tbuckley/cabot-search huggingface dataset:
Safety and efficacy results from the first-in-human study of the oral MEK 1/2 inhibitor GSK1120212.
Authors: J. R. Infante, L. A. Fecher, S. Nallapareddy, M. S. Gordon, K. T. Flaherty, D. S. Cox, D. J. DeMarini, S. R. Morris, H. A. Burris, W. A. Messersmith
Journal: Journal of Clinical Oncology (2010)

2503 Background: GSK1120212 is a potent and selective allosteric inhibitor of MEK1/2. The objectives of this study are to define the maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and response rate of GSK1120212 in advanced solid tumors and lymphoma. Methods: GSK1120212 is given orally, once daily (QD). This is a three-part study:Part 1, dose-escalation; Part 2, expansion in selected tumor types to evaluate recommended phase II doses (RP2D); Part 3, PK-PD assessment using tumor biopsies or FDG-PET. Results: 84 patients (pts) have received ≥ 1 dose of GSK1120212, including 29 melanoma and 15 pancreatic cancer pts. The MTD is 3 mg QD and the current RP2D is 2 mg QD. Dose-limiting toxicities are rash (N=2), diarrhea (N=1), central serous retinopathy (N=2) and are reversible. At doses ≥ RP2D (N=77), the most common adverse events are rash (77%; 42% G1, 30% G2, 5% G3) and diarrhea (45%; 34% G1, 9% G2, 3% G3). GSK1120212 has a small peak: trough ratio of ∼ 2 and an effective half life of ∼ 4.5 days. Steady state is reached by ∼ day 15. Tumor biopsy data showed reduction of pERK and Ki67 by > 90% at the 2 mg dose level. SUVmax was reduced by 23-48% after a 2-week treatment at 0.5 mg QD and 1 mg QD in 4 melanoma pts with evaluable FDG-PET data. In the 20 evaluable melanoma pts of known BRAF status, 5 partial responses (PRs) were observed, all having ≥ 50% tumor reduction; 3 have stayed ≥ 30 weeks on study, the other 2 are ongoing. In the 11 BRAF mutant melanoma pts, 3 PRs, 5 stable disease (SD; 2 with ≥ 20% tumor reduction, including a pt previously treated with the BRAF inhibitor, PLX4032), and 3 progressive disease (PD) were observed. Two of the 3 PDs were due to new brain lesions. In 9 BRAF wild-type melanoma pts, 2 PRs, including a pt with a GNAQ mutation, and 3 SDs were achieved. In 9 evaluable pancreatic cancer pts, 6 SDs were observed. Three of these SDs had CA19-9 decrease of >70%, of which 2 had 16% and 27% tumor reduction. Conclusions: The long effective half life and small peak:trough ratio of GSK1120212 allow constant target inhibition within a narrow range of exposure. The RP2D is well tolerated and associated with durable clinical activity in specific tumor types. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
High resolution banding technique in detection of minimal residual disease in acute myeloid leukemia
Authors: M. Elbordini, A. Elghandour, A. Abdelaziz
Journal: Journal of Clinical Oncology (2005)

6738 Background: A significant proportion of patients with acute myeloid leukemia (AML)who achieve remission subsequently experience frank relapse of their disease, and their ultimate prognosis is typically poor. Investigation of minimal residual disease has proven to be a valuable tool for predicting impending relapse before clinical and hematological manifestations. Aim of the work The aim of the study was the detection of minimal residual disease in AML patients following complete remission(CR) using high resolution chromosome banding technique of bone marrow specimens and their implication on clinical course of the disease. Methods: The present study included 27 patients with de novo AML as initial series. Their prognosis was based on morphological and immunophenotypical criteria. Results: Among these, 15 patients (55.5%) achieved morphologic complete remission,whom the present study was done on that cases for one year of follow up for detection of relapse. Three patients were M1, 5 were M2, 2 were M3, 2 were M4, and 3 were M5. High resolution banding technique of bone marrow cells revealed that seven patients(7/15;47%) had cytogenetic abnormalities; 3 had chromosomal translocations t(6;9),t(15;17),t(1;8),one with chromosome 5 monosomy,one deletion del(7q),one chromosome duplication dup(13q) and one with trisomy 8. During the follow up period,71%(5/7)of cases with cytogenetic abnormalities relapsed while 37.5%(3/8) of cases with normal cytogenetics relapsed. There was a significant difference between those who relapsed and had cytogenetic abnormalities and those who relapsed and had normal cytogenetics in their response to treatment. Conclusions: In conclusion, high resolution chromosome banding technique of bone marrow cells is valuable in the detection of minimal residual disease in AML and therefore patients at high risk of relapse coluld be identified for better management. No significant financial relationships to disclose.
Breast conservation surgery (BCS) versus modified radical mastectomy (MRM) decision: Role of patient and physicia
Authors: N. Mullai, C. Tong, J. Samuel, C. Clarke
Journal: Journal of Clinical Oncology (2004)

