tbuckley/cabot-search huggingface dataset:
Binocular radiation therapy followed by methotrexate-based chemotherapy for primary vitreoretinal lymphoma.
Authors: Macarena Ines De La Fuente, Juan Pablo Alderuccio, Arnold M. Markoe, Janet L. Davis, Izidore S. Lossos
Journal: Journal of Clinical Oncology (2018)

e14059 Background: Primary vitreoretinal lymphoma (PVRL) is a subset of primary central nervous system lymphoma involving the vitreous and retina of the eye and may occur either as an isolated disease or associated with brain disease. Diagnosis is made by cytologic, flow cytometric and gene rearrangement studies of vitreous biopsies. Ocular radiotherapy (RT) is an effective treatment for PVRL, but local and brain relapse may occur. High-dose methotrexate (M)-based chemotherapy (CT) regimens are used for patients with progression to CSF or brain. It is unknown if systemic CT administered for isolated ocular disease can prevent relapse. Methods: IRB approved single institution retrospective review of PVRL treated at the University of Miami Health System from 02/2005-03/2017. Results: A total of 15 patients (pts) were identified. Nine (60%) were men. Median age at diagnosis was 65 years (range 38-81). Symptoms at presentation included floaters in 11 (73%) pts, decreased visual acuity in 10 (67%) and blurry vision in 9 (60%). Fourteen pts presented with bilateral ocular involvement. Pathology showed diffuse large B-cell lymphoma in 13 and marginal zone lymphoma in 2. Bone marrow biopsy and CNS staging (positive in 3 that were excluded) were done at baseline. Eleven (92%) received binocular RT to the posterior two thirds of the globes (30-46 Gy) followed by M-based CT in 10 (91%) pts (8 received M, procarbazine (P) and vincristine (V) and 2 received rituximab MPV). One pt refused RT and was treated with intravitreal M. All pts achieved complete response (CR). Local eye control was 92%. Four (28%) pts had tumor recurrence involving the brain, 1 with synchronic leptomeningeal disease and 2 with ocular involvement and were treated with CT with or without ASCT. Two achieved CR, 1 died from recurrent CNS disease and 1 is currently under treatment. With a median follow up of 63 months, median PFS and OS have not been reached. Ten pts remain alive, 1 pt died of recurrent disease and another of long term complications of treatment. Conclusions: Binocular RT to the posterior two thirds of the globes (30-46 Gy) followed M-based CT seem to be an effective treatment reducing progression when compared to previously published retrospective series.
Differences in expression profiling and biomarkers between histological colorectal carcinoma[s] subsets from the serrated pathway
Authors: M.M. Kot, J. Garcia-Solano, M.D.C. Turpin, F. Garcia-Garcia, R. Carbonell-Muñoz, B. Alburquerque Gonzalez, D. Torres-Moreno, A. Conesa, P. Conesa-Zamora
Journal: Annals of Oncology (2018)

Background: Colorectal carcinomas (CRC) from the serrated route like serrated adenocarcinoma (SAC) and CC showing molecular features of microsatellite instability (hmMSI-H) share common features (preference for female gender, right side location, mucinous histology and altered CpG methylation patterns) but dramatically differ in terms of prognosis, development of immune response and treatment options. Despite this, to date no expression profiling comparison has been carried out to see which functions and genes may be responsible for such differences. Methods: Molecular signatures of SAC and hmMSI-H were obtained by transcriptomic arrays and qPCR and immunohistochemistry (IHC) were used to validate differentially expressed genes at mRNA and protein level. Results: An over-representation of innate immunity functions (granulomonocytic recruitment, chemokine production, TLR signaling, antigen processing and presentation) were obtained from this comparison and ICAM1 was more expressed in hmMSI-H whereas two genes (CRCP and CXCL14) were more expressed in SAC. These array results were subsequently validated by qPCR and CXCL14 and ICAM1 by IHC. Conclusions: Our findings show specific functions and genes which provide a better understanding of the role of the immune response in the serrated pathological route and may be of help in identifying particular molecular targets and future treatment options, especially in SAC which lacks molecular targeted therapy. Legal entity responsible for the study: UCAM University (Murcia, Spain), Department of Pathology, Santa Lucía University Hospital (Cartagena, Spain). Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Harmful drug shortages will worsen after Brexit, doctors warn
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Drug shortages are already affecting the care of NHS patients, even before the potentially destabilising results of Brexit, doctors have warned.

