tbuckley/cabot-search huggingface dataset:
Immune cell phenotyping of clear cell renal cell carcinoma.
Authors: Mazyar Ghanaat, Ming Liu, Brandon Manley, Mahyar Kashan, Maria Becerra, Almedina Redzematovic, Jonathan Coleman, Paul Russo, James Hsieh, Ming Li, A. Ari Hakimi
Journal: Journal of Clinical Oncology (2017)

511 Background: Clear cell renal cell carcinoma (ccRCC) tumors develop mechanisms that impair function and/or prevent entry of the host infiltrating immune cells (immune exclusion) within the tumor microenvironment. The goal of immunotherapy is to overcome this immune resistance. We aim to characterize the T−cell populations in a cohort of largely untreated high risk patients with ccRCC. Methods: We prospectively collected ccRCC tumor and adjacent normal kidney (NK) from patients undergoing surgical resection at our institution from 6/2015-8/2016. Immune cell phenotyping was performed by immune cell staining of single cell suspensions. Analysis of immune cell populations were determined by CD45+ staining and corresponding proportions of different T−cell populations (CD3+, CD4+, CD4+Treg, and CD8+ T cells). Staining for CD4+Treg was not available for two patients. Student t−test was utilized to compare the immune populations between tumor and adjacent NK tissue. Analysis was also conducted by stratifying patients who presented with localized versus metastatic disease. Results: A total of 31 tumor and adjacent NK were analyzed. Median tumor pathological size was 8.5cm (2.9cm−18cm), 27(87%) had pT3a−pT3b and 13(42%) presented with metastatic disease. Overall 84% of tumors had higher immune infiltrate with an average ratio of four-fold increase compared to adjacent NK as determined by CD45+ cells. Intriguingly, the other 16% presented with metastatic (4) or rapidly metastatic disease (1). Orthogonal validation with inferred immune populations using RNAseq data from the The Cancer Genome Atlas (TCGA) demonstrated similar aggressive behavior in tumors with lower immune infiltrate compared to NK. Comparison of immune cell populations of tumor and NK tissue is shown in table 1. No specific T-cell subtype was associated with specific clinical outcomes in this cohort. Conclusions: Our data shows a general trend of immune infiltration in ccRCC when compared to adjacent NK with a diversity of T-cell subsets and possible evidence of immune exclusion. Further genomic characterization of these tumors is currently underway. [Table: see text]
Action Tremor, Impaired Balance, and Executive Dysfunction in Midlife
Authors: Rachael Cherie Birch, Julian Norman Trollor
Journal: JAMA Neurology (2017)

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Epidermal growth factor receptor mutations may confer resistance or cross-resistance to cetuximab and panitumumab and can be detected in circulating tumor DNA.
Authors: Mascha Binder, Friederike Braig, Aneta Schieferdecker, Alexander Schulte, Alexander Stein, Tobias Grob, Malte Kriegs, Erik Engel, Udo J. Vanhoefer, Sonja Loges, Kristoffer Riecken, Boris Fehse, Carsten Bokemeyer
Journal: Journal of Clinical Oncology (2015)

3549 Background: Acquired resistance to epidermal growth factor receptor (EGFR) targeted antibodies represents a clinical challenge in the treatment of gastrointestinal tumors such as metastatic colorectal cancer, but its molecular mechanisms are incompletely understood. Methods: We scanned KRAS exon 2/3/4, NRAS exon 2/3/4 and the overlapping epitopes of the EGFR antibodies cetuximab and panitumumab for mutations in pre- and post-treatment tumor tissue of 21 patients with gastrointestinal cancer treated with chemotherapy +/- EGFR antibodies by targeted next-generation sequencing (“tumor tissue” cohort). Binding, signaling and drug sensitivity studies were performed in Ba/F3 cells stably transduced with wt and mutant EGFR. Results were validated in circulating tumor DNA (ctDNA) of an independent “liquid biopsy” cohort of 27 patients. Results: We describe a novel EGFR exon 12 mutation acquired in tumors of 1 out of 3 patients treated with panitumumab in the “tumor tissue” cohort. This mutation introduces a positive charge within the overlap of the panitumumab and cetuximab epitopes. It abrogates antibody binding and mediates cross-resistance to both antibodies in EGFR-mutant transfected Ba/F3 cells. In ctDNA from the “liquid biopsy” cohort, we found this novel mutation in 1 out of 6 panitumumab-treated patients while about one third of patients show acquired RAS mutations. Conclusions: We show that acquired resistance by epitope-changing mutations also emerges during panitumumab treatment and may follow similar biochemical principles as in cetuximab resistance. Such mutations can be easily detected by next-generation sequencing of ctDNA and may perspectively help in tailoring EGFR-targeted therapies.
