tbuckley/cabot-search huggingface dataset:
A phase 0/II study for ribicoclib in patients with recurrent glioblastoma.
Authors: Nader Sanai, An-Chi Tien, Norissa Honea, Shwetal Mehta, Jing Li
Journal: Journal of Clinical Oncology (2017)

TPS2083 Background: Disruption of CDK4/6-dependent G1-S cell cycle regulation is a hallmark of glioblastoma (GBM) progression in 78% of cases. Newly-developed CDK4/6 inhibitors have shown promise in non-CNS cancer trials and glioma animal models. To explore the utility of Ribociclib, a specific CDK4/6 inhibitor, in treating recurrent GBM patient, we designed a phase 0/II clinical trial to examine the pharmacokinetic (PK) and pharmacodynamics (PD) of Ribociclib. Methods: 24 adult patients are allocated to 3 time-escalation arms and receive 5 days of daily Ribociclib prior to planned GBM resection. Eligible patients are selected based on intact Rb expression and loss of Ink4a/Arf locus. Intensive PK sampling of blood, CSF, and tumor is performed intraoperatively and Ribociclib concentrations are determined by a validated LC-MS/MS method. PD endpoints, including RB phosphorylation and FoxM1 expression, are compared to matched archival tissue. Patients exhibiting positive PK and PD outcomes will graduate to a therapeutic regime of Ribociclib as part of the Phase II component of the study with a primary endpoint of progression-free survival, as determined by Response Assessment in Neuro-Oncology (RANO) criteria. Clinical trial information: NCT02933736.
Randomized phase III study of adjuvant chemotherapy with or without low-molecular weight heparin in completely resected non-small cell lung cancer patients: The NVALT-8 study.
Authors: Harry J.M. Groen, Erik van der Heijden, Theo J Klinkenberg, Bonne Biesma, Joachim Aerts, Ad Verhagen, Corinne Kloosterziel, Hans J.M. Smit, Franz Schramel, Vincent van der Noort, Harm van Tinteren, Egbert F. Smit, Anne-Marie C. Dingemans
Journal: Journal of Clinical Oncology (2016)

8506 Background: aCT improves overall survival in pts with completely resected stage II/ III NSCLC. LMWH may also improve survival. We hypothesized that in pts with completely resected NSCLC adding nadroparin (nadro) to aCT will improve recurrence-free survival (RFS). This effect may be different in high/low (SUVmax ≥ 10 vs < 10) FDG avidity NSCLC. Methods: Prospective multicenter phase III study in pts with resectable NSCLC who were randomized within 4-6 wks after surgery to nadro sc daily for 16 wks or no nadro (controle). All pts received 4 cycles pemetrexed (500 mg/m2) for non-squamous or gemcitabine 1000 mg/m2 for squamous histologies and cisplatin (75 mg/m2) on day 1 every 3 wks. Other inclusion criteria: PS 0-2, adequate organ function, INR<1.5. Exclusion criteria: R1 and wedge/segmental resection, prior chemo- or radiotherapy or contra-indication for nadro. Primary endpoint is RFS. Slow accrual enabled to decrease the number of pts from 600 to 202, still providing 80% power to compare RFS at 94 events (α = 0.05; 2-sided log-rank test) in both arms at 3 yrs from 60% to 75%, assuming exponential survival. Cox proportional hazard models were used to evaluate nadro as an independent factor for survival, both in pts with high/low FDG avidity NSCLC. Results: Among235 registered patients, 202 were randomized (nadro: n=100; control n=102), 120 (59%) men, 77 (38%) squamous, 125 (62%) non-squamous, staged pT1N0 (n=1), pT2N0 (n=57), pT1N1 (n=9), pT2N1 (n=51), pT3N0 (n=39) and pT3N1 (n=14), pT4N0 (n=3), 28 had unforeseen mediastinal disease. Among grade ≥ 3 toxicity neutropenia was most common (nadro n=20; control n=6, p= 0.002). No differences in bleeding events occurred. Pts randomized to nadro had a RFS of 47.8 mo vs 36.1 mo in control arm. At 3 yrs, RFS was resp 57 and 50%. Data on OS are immature. When stratified for FDG avidity RFS was different for nadro versus control (HR=0.60, p=0.03). Conclusions: Adjuvant nadroparine improved RFS in high and low FDG avidity NSCLC. Clinical trial information: NTR 1250/1217.
PD-1/PD-L1 expression and regorafenib clinical efficacy on refractory pancreatic cancer patient.
Authors: Veronica Varchetta, Fabrizio Montagnese, Simone Sibio, Giuseppe Sica, Maurizio Muscaritoli, Giuseppe Soda, Gianfranco Giordano, Rita Brandi, Silvia Tarsi, Giuseppina Mancuso, Andrea Petricca Mancuso
Journal: Journal of Clinical Oncology (2016)

