tbuckley/cabot-search huggingface dataset:
KI intolerance study: A phase 2 study to assess the safety and efficacy of TGR-1202 in pts with chronic lymphocytic leukemia (CLL) who are intolerant to prior BTK or PI3K-delta inhibitor therapy.
Authors: Colleen Dorsey, Dana Paskalis, Danielle M. Brander, Frederick Lansigan, Paul M. Barr, Nicole Lamanna, Bruce D. Cheson, Jeffrey J. Pu, Marshall T. Schreeder, John M. Pagel, Peter Sportelli, Molly J Fanning, Hari P. Miskin, Tracey Zimmer, Kristy Walsh, Stephen J. Schuster, Eline T. Luning-Prak, E. Paul Wileyto, Michael S. Weiss, Anthony R. Mato
Journal: Journal of Clinical Oncology (2017)

TPS7569 Background: Although kinase inhibitor (KI) therapies, such as ibrutinib, are generally well tolerated, intolerance is the most common reason for discontinuation (d/c) in practice (~50%, Mato et al, Blood 2016). Additionally KI interruptions (≥ 8 days) can shorten OS (Barr et al, ASCO 2015). Fortunately, data suggest that KIs have non-overlapping toxicity profiles. Therefore, pts who d/c KI due to intolerance, with ongoing CLL response, represent an unmet need. TGR-1202 is a next generation, highly-specific PI3K-delta inhibitor with nanomolar inhibitory potency. TGR-1202 is well-tolerated with a d/c rate due to AEs of 8% as demonstrated in an integrated safety analysis of 165 treated pts (Burris et al, ASCO 2016). Methods: A phase 2 investigator initiated study is being conducted to assess the safety and activity of TGR-1202 in CLL pts who are KI intolerant. KI Intolerance is defined as ≥ 1 Gr 3 or ≥ 2 Gr 2 non-heme toxicities, ≥ 1 Gr 3 neutropenia with infection or fever, and/or ≥ 1 Gr 4 heme toxicity leading to KI (BTK and/or PI3K inhibitor) d/c (Table). Toxicities must resolve to ≤ Gr 1 prior to TGR-1202 dosing. Prior KI must be d/c for ≥ 14 days without progression (PD). All eligible pts are treated with TGR-1202 (800mg oral daily) until PD, toxicity or study conclusion. Primary study endpoint is PFS. Secondary endpoints include ORR, duration of response, time to treatment failure and TGR-1202 safety profile. Peripheral blood samples are collected prior to TGR-1202, after 28 days and at PD for correlative analyses to identify markers associated with KI intolerance. The trial commenced 10/1/2016. 55 eligible pts will be enrolled in approximately 12 months with 24 months follow-up. As of 1/2017, 10 study sites are enrolling pts with 10 more to be activated. To date, 10 pts have been enrolled and treated with TGR-1202. Clinical trial information: NCT02742090. [Table: see text]
Performance of a prognostic 31-gene expression profile test in stage III cutaneous melanoma subjects.
