tbuckley/cabot-search huggingface dataset:
Clinical responses and outcome of 110 consecutive isolated limb perfusion (ILP) with TNF-α and melphalan (M) for locally advanced soft tissue sarcomas (LASTS) of extremities at the Institut Gustave Roussy
Authors: J. Muret, M. Yacoub, S. Bonvalot, P. Terrier, F. Drusch, C. Le Péchoux, D. Vanel, N. Lassau, A. Le Cesne, S. Chouaib
Journal: Journal of Clinical Oncology (2008)

10587 Background: ILP with TNF-α and M allows limb preservation in 80% of patients (pts) with LASTS. The exact mechanisms through which TNF-α and M are mediated have to be established. The aim of this analysis was to identify subgroups of pts who benefit more from ILP than others. Methods: Between 2000 and 2005, 110 pts with LASTS were treated with ILP in our institution. Systemic and perfusate blood samples and urines were collected before, during and day 1 and 2 after ILP. Paraffin-embedded material (PEM) of the tumor was collected before and/or after ILP at the time of the resection two months later. Results: The sex ratio was 58 M/52F and median age was 45 years (range 8–81). Location/median size was 37%/50mm and 63%/80mm for upper and lower limbs, respectively. Eighty- four per cent of tumors were high grade STS. The objective response rate was 70 %. Histologic necrosis was ≥ 90% in 32 pts (33%). A limb salvage procedure was obtained in 82% of pts. Half of pts had a pre ILP systemic chemotherapy (CT). After ILP, 48 pts received radiation therapy (RT), 3 pts a systemic CT and 6 both. Out of the 101 pts without distant metastases before ILP, a relapse occurred in 40 pts: local relapse (LR) in 18 (median time of relapse: 12 months), distant in 30 (median time: 10 months), both in 10 pts and 2 pts died without recurrence. A good correlation was found between absence of LR and RT after ILP (11% pts with RT and 45% without RT had a LR (p=0.0005). The 2 yr PFS and OS were 51% and 79%, respectively. Collection of material (serum, plasma, peripheral blood mononuclear cells and urines) were stored for 53 pts. Pre and post ILP PEM were obtained in 63 pts and pre or ILP PEM in 50 other pts. The outcome of pts (OS or PFS) was subsequently analyzed according to each investigated biologic factor. Conclusions: High response rate was observed in TNF-α+M-based ILP. Post-ILP RT improved local tumor control. We will take advantage of the material collected and we will investigate the putative determinants associated with the treatment efficacy considering to better understand such factors and to improve response to treatment (Conticanet program). Final analysis will be presented at the meeting. No significant financial relationships to disclose.
Rise in deaths of mental health patients needs investigating, says MP
Authors: Gareth Iacobucci
Journal: BMJ (2016)

The UK government has been urged to launch an investigation into the provision of mental healthcare in England, after new figures showed that the number of reports of patients dying unexpectedly has risen 21% over the past three years.

The figures, obtained by the Liberal Democrat MP Norman Lamb, show that the number of deaths among mental health patients rose from 1412 in 2012-13 to 1713 in 2014-15. The data, released by NHS England under the Freedom of Information Act, also showed that the number of those people committing suicide or trying to do so rose by 26% …
Identification of CD112R as a novel checkpoint for human T cells
Authors: Yuwen Zhu, Alessandro Paniccia, Alexander C. Schulick, Wei Chen, Michelle R. Koenig, Joshua T. Byers, Sheng Yao, Shaun Bevers, Barish H. Edil
Journal: The Journal of Experimental Medicine (2016)