e15684 Background: Regorafenib, a potent multikinase inhibitor, targets a broad range of receptor tyrosine kinases (RTKs), including but not limited to VEGFR, PDGFR, and FGFR, which play an integral role in angiogenesis and in making a immunosuppressive tumor microenvironment. The results of the correlation between PD-1/PD-L1 expression and RTKs inhibition remains controversial in lung cancer and limited data exist in pancreatic cancer. Methods: We analysed a cohort of 69 chemorefractory metastatic pancreatic cancer patients, including 56 KRAS mutated, treated with Regorafenib as third line of treatment. PD-L1 (MRQ-22 antibody) and PD-1 (SP142 antibody) expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in > 5% of tumour cells and tumor infiltrating lymphocytes (TILs) were considered as positive. Results: Pancreatic tumors expressed PD-L1 at a frequency of 20% (14/69), and PD-1 at a frequency of 46% (32/69). PD-1 positive (+) was significantly associated with previous alcohol abuse status (p = 0.04) and with the presence of KRAS mutations (p = 0.008). Patients with tumors overespressing PD-1/PD-L1 positivity, (Group A: 46/69) had a median progression free survival (PFS) was 4.58 months, whereas it was 1.45 months in the group without the combined expression (Group B: 23/69) (p = 0.0012). Median overall survival (OS) was 7,16 months and 2.18 months in group A and B respectively (p = 0.031). At multivariate analysis a baseline high platelet count was related to a worse OS (p = 0.057). Conclusions: Our analysis suggests that PD-L1/PD-1 positivity is a predictive factor for clinical outcome in pancreatic cancer patients treated with regorafenib. Further confirmations in larger trials are needed.
The impact on socio-demographic characteristics of clients seeking genetic counseling for hereditary breast and ovarian cancer due to the outing of Angelina Jolie.
Authors: Muy-Kheng Maria Tea, Christine Staudigl, Georg Pfeiler, Andreas Berger, Katharina Hrauda, Renate Lichtenschopf, Romana Renz, Christian F. Singer
Journal: Journal of Clinical Oncology (2016)

e13119 Background: The purpose of this study was to evaluate socio-demographic characteristics of clients seeking genetic counseling for hereditary breast and ovarian cancer (HBOC) in Austria. Furthermore, changes of these parameters before and after Angelina Jolie’s (AJ) outing of carrying a BRCA mutation were evaluated. Methods: A total of 268 consecutive clients seeking genetic counseling for HBOC at the Medical University of Vienna, Department of Obstetrics and Gynecology, Vienna, Austria were included between June 2012 and June 2014. Socio-demographic data and source of information about HBOC and genetic counseling were evaluated. Socio-demographic parameters were compared to the general Austrian population as well as changes in these parameters after AJ’s public outing of carrying a BRCA mutation were analyzed. Results: In general, clients were more frequent female, younger and higher educated in comparison to the Austrian general population (p < 0.001). Furthermore, level of education in participants was higher before than after AJ’s disclosure (p = 0.046). As expected, after AJ’s public announcement patients were more frequent advised to genetic counseling by social media (p = 0.043) and family or friends (p = 0.010) than before. Conclusions: In this study we demonstrate that particularly younger and female participants with high educational level attended significantly more often genetic counseling for HBOC. Increased presence of HBOC in media since AJ’s disclosure of carrying a BRCA mutation had lead that information about HBOC was obtained by a wider audience from different social background.
Survival Improvement of Patients with Chronic Lymphocytic Leukemia (CLL) in Routine Care. a Retrospective Analysis of All Patients with CLL Who Were Treated in an Oncology Group Practice in Germany Between 1995-2015
Authors: Rudolf Weide, Stefan Feiten, Geothy Chakupurakal, Vera Friesenhahn, Kristina Kleboth, Julia Lutschkin, Jörg Thomalla, Christoph van Roye, Jochen Heymanns, Hubert Köppler
Journal: Blood (2016)
Missing HLA C group 1 ligand in patients with AML and MDS is associated with reduced risk of relapse and better survival after allogeneic stem cell transplantation with fludarabine and treosulfan reduced toxicity conditioning
Authors: Avichai Shimoni, Luca Vago, Massimo Bernardi, Ronit Yerushalmi, Jacopo Peccatori, Raffaella Greco, Noga Shem‐Tov, Alessandro Lo Russo, Ivetta Danylesko, Arie Apel, Chiara Bonini, Maria Teresa Lupo Stanghellini, Arnon Nagler, Fabio Ciceri
Journal: American Journal of Hematology (2017)