Helgi Johannsson, a consultant anaesthetist and clinical director at Imperial College Healthcare NHS Trust, asked colleagues on Twitter to report how drug shortages were affecting them, after he reported that his hospital often experienced shortages of basic drugs such as diamorphine and metronidazole.

Johannsson received more than 600 responses to a snapshot poll that he posted, with almost nine in 10 respondents (87%) reporting that they often had shortages (https://twitter.com/traumagasdoc/status/1041753961605341185). He said he was alarmed that more than a quarter of …
Identifying SNPs associated with progression-free survival (PFS) and overall survival (OS) in patients with KRAS wildtype and mutant metastatic colorectal cancer (mCRC) using Random Survival Forests (RSF).
Authors: Dongyun Yang, Wu Zhang, Shu Cao, Fotios Loupakis, Marta Schirripa, Sebastian Stintzing, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2016)

3604 Background: Patients (pts) with newly diagnosed mCRC treated with 1st-line bevacizumab (Bev) based therapy have median OS over 2 years. All pts eventually progress: response rates are ≈60% and PFS ≈11 months. RAS mutation is a predictive and prognostic biomarker. RAS mt patients don’t benefit from anti-EGFR antibodies; however RAS signaling may play a role in pathways associated with bevacizumab efficacy. We examined whether genes involved in angiogenesis, Wnt, immune, and other related pathways predict efficacy of bevacizumab based chemotherapy (CX) in pts with KRAS wt and mt mCRC. Methods: Among pts with mCRC who enrolled in 2 phase III clinical trials (TRIBE and Fire-3), those treated in FOLFIRI+bevacizumab arm were included. Genomic DNA was extracted from blood samples. 27 single nucleotide polymorphisms (SNPs) were genotyped by PCR-based direct sequencing. PFS and OS were endpoints. RSF was used to identify markers associated with endpoints - stratifying by KRAS. RSF is a robust non-parametric method which does not require the proportionality assumption between covariates and survival, and has built-in algorithm to impute missing data. RSF grows an ensemble of trees to provide stable estimates of prediction accuracy versus a single tree with recursive partitioning. Results: Patient characteristics, outcomes, and associated SNPs by KRAS status are shown in table. T/T of TBK1 was associated with lower PFS and OS rates in both KRAS wt and mt compared to A/A or A/T. Associations between 4 SNPs and PFS and OS varied by KRAS (see Table). Conclusions: TBK1 gene may play a role in disease progression regardless of KRAS, but CCL2, CBP, β-catenin and FOXL2 may be involved in disease progression differently by KRAS. KRAS wt (n = 345) KRAS mt (n = 141) M/F 220/125 84/57 Median age 63 62 Median follow-up, months 45.0 49.9 Median PFS 10.5 9.3 Median OS 25.6 23.1 TBK1 rs7486100 (immune) PFS, OS PFS CCL2 rs4586 (immune) PFS, OS CBP rs129963 (Wnt) PFS, OS β-catenin rs3864004 (Wnt) OS FOXL2 rs1192493 (Wnt) PFS, OS
Preliminary results of the phase I/IIa dose finding trial of a folate binding protein vaccine (E39+GM-CSF) in ovarian and endometrial cancer patients to prevent recurrence.
Authors: Julia M. Greene, Erika J Schneble, John S. Berry, Alfred F. Trappey, Timothy J. Vreeland, Guy T. Clifton, William P. McGuire, George Larry Maxwell, Sathibalan Ponniah, George Earl Peoples
Journal: Journal of Clinical Oncology (2015)