721 Background: BCS with radiation and MRM are equally effective treatments for operable early stage breast cancer. However, a proportion of women shows displeasure after the treatment due to various reasons. This study evaluates the reason for their discontent. Method: Retrospective analyses of 92 patients diagnosed with early stage operable breast cancer, who have completed their primary local treatment to the breast, were asked about their satisfaction regarding their local treatment process and the result. Result: 70 patients studied were postmenopausal and 22 patients were premenopausal. BCS was done in 56 patients and MRM in 36. 93% of BCS patients did not recollect the in-depth discussion of treatment options, subsequent chemotherapy, radiation process and follow-up, before the definitive local treatment. 70% of patients were satisfied with the results and 30% were not satisfied with the process and outcome. The reasons for dissatisfaction were: continued breast pain, radiation changes in the breast, inconvenience of the daily radiation, local recurrence in spite of the lumpectomy and unacceptable cosmetic results. 15 of the dissatisfied patients were postmenopausal and mostly over the age of 60. 92% of patients who had MRM remembered the discussion about the surgical options and 94% were satisfied about the decision and final outcome. Conclusion: Survival has been shown to be equal regardless of the choice of the surgical options, BCS or MRM, in appropriate breast cancer patients. However inconvenience of daily radiation, treatment-related morbidity, and continued local recurrence do exist in patients undergoing limited surgery. This creates significant inconvenience to elderly patients who also have co-morbid condition like arthritis, respiratory and cardiovascular diseases. Hence surgical decisions has to be made after the patient has had a detailed discussion with all involved sub-specialties like radiation and medical oncology, to avoid patient dissatisfaction in the treatment out-come. No significant financial relationships to disclose.
Efficacy and tolerability of pregabalin in the management of pain associated with administration of high-dose imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia (CML)
Authors: F. Iuliano, M. Di Maio, S. Infusino, A. Perricelli, A. Pomillo, S. Molica, D. Cilloni, G. Saglio
Journal: Journal of Clinical Oncology (2008)

18007 Background: Recently published data suggest that high doses of imatinib mesylate (IHD) (800 mg/daily) may be more effective than standard dose (400 mg/daily) in newly diagnosed Philadelphia chromosome-positive chronic phase CML. Furthermore escalating the dose of imatinib to 800 mg per day can overcome some cases of resistance to imatinib but tolerability of high-dose imatinib continues to be an issue. Aim of this study was to evaluate the efficacy and safety of pregabalin dosed twice daily (BID) for relief of musculoskletal and neuropathic pain associated with IHD. Methods: 13 patients in chronic phase (CP) were enrolled because complained of severe, persistent pain, requiring nonoppioid analgesics. Patients were asked to quantify their pain using a visual analogue scale (VAS) (numeric range 0–10). QoL assessment was based on Therapy Impact Questionnaire. Pts received pregabalin in doses ranging from 75 to 300 mg twice daily for 12 weeks. Results: At baseline, the median pain-rate was 5 (range 3–8). Despite a short study duration, a significant reduction was seen in weekly pain score (p < 0.0001), as well as VAS score (p < 0.0001). This allowed pts to receive the scheduled dose of imatinib. Pregabalin was well tolerated, and the most common adverse event was only somnolence. The short study duration precluded the assessment of longer term safety issues such as weight gain. Conclusions: Pregabalin was safe and effective in decreasing pain associated with high dose of imatinib, and also improved mood, sleep disturbance, and quality of life. No significant financial relationships to disclose.
Artificial intelligence, system analysis and simulation modeling in prediction of gastric cancer patients survivial after complete combined gastrectomies
Authors: O. Kshivets
Journal: Journal of Clinical Oncology (2005)