Authors: Martin D. Fleming, Brooke Middlebrook, Kyle R. Covington, Pedram Gerami, Jeffrey D. Wayne, Jonathan S. Zager
Journal: Journal of Clinical Oncology (2017)

9578 Background: The management of stage III cutaneous melanoma (CM) patients has changed significantly with the introduction of contemporary therapies. A 31-gene expression profile (GEP) test that provides a prediction of low or high risk of melanoma metastasis has been validated as an independent prognosticator of distant metastasis-free (DMFS) and melanoma-specific survival (MSS). We examine the prognostic accuracy of the test in a cohort of stage III, and particularly stage IIIA, subjects from a multicenter validation study. Methods: 207 primary CM tumors from 16 centers were analyzed as part of an IRB-approved study. Quantitative RT-PCR and predictive modeling were performed to classify metastasis and survival risk as Class 1 (low risk) or Class 2 (high risk). Results for Kaplan-Meier and Cox regression survival analysis are reported. Results: Of the 207 subjects with stage III melanoma, 76 were stage IIIA. The table shows 5-year DMFS and MSS rates for all stage III and stage IIIA groups. Patients with Class 2 GEP had significantly worse outcomes compared to Class 1. In univariate analyses, GEP was a significant predictor of DMFS and MSS with a hazard ratio for DMFS of 2.8 (95%-CI; 1.7-4.6) and for MSS of 4.0 (95%-CI; 1.7-9.4) for all stage III, while HR of 2.2 for DMFS (95%-CI; 1.0-4.7) and 4.3 for MSS (95%-CI; 1.2-15.2) were observed for the stage IIIA group. For all stage III cases, Breslow thickness and GEP were significant predictors of DMFS and MSS in multivariate models including ulceration and mitotic rate (p &lt; 0.05). Conclusions: The results support the capability of the GEP to accurately predict stage III distant metastasis and survival, and that the test complements existing prognostic factors. GEP testing may be useful in identifying stage IIIA patients who are appropriate for adjuvant therapies and/or enrollment in clinical trials. [Table: see text]
High expression of pdl-1 in patients with triple negative breast cancer with residual tumor burden after neoadjuvant chemotherapy.
Authors: Gizem Oner, Semen Onder, Hüseyin Karatay, Mustafa Tukenmez, Mahmut Muslumanoglu, Abdullah Igci, Ahmet Dinccag, Vahit Ozmen, Adnan Aydiner, Ekrem Yavuz, Neslihan Cabioglu
Journal: Journal of Clinical Oncology (2018)

e24136 Background: Due to its higher frequency in triple negative breast cancer, we analyzed PDL-1 expression in patients with triple negative breast cancer and partial response to neoadjuvan chemotherapy and its correlation with response to chemotherapy and prognosis. Methods: PDL-1 expression was examined immunohistochemically by staining archival tissue of mastectomy specimen (n = 50) using PDL-1 monoclonal antibody (Ventana SP263 clone kit). PDL-1 positivity was defined as membranous staining > 1% in either tumor and /or stromal lymphocytes, whereas high PDL-1 positivity was considered as moderate/strong staining and/or > 5% in either tumor and /or stromal lymphocytes. Results: Median age was 47.5 (24-76) years. Of those, 29 were clinically T3-4 (58%), whereas almost all of them were N1-3 (96%) before neoadjuvant chemotherapy. All patients received anthracyclines&paclitaxel containing regimens, whereas 3 patients received additional carboplatin before definitive surgery. Of those, 29 patients (58%) were detected to be positive for PDL1 in tumor site and intratumoral lmyphocytes, whereas 25 of those (50%) were positive for tumoral PDL1 expression, and 23 were positive for PDL-1 in stromal lymphocytes. Among those, 22 patients (44%) highly expressed PDL1 in tumor and lymphocytes, and 26 have shown high expression of PDL1 in tumor and/or in stromal lymphocytes. Patients with lymphocyte-PDL1 positivity were more likely found to give a better chemotherapy response as measured by "Residual Cancer Burden Index" (59% vs 37%, p = 0.157). Median follow-up time was 28 months (7-161). Five-year disease-free survival (DFS) was 52.6%, while five-year disease-specific survival (DSS) was 49.3%. No significant difference could be found in DFS and DSS rates in regards to PDL1-positivity. Conclusions: These results demonstrate that PDL-1 were found to be highly expressed in patients with partial response to neoadjuvant chemotherapy. These patients represent a cohort with poor prognosis and resistant tumor clones to chemotherapy that would justify an addititional immune check point inhibitor therapy.
Repurposing the FLT3 inhibitor quizartinib to enhance 5-FU treatment of mouse models of intestinal tumors.
