tbuckley/cabot-search huggingface dataset:
Are immunohistochemical (IHC)/microsatellite instability (MSI) testing necessary as part of Lynch syndrome work-up in the era of multiplex genetic testing?
Authors: Ahmad Fitri Idris, Simon D. Hooper, M. P. Farrell, Carmel Nolan, Roisin Clarke, E Berkley, David J. Gallagher
Journal: Journal of Clinical Oncology (2014)

1551 Background: IHC for mismatch repair proteins and MSI are commonly used to direct genetic testing for Lynch Syndrome. Abnormal results in the setting of a positive family history often lead to genetic testing for Lynch syndrome. The often cumbersome process of completing IHC/MSI requires obtaining stored tissue +/- blood from a family member affected with cancer. Upfront genetic testing is not favoured due to concerns about identifying variants of uncertain significance. We performed a review of Lynch syndrome work-up in Ireland, and propose a model that is the reverse of the current international standard, and may expedite and simplify work up of these families. Methods: Data was ascertained from three cancer genetics services in Dublin and included the following variables: Date of birth, date of request and reporting results for IHC, MSI and genetic tests. Time intervals were determined for LS work-up for all patients who had the process initiated in these 3 centres. Results: Probands from 50 families referred for LS work-up were included.The median time from date of IHC request to date of IHC report (total of 50 patients) was 4 weeks (range: 4 days to 36 weeks). The median time between date of IHC request to date of MSI report (n = 32 patients) was 20 weeks (Range: 4 to 56 weeks). The median time from date of genetic test request to date of result (n = 9 patients) was 9 weeks (Range: 2 to 26 weeks). The median time for completion of all 3 tests in one individual (n=3 patients) was 14 weeks (Range: 10 to 60 weeks). Conclusions: The diagnostic pathway for Lynch syndrome is cumbersome and often lengthy. Appropriate upfront multiplex genetic testing would expedite the identification of mismatch repair gene mutation carriers. IHC/MSI testing could be used to characterise variants of uncertain significance.
All PARP inhibitors are not equal: An in vitro mechanistic comparison of PF-01367338 to iniparib.
Authors: K. A. Maegley, P. Bingham, J. H. Tatlock, H. D. Thomas
Journal: Journal of Clinical Oncology (2011)

e13576 Background: PARP is a key enzyme involved in base-excision repair. Pre-clinically it has been shown that BRCA1/2 deficient cells are hyper-sensitive to PARP inhibition. These cells can’t repair replication associated double-strand breaks that result from PARP inhibition due to defects in homologous recombination repair. Iniparib (BSI-201) is an allosteric PARP inhibitor that, in its activated form, reacts with PARP in the DNA binding domain. This interaction inhibits DNA damage induced activation of isolated PARP protein resulting in inhibition in vitro. PF-01367338 is an enzymatic active site directed inhibitor. This study compared iniparib with a potent competitive inhibitor, PF-01367338 (formerly AG014699), in a cellular environment. Methods: PARP inhibition was evaluated using purified enzyme and cell extracts in standard biochemical assays. Inhibition of poly(ADP-ribose)(PAR) formation in live cells (MDA-MB-231/436) was determined using an anti-PAR antibody ELISA assay. PARP activity in tumor cell homogenates was measured by radioactive polymer formation assay. Results: PF-01367338 inhibited PARP enzymatic activity and PAR formation in cells with a potency of 5 nM. PF-01367338 inhibited proliferation of MDA-MB-436 cells with an IC50 of 1.2 uM. In addition, PAR formation in tumor-bearing mice was fully inhibited within 30 min at 10 mg/kg. In contrast, iniparib did not inhibit enzymatic activity or PAR formation in vitro. Incubation of iniparib with cell lysates resulted in inhibition of PARP activity with an IC50 of 200 nM, demonstrating that the active nitroso compound can form in these cells. However, iniparib did not induce antiproliferative activity in treated cells. Conclusions: The lack of PARP inhibition by iniparib in two BRCA deficient cell lines suggests that while this inhibitor can inhibit PARP in vitro, it may not be able to inhibit PARP in a complex cellular environment. Additionally, iniparib inhibits other enzymes including GAPDH and caspase-3, suggesting that results seen for iniparib in the clinic may not be due solely to, or reflect PARP inhibition. In contrast, the primary mechanism-of-action of catalytic PARP inhibitors such as PF-01367338 is likely to be related to PARP inhibition.