e14031 Background: Folate Binding Protein (FBP) (aka Folate Receptor-α) is an immunogenic protein over-expressed in endometrial (EC) and ovarian cancer (OC). We are conducting a phase I/IIa trial with E39, an HLA-A2-restricted, FBP-derived peptide + GM-CSF. E39 is given adjuvantly to prevent clinical recurrences (CR) in disease-free high-risk, EC and OC patients (pts) after standard-of-care therapy (SOC). Here, we summarize toxicity, in vivo immunologic responses, and disease-free survival (DFS) in this dose-finding trial. Methods: This trial began as a 3x3, dose-escalation (100, 500, 1000 mcg of E39), safety phase I trial and transitioned to a phase IIa comparing expanded dose cohorts. Disease-free EC and OC pts were enrolled after SOC. HLA-A2+ pts were vaccinated (VG), and HLA-A2- pts followed prospectively as a control group (CG). 6 monthly intradermal inoculations of E39 + 250 mcg GM-CSF are administered followed by 2 boosters every 6 months. Demographic, safety, immunologic, and CR data are being collected. DFS is compared by Kaplan-Meir and logrank tests. Continuous variables are compared with analysis of variance and proportions with Fisher’s exact test. Results: 51 pts were enrolled; 29 in the VG (15 pts-1000 mcg v 14 pts- < 1000 mcg) and 22 in the CG. There are no differences in age, grade, stage, or histology between groups (all p ≥ 0.1).E39 is well-tolerated and safe with no differences in toxicity based on dose. DTH increased pre- to post-vax (5.9mm+1.5 v 12.3mm+8.1, p = 0.06). DTH increase was larger in 1000 mcg pts (4mm v 13.5 mm, p = 0.039) v < 1000 mcg pts (8mm vs 11mm, p = 0.56). With 9.8 months median f/u, CR rate is 38% (VG) v 50% (CG), p = 0.41. Among 1000mcg pts, there is only one CR (6.7% vs 50% CG, p = 0.01). The 2 yr DFS estimate is 19.2% (CG) v 85.7% (1000 mcg pts) (p = 0.09). Conclusions: This phase I/IIa trial reveals that E39 + GM-CSF is well-tolerated and elicits a strong and dose-dependent in vivo immune response. Early efficacy results are promising in the 1000mcg dose cohort. This dose-finding study proves the safety and establishes the dose of E39 for a prospective, randomized, GM-controlled, late stage trial in HLA-A2+ EC and OC pts to prevent recurrence. Clinical trial information: NCT01580696.
A real-world survival of subsequent therapy in ALK positive non-small cell lung cancer (NSCLC) patients with crizotinib resistance.
Authors: Lu Yang, Di Ma, Fei Xu, Haiyan Xu, Li Junling, Puyuan Xing, Xuezhi Hao, Yan Wang
Journal: Journal of Clinical Oncology (2018)

