tbuckley/cabot-search huggingface dataset:
Neutrophils diminish T-cell immunity to foster gastric cancer progression: the role of GM-CSF/PD-L1/PD-1 signalling pathway
Authors: Xu Zhang, Wenrong Xu
Journal: Gut (2017)

Neutrophils are the predominant leucocytes in the blood and act as the first line of host defence against invading pathogens. Neutrophils have also been shown to play important roles in the other pathological conditions, including cancer. In the past decade, many efforts have been made to clarify the roles of neutrophils in cancer development and progression. It appears that neutrophils have both antitumour and protumour functions.1 On one hand, neutrophils can directly kill tumour cells by releasing antimicrobial and cytotoxic contents that are prestored in their granules. Neutrophils can induce apoptosis in tumour cells and reduce tumour growth when administrated into tumour-bearing animals. Neutrophils are regarded as important effector cells for monoclonal antibody (mAb)-mediated immunotherapy, where they interact with mAb through the Fc receptor, leading to antibody-dependent cell cytotoxicity. Neutrophils also have antimetastatic activity. In mouse models of cancer metastasis, neutrophils at the premetastatic site produce cytotoxic substances to eliminate tumour cells and limit their metastatic spread. In addition, neutrophils are able to regulate the activation of T cells and other immune cells to elicit antitumour immune responses. On the other hand, emerging evidence suggests that neutrophils possess protumour properties including the induction of malignant transformation, enhancement of tumour growth, establishment of premetastatic niche, stimulation of angiogenesis and promotion of immune evasion by suppression of innate and adaptive immune cells (eg, T cells and NK cells). The dual roles of neutrophils in cancer might be explained by their plasticity and the existence of distinct neutrophil subsets with differing properties within the tumours, which could be driven by signals from the tumours.2 ,3 In particular, neutrophils seem to have both stimulatory and suppressive roles in T-cell immunity. During the early phase of tumour growth, neutrophils tend to inhibit primary tumour growth by recruiting and activating CD8+ T …
A translational study to investigate the association between smoking-induced lung inflammation and lung metastases (LM) from breast cancer (BC).
Authors: Patrick Glyn Morris, Xi Kathy Zhou, Ginger L Milne, Daniel A. Goldstein, Laura Hawks, Didem Uzunaslan, Chau T. Dang, Kathleen Keenan, Shanu Modi, Monica Nancy Fornier, Nancy T. Sklarin, Gabriella D'Andrea, Diana Lake, Maria Theodoulou, Tiffany A. Traina, Maura N. Dickler, Shari Beth Goldfarb, Clifford Hudis, Andrew J Dannenberg
Journal: Journal of Clinical Oncology (2012)

10514 Background: Retrospective and preclinical studies suggest that smokers are at increased risk for LM from BC, possibly mediated by lung inflammation and the bioactive lipid, PGE 2 . To investigate this link in pts, we examined urinary PGE-M, a stable end metabolite of PGE 2. Methods: A translational study was conducted, consisting of pts with LM (n=100), pts with mets but no known lung mets (NKL, n=100) and controls (CTRLS) with a history of BC (n=200). Pts receiving steroids and radiotherapy were excluded. Pts gave urine (PGE-M), blood (biomarkers), had BMI measured, and completed a validated questionnaire (smoking, NSAIDs, confounders). PGE-M was measured by mass spectrometry, normalized to urinary creatinine and compared between grps in both univariate and multivariate models, correcting for covariates. Results: From 09/2010 to 06/2011, 400 pts, med age 58 yrs (range 24-88) enrolled. There were no significant differences between grps in smoking and NSAID exposure (table). PGE-M (med; range) was highest among pts with LM (6.7; 0.7 - 43.4) compared to pts with NKL (4.6; 0.7 - 26.8) and CTRLS (4.2; 0.9 – 62.6, P&lt;0.001). In univariate analysis, smoking pack year was associated with PGE-M (ρ=0.13, P=0.01), and ever smokers with LM had the highest PGE-M (med 7.4; range 0.8-28.9). In a multivariable model ever smokers with LM had higher PGE-M than never smoking CTRLS (P=0.03). Pts with &gt;24 pack year smoking history and LM had the highest co-variate-adjusted log PGE-M (P=0.03). In this model, age (P&lt;0.001), pack year smoking hx (P=0.02), receipt of chemoRx ≤1 mth (P=0.003) and BMI (P=0.002) were all associated with higher PGE-M. Conversely, receipt of NSAIDs ≤7 days was associated with lower PGE-M (P&lt;0.001). Conclusions: Increased lung inflammation, as characterized by PGE-M, occurs in ever smokers with LM from BC, supporting the hypothesis that changes in the lung microenvironment (“soil”) predispose to metastasis. [Table: see text]
Use of chemotherapy (CT) in <i>BRCA1/2</i>-deficient ovarian cancer (BDOC) patients (pts) with poly-ADP-ribose polymerase inhibitor (PARPi) resistance: A multi-institutional study.