Abstract Reduced‐toxicity conditioning with fludarabine and treosulfan is a dose‐intensive regimen with enhanced anti‐leukemia effect and acceptable toxicity in AML/MDS. HLA‐C regulates natural‐killer (NK) cell function by inhibiting Killer immunoglobulin‐like receptors (KIR) and is divided into C1 and C2 epitopes. The missing‐ligand theory suggests that missing recipient KIR ligands drives NK‐alloreactivity after SCT, in the absence of HLA‐mismatch by activating unlicensed donor NK cells. We analyzed SCT outcomes in 203 patients with AML/MDS, median age 58 years, given SCT from matched‐siblings ( n = 97) or matched‐unrelated donors ( n = 106), using two treosulfan doses (total 36 or 42 g/m 2 ). 34% expressed one HLA‐C group 1 allele (C1C1), 19% one HLA‐C group 2 allele (C2C2), and 48% both KIR ligands (C1C2). Median follow‐up was 48 months. 5‐year relapse, nonrelapse mortality (NRM) and leukemia‐free survival (LFS) rates were 38%, 27%, and 36%, respectively. Relapse rates were 43%, 45%, and 26% in patients expressing C1C1, C1C2, and C2C2 ligands, respectively ( P = .03). Multivariate‐analysis identified chemo‐refractory disease (HR 3.1, P = .003), poor cytogenetics (HR 1.7, P = .08), female donor to male recipient (HR 0.4, P = .01) and C2C2 ligands (HR 0.4, P = .04) as independent factors predicting relapse. HLA‐C ligands were not associated with GVHD or NRM. LFS was 33%, 30%, and 46%, respectively ( P = .07). Chemorefractory disease (HR 3.1, P = .0004) and C2C2 group ligand (HR 0.6, P = .06) independently predicted LFS. Treosulfan dose did not predict any SCT outcome. In conclusion, missing HLA‐C group 1 ligand is associated with reduced relapse risk, similar NRM and improved LFS, after HLA‐matched SCT with treosulfan conditioning in AML/MDS.
Neurological complications of new chemotherapy agents
Authors: Alicia M Zukas, David Schiff
Journal: Neuro-Oncology (2017)

This last decade has yielded more robust development of cancer treatments and first-in-class agents than ever before. Since 2006, nearly one hundred new drugs have received regulatory approval for the treatment of hematological and solid organ neoplasms. Moreover, older conventional therapies have received approval for new clinical indications and are being used in combination with these newer small-molecule targeted treatments. The nervous system is vulnerable to many of the traditional cancer therapies, manifesting both already well-described acute and chronic toxicities. However, newer agents may produce toxicities that may seem indistinguishable from the underlying cancer. Early recognition of neurotoxicities from new therapeutics is vital to avoid irreversible neurological injury. This review focuses on cancer therapies in use in the last 10 years and approved by the FDA from January 2006 through January 1, 2017.
Rate of sentinel lymph node biopsy in patients undergoing mastectomy for ductal carcinoma in situ with and without micro-invasion.
Authors: Patience Odele, Seema Ahsan Khan, Kevin P. Bethke, Nora Hansen
Journal: Journal of Clinical Oncology (2016)