Development and validation of a treatment decision model for optimal delivery of liver stereotactic body radiation therapy (SBRT): Photons versus protons.
Authors: Saumil J Gandhi, Xing Liang, Xuanfeng Ding, Timothy C Zhu, Edgar Ben-Josef, John Peter Plastaras, James M. Metz, Stefan Both, Smith Apisarnthanarax
Journal: Journal of Clinical Oncology (2014)

264 Background: Treatment of liver tumors with SBRT provides excellent local control rates, but is often limited by liver dose constraints. Protons offer potential for more liver sparing, but clinical situations where protons may be superior to photons are not well described. We developed and validated a treatment decision model to determine whether patients with liver tumors of certain sizes and locations are more suited for photon vs proton SBRT. Methods: Six spherical mock tumors from 1-6 cm in diameter were contoured on axial CT images of one patient at each of 4 locations (24 total tumors): peripheral/dome, caudal, left medial, central. We generated photon and proton plans (48 plans) to deliver 50 Gy* in 5 fractions with ~135% dose max within the gross tumor volume. Mean liver dose was constrained to &lt; 14 Gy and at least 700 cc received &lt; 15 Gy. Using these plans, we developed a hypothesis-generating model to predict the optimal modality for maximal liver sparing based on tumor size and location. We validated this model in 10 actual liver tumor patients by generating and comparing photon and proton plans. Results: Proton plans spared significantly more liver volume and decreased mean liver dose, particularly for tumors ≥ 3 cm in the dome or central locations− peripheral/dome: 134 ± 21 cc (p = 0.03), 912 cGy vs 1303 cGy (p = 0.01); central: 108 ± 4 cc (p &lt; 0.01), 1179 cGy vs 1454 cGy (p &lt; 0.01). Our model correctly predicted the optimal SBRT modality for all 10 patients. There was a significant increase in the volume of liver spared (176 ± 21 cc, p &lt; 0.01) and decrease in mean liver dose (841 cGy vs 1223 cGy, p &lt; 0.01) with protons for patients with dome or central tumors ≥ 3 cm. As predicted, in patients with tumors &lt; 3 cm at any location or caudal and left medial tumors of any size, there was no significant difference in liver sparing between photon and proton SBRT (33 ± 18 cc, p = 0.13). Conclusions: Tumor size and location are important determining factors in generating deliverable liver SBRT plans. When feasible, protons should be considered as the radiation modality of choice for dome or central tumors ≥ 3 cm to allow maximal liver sparing and potentially reduce radiation toxicity. *All doses are in Gy (RBE).