Updated efficacy of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with <i>BRAF</i> V600E mutated (BRAFm) metastatic colorectal cancer (mCRC).
Authors: Chloe Evelyn Atreya, Eric Van Cutsem, Johanna C. Bendell, Thierry Andre, Jan H. M. Schellens, Michael S. Gordon, Autumn Jackson McRee, Peter J O'Dwyer, Kei Muro, Josep Tabernero, Robin van Geel, Roger Sidhu, James G Greger, Fatima A. Rangwala, Monica Motwani, Yuehui Wu, Keith W. Orford, Ryan Bruce Corcoran
Journal: Journal of Clinical Oncology (2015)

103 Background: BRAF V600E mutations occur in 5–10% of mCRC and confer a poor prognosis. Unlike BRAFm melanoma, BRAF and MEK inhibitors have minimal activity in BRAFm mCRC. Preclinical data suggest that combined inhibition of the EGFR and MAPK pathways is required to maximally inhibit growth of BRAFm mCRC. This study evaluates the activity of the combination of P with D and/or T in BRAFm mCRC. Methods: Eligible pts with BRAFm mCRC received doublet, D+P or T+P, or triplet, D+T+P. Results: Doublet (D+P): 20 pts received the full doublet dose (D 150mg twice daily [BID] + P 6mg/kg every 2 weeks [Q2W]). Triplet: 35 pts received D+T+P including 24 pts that received full triplet dose (D 150mg BID + T 2mg once daily [QD] + P 6mg/kg Q2W). No dose-limiting toxicities were observed. As of October 20, 2014, the most common adverse events were dermatitis acneiform (Grade [G] 1/2 55%) and fatigue (G 1/2 45%) for D+P, and diarrhea (G1/2 60%, G3 9%) and dermatitis acneiform (G1/2 47%; G3 9%) for triplet. The confirmed response rate for D+P was 10% and for D+T+P was 26% (Table 1). Treatment with either regimen reduced levels of pERK in on-treatment biopsies relative to pre-dose biopsies (median reduction D+P 23%; D+T+P 54%). Pts are currently being enrolled to T+P. Updated results including progression-free survival and duration of response will be presented. Conclusions: Encouraging clinical activity with acceptable tolerability is seen with the triplet D+T+P in BRAFm mCRC. Clinical trial information: NCT01750918.Investigator–assessed best response with confirmation (RECIST 1.1). D 150 mg BID+ P 6mg/kg Q2W N = 20 D 150 mg BID, T 1.5 mg QD, P 4.8 mg/kg Q2W N = 3 D 150 mg BID, T 2 mg QD, P 4.8 mg/kg Q2W N = 4 D 150 mg BID, T 1.5 mg QD, P 6 mg/kg Q2W N = 4 D 150 mg BID, T 2 mg QD, P 6 mg/kg Q2W N=24 D+T+P Total N = 35 Complete response, n (%) 1 (5) 0 1 (25) 0 0 1 (3) Partial response, n (%) 1 (5) 2 (67) 1 (25) 0 5 (21) 8 (23) Stable disease, n (%) 16 (80) 1 (33) 2 (50) 2 (50) 15 (63) 20 (57) Progressive disease, n (%) 2 (10) 0 0 2 (50) 3 (13) 5 (14) Not evaluable, n (%) 0 0 0 0 1 (4) 1 (3) Response rate (CR+PR), n (%) 2 (10) 2 (67) 2 (50) 0 5 (21) 9 (26) 95% confidence interval, % 1.2–31.7 9.4–99.2 6.8–93.2 0.0–60.2 7.1–42.2 12.5–43.3
Randomized phase III trial of intravenous (IV) versus hepatic intra-arterial (HIA) fotemustine in patients with liver metastases from uveal melanoma: Final results of the EORTC 18021 study.