Authors: Wallace York Langdon, Catherine Alice Rinaldi
Journal: Journal of Clinical Oncology (2018)

e14516 Background: Cancer patients treated with chemotherapy frequently experience the effects of myelosuppression that include anemia, neutropenia and thrombocytopenia. We recently found that priming mice with the FLT3 inhibitor quizartinib prevents myelosuppression caused by a number of cytotoxic drugs. In this study we tested whether quizartinib priming in combination with 5-FU provides a more effective treatment than 5-FU alone in mouse models of intestinal cancer. Methods: Two mouse models of intestinal cancer were examined: (1) Lgr5CreERT2 x Apc(fl/fl) B6 mice that develop tumors 3-6 weeks after deletion of the Apc gene. The Apc gene was deleted from Lgr5+ intestinal stem cells by tamoxifen injections. Survival endpoints were reached when mice displayed excessive disease or treatment burden. (2) A transplantation model in BALB/c mice injected with CT26 colon carcinoma cells. Mice were culled when tumors reached a volume of 1 cm3. Mice were dosed with quizartinib or vehicle by oral gavage, and 5-FU was injected intraperitoneally. Results: Three treatment groups of Apc deficient mice were examined: (i) priming with 30 mg/kg of quizartinib 6 hours before 150 mg/kg of 5-FU, and repeated every 10 days, (ii) daily injections of 40 mg/kg of 5-FU for 5 days, repeated every 9 days, and (iii) priming with vehicle 6 hours before an injection of PBS, repeated every 10 days. We found that combining quizartinib with 5-FU significantly enhanced survival compared to mice treated with 5-FU alone. For CT26 transplanted mice 3 treatment groups were examined: (i) priming with 25 mg/kg of quizartinib 6 hours before an injection of 100 mg/kg of 5-FU, (ii) priming with vehicle 6 hours before an injection of 100 mg/kg of 5-FU and (iii) priming with vehicle 6 hours before an injection of PBS. The treatments were repeated every 10 days. Quizartinib priming in combination with 5-FU was found to significantly slow tumor progression compared to the vehicle-primed + 5-FU group. Furthermore, tumors were no longer detectable in 40% of the quizartinib-primed mice. Conclusions: Quizartinib priming in combination with bolus doses of 5-FU is an effective treatment for mouse models of intestinal cancer.
Novel technology, high sensitive tissue testing, to analyze intra-tumor pharmacokinetics of anti-HER2 antibody drugs in breast cancer.
Authors: Mitsuhiro Hayashi, Ryosuke Matsukane, Kenji Tamura, Masayuki Yoshida, Kan Yonemori, Toshio Imai, Takayuki Kinoshita, Akinobu Hamada
Journal: Journal of Clinical Oncology (2018)

e24228 Background: It is indispensable for drugs to reach their target at a sufficient concentration to demonstrate effectiveness. Complex microenvironment of clinical tumor exacerbates certain drug delivery including antibody drugs (ADs) that have an overwhelming large molecular size; however, immature methodology has made it difficult to evaluate the distribution of ADs and to verify the causal relationship between drug delivery and treatment resistance. Here, we report the application of novel technology, High Sensitive Tissue Testing (HSTT), for detecting and precise quantifying of ADs in tumor and its feasibility for clinical study to promote the development of new drugs. Methods: Various HER2 expressed patient-derived xenografts (PDX) established at our institute and cell-line derived xenografts (CDX) were administrated 10 mg/kg trastuzumab (Tmab) or trastuzumab emtansine (TDM1) as experimental models. After sampling in several time points and preparing sliced sections, Tmab was recognized by anti-drug antibody and labeled by newly developed fluorescent nanoparticles named Phosphor Integrated Dots (PIDs), which have 30,000 times the intensity of conventional dye. The number of Tmab bound to single cell and the distribution pattern according to the histology were evaluated. Results: PIDs made it possible to detect Tmab and TDM1 not only in whole tumor but in single cell resolutions. The quantitative value of Tmab using PIDs count was validated by liquid chromatography tandem mass spectrometry. In BT474, HER2 expressed CDX, heterogeneous distribution was observed in 8, 24 and 72 hours after administration despite of homogeneous HER2 expression and significantly much more Tmab was delivered compared to low HER2 tumors. In PDXs, also heterogeneous but much worsen drug delivery was detected both in Tmab and TDM1 cases. The distribution was significantly affected from stroma and tumor cluster formations Conclusions: High sensitive visualization and quantification of anti-HER2 drugs were achieved using HSTT. This technology can be valuable for translational research uncovering resistance mechanism and drug development research including antibody-drug conjugates.
