tbuckley/cabot-search huggingface dataset:
CyberKnife concomitant with neoadjuvant chemotherapy for breast tumor: Phase I.
Authors: P. Bondiau, J. Ferrero, P. Bahadoran, I. Raoust, B. Flipo, M. Lallement, I. Peyrottes, C. Chapellier, E. Chamorey, A. Courdi
Journal: Journal of Clinical Oncology (2010)

e11032 Background: Robotic stereotactic radioablation (RSR) by CyberKnife has never been used for breast tumors and may have a real potential. We conducted a phase I study, including neoadjuvant chemotherapy, with a 4-level dose-escalation study (19.5 Gy, 22.5 Gy, 25.5 Gy, 28.5 Gy in 3 fractions) using RSR, and breast-conserving surgery followed by conventional radiotherapy. Neoadjuvant chemotherapy consist of anthracyclines plus taxanes sequential (NACT). We propose this protocol if tumor/breast ratio does not allow a conservative treatment. Major objective: defines the maximal tolerated dose to find recommended dose. Minor objectives: results of RT-CT on the number of sterilized histological exams, evaluation of the quality of surgical resection, evaluation of quality of life. Methods: For each patient, we performed 4 clinical dermatologic examinations by two independent observers; before the neoadjuvant chemotherapy treatment onset, after RSR irradiation, after 3 cures of neoadjuvant chemotherapy, and prior to surgery. Surgery was performed 4 to 8 weeks after the last chemotherapy session, the evaluation of surgery quality is made by 3 different surgeons. A pathologic examination was also performed. Complication are noticed. Quality of life is made with QLQ C30 B33. Results: 14 patients have been included is this study. We noticed one grade III skin toxicity at level IV (28.5 Gy in 3 fractions). The conservative surgery rate is 93%, the clinical complete response rate is 85% and the complete histological response rate is 35%. Maximum tolerable dose was not reached. All patients tolerated RSR with no fatigue, postoperative irradiation (50 Gy) has been delivered without toxicity. Conclusions: The study showed the feasibility of irradiation with RSR combined with chemotherapy and surgery for breast tumors. We noticed one grade III skin toxicity at a dose of 28.5 Gy delivered in 3 fractions combined with chemotherapy. The surgical morbidity was not increased. Pathologic response was acceptable. Patient enrolment is currently underway for further escalation of the neoadjuvant RSR irradiation dose. No significant financial relationships to disclose.
Pharmacogenetic analysis of interindividual irinotecan (CPT-11) pharmacokinetic (PK) variability: Evidence for a functional variant of <i>ABCC2</i>
Authors: F. Innocenti, S. D. Undevia, P. X. Chen, S. Das, J. Ramirez, M. E. Dolan, M. V. Relling, D. L. Kroetz, M. J. Ratain
Journal: Journal of Clinical Oncology (2004)

2010 Background: CPT-11 is oxidized to inactivated metabolites (including APC) by CYP3A enzymes and activated to SN-38 by carboxylesterase-2 (CES-2). SN-38 is inactivated to it glucuronide (SN-38G) by UGT1A1 and UGT1A9. Other enzymes and ABC transporters are involved in pathways of CPT-11 disposition. We had previously measured the plasma PK of patients treated with CPT-11 and analyzed the correlation with UGT1A1 variants. This study aims to generate hypotheses regarding the phenotypic effects of variation in other drug metabolizing and transporter genes. Methods: CPT-11, SN-38, and SN-38G AUCs were measured after a 350 mg/m2 IV dose in 64 adults with refractory solid tumors as part of a pharmacogenetic study. Genotyping of common variants (q>0.10) was performed for the following genes (number of variants in parenthesis): CES-2 (n=2), ABCC1 (n=7), ABCC2 (n=6), and ABCB1 (n=8). CYP3A4*1B, CYP3A5*3, UGT1A9 -11810T/9T and HNF1 79A>C were also typed. Results: The synonymous 3972T>C variant in ABCC2 was correlated with CPT-11 AUC (p=0.02), APC AUC (p<0.0001) and APC/CPT-11 AUC ratios (p<0.0001, ANOVA). For SN-38 and SN-38G AUC, the correlation with 3972T>C was analyzed in the subset of patients with 6/6 and 6/7 UGT1A1 genotype (n=54) to minimize the confounding effect of 7/7. SN-38G and SN-38G/SN-38 AUC ratios were correlated with 3972T>C (p≤0.001, ANOVA). No significant correlation was observed between SN-38 AUC and 3972T>C (p=0.9). Other gene variants showed either no or borderline statistical significance in the ANOVA test. The TT 3972 genotype was associated with higher AUC of CPT-11 (p=0.02), APC and SN-38G (both p<0.0001, t test) compared to CT+CC patients. The frequencies of CC, CT, and TT genotypes were 0.44, 0.44, and 0.13, respectively. Conclusions: This study identifies 3972T>C as a variant potentially affecting ABCC2 activity and suggests that ABCC2 may have a significant impact on CPT-11 clearance. These results also suggest that APC may be a substrate for ABCC2. The phenotypic effect of 3972T>C was previously unknown and further studies will test its biological function and clinical relevance. No significant financial relationships to disclose.
Novel evaluation of targeted receptor internalization as a predictive tool for HER2/EGFR antibody-based therapeutics
Authors: V. Kallab, C. Benz, D. Kirpotin, J. Marks, J. Park
Journal: Journal of Clinical Oncology (2004)