T cell immunoglobulin and ITIM domain (TIGIT) and CD226 emerge as a novel T cell cosignaling pathway in which CD226 and TIGIT serve as costimulatory and coinhibitory receptors, respectively, for the ligands CD155 and CD112. In this study, we describe CD112R, a member of poliovirus receptor–like proteins, as a new coinhibitory receptor for human T cells. CD112R is preferentially expressed on T cells and inhibits T cell receptor–mediated signals. We further identify that CD112, widely expressed on antigen-presenting cells and tumor cells, is the ligand for CD112R with high affinity. CD112R competes with CD226 to bind to CD112. Disrupting the CD112R–CD112 interaction enhances human T cell response. Our experiments identify CD112R as a novel checkpoint for human T cells via interaction with CD112.
Effects of Prospidine on Survival and Growth of Mammalian Cells in Culture&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Frank Traganos, Lisa Staiano-Coico, Zbigniew Darzynkiewicz, Myron R. Melamed
Journal: JNCI Journal of the National Cancer Institute (1980)

The effects of prospidine, chemically known as 3,12-diaza-6,9-diazoniadispiro[5.2.5.2]hexadecane,3,12-bis(3-chloro-2-hydroxypropyl)-dichloride (NSC-166100), on cell viability, growth, and colony formation were investigated in several mammalian cell lines. Cell cycle progression and the terminal point of action of the drug were monitored by flow cytometry. Prospidine was cytostatic for two suspension cultures (Friend leukemia and L1210 cells) at a concentration of 10 mg/ml during the first cell cycle after exposure to the drug. Cells were blocked in G2 at lower concentrations of prospidine (e.g., 1.0 mg/ml) but only after 12–24 hours of continuous exposure, i.e., during the second cell cycle in the presence of drug. Cells could be observed to accumulate in G2 by 24 hours even if prospidine (0.1 mg/ml) was removed after 12 hours. A short incubation with a liver cytosol fraction (30 min) or with cultured cells (12 hr) failed to enhance the potency of the drug. Formation of colonies of the adherent Chinese hamster ovary cell line was inhibited by 50% following 24-hour exposure to 1.1 mg prospidine/ml. Under culture conditions in which cells were blocked in G2, their RNA content increased only slightly, but the incorporation of [5-3H]uridine into RNA was suppressed by 15–20%. Incubation of cells with prospidine increased the stability of DNA in situ to acid-induced denaturation, which thus suggested that the drug may interact with cellular DNA.
Non-surgical treatment for localized gastric mucosa-associated lymphoid tissue (MALT) lymphoma: Preliminary results of a multicenter prospective study in Japan
Authors: K. Mera, A. Ohtsu, S. Nakamura, T. Yoshino, T. Nakamura, T. Sugiyama, I. Oda, T. Doi, S. Yamamoto, S. Ishikura
Journal: Journal of Clinical Oncology (2004)

6559 Background: Although eradication of Helicobacter pylori (HP) and radiation therapy (RT) have curative potential for gastric MALT lymphoma (G-MALT), no prospective study has yet been reported. This prospective study evaluated the efficacy and safety of this non-surgical treatment for localized G-MALT. The primary endpoint was failure-free survival (FFS). Methods: Eligibility criteria were histologically proven G-MALT, stage I–II1 (modified Ann-Arbor classification), age 20–75 years, PS 0–1, no prior therapy, adequate organ function, and written informed consent. Patients received HP eradication therapy (ET) consisting of a PPI-based triple regimen, and RT of 30 Gy in cases of residual or recurrent disease after ET. Results: Between 01/2001 and 12/2003, 149 patients were registered and 141 were included in the preliminary analysis. Of these, 16 (11%) were ineligible: 14 by central pathological review and two for other reasons. Baseline characteristics of the 125 eligible patients were: median age of 60 (35–75); male/female = 48/77; stage I/II1 = 120/5; HP +/–, 103/22; depth of invasion within/beyond the submucosa, 112/13. ET was administered completely to all patients. Twenty-five patients (20%) underwent RT due to persistent or recurrent disease after ET and 22 (88%) of these achieved complete remission with RT. No serious adverse events, such as hemorrhage or perforation of the stomach, were observed. With a median follow-up of 21.5 months, five events were considered “treatment failures”: death not related to the treatment, 1; salvage gastrectomy, 1; transformation to diffuse large B-cell lymphoma, 2; and development to stage IV, 1. Two-year FFS and overall survival were 97.0%, and 99.2%, respectively. Conclusion: This organ-preserving treatment for localized G-MALT is safe and effective. It has the potential to become the standard treatment for this disease, although long-term follow up is necessary. This study was supported by a Grant-in-Aid (14–9) from the Ministry of Health, Labour, and Welfare, Japan. No significant financial relationships to disclose.
Immunohistochemical localization of IL-8 and TGF-beta in streptococcal glomerulonephritis.
Authors: S Mezzano, M E Burgos, F Olavarría, I Caorsi
Journal: Journal of the American Society of Nephrology (1997)