Authors: Serge Leyvraz, Stefan Suciu, Sophie Piperno-Neumann, Jean-Francois Baurain, Marcin Zdzienicki, Alessandro Testori, Ernest Marshall, Max E. Scheulen, Thomas Jouary, Sylvie Negrier, Jan Baptist Vermorken, Eckhart Kaempgen, Xavier Durando, Dirk Schadendorf, Ravichandra Karra Gurunath, Larissa Polders, Gaetan De Schaetzen, Simon Vanderschaeghe, Marie-Pierre Gauthier, Ulrich Keilholz
Journal: Journal of Clinical Oncology (2012)

8532 Background: HIA fotemustine has shown promising results in Phase II studies that led to the EORTC randomized phase III trial (18021) in unpretreated patients (pts) with liver metastases from uveal melanoma. Methods: The treatment consisted in an induction cycle of either HIA (fotemustine 100 mg/m² over 4 hours, day 1, 8, 15, 22) vs IV control arm (fotemustine 100 mg/m² over 1 hour, day 1, 8, 15). After a 5-week break, maintenance cycles were given every 3 weeks. Randomization was stratified by PS (0 vs 1), LDH (normal vs abnormal) and center. Main endpoint was overall survival (OS). Required accrual per protocol was set to 262 pts, with final analysis planned after 220 deaths (hazard ratio (HR) =0.67, power=85%, 1-sided α=2.5%). Due to poor accrual an interim analysis was done after 134 deaths, in order to test futility (power=79%). Results: Between Feb-2005- Feb-2011, 171 pts were randomized (HIA: 86, IV: 85). Characteristics: PS 1: 20%, abnormal LDH: 42%, male: 50%, median age: 59 y.; balanced between arms. In the HIA arm 20 (23%) pts never started treatment mainly due to catheter problems and 2 pts in the IV arm. In those who started the treatment, leucopenia grade 3-4 was 18% and thrombopenia grade 3-4: 21% in the HIA arm compared to 32% and 42% in the IV arm. Non-hematological grade 3-4 toxicities were minimal (GI toxicity, catheter complications). In May 2011, as the OS HR=1.097 was &gt; critical value 0.87, the IDMC recommended stopping accrual for futility. The final results from Jan-2012 are presented in the table below. Treatment comparison adjusted by PS and LDH provided similar results. Conclusions: Even if HIA fotemustine administration could not start in 23% of pts, it led to a higher ORR and longer PFS compared to IV administration. HIA did not translate into an improvement in OS. [Table: see text]
Identification of <i>RICTOR</i> amplification as a recurrent and potentially actionable alteration in small cell lung cancer patients.