3157 Background: Receptor-tyrosine kinase (RTK) internalization is a key event in signaling and a requisite event for certain RTK-targeted therapeutics. Endocytosis is the hallmark of trastuzumab and immunoliposomes (ILs) efficacy. To provide a biomarker of ErbB internalization, we developed a quantitative assay of HER2 and EGFR endocytosis triggered by specific probes. Methods: scFv against HER2 (F5) or EGFR (C10) were linked to nickel-containing and fluorescence-labeled liposomes to generate ErbB-targeted immunoliposome probes (ILs-fluor). After incubation with ILs-fluor (2h, 37C), tumor cells were washed +/-EDTA to dissociate scFv from liposomes; this allows FACS-based quantitation of internalized ILs-fluor (EDTA-insensitive fraction) vs. cell-surface bound scFv (EDTA-sensitive). Results: Assay was validated against a panel of cell lines, and was highly specific (HER2- or EGFR-specific vs. irrelevant MAb) and sensitive (internalization measurable at very low HER2/EGFR content). In trastuzumab-sensitive BT474, SKBr3, AU565, HER2 was efficiently internalized by anti-HER2 ILs-fluor: mean total uptake=1713 fluorescence units, internalized=957 (55%). HER2-overexpressing but trastuzumab-resistant SKOV3 cells showed only 35% internalization. Low HER2-expressing cells (MCF7, MB468) showed minimal uptake (105) and internalization (5%). Internalization of anti-EGFR ILs-fluor in EGFR-overexpressing MB468 cells was 92%, with only 19% in control cells. FACS analysis of cell suspensions of xenografts (BT474, MB468) and primary breast tumors showed high ErB uptake of ILs-fluor in ErB/EpCAM (+) epithelial cells, while minimal internalization was seen in ErB/EpCAM (-) stromal cells. Conclusions: This novel assay allows quantitative assessment of HER2/EGFR internalization in complex cell populations, and may predict response to ErbB-targeted therapies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hermes Hermes Hermes
Abstract 14298: Circulating miRNA Transport Modality is Altered in Subjects with CHD with Implications for Endothelial Cell microRNA Uptake
Authors: Nnenna A Finn, Danny Eapen, Pankaj Manocha, Arshed Quyyumi, Charles D Searles
Journal: Circulation (2012)

MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression. The discovery of extracellular, circulating miRNAs and the finding that circulating miRNAs can be taken up by recipient cells, suggests an additional role for these molecules in mediating intercellular signaling events. Distinct transport modalities for circulating miRNAs govern the ability of extracellular miRNAs to be taken up by recipient cells with subsequent impact on cell function. We hypothesized that a homeostatic circulating miRNA transport profile exists in healthy subjects and that CHD is associated with an alteration to this profile which, in turn, impacts miRNA uptake. We analyzed the extracellular transport modalities of 8 miRNAs whose circulating levels are known to be altered in CHD: miR-17, -19a, -21, -92a, -126, -146a, -222, -223. Using an ultracentrifugation technique, sera from healthy subjects and subjects with significant CHD (n = 20 per group) were separated into apoptotic bodies/microvesicles, exosomes, aggregate...
Phase II trial of adjuvant gemcitabine plus cisplatin (GC) with amifostine cytoprotection in patients (pts) with locally advanced bladder cancer (BC)
Authors: J. O. Jin, J. Lehmann, M. Stockle, G. Steinberg, W. Stadler
Journal: Journal of Clinical Oncology (2005)