4246 Background: Predictors of poor outcome for gastric cancer patients (GCP) with pathologic stage II-IV (T2–4N0–3G1–3M0) after complete combined gastrectomies (CG) were investigated. Methods: In trial (1975–2004) survival of consecutive 127 GCP after CG with resection 1–5 adjacent organs (age=56.6±0.8 years; m=87, f=40; distal CG=54, proximal CG=31, total CG=42; D2 lymphnodedissection=82, D3=45; resection of diaphragm=26, esophagus=65, liver=13, mesocolon=42, duodenum=33, colon transversum=28, pancreas=31, splenectomy=39, cholecystectomy=11, nephrectomy=3, hysterectomy=2; tumor size=7.6±0.3 cm; st II=6, st III=85; st IV=36; intestinal adenocarcinoma=88, diffuse=38, mixed=1; T2=16, T3=26, T4=85; N0=61, N1=16, N2=44, N3=6; G1=29, G2=20, G3=78) was analyzed. Survival curves were estimated by the Kaplan-Meier method. Differences in curves between groups of GCP were evaluated using a log-rank test. Cox regression, clustering, discriminant analysis, structural equation modeling, Monte Carlo, bootstrap simulation and neural networks computing were used to determine any significant overall regularity. Results: General life span was 1713.2±179.7 days (median=816). 56 GCP (44.1%) were alive, 39 from them lived more than 5 years (30.7%) and 17 - more than 10 years (13.4%) without any features of progressing. 88 GCP (69.3%) died because of relapses and generalization during the first 5 years after CG. Cox modeling displayed that 5-year survival of GCP (n=127) after CG significantly depended on: N0–3 (P=0.010), age (P=0.015), tumor growth (P=0.026), character of CG (P=0.044), localization (P=0.002). Neural networks computing, genetic algorithm selection and bootstrap simulation revealed relationships between 5-year survival of GCP and sex (rank=1), procedure type (2), N0–3 (3), localization (4), resection of adjacent organ (5), tumor growth (6), T2–4 (7), tumor size (8), age (9), weight (10). Conclusions: Correct prediction of GCP survival after combined procedures was 71.7% by discriminant analysis and logistic regression (odds ratio=5.75) and 100% by neural networks computing (area under ROC curve=1.0; error=0.0065). No significant financial relationships to disclose.
Using hapmap tools to predict oncology-related phenotypes: TPMT activity vs hapmap SNPs
Authors: T. Jones, W. Yang, W. Evans, M. Relling
Journal: Journal of Clinical Oncology (2006)

13035 Background: Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme responsible for the S-methylation of thiopurines. There are several functional genetic polymorphisms in TPMT activity, which can lead to drug toxicities; however, among individuals with high TPMT activity, a substantial portion of enzymatic variability remains unexplained. B-lymphoblastoid CEPH cell lines have been genotyped at over 2 million single nucleotide polymorphisms (SNPs) as part of the International HapMap project. Therefore, extensive phenotype-genotype association studies can be conducted in these cell lines by systematic determination of cancer-related phenotypes. Methods: We measured the phenotype of TPMT activity in 82 CEPH cell lines. Of these, 53 had expression data available on over 8000 genes from Affymetrix Focus Array technology. We evaluated whether TPMT activity was associated with HapMap SNPs in TPMT (cis SNPs), genome-wide HapMap SNPs (trans SNPs), and level of gene expression using Kruskal-Wallis test and Spearmans rank correlation. Results: We found associations of TPMT activity with four SNPs (p &lt; 0.05) in TPMT (± 100K bp), one of which (rs1142345, p = 0.009) is a known functional SNP responsible for TPMT deficiency. Two other significant SNPs are in linkage disequilibrium with rs1142345. Associations were also found with 1598 trans SNPs across the genome (p &lt; 0.001). TPMT activity was associated with the expression of eight genes (p &lt; 0.0001, FDR &lt;20%). The only overlapping trans gene is PACSIN2, whose expression most significantly correlated with TPMT activity and also contains two significantly predictive trans SNPs. Conclusions: The CEPH cell lines were useful in that a known functional variant, rs1142345, (serving as a positive control) was associated with TPMT activity, and that additional polymorphisms in TPMT and in potentially important trans-acting factors have been identified as possible additional genomic determinants of TPMT activity. Similar experiments with other phenotypes can likewise capitalize on this publicly available resource. With further validation, these studies may lead to discovery of additional candidate polymorphisms that can lead to further optimization of thiopurine therapy in the clinic. No significant financial relationships to disclose.
Dynamic susceptibility contrast MRI measures of relative cerebral blood volume continue to show promise as an early response marker in the setting of bevacizumab treatment
Authors: Jerrold L. Boxerman, Kathleen M. Schmainda, Zheng Zhang, Daniel P. Barboriak
Journal: Neuro-Oncology (2015)