Authors: Snehal Dabir, Gary Wildey, Karen McColl, Pingfu Fu, Yan Feng, Afshin Dowlati
Journal: Journal of Clinical Oncology (2015)

7576 Background: Genomic analysis of SCLC is in its infancy relative to NSCLC and no known correlations to clinical outcomes have been reported for any SCLC mutation. Thus, we tested SCLC cancer diagnostic biopsies for genomic mutations by targeted exome sequencing of a panel of cancer-related genes using FFPE tissue. We identified recurrent RICTOR amplification in 5 of 36 total patient tumors examined. Here we report the clinical importance of RICTOR amplification in our SCLC cohort and its potential to represent a new actionable subgroup in this disease. Methods: Survivor distribution was estimated using Kaplan-Meier methods and the difference of OS, PFS between/among groups was examined by log-rank test. All tests are two-sided and p-value ≤ 0.05 were considered statistically significant. SCLC cell lines were assayed for growth inhibition in the IncuCyte ZOOM using drugs that target the PI3K/AKT/mTORC1/2 pathways. Results: RICTOR amplification was found in 4 men and 1 women, with a median age of 63 years. RICTOR typically co-amplified with the nearby genes IL7R and FGF10; suggesting a focal amplification of these genes on chromosome 5p13. RICTOR was the most frequent amplified gene identified in our SCLC cohort; greater than FGFR1 and MYC. The OS of patients with RICTOR amplification was significantly decreased (p = 0.036) while PFS approached significance (p = 0.062). Cell growth inhibition studies with SCLC cell lines demonstrated sensitivity towards mTORC1/2 inhibitors (INK128 and AZD2014) by cells with higher CNV for RICTOR. Ongoing experiments will expand the number of cell lines studied to determine the correlation between RICTOR CNV, protein and growth inhibition. Conclusions: Amplification of RICTOR may represent a clinically significant mutation in SCLC and may represent a predictive marker for targeted therapy with mTORC1/2 inhibitors in small cell lung cancer patients.
Neoadjuvant chemotherapy for elderly patients with locally advanced disease: Are we doing enough?
Authors: Andres Correa, Elizabeth Handorf, Shreyas Joshi, Benjamin T. Ristau, Miki Haifler, Alexander Kutikov, Richard E. Greenberg, David Chen, Robert G. Uzzo, Rosalia Viterbo, Daniel M. Geynisman, Marc C. Smaldone
Journal: Journal of Clinical Oncology (2017)

389 Background: The administration of neoadjuvant chemotherapy (NAC) for patients with muscle invasive urothelial carcinoma improves overall survival. Recent reports have shown that the survival benefit may be greater in patients with locally advanced disease. Our objective was to assess the utilization of NAC by stage and age using a large national tumor registry. Methods: Patients who underwent radical cystectomy for cT2-4 N0-1 M0 urothelial carcinoma diagnosed between 2003-2012 were selected from the National Cancer Data Base. We excluded those with planned radiation therapy or who received palliative care. A multivariate logistic regression analysis was constructed to identify factors that affected administration of NAC. Covariates included were clinical stage, age, race, sex, insurance status, income, Charlson index, clinical stage group, demographic location, facility location, and diagnosis year. We also used interaction terms in the regression model to determine if stage effects differed by age group. Results: A total of 16,248 patients met inclusion criteria for the study. The use of NAC increased over the study period with 6% of eligible patients receiving NAC in 2003 vs. 27.7% in 2012 (p &lt; 0.001).Increasing utilization of NAC was noted with increasing stage (cT2N0: 15.7%; cT3N0: 19.8%; cT4N0/TanyN1: 20.9%, p &lt; 0.001) and decreasing NAC utilization was noted with increasing age ( &lt; 65 years: 18.5%; 65-74 years: 18.5%; ≥ 75 years: 9.0%, p &lt; 0.001). Following adjustment, increasing clinical stage was associated with an increase in the administration of NAC, (cT3N0 OR 1.46 [CI 1.24-1.71]; T4/TanyN1 OR 1.88 [CI 1.62-2.18]) compared to cT2 disease. In comparison, increasing age (age 65-74 years OR 0.78 (CI 0.68-0.88]; age ≥ 75 years OR 0.37 [CI 0.33-0.43]) was associated with decreased utilization of NAC compared to patients &lt; 65 years. On interaction analysis the effect of higher stage on the likelihood of receiving NAC was attenuated in older patients ( ≥ 75 years). Conclusions: The administration NAC has increased over the last 10 years and is more likely to be given to patients with locally advanced disease or early nodal stage. However, this trend is substantially attenuated in older patients ( ≥ 75 years).