Authors: Joo Ern Ang, Charlie Gourley, Hilda Anne High, Ronnie Shapira-Frommer, C. Bethan Powell, Vincent Castonguay, Jacques De Greve, Timothy Anthony Yap, Peter C.C. Fong, David Olmos, Susana N. Banerjee, Lee-may Chen, Michael Friedlander, Bella Kaufman, Amit M. Oza, Johann Sebastian De Bono, Martin Eric Gore, Stanley B. Kaye
Journal: Journal of Clinical Oncology (2012)

5022 Background: Emerging clinical data point to the clinical utility of PARPi in BDOC. However, the impact of PARPi exposure on the prospects of response to further CT remains unclear. In our previous single centre study, we provided the first clinical data relating to the use of post-PARPi CT (JCO 2010: 28(15S), A5041). Our aim here was to re-examine this issue in a larger multi-institutional population. Methods: We included pts with advanced BDOC who received CT, having progressed on ≥200 mg bd olaparib. Pt, tumor and treatment characteristics and clinical outcomes were documented. Relationships between post-PARPi CT overall survival (OS) and other variables were explored using Cox regression. Results: We collected data on 75 pts (median age 51 y [range 31-77], BRCA1:BRCA2 54:21, mean 3 previous lines of CT [95% CI 2.5-3.4], pre-PARPi platinum (Plt) resistance rate 49% and olaparib RECIST-response rate [RR] 39% [95% CI 28-50]). Following olaparib, most pts received Plt alone or in combination with taxane (Tx) or liposomal doxorubicin (PLD). Weekly Plt was used in 36% of all Plt-treated pts, mainly in combination with weekly Tx. Overall RECIST and CA125 (GCIG) RRs were 38% and 48%, respectively; these responses occurred independently of PARPi response or pre-PARPi Plt sensitivity (all p&gt;.1). The median progression free survival and OS of RECIST responders were 7.9 m (95% CI 5.8-10.9) and 10.5 m (95% CI 1.4-19.6), respectively. In all pts, the median OS from the start of post-PARPi CT was 7.9 m (95% CI 5.7-10.1) while that from diagnosis was 64.9 m (95% CI 52.9-76.9). Factors associated with improved OS on post-PARPi CT in the MVA included best olaparib response of non-disease progression (p=.003, HR 0.28), optimal initial debulking (p=.01, HR 0.36) and pre-PARPi Plt sensitivity (p=.05, HR 0.46). Conclusions: These data indicate potential for meaningful responses to CT in BDOC pts with PARPi resistance. Analysis to identify molecular predictors of response is ongoing. [Table: see text]
Phase II breast cancer chemoprevention study with celecoxib in women at increased risk for breast cancer
Authors: B. Arun, V. Valero, G. Yin, G. Babiera, J. L. Murray, D. Browne, Y. Gong, E. Cook, G. N. Hortobagyi, N. Sneige
Journal: Journal of Clinical Oncology (2006)

