related to the CL and V inter-subject variations than weight, supporting a major role of the non-fat mass in the elimination and distribution parameters. Overall, the covariate effects explained approximately half of the CL/F between subject variability. Median PFS was 3.0 months (95%CI: 2.5-3.2) vs. 7.7 months (95%CI : 6.1-11.2) in pts receiving PPIs, or not, respectively. Mutational status had no impact on PFS. Conclusions: Our results suggest that SU plasma concentrations in pts receving PPis could be sub-optimal, leading to early anti-tumor treatment failure. In this setting, either PPI discontinuation or SU dose escalation (up to 75 mg daily, in lack of limiting toxicity) should be considered.
Metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas (NECs) as novel indications for rovalpituzumab tesirine: A delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC).
Authors: Stanford L. Peng, Laura Saunders, Sheila Bheddah, Sam Williams, Rahul Raj Aggarwal, Jill E. Shea, Eun Y Lee, Jiaoti Huang, Allison J Zemek, Teri A. Longacre, Douglas Wilmot Ball, Courtney L. Scaife, Barry Nelkin, Lowell Brian Anthony, Pamela L. Kunz, Eric Jay Small, Scott Dylla
Journal: Journal of Clinical Oncology (2016)

11611 Background: DLL3 is highly expressed in tumor-initiating cells (TIC) in small cell lung cancer (SCLC), where the DLL3-targeted ADC rovalpituzumab tesirine (Rova-T; SC16LD6.5) is able to eradicate TIC in patient-derived xenografts (PDXs; Saunders et al. [2015] Sci Transl Med 7:302ra136) and exert clinically meaningful antitumor effects in SCLC patients (NCT01901653). Based on data in The Cancer Genome Atlas, melanoma, glioblastoma and other high-grade NECs may also have elevated DLL3 expression. Methods: DLL3 expression was profiled by qRT-PCR, ELISA and immunohistochemistry, where positivity was defined as > 1% of tumor cells with staining of any intensity. PDXs from melanoma and extrapulmonary NECs were established and the ability of Rova-T to impact tumor growth, TIC frequency and recurrence was assessed. Results: DLL3 expression was confirmed in metastatic melanoma (~50%), glioblastoma (~71%), medullary thyroid (~64%) and neuroendocrine pancreatic cancer (~20%) – the latter correlating with grade. Adrenal, neuroendocrine prostate and gastrointestinal tumors were also noted to be positive. With the exception of melanoma, where DLL3 expression inversely correlated with outcome, DLL3 expression significantly correlated with that of the ASCL1 transcription factor – a known driver of neuroendocrine tumorigenesis. In DLL3-expressing melanoma PDX tumor-bearing mice, a single dose of Rova-T halted tumor growth with no recurrences noted for > 120 days, and was accompanied by a significant reduction in TIC. Conclusions: DLL3 is expressed in a large proportion of melanoma, glioblastoma and other high-grade extrapulmonary NEC types. Treatment of DLL3-positive extrapulmonary PDX tumor-bearing mice with Rova-T resulted in effective and durable responses. Given encouraging clinical data with Rova-T in SCLC, clinical evaluation of Rova-T in DLL3-positive melanoma, glioblastoma, medullary thyroid and other high-grade neuroendocrine carcinomas is warranted. A “basket” trial enrolling patients with DLL3-positive solid tumors has been initiated.
TCT-143 Higher Institutional TAVR Volume Reduces Index Mortality but Does Not Impact Readmission Outcomes
Authors: Hanning Xing, Yas Sanaiha, Sarah Rudasill, Habib Khoury, Alexandra Mardock, Shervin Yazdani, Leela Gowland, Ramin Ebrahimi, Peyman Benharash
Journal: Journal of the American College of Cardiology (2018)
Maintenance treatment with capecitabine plus cetuximab (CET) for patients with RAS wild-type (wt) advanced colorectal cancer (CRC): A multi-center, phase II clinical trial.
Authors: Xianglin Yuan, Ying Liu, Xianli Yin, Jianping Xiong, Ben Zhao, Hong Qiu
Journal: Journal of Clinical Oncology (2018)