Prospective study of ophthalmic artery chemosurgery (OAC) as alternative to enucleation in retinoblastoma.
Authors: Isabelle Aerts, Raphael Blanc, Caroline Saint Martin, Alexia Savignoni, Nathalie Cassoux, Laurence Desjardins, Francois P. Doz, Christine Levy-gabriel, Livia Lumbroso-LE Rouic
Journal: Journal of Clinical Oncology (2018)

10555 Background: Over the past twenty-five years, the introduction of systemic chemotherapy combined to local treatments has enabled to dramatically increase globe retention for retinoblastoma (RB) patients (pts) without using external beam radiation (EBR). OAC has more recently emerged as a primary conservative treatment of RB. Methods: We conducted a prospective phase II non randomized study to determine (i) the efficacy of Melphalan OAC in terms of globe salvage rates, without EBR 18 months after inclusion, (ii) patient survival and (iii) adverse events. Pts with unilateral RB group B, C or D without diffuse vitreous seeding or very asymetric bilateral RB including one group D eye were eligible. Pts were nationally referred to Institut Curie and treated by OAC at the Interventional Neuroradiology Department of the Fondation Rothschild. Results: Between February 2012 and December 2016, 39 pts with unilateral RB classified by the International Classification of Retinoblastoma as Group B (10.3%), Group C (33.3%), Group D (56.4%), were included. Two pts did not receive OAC, one due to initial catheterization failure, the second to prolonged general anesthesia contra-indication (severe RSV bronchiolitis). Median age at OAC was 19.3 months (3.2-61.6). Median number of OAC cycles was 4 (range 1-6). For 31 pts, OAC was associated to ophthalmological local treatment, starting after the second cycle, by diode laser (31) or cryotherapy (10). All pts are alive, with a median follow-up of 27.1 months from inclusion (2.9 -60.2). Twelve pts did not receive the planed complete treatment: 2 because of secondary catheterization failure, 1 for progressive disease, 3 for medical decision, 4 for intra-arterial procedure related serious complications, 1 for ptosis, 1 for retinal hemorrhage. Twelve serious adverse events were declared including 4 vascular retinal occlusions. 8 pts presented leucopenia. No extraocular RB, second cancer or life-threatening complication occurred. As follow-up of the last pts is actually under 18 months, enucleation rate cannot be yet assessed. Conclusions: For advanced RB focal OAC is feasible and generally well tolerated but may expose to some systemic and retinal vascular toxicity. Clinical trial information: NCT02866136.
Predictive and prognostic value of systemic inflammatory response biomarkers in patients receiving nivolumab for metastatic non-small cell lung cancer (NSCLC).