ATP-binding cassette (ABC) proteins in untreated acute myeloid leukemia (AML) in patients 60 years and older (CALGB 9760)
Authors: M. R. Baer, J. S. Shoemaker, R. Barrier, N. W. Cuviello, K. L. O’Loughlin, H. Minderman, R. A. Larson, M. A. Caligiuri
Journal: Journal of Clinical Oncology (2005)

6551 Background: Drug efflux mediated by the ABC protein P-glycoprotein (Pgp) is an adverse prognostic factor and a presumed mechanism of treatment failure in older AML patients, but little is known about the other multidrug resistance (MDR)-associated ABC protein drug efflux pumps multidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP). We studied these additional drug efflux mechanisms and the effects of diverse MDR modulators. Methods: Pre-treatment samples from 106 untreated AML patients 60 years and older [ages, 67 to 84 (median, 71) years; 82 (77%) de novo AML, 24 (23%) following myelodysplastic syndromes, and 4 (4%) therapy-related] were studied for expression of Pgp, MRP-1 and BCRP, for drug efflux and for modulation of drug efflux by the Pgp-, MRP-1- and BCRP-specific modulators PSC-833, probenecid and fumitremorgin C (FTC) and by cyclosporine A (CsA) which has activity against all three proteins, by flow cytometry. Pgp, MRP-1 and BCRP expression was studied with the MRK-16, MRPm6 and BXP-21 antibodies. Flow cytometry data were analyzed by the Kolmogorov-Smirnov statistic, expressed as a D-value, with cutoffs defining expression, efflux and modulation established in cell lines. Results: Pgp, MRP-1 and BCRP were expressed in 43%, 30% and 52% of samples, and at least one protein in 86%. Pgp and BCRP, Pgp and MRP-1, and MRP-1 and BCRP were coexpressed in 38%, 16% and 31%, and all three proteins in 13% of samples. Efflux of mitoxantrone, a substrate for Pgp, MRP-1 and BCRP, was seen in 77% of samples, and was reduced by PSC-833, probenecid and FTC in 30%, 8% and 15%,and by CsA in 34%. Effects of MDR protein-specific modulators correlated poorly with MDR protein expression. Conclusions: AML cells in older patients frequently express diverse ABC proteins and frequently exhibit drug efflux, but effects of specific modulators on efflux in vitro correlate poorly with expression of specific proteins, and the modulators studied were effective in no more than half of cases in which efflux was seen. These data support ongoing efforts to develop and test broad-spectrum ABC protein modulators with efficacy in modulating all of the ABC proteins expressed in AML cells. No significant financial relationships to disclose.
Low-power laser irradiation inhibits arecoline-induced fibrosis: an in vitro study
Authors: Mei-Chun Yeh, Ker-Kong Chen, Min-Hsuan Chiang, Chia-Hsin Chen, Ping-Ho Chen, Huey-Er Lee, Yan-Hsiung Wang
Journal: International Journal of Oral Science (2017)

Oral submucous fibrosis (OSF) is a potentially malignant disorder that is characterized by a progressive fibrosis in the oral submucosa. Arecoline, an alkaloid compound of the areca nut, is reported to be a major aetiological factor in the development of OSF. Low-power laser irradiation (LPLI) has been reported to be beneficial in fibrosis prevention in different damaged organs. The aim of this study was to investigate the potential therapeutic effects of LPLI on arecoline-induced fibrosis. Arecoline-stimulated human gingival fibroblasts (HGFs) were treated with or without LPLI. The expression levels of the fibrotic marker genes alpha-smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF/CCN2) were analysed by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) and western blots. In addition, the transcriptional activity of CCN2 was further determined by a reporter assay. The results indicated that arecoline increased the messenger RNA and protein expression of CCN2 and α-SMA in HGF. Interestingly, both LPLI and forskolin, an adenylyl cyclase activator, reduced the expression of arecoline-mediated fibrotic marker genes and inhibited the transcriptional activity of CCN2. Moreover, pretreatment with SQ22536, an adenylyl cyclase inhibitor, blocked LPLI's inhibition of the expression of arecoline-mediated fibrotic marker genes. Our data suggest that LPLI may inhibit the expression of arecoline-mediated fibrotic marker genes via the cAMP signalling pathway.