1010 Background: Short-term chemoprevention trials offer a convenient model to screen chemopreventive agents and identify endpoint biomarkers. One of the potential agents is celecoxib (C), which has antiproliferative and apoptosis inducing properties. In this prospective study, our primary aim was to evaluate changes in proliferation induced by C in breast tissue of high risk women. Here, we report changes in estrogen receptor (ER) proliferation index. Methods: 42 eligible high risk women were enrolled into the study, underwent fine needle aspiration (FNA) and started celecoxib treatment at 400 mg BID. Median age: 51.9 years. Risk factors: Gail risk &gt; 1.67% (n=13), lobular carcinoma insitu (n=13), atypical hyperplasia (n=11), previous history of breast cancer (n=5). For ER and Ki-67 testing, thin preparations slides were incubated with primary mouse monoclonal antibody 6F11 against the ER and clone MIB-1, respectively. Appropriate negative and positive controls were included. At least 100 epithelial cells were evaluated per slide. Immunoreactivity for each marker was scored as the percentage of positive nuclei. We assessed the difference in ER and Ki-67 levels before and after treatment using a Wilcoxon signed rank test. Results: The average pre-treatment ER expression in FNA samples was 35.9% and Ki-67 was 2.4%. 19 (45%) showed hyperplasia or atypical hyperplasia. 39 patients underwent also post-treatment FNAs. The pre-and post treatment ER expression in this group was 35.7% (range 0–100%) and 27.4% (range: 0–100%), respectively. The difference in ER levels was statistically significant (p = 0.04). Twenty-six patients had Ki-67 levels measured both before and after treatment. The median difference in Ki-67 levels was 0 (range 0- 5). This change was not statistically significant (p = 0.63). Conclusions: We have completed accrual to a prospective short-term chemoprevention trial with celecoxib. We have found a significant downregulation of ER expression with 6 months celecoxib. Since ER expression is a marker of proliferation, this finding confirms celecoxibs antiproliferative properties. Currently, we have not observed a change in Ki-67; this could be partly due to the small number of samples and the fact that Ki-67 is low in normal epithelium. [Table: see text]
¿ES SEGURA A LARGO PLAZO LA COLOCACION DE LAS PROTESIS COLONICAS? EXPERIENCIA DE LOS ULTIMOS 6 AÑOS
Authors: B Alvarez, E Martí, A Dacal, D Tardáguila, E Castro, A López-Baz, R González-Soler, A González-Ramírez, A Lancho, L Lopez Roses
Journal: Endoscopy (2015)

Introducción: Algunos estudios demostraron mayor riesgo de recurrencia tumoral tras colocación de prótesis colónicas como puente a la cirugía. Además, la quimioterapia con agentes antiangiogénicos en casos de prótesis paliativas parece que aumenta el riesgo de perforación.
Inhibition of autophagy: Phase I safety, tolerability, and pharmacokinetics (PK) of hydroxychloroquine (H) in combination with vorinostat (V) in patients with advanced solid tumors.