e21093 Background: Crizotinib resistance among non-small cell lung cancer(NSCLC) patients with ALK gene rearrangement has attracted more attention. Subsequent therapies beyond crizotinib resistance could be available. Which therapy pattern could show more survival benefit beyond crizotinib resistance to both intracranial and extracranial progression patients? This study will provide a real-world clinical survival of different therapy patterns beyond crizotinib treatment failure. Methods: This retrospective single-center study enrolled 155 Chinese metastatic NSCLC patients with ALK gene rearrangement failing prior ALK-TKI treatment. Based on the site of disease progression, patients were divided into two groups: intracranial (n = 70, 45%) and extracranial (n = 85, 55%). Subsequent therapy mainly included crizotinib continuation added with local treatment, next generation ALK inhibitors, chemotherapy or no anti-tumor therapy at all. The primary end-point was median overall survival (OS) from the time of crizotinib resistance to death or last follow-up. Results: Among intracranial progression patients, 36(51.4%) continued crizotinib plus brain radiotherapy, showing a median OS beyond crizotinib of 28.9 months (95%CI, 0-59.3), while that of 23(32.8%) next generation ALK inhibitor users and 5(7.1%) chemotherapy receivers was 32.8months (95%CI, 9.9-55.7) and 15.5 months (95%CI, 0-33.4), respectively. For extracranial progression patients, 26(30.6%) with crizotinib continuation illustrated a median OS beyond crizotinib of 10.8 months (95%CI, 0.1-21.5), while 31 (36.5%) next generation ALK inhibitor users and 15 (17.6%) chemotherapy receivers exhibited an OS of 27.6 months (95%CI, 15.4-39.8) and 9 months(95%CI, 3.0-14.9), respectively. The remaining 19 patients from both groups received no anti-tumor therapy after crizotinib discontinuation, and died rapidly within 1 month. Conclusions: Next generation ALK inhibitors may show more survival benefit to patients who developed intracranial or extracranial resistance beyond crizotinib treatment.
Comparison of expectations between medical oncologists (MO) and hepatobiliary surgeons (HS) regarding the indications for liver metastatectomy.
Authors: Maria Yi Ho, Sean P. Cleary, Sunita Ghosh, Matthew Mazurek, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2016)

e18129 Background: Resection of liver metastases is curative for specific patients with advanced cancers. There is increasing aggressiveness in the use of metastatic resections, but guidelines describing appropriate indications for metastatectomy are lacking or obsolete in the era of novel systemic therapies and advanced surgical techniques. We compared expectations of MO vs HS in the management of liver metastases from colorectal cancer (CRC). Methods: MO and HS across Canada were surveyed to evaluate their criteria to determine resectability of liver metastases, their current access to and availability of multidisciplinary care, and their views regarding imaging in guiding management of these patients. Results: Of 220 experts surveyed, 145 (66%) responded of whom 137 (95%) had received specialized training in oncology. Among them, 109 (75%) reported the lack of institutional criteria to determine resectability of liver metastases while only 37 (26%) indicated that they had access to multidisciplinary tumor boards and clinics. MO and HS disagreed in terms of absolute contraindications (CI) for liver metastatectomy. For example, MO were more likely to consider significant liver parenchymal involvement, proximity to major vessels, and poor performance status as absolute CI when compared to HS (all p<.05). All physicians viewed CT scans as the preferred first-line imaging modality for evaluating CRC liver metastases, but significantly more HS indicated the value of also ordering MRI scans (p<.01). Likewise, there were notable discrepancies between physicians with respect to the types of clinical or radiographic findings that would modify their perspectives on resectability (Table). Conclusions: Criteria used by MO and HS to determine resectability of CRC liver metastases are highly discordant and may compromise care. Likelihood to affect resectability MO % HS % P Bilobar involvement L 26 34 <.01 H 28 0 No extrahepatic site L 1 6 <.01 H 90 27 Node positive 10 L 50 37 <.01 H 18 2 >1 lesion L 57 40 <.01 H 12 0 Lesion >5cm L 45 40 <.01 H 17 0 CEA L 51 37 <.01 H 16 1 Age and ECOG L 2 3 .02 H 89 32 Short interval from 10 to metastasis L 25 32 <.01 H 31 2 L=low; H=high. May not add to 100% if item skipped.
Melanoma antigen-specific effector T cell cytokine secretion patterns in patients treated with ipilimumab.
Authors: Yana G. Najjar, Fei Ding, Yan Lin, Lisa H. Butterfield, Ahmad A. Tarhini
Journal: Journal of Clinical Oncology (2016)