Addition of grapefruit juice (GJ) to increase the bioavailability of high-dose weekly rapamcyin (R)
Authors: C. M. Hartford, E. E. Cohen, K. Fox-Kay, J. Ott, X. Jiang, M. Kocherginsky, M. J. Ratain
Journal: Journal of Clinical Oncology (2008)

3587 Background: R has potential anticancer activity due to inhibition of mTOR, but has low oral bioavailability. GJ increases the bioavailability of many drugs due to its furanocoumarins (F). We hypothesize that GJ can increase the AUC of high-dose weekly R, allowing inexpensive delivery of a weekly mTOR inhibitor. Methods: In this Phase I dose escalation trial, R was administered orally once weekly. After one week of R alone, R was administered in conjunction with GJ (240 ml qd). The R AUC was determined with and without GJ. R dose was then escalated in successive cohorts of patients using an adaptive escalation design based on R concentrations in whole blood measured by HPLC. Results: 14 males and 7 females (age 27 - 76) with advanced solid tumors have been enrolled and pharmacokinetic data are available for 15. Initially, 5 and 3 patients were analyzed in R dose cohorts of 15 and 30 mg, respectively, co-administered with canned GJ (CGC). The addition of CGJ did not significantly increase R AUC. Mean AUC of R vs. R+CGJ was 1,045 μg·hr/L vs. 1,532 μg·hr/L (P>0.05, paired t-test) and 2,255 μg·hr/L vs. 2,498 μg·hr/L (P>0.05) in the 15 and 30 mg cohorts, respectively. Analysis of the CGJ revealed low concentrations of F. Subsequent cohorts were administered a formulation of frozen GJ (FGJ), tested prospectively to confirm adequate levels of F. In these cohorts the mean AUC of R vs. R+FGJ was 798 μg·hr/L vs. 4397 μg·hr/L (P = 0.02) and 745 μg·hr/L vs. 4,617 μg·hr/L (P = 0.06) in 15 mg (n=5) and 20 mg (n=2) cohorts, respectively. Among the 21 patients enrolled, the most common observed toxicities were hyperglycemia (67%), fatigue (52%) and lymphopenia (52%). One dose limiting toxicity was observed: grade 2 anorexia preventing completion of cycle 1 in a patient treated with 30 mg. Stable disease has been observed in 38% of evaluable patients. Conclusions: The addition of FGJ to R increases the exposure of R approximately 4-fold and will decrease the total required dose. The combination of R+FGJ is well tolerated without unexpected toxicities, and may have similar efficacy to weekly iv temsirolimus. No significant financial relationships to disclose.
Predictors of early mortality in colorectal cancer patients undergoing chemotherapy: Results from a global prospective cohort study.
Authors: Davendra Sohal, Nicole Maria Kuderer, Frances A. Shepherd, Ingrid Pabinger, Giancarlo Agnelli, Howard A. Liebman, Eric Vicaut, Guy Meyer, Gary H. Lyman, Alok A. Khorana
Journal: Journal of Clinical Oncology (2014)

532 Background: Early mortality is a major problem in colorectal cancer and our understanding of risk factors and predictors is incomplete. A venous thromboembolism (VTE) Risk Score, comprising primary site, baseline hemoglobin, leukocyte and platelet counts, and body mass index [Khorana et al, Blood, 2008], has been shown to be associated with early mortality in solid tumors [Kuderer et al, 2008; Ay et al, 2013]. We evaluated the value of this Risk Score and other key prognostic variables in predicting early mortality for colorectal cancer (CRC) patients. Methods: CANTARISK was a prospective, non-interventional, global cohort study in patients with CRC and lung cancer initiating a new chemotherapy regimen. Clinical data were collected at 0, 2, 4, and 6 months. All data were compiled centrally and analyzed after the study closed. Risk score categories were as defined previously [Blood, 2008]. Statistically significant univariable associations and a priori prognostic variables were tested in multivariable models; adjusted odds ratios (OR) are presented. Results: A total of 1,789 CRC patients were enrolled from 2011-12; data on 1,533 evaluable patients are presented. Median age was 62 years; 71% were Caucasian. Geographic distribution was Europe 37%, North America 28%; Asia 23%; South America 12%. One-third (33%) had a rectal primary and 65% had metastatic disease. There were 184 deaths (10.3%) on study. For low, intermediate and high Risk Score, there were 8.1%, 11.2%, and 32.5% deaths, respectively. In multivariate analyses, the Risk Score remained an independent predictor of death (OR for high/intermediate vs. low score = 1.70, p = 0.0027), in addition to age (OR for each incremental year = 1.03, p = 0.0014), presence of metastatic disease (OR = 3.28, p &lt; 0.0001), and ECOG performance status ≥2 (OR = 3.85, p &lt; 0.0001). VTE itself was not associated with death. Conclusions: This prospective global cohort study demonstrates that the Risk Score is prognostic of early mortality in CRC patients, in addition to age, stage, and performance status. Intermediate or high-risk patients, as defined by the Risk Score, may benefit from additional interventions aimed at reducing early mortality.