Authors: Devalingam Mahalingam, Monica M. Mita, John Sarantopoulos, Leslie Wood, Alain C. Mita, Tyler J. Curiel, Athanassios Argiris, Steffan T Nawrocki, Jennifer S. Carew, Francis J. Giles
Journal: Journal of Clinical Oncology (2012)

3073 Background: The histone deacetylase (HDAC) inhibitor V has pleiotropic effects, and induces both apoptosis and autophagy. As autophagy can promote cancer cell survival, we hypothesized that inhibiting autophagy would enhance the anti-cancer activity of V. Our pre-clinical studies showed that inhibition of autophagy using H significantly increased the pro-apoptotic effects of V. The primary objective of this NCI-funded study was to determine the maximum tolerated dose (MTD) of H in combination with V in patients (pts) with advanced solid tumors. Methods: Pts with ECOG PS 0-2 and adequate organ function received PO V 300-400 mg QD and H 400-1000 mg QD in 21d cycles. 3+3 dose escalation. Dose limiting toxicities (DLTs) = non-hem toxicity ≥ grade (Gr) 3 or hem toxicity ≥ Gr 4 in the first 2 cycles. PBMCs were analyzed for autophagic changes at baseline, week 1 + 6. PKs done on cycle 1.Tumor biopsies were performed at baseline and post-cycle 2 on 3 pts at MTD. Results: 31 pts enrolled, 27 evaluable for DLT. No DLT was observed in cohort 1 (300 mg V/400 mg H) or cohort 2 (400 mg V/400 mg H). In cohort 3 (400 mg V/600 mg H) 1/6 pts experienced a DLT of Gr 3 fatigue. Cohort 4 (400 mg V/800 mg H) 3/6 pts had DLT of Gr 3 fatigue, and 1 had a Gr 2 seizure. Expansion of cohort 3 resulted in no further DLTs. 10 pts got the MTD. Treatment-related toxicities were mostly Gr 1- 2: nausea/vomiting (10 pts), diarrhea (7), fatigue (5), anorexia (4), weight loss (3), anemia (4), elevated creatinine (4) and thrombocytopenia (2). Gr 3 toxicities were fatigue (4), anemia, thrombocytopenia and neutropenia (1 each). No drug-related deaths or Gr 4 toxicities were noted. One pt (RCC) had a confirmed PR (cohort 2 active on cycle 32) and 2 pts with CRC had prolonged SD (&gt;4 cycles). PK analysis indicated dose-proportional exposure for H. Changes from baseline in biomarkers of autophagy and HDAC inhibition were observed in PBMC and primary tumors with therapy. Conclusions: Recommended dose is V 400 and H 600 mg QD. Dose-dependent fatigue was observed with the combination, but well tolerated at the MTD without any further increase in toxicities compared to V alone. Analyses of PK-PD interactions are underway.
Annals Consult Guys – Not So Grand: A Postoperative Seizure
Authors: Geno J. Merli, Howard H. Weitz
Journal: Annals of Internal Medicine (2017)

Web Exclusives21 March 2017Annals Consult Guys – Not So Grand: A Postoperative SeizureFREEGeno J. Merli, MD and Howard H. Weitz, MDGeno J. Merli, MDSearch for more papers by this author and Howard H. Weitz, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W17-0003 SectionsSupplemental MaterialAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Annals Consult Guys brings a new perspective to the art and science of medicine with lively discussion and analysis of real-world cases and situations. They address medically relevant topics—whether they be poignant, thought-provoking, or just plain entertaining.For more videos from and information on Annals Consult Guys, visit go.annals.org/ConsultGuys. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Disclosures: Geno J. Merli, MD, reports the following: Research grants/contracts: Bristol-Myers Squibb, Janssen, Portola; Consultancies: Bristol-Myers Squibb, Janssen. Howard H. Weitz, MD, reports that he has no financial relationships or interests to disclose. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byCorrection: Annals Consult Guys—Measuring Lipids: To Fast or Not to Fast 21 March 2017Volume 166, Issue 6Page: CG1KeywordsDisclosureEpileptic seizuresResearch grantsResearch reporting guidelines ePublished: 21 March 2017 Issue Published: 21 March 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.Loading ...
Phase I, dose-escalation study of the investigational drug TAK-733, an oral MEK inhibitor, in patients (pts) with advanced solid tumors.