e21059 Background: Patients (pts) with regionally advanced melanoma were treated with neoadjuvant ipilimumab (ipi) (previously reported: Tarhini. PLOS One 2014). Significant changes in circulating Treg, MDSC and peptide specific type I CD4+ and CD8+ T cells were observed at 6 weeks that correlated with clinical outcome. Characterization of effector T cell secreted cytokines may shed insights into ipi associated T cell activation and function. Methods: Pts were treated with ipi (10mg/kg IV q3 weeks x2) bracketing surgery. Blood specimens were collected throughout treatment. Samples from baseline and week 6 were used for this analysis. Each sample was divided into 5 groups and stimulated with shared melanoma antigen overlapping peptide pools (NY-ESO 1, gp-100, MART-1), and 2 controls. Secreted cytokines, chemokines and growth factors were assessed using Luminex and flow cytometry. We used the Wilcox rank-sum test to compare the cytokine expression levels between the 3 antigen groups. Results: At baseline, 17 cytokines were differentially expressed with stimulation by each antigen (p-value < 0.05): IL1β, MIP1β, IL1RA, VEGF, IL13, IL17, MIP1α, GM-CSF, MCP1, IL5, IL2R, IL4, IL10, IFNγ, TNFa, IL8 and IL2. At week 6 (after ipi), 15 cytokines were differentially expressed (p < 0.05): IL1β, VEGF, G-CSF, HGF, IL13, IL17, GM-CSF, MCP1, IL5, IL7, IL4, IL10, IFNγ, IL8 and IL2. Cytokine expression levels at baseline and at week 6 were used to cluster pts and recurrence free survival (RFS) was compared. We observed clear differences in RFS based on cytokine level clustering both at baseline (p = NS) and at week 6 (p = 0.07), more notably in the NY-ESO-1 stimulated subgroup. Conclusions: PBMCs of pts treated with ipi had more detectable T cells specific to NY-ESO-1 than to gp-100 or MART-1. Cytokines differentially expressed in the supernatants of PBMCs exposed to these antigens belong to a broad functional range, including inflammatory, type 1, type 2 and regulatory, that warrant further study. Patients whose PBMCs secreted more cytokines (more notably in response to NY-ESO-1) tended to have better RFS, supporting further exploration in terms of therapeutic predictive value.
Functional Silencing of <i>HSD17B2</i> in Prostate Cancer Promotes Disease Progression
Authors: Xiaomei Gao, Charles Dai, Shengsong Huang, Jingjie Tang, Guoyuan Chen, Jianneng Li, Ziqi Zhu, Xuyou Zhu, Shuirong Zhou, Yuanyuan Gao, Zemin Hou, Zijun Fang, Chengdang Xu, Jianyang Wang, Denglong Wu, Nima Sharifi, Zhenfei Li
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Steroidogenic enzymes are essential for prostate cancer development. Enzymes inactivating potent androgens were not investigated thoroughly, which leads to limited interference strategies for prostate cancer therapy. Here we characterized the clinical relevance, significance, and regulation mechanism of enzyme HSD17B2 in prostate cancer development. Experimental Design: HSD17B2 expression was detected with patient specimens and prostate cancer cell lines. Function of HSD17B2 in steroidogenesis, androgen receptor (AR) signaling, and tumor growth was investigated with prostate cancer cell lines and a xenograft model. DNA methylation and mRNA alternative splicing were investigated to unveil the mechanisms of HSD17B2 regulation. Results: HSD17B2 expression was reduced as prostate cancer progressed. 17βHSD2 decreased potent androgen production by converting testosterone (T) or dihydrotestosterone (DHT) to each of their upstream precursors. HSD17B2 overexpression suppressed androgen-induced cell proliferation and xenograft growth. Multiple mechanisms were involved in HSD17B2 functional silencing including DNA methylation and mRNA alternative splicing. DNA methylation decreased the HSD17B2 mRNA level. Two new catalytic-deficient isoforms, generated by alternative splicing, bound to wild-type 17βHSD2 and promoted its degradation. Splicing factors SRSF1 and SRSF5 participated in the generation of new isoforms. Conclusions: Our findings provide evidence of the clinical relevance, significance, and regulation of HSD17B2 in prostate cancer progression, which might provide new strategies for clinical management by targeting the functional silencing mechanisms of HSD17B2. See related commentary by Mostaghel, p. 1139
Fellowships, Grants, Awards
Journal: JNCI Journal of the National Cancer Institute (1995)