4695 Background: Despite the general acceptance of GC in metastatic BC its role in the adjuvant setting is unclear. Also, mild renal insufficiency is common in these pts. We thus performed a phase II pilot and toxicity study of GC with amifostine cytoprotection in pts with locally advanced BC after radical cystectomy. Methods: Eligibility included locally advanced transitional cell carcinoma (T2-T4, N0-N2) at least 4 but no more than 12 weeks following cystectomy, performance status 0–2, and normal organ function defined as creatinine ≤2.0 mg/dL, Hgb ≥9.0 mg/dL, WBC ≥3, 500/ul, platelets ≥100,000/ul, and bilirubin < 2 times the upper limit of normal. Chemotherapy consisted of 4 cycles of gemcitabine 1000g/m2 (Days 1, 8 and 15), cisplatin 70 mg/m2 (Day 1) and amifostine 910 mg/m2 (Day 1, immediately preceding cisplatin) of each 28-day cycle. All toxicities were evaluated by World Health Organization criteria. Tumor samples were immunohistochemically stained for pRB, p53 and p16. Results: Between 1998 and 2004, 39 pts were enrolled. Baseline characteristics included median age 63 (42–84), M/F (25/14), 11 T3N0, 4 T4N0, 1 T4Nx, 23 N+, and median creatinine 0.9 mg/dL (0.4–1.8mg/dL). 36 (92%) completed 4 cycles of chemotherapy with 3 patients withdrawing early due to toxicities. Thirteen patients (33%) had grade 3 or 4 hematological toxicity. Fourteen patients (36%) had grade 3 non-hematological toxicity. The median increase in creatinine was 0.3 mg/dL and 5 developed grade 2 elevations. Median follow-up was 22.6 months (5 to 72 months). Twelve patients (31%) had recurrent disease, one 6 years after completion of therapy. Eleven patients (28%) died, including 9 with recurrent disease. Evaluation of tumor samples for pRB, p53 and p16 alterations is in progress. Conclusions: GC with amifostine is tolerated in the adjuvant setting for the patients with locally advanced bladder cancer. Its role and the value of amifostine require randomized studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly
Brief Communication: Tumor Induction by Moloney Sarcoma Virus in Athymic Nude Mice2
Authors: Erik De Clercq
Journal: JNCI Journal of the National Cancer Institute (1975)

Athymic nude (nu/nu) mice, normal NMRI (plus/plus) mice, and nu/plus heterozygotes, inoculated at birth with the Moloney strain of murine sarcoma virus (M-MSV), did not differ either in tumor growth rate or incidence or in mortality due to tumor development; neither did nude (nu/nu) and normal NMRI mice inoculated with M-MSV at 30 days of age differ in the initial tumor growth rate. However, tumors induced in adult nude mice grew progressively and eventually killed the hosts, whereas tumors induced in adult normal NMRI mice completely regressed. These results indicated that thymus-dependent immunity, though not active in M-MSV tumor induction, determined whether the tumor, once formed, would regress or kill the host.
Biomarker potential of EGFR gene copy number by FISH in the phase III EXTREME study: Platinum-based CT plus cetuximab in first-line R/M SCCHN
Authors: L. Licitra, F. Rolland, C. Bokemeyer, E. Remenar, H. Kienzer, S. Stoerkel, S. Scheid, C. Stroh, R. Mesia
Journal: Journal of Clinical Oncology (2009)