Acute poststreptococcal glomerulonephritis (APSGN) is characterized by diffuse glomerular hypercellularity, primarily as a result of accumulation of neutrophils (exudative glomerulonephritis), increase in intrinsic glomerular cells, and transient pathological mesangial matrix expansion. Cytokines and growth factors are supposed to play an important role as mediators of inflammation and as progression factors in various renal disorders. Interleukin-8 is a recently described cytokine, defined as a selective activator and chemoattractant of polymorphonuclear leukocytes (PMNL) and transforming growth factor (TGF)-beta plays a central role in the accumulation of pathological extracellular matrix in glomerulonephritis. This study analyzed the biopsies of ten patients with APSGN, using immunohistochemistry (avidin-biotin complex/horseradish peroxidase method) using monoclonal antibodies anti-IL-8, anti-TGF-beta 1, beta 2, beta 3. Controls consisted of non-immune mouse serum, or anti-TGF-beta preabsorbed with human recombinant TGF-beta. Compared with normal renal tissue, and minimal change disease, an increased glomerular IL-8 and TGF-beta staining was observed in all of the biopsies. Furthermore, in one patient, we observed a weak deposit of TGF-beta in tubulointerstitium. Immunoreactive IL-8 and TGF-beta in glomeruli was correlated with light microscopic and clinical features. There was a significant association (P < 0.05), between IL-8 glomerular immunoreactivity and neutrophil infiltration and between TGF-beta glomerular staining and mesangial matrix expansion. Otherwise, there was no correlation with the mesangial cellularity. It was concluded that increased protein expression of IL-8 and TGF-beta are observed in APSGN and may play a role in the acute glomerular inflammation.
Evaluation of a novel RNA biomarker of CDK2 inhibition in phase 1 clinical trials with BMS-387032
Authors: S. Letrent, F. Callegari, T. Wong, H. Burris, R. Cohen, P. Lorusso, V. Papadimitrakopoulou, G. Shapiro, T. Griffin, A. Decillis
Journal: Journal of Clinical Oncology (2004)