Authors: Alex A. Adjei, Patricia LoRusso, Antoni Ribas, Jeffrey Alan Sosman, Anna C. Pavlick, Grace K. Dy, Xiaofei Zhou, Esha A. Gangolli, Russell M Walker, Michelle Kneissl, Stephanie Faucette, Rachel Neuwirth, Viviana Bozon
Journal: Journal of Clinical Oncology (2013)

2528 Background: This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), MTD, and efficacy of TAK-733 – an oral, selective, allosteric inhibitor of MEK1/2 – in pts with advanced solid tumors (NCT00948467; completed study). Methods: Eligibility: age ≥18 y; ECOG PS 0–2; evaluable tumors. Pts received escalating doses of TAK-733 QD in a modified 3+3 design for 21 d in a 28-d cycle to determine the MTD based on DLTs in cycle 1. Plasma (PK) and peripheral blood samples (PD: pERK reduction in PBMCs) were obtained pre-dose (d 1, 8, 15, 21) and post-dose (d 1, 21) in cycle1. Results: 51 pts (median age 58 y; 51% M) received escalating doses of TAK-733 (0.2–22 mg; median 2 cycles, range 1–11 [5 pts ≥6 cycles]). 4 pts had DLTs: grade 3 acneiform dermatitis, 1 each at 11.8 and 16mg; grade 3 pustular rash and grade 2 rash/stomatitis (qualifying as a DLT) at 22mg, leading to the 16 mg dose being selected as MTD. 45 pts (88%) had a drug-related AE; most frequent was acneiform dermatitis (47%). 10 pts (20%) had a grade ≥3 drug-related AE; most frequent were creatine phosphokinase increase and acneiform dermatitis (each n=3, 6%). 7 pts discontinued due to AEs. TAK-733 exhibited a moderately fast absorption with a median T max of 3 hr. Steady-state exposure of TAK-733 (0.2–22mg) did not increase in a dose proportional manner based on the power model analysis. The mean terminal t 1/2 (11.8, 16, and 22 mg) was 43 hr. Overall mean accumulation ratio was 3.5 following QD dosing for 21 d. On d 21, E max of blood pERK modulation was 56–99%, and time-averaged modulation over the dosing interval at steady-state was 76–98% at MTD. This range correlates well to the 76–89% for pERK modulation associated with maximal efficacy in xenograft models. 1 pt (16 mg) with melanoma (BRAF L597R) had a confirmed partial response after 4 cycles (treated for 9 cycles). 15 pts had a best response of stable disease (4–11.7 months in 6 pts). Conclusions: From preliminary data, TAK-733 appears generally well tolerated, pharmacodynamically active and shows signs of anti-tumor activity in pts with advanced solid tumors. MTD was associated with significant pERK inhibition in peripheral blood. Clinical trial information: NCT00948467.
Pharmacokinetic advantage of hyperthermic intraoperative intraperitoneal cisplatin and oxaliplatin.
Authors: Sharyn Nan Lewin, Joshua Leinwand, Vesna Slavkovic, Christopher Webb, Paul Weyker, Richard K Raker, Joseph Graziano, Robert N. Taub
Journal: Journal of Clinical Oncology (2012)

e13066 Background: Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) is used to treat peritoneal surface-spreading malignancies in order to maximize local drug concentrations while minimizing systemic effects. The pharmacokinetic advantage (PKA) of HIPEC is defined as the intraperitoneal to intravascular ratio of drug concentrations. We hypothesized that body surface area (BSA) and intravenous fluid (IVF) administration, by affecting intravascular volume, would correlate with PKA. Methods: On an IRB-approved study, we collected blood and peritoneal perfusate from 13 patients undergoing HIPEC with a set dose of 100 mg cisplatin (n=4) or a BSA-based dose of 250 mg/m 2 oxaliplatin (n=9), and measured Pt concentrations by Inductively Coupled Plasma Mass Spectrophotometry. Areas under concentration-time curves from 0-60 minutes (AUC0-60) were calculated by Trapezoidal Rule. PKA was calculated by (AUC0-60[peritoneal fluid]/AUC0-60[plasma]). Linear regression and Wilcoxon rank-sum test were performed using SAS. Results: Models with both BSA and IVF as predictors of PKA fit better than BSA alone for cisplatin (p=.022 vs. p=.076) but not for oxaliplatin (p=.119 vs. p=.037). The BSA and IVF model was a better fit for peritoneal cisplatin (p=.003) than for plasma cisplatin (p=.146). The BSA-only model was a better fit for plasma oxaliplatin (p=.013) than for peritoneal oxaliplatin (p=.778). There was no statistically-significant difference between the median PKA of cisplatin vs. oxaliplatin (p=.706). Conclusions: Our results suggest that BSA is a better PKA predictor than the compound’s diffusion properties. When a set drug dose is used, rather than a BSA-based dose, IVF is also an important predictor. This is likely due to HIPEC’s limited duration, thus the drug does not reach equilibrium between the peritoneal and vascular compartments. When monitoring the pharmacokinetic parameters of HIPEC administration, factors influencing intravascular volume, including BSA and IVF, should be considered. Maintaining intravascular volume repletion is a key strategy for maximizing PKA, and thereby minimizing systemic side effects due to HIPEC.