Reducing futile thoracotomy rates in PET-CT staged non small cell lung cancer: Clinical risk factors from a population-based review.
Authors: Martin Smoragiewicz, Janessa J. Laskin, Don Wilson, Katherine Ramsden, Yongliang Zhai, Cheryl Ho
Journal: Journal of Clinical Oncology (2013)

7551 Background: The use of PET-CT in staging NSCLC reduces futile thoracotomy (FT) rates to approximately 30%. We aimed to identify pre-operative clinical risk factors for FT in patients (pts) staged with PET-CT. Methods: The British Columbia Cancer Agency (BCCA) provides care to 4.5 million people. A retrospective chart review was conducted on all pts referred to the BCCA in 2009-2010 who had staging PET-CT and thoracotomy for NSCLC. Exclusion criteria: tri-modality therapy, clinical N2 disease, or cancer within 5 years. FT was defined as benign lung lesion, exploratory thoracotomy, pathologic N2 disease, stage IIIB/IV, or recurrence or death &lt; 1 year of surgery (sx). The FT and non-FT groups were compared with the Fisher test in univariate analysis and logistic regression model multivariate analysis. Results: 108 pts met inclusion criteria. Baseline characteristics: male 42%, median age 67 (45-82), ECOG 0-1/+2: 85%/15%, never/former/current smoker 18.5/42.5/39%, weight loss &gt;10% 9%. Disease characteristics: nonsquamous/ squamous histology 72/28%, median primary tumor size 3.2 cm, median SUVmax 10.1, PET + N1 24%. Median time from PET to sx 29 days. 29% pts received adjuvant chemotherapy. Thoracotomy was futile in 27 pts (25%); 14 recurred &lt; 1 yr of sx, 10 pathologic N2 and 1 each incomplete resection, pleural disease at sx, death within 1 yr. On univariate analysis, PET + N1 (odds ratio [OR] 3.77, p 0.008) and primary tumor size &gt; 3.2cm (OR 2.93, p 0.026) were associated with FT. On multivariate analysis, ECOG &gt;1 (OR 4.57, p 0.017), PET + N1 status (OR 4.24, p 0.006) and primary tumor size &gt; 3.2cm (OR 2.87, p 0.039) were associated with FT. Among the 26 pts wth PET + N1, 44% underwent FT; 23% due to N2 disease, 19% relapsed within 1 yr, 4% incomplete sx. 27% had mediastinoscopy or EBUS staging. Among the 82 pts with PET – N1,18% underwent FT; 5% due to N2 disease, 11% relapsed &lt; 1 yr, 2% pleural dx or death &lt; 1 yr. Conclusions: Pre-operative ECOG &gt;1, primary tumor size &gt; 3.2 cm and PET + N1 are associated with higher rates of FT in NSCLC. PET + N1 disease corresponds to higher rates of N2 disease and surgical staging may reduce FT in this population. These factors should be taken into consideration to reduce FT rates in NSCLC.
A phase Ib study of selumetinib in patients (pts) with previously untreated metastatic Non-Small Cell Lung Cancer (NSCLC) receiving standard chemotherapy: NCIC Clinical Trials Group IND.215. NCT01783197.