1065 Background: Patients treated with mastectomy for ductal carcinoma in situ (DCIS) undergo sentinel lymph node biopsy (SLNB) due to the concern for invasive cancer on final histology and difficulty performing SLNB post mastectomy. However, the documented rate of positive SLN in patients with DCIS is about 1.3-13%. The purpose of the present study is to determine the rate of positive SLN in patients with DCIS undergoing mastectomy and to identify risk factors for positive SLN. Methods: Retrospective chart review included 377 patients treated with mastectomy for DCIS or DCIS-M registered within the Northwestern University Bioinformatics Center from 2000 to 2015. Correlation between patient and histologic features in relation to positive SLN was evaluated using univariate analysis. Results: Of the 377 patients evaluated 10 women had SN positivity, 2 with isolated tumor cells, 5 with macrometastasis, and 3 with micrometastasis. Only one patient had non-SN involvement (for a total of 3 nodes). The overall rate of positive SLNB was 2.6%. Of the 283 patients with pure DCIS, 3 had positive SLNB with a rate of 1.1% vs 7.4% (7 patients) in those with DCIS-M or IDC (p = 0.003). Univariate analysis show that size > 30 mm (p = 0.008) and DCIS-M or IDC on final histology are significant risk factors for positive SLN. Although grade was not significant, all 38 patients with grade1 DCIS had negative SLN. Conclusions: Of the 2.6% patients with positive SN, large DCIS lesions with micro-invasion on core tend to have a significantly higher frequency of positive SLNB. For women with pure DCIS, particularly with Grade 1 lesions, SN positivity is extremely unlikely and patients can be counseled accordingly. Predictive factors for positive SLNB. Characteristics Positive SLNB No. (%) Negative SLNB No. (%) P- value Age (years) 5(4.4) 109 (95.6) 0.3 ≤ 50 5(2) 248 (98) > 50 Micro-calcifications 8 (2.7) 288 (97.3) 0.6 Mass 0 (0) 54 (100) Tumor Size (mm) 4 (1.5) 271 (98.5) 0.008 ≤ 30 6 (8) 69 (92) > 30 Grade 0 38 (100) 0.4 I 6 (4.1) 141 (96.9) II 4 (2.1) 187 (97.9) III Final Histology 3 (1.1) 280 (98.9) 0.003 Pure DCIS 7 (7.4) 87 (92.6) DCIS-M / IDC Hormonal status 8(2.7) 288 (97.3) 0.9 ER+ 2(2.7) 72 (97.3) ER/PR -
Germline Chd8 haploinsufficiency alters brain development in mouse
Authors: Andrea L Gompers, Linda Su-Feher, Jacob Ellegood, Nycole A Copping, M Asrafuzzaman Riyadh, Tyler W Stradleigh, Michael C Pride, Melanie D Schaffler, A Ayanna Wade, Rinaldo Catta-Preta, Iva Zdilar, Shreya Louis, Gaurav Kaushik, Brandon J Mannion, Ingrid Plajzer-Frick, Veena Afzal, Axel Visel, Len A Pennacchio, Diane E Dickel, Jason P Lerch, Jacqueline N Crawley, Konstantinos S Zarbalis, Jill L Silverman, Alex S Nord
Journal: Nature Neuroscience (2017)
Epidemiology of neuroendocrine tumors (NET) of the lung in the US: Analysis of 2 large insurance claims databases.
Authors: Beilei Cai, Michael S. Broder, Eunice Chang, Caroline Burk, Kris Grzegorzewski, Maureen Neary
Journal: Journal of Clinical Oncology (2016)

e13071 Background: The majority of NETs occur in the gastrointestinal (GI) and bronchopulmonary system. The overall incidence of lung NET in the US appears to have increased from the 1970s to 2004 with the latest estimate of 13 per million person-years in year 2004. Whether incidence has continued to increase in the last decade is not known. Methods: A retrospective, cross-sectional study was conducted using data 2010-2014 from 2 major US health insurance claims databases: Truven Health Analytics MarketScan and IMS PharMetrics. Patients were included if, during a calendar year, they were 18-64 years old, and had ≥ 1 inpatient or ≥ 2 outpatient claims with NET of the bronchus or lung identified by International Classification of Diseases-9 (ICD-9) codes 209.21 and 209.61. Prevalence was calculated as the number of patients with lung NET divided by number of enrollees per year. Incidence rates were calculated as the number of patients with a first observed NET diagnosis who were disease-free for 2 years prior to the diagnosis, divided by the number of enrollees. Analyses were conducted separately by year and database. Results: For years 2010-2014, there were 397-538 and 393-507 lung NET cases per year in MarketScan and PharMetrics, respectively. Prevalence increased from 19.0 to 30.4 per million per year (PMPY) between 2010 and 2014 in MarketScan and from 18.9 to 26.2 PMPY in PharMetrics; it increased with age and was highest in 55-64 year olds (32.0-79.0 PMPY); and it was greater in females (22.6-39.3 PMPY) than in males (13.8-20.6 PMPY). Incidence increased in both datasets from 2011 to 2014: from 15.9 to 19.2 per million person-years in MarketScan and from 13.1 to 16.0 per million person-years in PharMetrics. Conclusions: In both MarketScan and PharMetrics databases, the incidence and prevalence rates of lung NET have increased considerably over the last decade. Increased awareness lung NET in clinical oncology setting is needed to accommodate this increasing trend.
Symptom clusters in patients with advanced cancer in an early-phase clinical trials clinic.
Authors: Goldy George, Eucharia Chiege Iwuanyanwu, Alizeh Yusuf, Karen O Anderson, Sarina Anne Piha-Paul, Aung Naing, Filip Janku, Vivek Subbiah, Xin Shelley Wang, Qiuling Shi, Tito R. Mendoza, David S. Hong, Charles S. Cleeland
Journal: Journal of Clinical Oncology (2016)