Journal Article Fellowships, Grants, Awards Get access JNCI: Journal of the National Cancer Institute, Volume 87, Issue 23, 6 December 1995, Page 1812, https://doi.org/10.1093/jnci/87.23.1812 Published: 06 December 1995
Pragmatic study of a lymph node (LN) collection kit for non-small cell lung cancer (NSCLC) resection.
Authors: Raymond U. Osarogiagbon, Matthew Smeltzer, Nicholas Ryan Faris, Meredith Ray, Carrie Fehnel, Cheryl Houston-Harris, Philip Ojeabulu, Olawale Akinbobola, Lynn Wiggins, David Talton, Ed Owen, Lawrence Deese, Richard Eubanks, Bradley Aaron Wolf, Todd Robbins
Journal: Journal of Clinical Oncology (2018)

8502 Background: Surgical resection is the best curative modality for NSCLC, but overall survival (OS) rates vary with quality of pathologic (p) LN staging. We studied the impact of a pre-labeled LN collection kit on pLN staging quality, operative (OP) complications and OS. Methods: Prospective, population-based multiple baseline, staggered implementation study involving all patients undergoing curative-intent NSCLC resection in all 11 eligible hospitals (with ≥5 resections/yr) in 4 contiguous Hospital Referral Regions in E. Arkansas, N. Mississippi, W. Tennessee. After 12 months of prospective baseline observation, institutions sequentially implemented the kit in 3 balanced cohorts 3 months apart. We examined OS with Kaplan-Meier method, logrank test. Crude (HR) and adjusted Hazard Ratios (aHR) with 95% CI from Cox Models are adjusted for surgeon clustering, controlled for: age, sex, histology, tumor grade, extent of resection, pT, pM, number of comorbidities. Results: Of 1,171 OPs by 32 surgeons from 2014-2017, LN kit used in 650 (56%) OPs by 20 surgeons. Kit cases were older v non-kit cases (mean 68 v 67 years, p = .026). Race (p = .12), sex (p = .089), insurance (p = .52), clinical stage distribution (p = .18) were similar between groups. Comparing kit v non-kit cases, median OP time was 124 v 144 min (p < .0001), transfusion 9 v 5% (p = .02), all other periOP complication rates were similar, incomplete (non-R0) resection rates 3 v 4% (p = .39). LN staging quality: pNX rate 0 v 7%; no mediastinal LN 2 v 18%; attainment of NCCN quality criteria (R0 + anatomic resection + ≥1 N1 + ≥3 mediastinal LN stations) 77 v 31% (p < .0001 for all); 60-day readmission 15 v 13% (p = .35); 60 day mortality 3% v 5% (p = .02). With 20 months median follow up, 3-year OS was 80% in kit v 73% in non-kit cases (p = .005). Kit cases had > 30% reduction in both HR (.67 [.50 - .89], p = .005) and aHR (.57 [.42 - .77], p < .001). In sensitivity analyses excluding sub-lobar resections, 60-day mortality, and non-adopting surgeons (to evaluate the possible impact of higher performing surgeons using the kit), aHR ranged from .54 to .61 (all p < .013). Conclusions: A LN collection kit improves staging quality and OS without adding to morbidity of curative NSCLC resection.
TCT-471 BIOVITESSE – Multicenter prospective First In Man study of a new polymer free drug-coated stent with ultrathin struts: One month optical coherence tomography results of Cohort 1
Authors: Lorenz Raber, Jonas Haener, Ron Waksman, Marco Moccetti, Marco Roffi, Stefan Stortecky, Olivier Muller, Hector Garcia-Garcia, Patrick Siegrist
Journal: Journal of the American College of Cardiology (2018)