e15566 Background: Cetuximab showed activity as single agent for maintenance treatment in RAS wt ACRC in MACRO2, however cetuximab combined with capecitabine has always been controversial. Our retrospective data of maintenance treatment with capecitabine plus cetuximab appeared preliminary evidence on 2016 ASCO GI. So this prospective study was to further determine the efficacy and safety in RAS wt ACRC. Methods: Patients involved 4 hospitals in 4 provinces of central China were recruited from Apr 2016. Patients were included with RAS wt ACRC achieved SD/PR/CR after first-line induction treatment with 4-6 months of standard fluorouracil-based chemotherapy plus cetuximab, WHO performance status of 0-1. The eligible patients received maintenance treatment with capecitabine (1000mg/m² orally twice daily on days 1-14 every 3 weeks), and cetuximab (400 mg/m² on day 1 of the first week, then 250 mg/m² on day 1 every week or 500 mg/m² on day 1 every 2 weeks). Disease status was assessed every 6 weeks and treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was PFS, and secondary endpoints were OS and safety. The trial is currently on-going, primary analysis was performed with intention to treat (ITT) population. Results: Totally 28 patients received maintenance treatment with capecitabine plus cetuximab till Jan 2018. Median follow-up was 17.5 months. Median PFS was 6.6 months. Grade≥3 AEs were skin reactions (18%, 5/28) and hand-foot syndrome (11%, 3/28), without any other severe toxicity. None of the 28 patients discontinued maintenance treatment due to toxic effects. The global quality of life did not deteriorate during maintenance treatment. Conclusions: From this interim analysis, maintenance treatment with capecitabine plus cetuximab is effective and well tolerated, OS has not been achieved which need a longer follow up. The final result even further Phase III study are anticipated later. Clinical trial information: 02717923.
A novel MAGE-A1-IgG antibody for lung adenocarcinoma.
Authors: Yuan Mao, Qi Tang, Weifei Fan, Xiaojun Tang, Li Xu, Jin Zhu, Zhenqing Feng, Jun Wang
Journal: Journal of Clinical Oncology (2017)

e20085 Background: Melanoma-associated antigen A1 (MAGE-A1) has been reported to perform oncogenically and act as an ideal candidate in tumor immunotherapy. Methods: One-step quantitative real-time polymerase chain reaction (qPCR) test and immunohistochemistry (IHC) analysis were used to detect the relationship between MAGE-A1 expression and the clinicopathological characteristics of lung adenocarcinoma (LAC). Then a novel MAGE-A1 IgG antibody was constructed on the previous MAGE-A1 scFv antibody by eukaryotic expression vectors. CCK-8, wound healing, transwell, matrigel, apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC) and CDC (complement-dependent cytotoxicity) assays were performed to evaluate the inhibitory effects of MAGE-A1-IgG on LAC in vitro. Results: High MAGE-A1 expression was observed in LAC tissues and MAGE-A1 expression was associated with several malignant properties of LAC patients, including overall survival. MAGE-A1-IgG revealed significant roles in inhibiting proliferation, inducing apoptosis and activating ADCC and CDC of LAC in a dose- and time- dependent manner in vitro. Conclusions: MAGE-A1-IgG may provide a promising therapeutic strategy for the treatment of MAGE-A1-positive LAC.
Plasma cell-free DNA (cfDNA) concentration and radiographic tumor burden in patents with glioblastoma (GBM).
Authors: Stephen Joseph Bagley, Jazmine Mays, Seyed Ali Nabavizadeh, Stephanie S. Yee, Scott S Levy, Arati Suvas Desai, Erica L. Carpenter
Journal: Journal of Clinical Oncology (2018)

2048 Background: Distinguishing between radiographic pseudoprogression and true tumor progression is a significant challenge in patients with GBM. A non-invasive means of assessing GBM disease activity is needed. Recent data has suggested that plasma cfDNA concentration may serve as a viable surrogate for tumor burden and disease activity in other solid tumors. We performed a pilot study to determine the feasibility of using plasma cfDNA concentration as a surrogate of radiographic tumor burden in patients with GBM. Methods: We collected blood in Streck cfDNA tubes from patients with radiographically suspected high grade glioma prior to planned surgical resection. Plasma was isolated using a 3 step centrifugation protocol. cfDNA was extracted from using a QIAamp Circulating Nucleic Acid Kit. cfDNA was stored at -20 degrees C and quantified the following day using an Invitrogen Qubit dsDNA kit. Tumor burden was defined as the sum of products of diameters (SPD) of the target enhancing lesions plus the SPD of the T2 FLAIR signal abnormality on preoperative magnetic resonance imaging (MRI). Correlation between cfDNA concentration and tumor burden was assessed using Spearman’s correlation coefficient. Results: 10 preoperative patients were enrolled. Following surgery, 9 patients were diagnosed with GBM and 1 with diffuse midline glioma, H3K27M mutant. The median cfDNA concentration was 12.4 ng/mL (IQR 5.5-19.7, range 4.3 - 34.5). Median SPD of target enhancing lesions was 15.7 cm2 (IQR 10.8-24, range 1.2 – 29.8), and median SPD of T2 FLAIR lesions was 35.7 cm2 (IQR 21.6-43.5, range 12.7 – 81.8). There was a significant correlation between cfDNA concentration and the sum of the SPDs of the target enhancing lesions and T2 FLAIR lesions (Spearman’s rho = 0.70, p = 0.025). Conclusions: In this small pilot study, we demonstrated a correlation between the preoperative plasma cfDNA concentration and radiographic tumor burden by MRI in patients with newly diagnosed high grade glioma. This preliminary finding suggests that cfDNA yield may serve as a viable surrogate for tumor burden in patients with GBM. A larger, longitudinal study of cfDNA quantification and its relationship to GBM disease status is ongoing at our institution.