A phase I/II study for panitumumab combined with TAS-102 in patients with <i>RAS</i> wild-type metastatic colorectal cancer (APOLLON study): Phase I results.
Authors: Takeshi Kato, Yoshinori Kagawa, Yoshito Komatsu, Eiji Oki, Takayuki Yoshino, Kentaro Yamazaki, Hirofumi Yasui, Hironaga Satake, Kazunori Shibuya, Koji Oba, Kensei Yamaguchi
Journal: Journal of Clinical Oncology (2017)

770 Background: Both panitumumab (Pmab), the anti-EGFR antibody and TAS-102, the combination drug of trifluridine and tipiracil are approved agents for the treatment of metastatic colorectal cancer (mCRC). In preclinical models, the combination of Pmab with TAS-102 demonstrated enhanced activities compared with either drug alone. This phase I/II study is designed to investigate the safety and efficacy of Pmab combined with TAS-102 in patients (pts) with RAS ( KRAS/NRAS) wild-type mCRC refractory to standard chemotherapies. Here we reported the results of phase I part. Methods: Eligible pts are aged 20-74 y, ECOG performance status (PS) 0-1 with confirmed RAS wild-type mCRC, and refractory or intolerant to fluoropyrimidines, irinotecan, oxaliplatin and anti-angiogenesis therapy, and had no prior treatment with anti-EGFR antibody, TAS-102 or regorafenib. Phase I part is designed to evaluate the incidence of dose limiting toxicities (DLTs) during the first course and to determine recommended phase II dose (RP2D) in the dose de-escalation design (3 + 3 manner) of Pmab (6 mg/kg on days 1 and 15, every 4 weeks per course) combined with TAS-102 (35 mg/m 2 BID on days 1-5 and 8-12, every 4 weeks). DLTs were defined as drug-related adverse events (AEs) as follows; febrile neutropenia, G4 neutropenia &gt; 7days, G4 thrombocytopenia, inability to start the 2nd course more than 14 days delay, and G3/4 non-hematological toxicities. Results: Seven pts (3 male, 4 female) with a median age of 68 (range 57-71) were enrolled. Pts were ECOG PS 0 (3/7) or 1 (4/7) with primary tumor located in the colon (3/7) or rectum (4/7). One pt was excluded for the DLT evaluation due to protocol deviation. No DLT was observed in the 6 DLT-evaluable pts. Most frequent drug-related AEs during the DLT evaluation period were G2/3 neutropenia, G1/2 stomatitis, G1 nausea, G1 anorexia and G1/2 rash. Three pts achieved a partial response, and 3 pts had a stable disease. Conclusions: The RP2D for Pmab combined with TAS-102 was determined as the standard dose of Pmab and TAS-102. The enrollment of phase II part is ongoing to evaluate the PFS rate at 6 months by investigator assessment as a primary endpoint with the target number of 46 pts. Clinical trial information: 02613221.