PLUTO: A randomised phase II study of pazopanib versus paclitaxel in relapsed urothelial tumours.
Authors: Thomas Powles, Syed A. Hussain, Andrew Protheroe, Alison Birtle, Prabir R Chakraborti, Robert Huddart, Satinder Jagdev, Amit Bahl, Andrew Stockdale, Santhanam Sundar, Simon J. Crabb, Judith Dixon-Hughes, Laura Alexander, Caroline A Bray, Jamie Stobo, Akhila Ganeshi Wimalasingham, Charlotte Ackerman, James Paul, Rob Jones
Journal: Journal of Clinical Oncology (2016)

430 Background: Two previous single arm trials have drawn conflicting conclusions regarding pazopanib in urothelial bladder cancers (UBC) after failure of platinum-based chemotherapy. PLUTO is a randomized phase II trial to compare the efficacy of pazopanib with paclitaxel in this setting. Methods: It was planned for 140 patients with progressive, advanced UBC (with at least a component of transitional cell carcinoma) who had previously received a single prior platinum containing chemotherapy regimen for advanced UBC to be randomised(1:1). Patients in arm A received weekly paclitaxel 80mg/m2 and those in arm B received pazopanib (800mg once daily) until progression. The primary endpoint was overall survival analysis of which would occur after 110 events. The efficacy was assessed by an independent data monitoring committee during the trial. Results: Between Aug 2012- Oct 2014, 131 patients were randomised. 74.0% of patients had visceral metastases. The study was terminated early by the IDMC due to futility of pazopanib. Final analysis after 110 deaths occurred in July 2015. The median number of cycles of paclitaxel received was 4 (12 weeks). The median time on pazopanib was 11 weeks. Median overall survival was 8.0 months for paclitaxel [80% confidence interval (CI) 6.9 to 9.7 months] and 4.7 months for pazopanib [80% CI 4.2 to 6.4 months]. The hazard ratio (HR) adjusted for baseline stratification factors was 1.25 [80% CI 0.96 to 1.63; 1-sided p = 0.86] in favour of paclitaxel. Median progression free survival was 3.2 months for paclitaxel [80% CI 2.9 to 5.0 months] and 3.1 months for pazopanib [80% CI 2.7 to 3.8 months]. The adjusted HR for PFS was 1.06 [80% CI 0.83 to 1.36; 1-sided p = 0.62] (in favour of paclitaxel). Discontinuations for toxicity occurred in 6.3% and 20.0% for paclitaxel and pazopanib respectively. VHL, HIF1alpha, VEGFR2 and PD-L1 expression were measured from archived tissue and correlated with outcome. Conclusions: Pazopanib does not have greater efficacy than paclitaxel in the second line treatment of UBC. There is a trend towards superior OS with paclitaxel. Clinical trial information: NCT00949455.
Phase I trial of sunitinib (S) and temsirolimus (T) in metastatic renal cell carcinoma (mRCC).