We read with interest Whitney Pope's recent editorial1 in Neuro-Oncology on the paper by Kickingereder et al2 addressing the utility of relative cerebral blood volume (rCBV) derived from susceptibility-contrast perfusion-weighted MRI for determining therapeutic response in bevacizumab-treated recurrent glioblastoma multiforme (GBM). Kickingereder and Pope contend that although pretreatment rCBV may be a predictive marker of overall survival (OS), there is no evidence supporting post-bevacizumab change in rCBV from baseline as an early response marker. We caution against premature dismissal of rCBV change as an early predictor of treatment response.
Hypokalemia among patients receiving capecitabine (CAP) for GI malignancies
Authors: M. Fekrazad, R. H. Lyerly, M. W. Saif
Journal: Journal of Clinical Oncology (2005)

8132 Background: Most common toxicities of CAP include diarrhea, nausea, vomiting, and HFS. Hypokalemia has not been reported frequently with CAP. We performed a retrospective study to determine incidence, risk factors, complications and management of hypokalemia in pts receiving CAP. Methods: We identified 63 pts who received CAP b/w Apr 2002 and Nov 2004. Hypokalemia was defined as K+ level < 3.2 mEq/L. Exclusion criteria included presence of vomiting or diarrhea, concomitant use of diuretics or antibiotics (PCN, Gent, Amph), hypomagnesemia, h/o hypokalemia prior CAP, renal insufficiency, thyroid or adrenal dysfunction and diabetic nephropathy. Pts were classified into 3 groups based on K+ levels: mild (3.0–3.2 mEq/L), moderate (2.5- 2.9 mEq/L) and severe (< 2.5 mEq/L). Results: Among 63 pts (age: 32–89 yr; M/F: 33/30), 54 met the criteria. Diagnoses included: 31 pancreas, 19 colon, 3 liver and 1 stomach cancer. 5 pts (9%) received CAP alone, 15 (28%) with XRT and 34 (63%) with oxaliplatin or CPT-11. Dose of CAP ranged b/w 1000 - 2000 mg/m2. Diagnosis of hypokalemia occurred after an average of 84 days of CAP administration. Overall, 11 pts (20%) developed hypokalemia. According to classification: 8 (73%) had mild, 2 (18%) moderate and 1 (9%) severe. No cardiac or neuromuscular complications noticed. Replacement of K+ was required in 6 pts (11%) (2 IV, 4 oral). Continued replacement > 4 wks was required in 2 pts (4%). No pt had to stop CAP due to hypokalemia. One pt (2%) had persistent hypokalemia (> 4 wks) after stopping CAP. Normalization of K+ levels was achieved in 91% of pts. Four pts (7%) were on K+ sparing diuretics for ascites and never developed hypokalemia. No correlation in creatinine and hypokalemia noticed. Mean urine K+ was 28 mEq/L suggesting renal loss. Conclusions: Hypokalemia was encountered in 20% of pts on CAP without any obvious etiology. The incidence of hypokalemia might be higher as few pts were on K+ sparing diuretics. Since regulation of K+ homeostasis depends on normal renal function, we postulate that hypokalemia may be related to the effect of CAP on renal tubules. Due to potential complications, hypokalemia in pts on CAP deserves special diagnostic and therapeutic attentions. Further analysis to characterize the mechanism is needed. No significant financial relationships to disclose.
Long-term clinical results of the combination of cisplatin (C), vinblastine (V), DTIC (D) and interferon-alfa (I) with or without tamoxifen (T) for metastatic melanoma
Authors: A. M. Sanguino, A. Y. Bedikian, S. S. Legha, M. A. Detry, N. E. Papadopoulos, P. Hwu, W. Hwu, K. B. Kim
Journal: Journal of Clinical Oncology (2006)