2031 Background: BMS-387032 is a potent and selective inhibitor of CDK2 with demonstrated activity in several preclinical models. A biomarker for CDK2 inhibition with BMS-387032 was identified in previous transcription profiling experiments in which A2780 human ovarian tumor cells were treated with BMS-387032 or antisense oligonucleotides that target CDK2, human PBMCs were treated with BMS-387032, and A2780 tumor xenografts were treated with BMS-387032. Of ∼300 genes which were regulated, the W28729 gene, was consistently induced. Thus, the W28729 gene was selected for further evaluation in the initial phase I clinical trials with BMS-387032. Methods: Whole blood samples were collected for W28729 expression analyses from 3 ongoing phase I trials evaluating BMS-387032 administered iv as either a 1 h infusion q3 weeks, 24 h infusion q3 weeks, or 1 h infusion q week. Blood samples were obtained prior to and periodically during BMS-387032 treatment. RNA extracted from whole blood was analyzed for W28729 expression using a qRT-PCR assay. GAPDH, used to normalize RNA input, was amplified in the same reaction well as W28729. Statistical regression analyses assessed the relationship between exposure and W28729 gene expression normalized to GADPH. Results: Following infusion of BMS-387032 over 1 h q3 weeks, the observed maximum level of expression occurred at 1 h after the end of the infusion with expression returning to baseline values at the next observation timepoint (6 h). Linear regression analyses indicated an increasing non-linear relationship between W28729 expression and BMS-387032 exposure up to 24 h post dose. Data evaluating BMS-387032 administration as a 1 h infusion once weekly were similar. The peak level of induction was lower with infusion of BMS-387032 over 24 h relative to the infusion over 1 h; however, the induction persisted for a longer duration. Conclusions: Exposure-related effects on a novel RNA marker of CDK2 inhibition have been observed in the initial phase I clinical trials with BMS-387032. W28729 may serve as a useful biomarker for CDK2 inhibition and assist dose and schedule selection in the continued development of BMS-387032. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
A phase II trial of nilotinib in the treatment of patients with <i>KIT</i> mutated advanced acral and mucosal melanoma (NICAM).
Authors: J. M. G. Larkin, S. Turajlic, P. D. Nathan, P. Lorigan, G. Stamp, D. Gonzalez de Castro, N. Martin, J. Griffiths, K. Edmonds, S. Sarker, M. G. James, R. A'Hern, G. Coombes, C. Snowdon, J. M. Bliss, M. E. Gore, R. Marais
Journal: Journal of Clinical Oncology (2011)

TPS229 Background: Recent studies have indicated that KIT mutations occur in approximately 20% of acral and mucosal melanomas (Curtin, al. 2006; Beadling, et al. 2008). Several case reports have shown that KIT mutated melanomas can respond to treatment with KIT inhibitors (Hodi et al. 2008; Lutzky et al. 2008; Quintas-Cardama et al. 2008; Handolias et al. 2010; Itoh, et al. 2010; Satzger et al. 2010; Terheyden et al. 2010; Woodman and Davies 2010) suggesting that such tumours critically depend on upregulated KIT signalling. Nilotinib, which potently inhibits the tyrosine kinase activity of BCR-ABL and KIT, has been evaluated in patients with advanced KIT mutated GIST and has shown clinical efficacy at well tolerated doses (Demetri et al. 2009; Montemurro et al. 2009; Schlemmer et al. 2010). Methods: NICAM is a single arm 2-stage open label phase II study of nilotinib in KIT mutated advanced mucosal or acral melanoma. Patients with KIT mutations known to confer resistance to nilotinib are excluded. The primary objective in this feasibility study is to evaluate the efficacy of nilotinib in KIT mutated advanced mucosal and acral melanoma with a primary endpoint of progression free survival at 6 months. Secondary endpoints include response rate at 12 weeks; overall survival; toxicity of treatment; correlation between the response to nilotinib and KIT genotype, KIT gene copy number and KIT expression. In addition, the following will be explored: 1. Suppression of phosphorylation of KIT and downstream pathways on day 15 tumour biopsies; 2. Possible mechanisms of resistance by analysis of biopsies obtained at disease progression; 3. The use of circulating tumour DNA for non–invasive KIT mutational testing; 4. Genetic lesions that potentially cooperate with oncogenic KIT in melanoma (using Next Generation Sequencing). All patients are treated until disease progression or unacceptable toxicity. If 2 or more of the first 9 patients are progression free at 6 months, patient entry will continue into the second stage until a total of 24 patients have been recruited. To date, 45 patients have been registered and screened for KIT mutation and 5 patients have entered the study.
Regression of Bovine Ocular Carcinoma by Treatment With a Mycobacterial Vaccine 2
Authors: Stephen J. Kleinschuster, Herbert J. Rapp, David C. Lueker, Robert A. Kainer
Journal: JNCI Journal of the National Cancer Institute (1977)