2540 Background: Few data exist on patient-reported outcomes, specifically symptoms, in patients with advanced cancer who seek or are in treatment in phase I clinical trials of molecular targeted agents (phase I patients). We explored patient clusters based on symptom severity, and examined associated factors. Methods: Phase I patients completed the validated core MD Anderson Symptom Inventory (with 13 symptom and 6 symptom interference items, each rated on a 0-10 scale) and the Profile of Mood States. ECOG performance status was assessed. Cluster analysis was used. Results: In phase I patients (N = 248, 51% female, 90% ECOG 0-1, and 52% ≥ 60y), symptoms with highest reported mean severity were fatigue (4.6), drowsiness (3.7), pain (3.6), and lack of sleep (3.0). Highest symptom-related interference was with work (3.5), activity (3.4), and enjoyment of life (3.4). Two natural patient clusters based on reported symptom severity were seen: 38% of patients were in the high symptoms cluster (HSC), and 62% were in the low symptoms cluster (LSC). HSC patients reported greater tension, depression, anger, confusion and lower vigor (p < 0.001), were more likely to have poor PS (ECOG > = 2) (16.5% vs. 4.7%, p < 0.003) and reported higher symptom-related interference (5.1 vs. 1.8, p < 0.001) than LSC patients. Cluster membership did not vary by current enrollment on a phase I clinical trial (p > 0.05) or by the number of cycles completed (6.8 vs. 6.4 cycles, p > 0.05). Patients on a phase I trial reported less dyspnea (1.0 vs. 1.95, p < 0.001) and vomiting (0.53 vs. 1.07, p < 0.029) than patients not enrolled, but did not differ in other symptoms. Patients < 60y of age on a trial were more likely to be in the HSC than patients ≥ 60 y (60% vs. 41%, p < 0.038). Conclusions: Patient-reported symptoms, particularly fatigue, drowsiness, pain and lack of sleep should be routinely assessed in phase I clinics, potentially improving attribution of adverse events. Also, current enrollment on a phase 1 trial does not appear to adversely impact symptoms. Treatment of symptoms may include counseling, especially for younger patients, given their higher reported symptom severity. Patient-reported outcomes can complement physician assessment to enhance treatment plans.
Visualisation of normal and abnormal brain vasculature with different ferumoxytol doses.
Authors: Peter Varallyay, Csanad Varallyay, Andrea Horvath, Laszlo Szidonya, Rochelle Fu, Gerda Toth, Edward A. Neuwelt
Journal: Journal of Clinical Oncology (2017)

e13517 Background: Ferumoxytol is an iron oxide nanoparticle, marketed for iron replacement therapy. Off label use as an MRI contrast agent allows visualization of cerebral vasculature in the early blood pool phase without early contrast enhancement obscuring the vessels as seen with small molecular gadolinium. This study tested the optimal ferumoxytol dose for visualization of normal and abnormal cerebral vasculature. Methods: MRI images of 75 subjects enrolled in imaging research protocols were analyzed. Vascular visualization was tested in high resolution gradient echo T2*-weighted images acquired after 1mg/kg, 3mg/kg and 7mg/kg (up to 510mg) ferumoxytol doses. Visualization of normal and abnormal vasculature was separately evaluated as “poor, moderate or clear”. Degree of blooming artifact was graded as “none, mild and marked”. Overall clarity of the image was visually assessed as “poor, moderate and very clear”. The probability of abnormal vasculature visualization being “moderate” or “clear” was tested among the three Fe dosages with a mixed effects model while taking correlation among different dosages into account. Results: Visualization of normal brain vasculature was poor with 1mg/kg, moderate with 3mg/kg and very clear with 7mg/kg in 97% of the cases. However, blooming with 7 mg/kg was already marked for all cases causing confluence of larger veins and even smaller vessels close to each other, while images with 3mg/kg showed only mild blooming in all cases, resulting in altogether a better quality/clarity of the images (very clear in 93.3%) with good contrast between normal vessels and brain parenchyma. Not all subjects had abnormal vasculature due to prior surgery. However, when considering all subjects, visualization of abnormal vasculature was moderately or clearly visible in 23% of subjects when using1mg/kg, significantly less than 3mg/kg (42.7%, P = 0.0012) and 7mg/kg (43.9%, P = 0.0007). Conclusions: 3mg/kg ferumoxytol allows adequate visualization of normal and abnormal vasculature with acceptable degree of blooming artifact. Visualization of tumor vasculature may help targeting the most malignant area for surgery/radiotherapy and may help differentiating tumor progression from pseudoprogression. Clinical trial information: NCT00659776, NCT02359097.