Authors: Claire Gervais, Pascaline Boudou-Rouquette, Anne Jouinot, Olivier Huillard, Jerome Alexandre, Jennifer Arrondeau, Frédérique Giraud, Jeanne Chapron, Marco Alifano, Marie-Pierre Revel, Daniel Dusser, Diane Damotte, Audrey Mansuet-Lupo, Francois Goldwasser
Journal: Journal of Clinical Oncology (2017)

3055 Background: Nivolumab is the first checkpoint immunotherapeutic agent approved for NSCLC. By enabling host immune-mediated cytotoxic activity against tumor cells, nivolumab induces a tumor response in 15% of patients (pts). However, host-related parameters to predict nivolumab activity are still missing. We evaluated the predictive and prognostic value of the presence of a systemic inflammatory response. Methods: From July 2015 to December 2016, we measured at nivolumab initiation the Glasgow Prognostic Score (GPS), a cumulative prognostic score based on C-reactive protein and albumin, the neutrophil-lymphocyte ratio (NLR), the Nutrition Risk Index (NRI) and the Prognostic Nutritional Index (PNI). Univariate and multivariate analyses tested the association between initial patient characteristics and clinical outcome. Results: The characteristics of the 57 consecutive pts analyzed are: median age of 66 years (range 41-78), 65% non-squamous cell lung cancer, 61.4% males and 52.6% Performance Status (PS) 0-1. GPS was 0 in 27 (47.4%), 1 in 21 (36.8%) and 2 in 9 (15.8%) pts. In multivariate analysis, parameters associated with disease progression (per RECIST 1.1) were GPS (1-2 vs 0; HR 1.45 [1.11-1.90], p= 0.009) and number of metastatic sites (&gt;2 vs ≤ 2; HR: 0.75 [0.57-0.98], p = 0.04). Overall survival was significantly worse for pts with PS 2-3 vs PS 0-1 (p=0.01) and for pts with GPS 2 vs GPS 0-1 (p=0.01). The GPS was an independent predictive marker of progression and was superior to other inflammation-based prognostic scores in our cohort (Table). Conclusions: The Glasgow Prognostic Score (GPS) allows identifying patients with disease progression and long survivors among metastatic NSCLC patients treated with nivolumab. [Table: see text]
Randomized phase III trial of concurrent chemoradiation followed by nivolumab or placebo for locally advanced non-small cell lung cancer (NSCLC) (RTOG 3505).
Authors: David E. Gerber, James John Urbanic, Corey J. Langer, Chen Hu, I-Fen Chang, Bo Lu, Benjamin Movsas, Robert Jeraj, Walter John Curran, Jeffrey D. Bradley
Journal: Journal of Clinical Oncology (2017)

TPS8579 Background: Despite aggressive therapy with concurrent chemoradiation, fewer than 25% of patients with stage 3 NSCLC achieve 5-year survival and are presumably cured. To date, treatment modifications—including consolidation chemotherapy, maintenance therapy with molecularly targeted agents, concomitant administration of monoclonal antibodies, and escalation of radiation therapy (RT) dose—have not improved these outcomes. Immune checkpoint inhibitors represent an effective treatment for advanced NSCLC and may enhance RT-associated anti-tumor immunity. RTOG 3505 will test whether the addition of the anti-programmed death 1 (PD1) antibody nivolumab after chemoradiation improves overall survival (OS) and progression-free survival (PFS) in this population. Methods: Key eligibility criteria include surgically unresectable stage 3 NSCLC, ECOG 0-1, adequate organ function, available archival tissue, and absence of active autoimmune disease. Patients will receive thoracic RT to 60 Gy with concurrent cisplatin 50 mg/m 2 IV on Days 1, 8, 29, and 36, and etoposide 50 mg/m 2 IV on Days 1-5 and 29-33. This regimen was selected to (1) minimize risk of pulmonary toxicity and steroid requirements, and (2) optimize timing of immunotherapy. Between 4 and 12 weeks after completion of chemoradiation, eligible patients will be randomized to nivolumab 240 mg IV or placebo every 2 weeks for 1 year. Stratification factors include performance status, histology, and tumor PD-L1 status. Co-primary endpoints are OS and PFS, as determined by central radiology review. Secondary objectives include toxicity assessment, patient-reported outcomes and quality of life, and OS and PFS according to PD-L1 expression. Exploratory objectives include biomarkers to predict treatment efficacy and toxicity. A total of 660 patients will be enrolled to provide ≥90% power to detect (1) a hazard ratio (HR) of 0.7 for OS with two-sided type I error of 0.04, and (2) HR of 0.667 for PFS two-sided type I error of 0.01, allowing a 16.7% drop-out rate before randomization. Clinical trial information: NCT02768558.