Authors: Matthew T. Campbell, Randall E. Millikan, Emre Altinmakas, Lianchun Xiao, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2014)

433 Background: Anti-VEGF agents and mTOR inhibitors are mainstay therapies in mRCC. Pre-clinical data suggests synergistic anti-tumor effect when combining these 2 classes. A previous phase I trial using sunitinib (S) 25 mg/d 4 wks on, 2 wks off, and temsirolimus (T) 15 mg/wk was stopped after 2 of the first 3 pts developed dose limiting toxicity (DLT). Methods: Pts with any subtype mRCC (PS 0-1) were eligible. Each cycle consisted of daily S for 14 days on, 7 days off, and weekly T. The continuous reassessment method (CRM) was used. The primary objective was to find the maximum tolerated doses (MTD) of S and T. The total planned accrual was 60 pts. Results: Accrual was stopped after 20 pts received study drugs. Median age was 63.5 years; 13 pts received prior targeted therapy, 7 pts were treatment naïve; median number of prior treatments 1 (range 0-6). Treatment cohorts (#pts, S, T, dose in mg): 2 (S12.5,T6), 1 (S25,T12.5), 1 (S12.5,T8), 8 (S12.5alt25,T9), 2 (S25,T6), 2 (S25alt37.5,T6), 2 (S37.5,T6), 2 (S37.5,T8). Dose reduction was required in 6 of 20 pts; the most common DLT was mucositis in 3 of 20 pts, followed by thrombocytopenia in 2 of 20 pts. The mean number of cycles for all pts was 6.6±5.36, with mean time on study 159±120 days. One pt experienced DLT in cycle 1 and received no study related imaging, 1 had a partial response, 16 pts had stable disease, and 2 pts had progressive disease (PD) as best response. A total of 21 grade 3/4 adverse events (AEs) attributed to drug occurred in 11 of 20 pts. Reasons for study discontinuation were PD in 12 pts, toxicity in 6 pts, and pt preference in 2 pts. There were no treatment related deaths. Conclusions: The MTD of S and T using the CRM were not reached due to premature trial closure. However, we believe S 37.5 mg/d, 2 wks on, 1 wk off, and T 8-10 mg weekly may well be close to MTD. Clinical trial information: NCT01122615.
Combination of tivozanib (AV-951) with weekly paclitaxel for metastatic breast cancer: Results of a phase I study.
Authors: E. L. Mayer, M. E. Scheulen, J. Beckman, H. Richly, A. Poli, P. Bhargava, A. Duarte, M. M. Cotreau, A. L. Strahs, M. N. Dickler
Journal: Journal of Clinical Oncology (2011)

1092 Background: Tivozanib (T; AV-951) is a potent and selective oral small molecule tyrosine kinase inhibitor (TKI) of VEGFR-1, -2, and -3. This phase Ib open-label, multicenter study investigated the safety/tolerability, pharmacokinetics (PK), and activity of T in combination with weekly paclitaxel (P) in metastatic breast cancer (MBC). Methods: Eligible patients (pts) had evaluable MBC with normal organ function, ECOG PS 0-2, ≤4 prior lines of chemotherapy for MBC, including taxanes, and no limit on prior endocrine/biologic therapies. Prior bevacizumab (B) was permitted; prior VEGFR TKIs were excluded. Unstable brain metastases, grade >1 baseline neuropathy, uncontrolled hypertension (HTN), and symptomatic heart failure were excluded. Standard 3+3 dose escalation was used: P 90 mg/m2 3 of 4 weeks (28 days = 1 cycle); escalation cohorts of T: 0.5 mg, 1.0 mg, and 1.5 mg. Maximum tolerated dose (MTD) was defined as the maximum dose at which ≤1 of 6 pts experienced dose-limiting toxicity (DLT). Response was assessed every 2 cycles. PK was evaluated on Day -5 and Cycles 1-2. Results: Eighteen pts enrolled: median age was 48 years (32-65); median ECOG PS was 0 (0-1). 56% were hormone receptor–positive, 22% HER2-positive, and 39% triple negative. Median of 2 (0-4) prior lines of therapy for MBC. 100% had prior taxane exposure: 61% adjuvant, 17% neo-adjuvant, and 22% for MBC. 56% had prior B exposure. Therapy was well tolerated; toxicities (all grades) occurring in ≥20% of pts: fatigue (72%), diarrhea (44%), nausea (44%), HTN (33%), cough (33%) and vomiting (28%). Grade 3 toxicities: diarrhea (11%), fatigue (11%), HTN (11%), neutropenia (11%), and neuropathy (6%); no grade 4 toxicity was observed. The MTD was T 1.5 mg with P 90 mg/m2. All pts were evaluable for response: 5 pts (28%) had a partial response, 2 with prior B exposure; 3 pts (17%) had stable disease ≥24 weeks. PK data suggest no influence of P on circulating levels of T. Conclusions: The combination of T and weekly P was tolerable at all dose levels, supporting combination at full dose and schedule of both agents. In this small patient population with prior taxane exposure, encouraging evidence of clinical activity was observed, supporting further evaluation.