Hereford cows with naturally occurring ocular squamous cell carcinoma were treated by injection of BCG cell-wall vaccine into the tumor. Regression or arrest of disease was observed in 71% of treated animals. The disease progressed in all untreated animals and animals treated with improperly compounded vaccine. At autopsy, most animals with progressive disease had lymph node metastases.
Phase I trial of the multi-drug resistance (MDR) Protein-1 (MRP-1) modulating agent sulindac (S) plus epirubicin (E) in patients (pts) with advanced cancer
Authors: M. O' Leary, R. O' Connor, S. Roy, J. Ballot, W. Ooi, D. Fennelly, L. Sheehan, C. Collins, M. Clynes, J. Crown
Journal: Journal of Clinical Oncology (2004)

2129 Background: MDR refers to the development of R to multiple chemotherapy (CRx) drugs, either de novo, or, following exposure to a single agent. MDR mediated by the ATPase binding cassettes mdr/pGP and MRP-1 are amongst the best characterised. Clinical trials of pGP substrate CRx together with pGP inhibitors have not been conclusively shown to overcome clinical MDR. We hypothesise that the heterogeneity of R phenotypes in human cancers will mandate an alternative approach in which multiple R mechanisms are simultaneously antagonised. As research in NICB had demonstrated that S antagonises MRP-1 mediated MDR, we performed a translational phase I, dose escalation and pharmacokinetic (PK) trial to determine the maximum tolerated dose (MTD) of this agent when used in combination with Epirubicin. Methods: Eligibility: advanced Ca without anthracycline exposure, adequate organ function and performance status. Treatment:Up to 6 cycles of E (75mg/m2) + escalating dose S. (0, 200, 400, 600, 800mg, no intra-patient escalation). S was administered orally 2 hours prior to each E administration. PK analysis was carried out following 1st and 3rd cycles. Results: A total of 17 pts (breast 8, lung 3, colon 2, melanoma 1, renal 1, unknown primary 2; prior CRx 15) were enrolled between 5/2001–6/2003. Eight pts received 6 cycles, 14 pts >/=3 cycles. Dose limiting toxicity was observed in 2 pts at S800 (1-increased creatinine; 1-fatal haemorrhage). Another patient died from neutropenic sepsis at S 400. PK analysis is ongoing. Partial response (11 month) was seen in one patient (melanoma). A second patient with platinum/taxotere pre-treated evaluable NSCLung Ca had PR of 9 month duration Conclusions:The MTD of this combination was identified as S 600mg, and this is the recommended dose for phase II studies. We are studying this combination in melanoma, and will conduct a phase I with pGP and MRP-1 inhibition. No significant financial relationships to disclose.
Fluorescence in situ hybridization (FISH) subgroup analysis of TRIBUTE, a phase III trial of erlotinib plus carboplatin and paclitaxel in NSCLC
Authors: F. R. Hirsch, M. Varella-Garcia, P. A. Bunn, R. Dziadziuszko, Y. Xiao, S. Gajapathy, M. Skokan, M. Lin, P. Waring, V. O'Neill
Journal: Journal of Clinical Oncology (2007)