The Xpert HCV Viral Load Finger-Stick point-of-care test was accurate for detecting HCV RNA
Authors: Thomas Fekete
Journal: Annals of Internal Medicine (2018)

ACP Journal Club18 September 2018The Xpert HCV Viral Load Finger-Stick point-of-care test was accurate for detecting HCV RNAThomas Fekete, MD, MACPThomas Fekete, MD, MACPTemple University School of Medicine, Philadelphia, Pennsylvania, USA (T.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2018-169-6-035 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationLamoury FMJ, Bajis S, Hajarizadeh B, et al; LiveRLife Study Group. Evaluation of the Xpert HCV Viral Load Finger-Stick point-of-care assay. J Infect Dis. 2018;217:1889-96. https://pubmed.ncbi.nlm.nih.gov/29534185Clinical Impact RatingsGIM/FP/GP: Infectious Disease: Reference1 Kugelmas M, Pedicone LD, Lio I, Simon S, Pietrandoni G. Hepatitis C point-of-care screening in retail pharmacies in the United States. Gastroenterol Hepatol (N Y). 2017;13:98-104. [PMID: 28450816] Google Scholar Author, Article, and Disclosure InformationAffiliations: Temple University School of Medicine, Philadelphia, Pennsylvania, USA (T.F.)This article was published at Annals.org on 4 September 2018. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 18 September 2018Volume 169, Issue 6Page: JC35KeywordsBlood plasmaDrugsHepatitis C virusLiverPatientsPhlebotomyPrevention, policy, and public healthRNASpecificityViral load ePublished: 18 September 2018 Issue Published: 18 September 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Lobular Carcinomas <i>In Situ</i> Display Intralesion Genetic Heterogeneity and Clonal Evolution in the Progression to Invasive Lobular Carcinoma
Authors: Ju Youn Lee, Michail Schizas, Felipe C. Geyer, Pier Selenica, Salvatore Piscuoglio, Rita A. Sakr, Charlotte K.Y. Ng, Jose V. Scarpa Carniello, Russell Towers, Dilip D. Giri, Victor P. de Andrade, Anastasios D. Papanastasiou, Agnes Viale, Reuben S. Harris, David B. Solit, Britta Weigelt, Jorge S. Reis-Filho, Tari A. King
Journal: Clinical Cancer Research (2018)

Lobular carcinoma in situ (LCIS) is a preinvasive lesion of the breast. We sought to define its genomic landscape, whether intralesion genetic heterogeneity is present in LCIS, and the clonal relatedness between LCIS and invasive breast cancers.Experimental Design: We reanalyzed whole-exome sequencing (WES) data and performed a targeted amplicon sequencing validation of mutations identified in 43 LCIS and 27 synchronous more clinically advanced lesions from 24 patients [9 ductal carcinomas in situ (DCIS), 13 invasive lobular carcinomas (ILC), and 5 invasive ductal carcinomas (IDC)]. Somatic genetic alterations, mutational signatures, clonal composition, and phylogenetic trees were defined using validated computational methods.WES of 43 LCIS lesions revealed a genomic profile similar to that previously reported for ILCs, with CDH1 mutations present in 81% of the lesions. Forty-two percent (18/43) of LCIS were found to be clonally related to synchronous DCIS and/or ILCs, with clonal evolutionary patterns indicative of clonal selection and/or parallel/branched progression. Intralesion genetic heterogeneity was higher among LCIS clonally related to DCIS/ILC than in those nonclonally related to DCIS/ILC. A shift from aging to APOBEC-related mutational processes was observed in the progression from LCIS to DCIS and/or ILC in a subset of cases.Our findings support the contention that LCIS has a repertoire of somatic genetic alterations similar to that of ILCs, and likely constitutes a nonobligate precursor of breast cancer. Intralesion genetic heterogeneity is observed in LCIS and should be considered in studies aiming to develop biomarkers of progression from LCIS to more advanced lesions.