Authors: Garth Andrew Nicholas, John R. Goffin, Scott Andrew Laurie, Andrew George Robinson, Glenwood D. Goss, M. Neil Reaume, Mihaela Mates, Paul Wheatley-Price, Peter Michael Ellis, Rosalyn A. Juergens, Anna T. Tomiak, Richard William Gregg, Barbara L. Melosky, Dongsheng Tu, Heather Ritter, Lesley Seymour, Penelope Ann Bradbury
Journal: Journal of Clinical Oncology (2015)

8046 Background: Selumetinib (AZD6244, ARRY-142886, S) is a potent inhibitor of MEK, with promising activity with docetaxel in pts with previously treated NSCLC. Non-clinical data suggest potential negative interaction with platin. We conducted a phase Ib study testing continuous or intermittent S with either cisplatin/pemetrexed (CPe; non-squamous) or carboplatin/paclitaxel (CPa) in previously untreated NSCLC. Methods: Pts received CPa (C AUC 6; Pa 200mg/ m2) or CPe (C 75mg/ m2 ; Pe 500mg/ m2) or for 4-6 21day cycles; single-agent S continued. A 3+ 3 design was used, dose levels (DL) were: DL1 50mg bid d2-19, DL2 75 mg bid d2-19, DL3 75 mg bid d1-21 (continuous) with an expansion cohort at RP2D. DLTs were assessed in cycle 1. Results: 30 pts were enrolled and 27 currently evaluable for adverse events (AE). In both cohorts, the most common S related toxicities were mild GI and skin. For CPa, 11 pts were treated, and no DLTs were seen at any DL. CPa related AEs were as expected. 2 pts had dose reductions of S (1 each of fatigue, skin toxicity). Most AEs related to S were grade (G) 1-2 and included gastrointestinal and skin. 4 pts had ≥ G3 AEs considered related to S (includes 1 pt with fatal lung infection also related to CPa and 1 pt with fatal stroke also related to disease & CPa). 2 pts had G3 neutropenia; 1 pt had G4 thrombocytopenia; 1 pt had G3 LFTs. For CPe, 16 pts are currently evaluable; 2 possible DLTs were seen at the continuous DL (vomiting but inadequate antiemetics). Expansion to that DL ongoing. CPe related AEs were as expected. 3 pts had dose reductions of S (1 each of CPK, fatigue, dehydration). 3 additional pts had G3 AE (retinal vascular disorder, thromboembolism, diarrhea/dehydration/ hypertension) related to S. There were no S related G5 events. There were no G4 hematologic toxicities. One pt had a G3 increase in CPK. Conclusions: S can be given in combination with CPe or CPa at full single agent doses, with generally mild incremental GI and skin toxicity. Patients continue to be enrolled to the RP2D expansion cohorts at a dose of 75 mg bid d1-21. NCIC CTG plans further P2 studies of CPe with S in NSCLC. Clinical trial information: NCT01783197.
Ethnic and diet-related differences in the healthy infant microbiome
Authors: Jennifer C. Stearns, Michael A. Zulyniak, Russell J. de Souza, Natalie C. Campbell, Michelle Fontes, Mateen Shaikh, Malcolm R. Sears, Allan B. Becker, Piushkumar J. Mandhane, Padmaja Subbarao, Stuart E. Turvey, Milan Gupta, Joseph Beyene, Michael G. Surette, Sonia S. Anand
Journal: Genome Medicine (2017)

The infant gut is rapidly colonized by microorganisms soon after birth, and the composition of the microbiota is dynamic in the first year of life. Although a stable microbiome may not be established until 1 to 3 years after birth, the infant gut microbiota appears to be an important predictor of health outcomes in later life. We obtained stool at one year of age from 173 white Caucasian and 182 South Asian infants from two Canadian birth cohorts to gain insight into how maternal and early infancy exposures influence the development of the gut microbiota. We investigated whether the infant gut microbiota differed by ethnicity (referring to groups of people who have certain racial, cultural, religious, or other traits in common) and by breastfeeding status, while accounting for variations in maternal and infant exposures (such as maternal antibiotic use, gestational diabetes, vegetarianism, infant milk diet, time of introduction of solid food, infant birth weight, and weight gain in the first year). We demonstrate that ethnicity and infant feeding practices independently influence the infant gut microbiome at 1 year, and that ethnic differences can be mapped to alpha diversity as well as a higher abundance of lactic acid bacteria in South Asians and a higher abundance of genera within the order Clostridiales in white Caucasians. The infant gut microbiome is influenced by ethnicity and breastfeeding in the first year of life. Ethnic differences in the gut microbiome may reflect maternal/infant dietary differences and whether these differences are associated with future cardiometabolic outcomes can only be determined after prospective follow-up.