7570 Background: TRIBUTE was a phase III, placebo-controlled study of patients with previously untreated advanced NSCLC. Patients received erlotinib (E) (150 mg/d) or placebo, plus a course of 6 cycles of carboplatin and paclitaxel (CP), followed by maintenance E monotherapy (for those in the CP+E arm who were responding to treatment). 1,059 patients were randomized and treated (526 E; 533 placebo). There were no significant differences in OS, RR, or TTP between the two arms. In subgroup analyses of the pivotal 2nd line trial (BR21) of E in patients with relapsed NSCLC in which E significantly increased median survival (HR=0.71, p &lt;0.0001), patients who scored positively for increased EGFR copy number by fluorescence in situ hybridization (FISH) exhibited prolonged OS (HR=0.44, p=0.008). Here we report on a similar subgroup analysis for TRIBUTE. Methods: FISH analysis was performed on all available tissue samples. FISH+ samples had a high level of polysomy (=four copies of the gene in =40% of cells), or gene amplification (presence of tight gene clusters, gene/chromosome per cell ratio =2, or =15 copies of the genes per cell in =10% of analyzed cells). Results: FISH analysis was successfully performed on 245 patients (121 E, 124 placebo). Outcome in the placebo patients from this subgroup was better than the overall population, suggesting that this subgroup may not be representative. Of the 100 patients (41%) that were FISH+, 33 had amplification and 67 had high polysomy. In FISH+ patients, OS was similar between those treated with CP+E and those treated with CP alone. However, FISH+ patients in the CP+E arm experienced a decrease in RR compared to those in the CP alone arm, and had a marginally significant longer TTP (HR=0.59, 0.35–0.99). The benefit in TTP appeared after approximately 6 months, during the maintenance portion of the trial. Conclusions: In this retrospective analysis, FISH+ did not predict survival benefit in TRIBUTE. A longer TTP, but a lower RR, was observed in the FISH+ patients. The lower RR in the CP+E arm in this group, taken together with the improved TTP during maintenance therapy, suggests that a non-concurrent combination approach (CP followed by E) warrants further investigation. No significant financial relationships to disclose.
Personalized dosing of tamoxifen (Tam) based on polymorphisms of CYP2D6 (2D6) and/or low serum endoxyfen levels.
Authors: M. F. Barginear, C. Yu, G. Raptis, M. Jaremko, K. B. Adelson, L. Bulone, Q. Zuo, I. Peter, M. Kemeny, R. J. Desnick
Journal: Journal of Clinical Oncology (2010)

e13507 Background: The efficacy of Tam varies widely. Tam is biotransformed to endoxifen and 4-OH-Tam by the cytochrome P450 2D6 enzymes. Compared to Tam, endoxifen and 4-OH-Tam have a 100-fold greater affinity for the estrogen receptor (ER) and in suppressing estrogen-dependent cell proliferation. 2D6 variants are an independent predictor of relapse and death. Serum endoxifen levels ≥40nM block ERα-mediated transcriptional activation and inhibit estrogen-induced breast cancer cell proliferation. Methods: Serum Tam, Tam metabolites, and 19 2D6 alleles were analyzed in pts taking Tam 20 mg/day for 90 days. 2D6 genotyping was performed by PCR-based procedures and metabolites were assessed on Liquid Chromatography/Tandem Mass Spectrometry. Tam was increased to 30 mg/day if serum endoxifen < 40 nMol or 2D6 alleles had no enzymatic function. Results: 110 patients have enrolled to date. Age, ethnicity, BMI, concomitant medications, and adherence were recorded. 17% pts had low serum endoxifen and 2% of pts had no 2D6 allele function, all of these pts were increased to Tam 30 mg/day. All patients' serum endoxifen increased >40 nMol by day 14. Conclusions: Subtherapeutic serum endoxifen can be found in any 2D6 phenotype, although it is more common in pts with decreased or no 2D6 allele function. Subsequently, it is likely that other gene variants are involved in Tam metabolism. It is possible to achieve therapeutic serum endoxifen/Tam metabolite levels by optimizing the dose of Tam. Tam dosages can be individualized. Further investigation is warranted as personalizing the dose of Tam is feasible and may potentially significantly improve the outcome of pts taking Tam. Genotype score Avg(endoxifen)day 0 Avg(endoxifen)day 14 Avg (endoxifen) day 30 Avg (endoxifen) day 42 Avg(endoxifen) day 56 Avg (endoxifen) day 90 0 33* 40 64 43 60 Pending 0.5 39 50 64 66 70 72 1 30 43 46 66 53 61 2 32 56 53 55 59 61 No significant financial relationships to disclose.