8039 Background: According to 2001 AJCC data, 1-yr, 2-yr, 5-yr, and 10-yr survival of melanoma patients (pts) with stage M1c were 40.6%, 23.6%, 9.5% and 6.0%, respectively. Previously, we reported the interim results of a randomized phase II trial comparing the response rates (RR) of CVDI vs. CVDI +T. Here we report long-term survival results of these pts. Methods: Chemo-naïve pts between 16 and 75 yrs of age, with histologically documented diagnosis of advanced melanoma and without symptomatic brain metastasis, were randomized to receive either CVDI (group A) or CVDI+T (group B). The dose of each drug is as follows: C 15 mg/m 2 IV (d 2–5), V 1.2 mg/m 2 IV (d 1–5), D 600 mg/m 2 IV (d 1), I 5 MU/m 2 SQ 3 times a wk and T 20 mg twice a day. The treatment was administered every 3–4 wks. After the interim analysis, the arm with a higher RR was selected for an expansion cohort (group C). The primary endpoint was the RR of CVDI regimen with or without T. The secondary endpoint was overall survival (OS) evaluation. Results: A total of 104 pts were enrolled, among which 36 and 34 were randomized to group A and B, respectively. After interim analysis of 70 pts, the CVDI regimen was selected for group C. There were no significant differences in both RR (p= 0.126) and OS (p= 0.095) between group A and B. When all 104 pt data were combined, the overall response rate (ORR) was 37.5% with a complete response rate (CRR) of 8.7% and the median survival of 10.4 months. One-yr, 2-yr, 5-yr, and 10-yr OS were 43%, 20%, 7% and 4%, respectively. Conclusions: Although the combination of CVDI with or without T is an active regimen for treatment for metastatic melanoma, long-term survival of pts receiving this regimen is similar to historical controls. [Table: see text] No significant financial relationships to disclose.
A randomized phase I study of the humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody EMD 72000 in subjects with advanced gastrointestinal cancers
Authors: T. Trarbach, T. Beyer, N. Schleucher, J. Stattaus, S. P. Mueller, D. Appel, J. Tillner, K. W. Schmid, S. Seeber, U. Vanhoefer
Journal: Journal of Clinical Oncology (2004)

3018 Background: Growth factor signaling through EGFR drives tumor proliferation, motility, angiogenic stimulation, and protects the cells from stress induced apoptosis. EMD 72000 is a humanized monoclonal anti-EGFR IgG1 antibody that blocks ligand binding, EGFR signaling, induces receptor downregulation, and potentially participates in antibody-dependent cell-mediated tumor cell killing. Methods: A phase I study was conducted to assess the safety and anti-tumor activity of EMD 72000 in 24 patients with advanced refractory gastrointestinal tumors. Antitumor activity was assessed using CT and 18FDG PET dual-modality tomography. Subjects were randomized in groups of 6 to receive absolute doses of 100, 200, 400, or 800 mg EMD 72000 weekly for 4 wks followed by treatment with 400 mg per wk until disease progression. EMD 72000 was administered by 1-hr IV infusion without routine premedication. CT and 18FDG PET images were obtained before treatment and in wks 4 and 8. Skin and tumor biopsies were obtained before treatment and at wks 4 (skin only) and 8. Blood samples for pharmacokinetics were obtained weekly for 8 wks. Results: Patient population: 21 colorectal, 2 cholangiocellular, and 1 gastric cancer; median age was 58 (range 29–70) years with a median of 3 prior chemotherapy protocols (range 0–6) and 2 sites of metastatic disease (range 1–4). Tumors were EGFR+ by immunohistochemistry. No NCI-CTC grade 3 or 4 drug-related toxicities were observed; grade 1/2 skin reaction was seen in > 80% of subjects with doses ≥ 200 mg. Assessment of metabolic response by PET-CT using EORTC criteria in 18 patients after 4 wks on study showed 1 CR (800 mg), 6 PR (2 each at 400 and 800 mg, 1 each at 100 and 200 mg), and 9 SD. One patient who did not show 18FDG uptake at baseline achieved a CR during follow up with magnetic resonance imaging. Median time to progression was 13 wks. Conclusions: In this study administration of EMD 72000 was associated with no grade 3 or 4 toxicities. Preliminary evidence of metabolic response by PET and antitumor activity by CT and MRI was seen in heavily pretreated subjects with gastrointestinal cancers. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck KGaA, Darmstadt, Germany Merck KGaA, Darmstadt, Germany