6005 Background: Platinum-based CT + cetuximab is the first systemic therapy in ∼30 years to show a survival benefit vs platinum-based CT in first-line R/M SCCHN (Vermorken JB, et al. N Engl J Med 2008;359:1116–1127). A retrospective analysis has evaluated the influence of EGFR gene copy number, determined by FISH, on clinical outcome in the EXTREME study. Methods: Pts were randomized to 3-weekly cycles of platinum-based CT (cisplatin 100 mg/m 2 or carboplatin AUC 5, day 1; 5-fluorouracil 1000 mg/m 2 /day continuous infusion, days 1–4) with or without cetuximab (initial dose 400 mg/m 2 , then 250 mg/m 2 weekly). The proportion of FISH+ cells per pt (FISH score) was determined using 5 different enrichment models. Tumors were also classified as FISH+ or FISH- using the Colorado scoring system. Results: In the overall population (n=442), addition of cetuximab significantly improved median OS (10.1 vs 7.4 months; p=0.04). No association between FISH score and OS, PFS, or best overall response was determined for any enrichment model. Pts with Colorado FISH+ tumors were evenly distributed between the CT + cetuximab (50/158) and CT-alone (51/154) arms of the FISH- evaluable population (71% of ITT population). Colorado FISH status had no influence on OS in either treatment arm, on PFS in the CT-alone arm, or on RR in the CT + cetuximab arm (see table ). In the CT + cetuximab arm, pts with FISH+ tumors had a lower risk of progression than pts with FISH- tumors. Higher RRs among pts with FISH- tumors in the CT-alone arm may have been due to twice as many nonevaluable response observations in the FISH+ vs the FISH- population (percentage of pts with SD or PD was comparable). Conclusions: EGFR gene copy number, as determined by FISH, is not a predictive biomarker for cetuximab efficacy in R/M SCCHN. [Table: see text] [Table: see text]
The combination of oxaliplatin, fludarabine (FLU), cytarabine (Ara-c), and rituximab (R) (OFAR) in patients with Richter’s Transformation and FLU-refractory CLL
Authors: W. Wierda, A. Tsimberidou, S. O’Brien, A. Ferrajoli, S. Faderl, F. Ravandi, J. Cortes, H. Kantarjian, W. Plunkett, M. Keating
Journal: Journal of Clinical Oncology (2006)

6608 Background: Patients with (FLU-ref) CLL and Richter’s transformation (RT) have a very poor prognosis. Oxaliplatin (OX), a platinum analog with a 1,2-diaminocyclohexamine carrier ligand, has a different activity and side effect profile from cisplatin. OX covalently binds DNA, inducing DNA intra- and inter-strand cross-links. FLU and Ara-c act synergistically to inhibit excision-repair of DNA cross-links, thereby providing the rationale for combining OX, FLU, Ara-c, and R (OFAR). Methods: The phase I portion of a phase I/II study of the OFAR regimen had increasing doses of OX. The OFAR regimen consists of OX 17.5, 20, or 25mg/m 2 , d1–4; fludarabine 30mg/m 2 , d2,3; Ara-c 1gm/m 2 , d2,3; and rituximab 375mg/m 2 , d3. Courses were given every 4 wks; patients received Neulasta 6mg each course and prophylaxis for tumor lysis, DNA virus’, and PCP. Results: 19 patients enrolled in phase I; 1 received no treatment, 8 had RT, and 10 had FLU-ref CLL. Patients received OX 17.5mg/m 2 (3), 20mg/m 2 (8), or 25mg/m 2 (7). Patients receiving at least 1 course were evaluable for toxicity and could receive up to 6 courses. There were no dose-limiting toxicities, defined as any ≥ G3, non-hematologic, treatment-related toxicity. The major toxicity was hematologic and appeared OX-dose dependent. Neutropenia (G3–4) was experienced by 1/3, 6/8, and 7/7 patients treated at 17.5, 20, and 25mg/m 2 OX levels, respectively. Thrombocytopenia (G3–4) was experienced by 2/3, 8/8, and 7/7 of patients treated at 17.5, 20, and 25mg/m 2 m OX levels, respectively. There were no treatment-related deaths. Five patients continue treatment on the phase I portion, and results will be evaluable, with 3 responders, including 2 complete, in the 7 evaluable patients with RT. Among the 10 FLU-ref patients, there are 5 PRs; treatment continues for 3 of them. Pharmacodynamic analyses demonstrate enhanced killing by OX in the presence of FLU and Ara-c. Conclusions: The OFAR regimen is safe and active for treating patients with RT and FLU-ref CLL. This trial continues to accrue patients to confirm efficacy. No significant financial relationships to disclose.
Time, a Phase 2B/3 Study Evaluating Tg4010 in Combination with First Line Therapy in Advanced Non Small Cell Lung Cancer (Nsclc). Phase 2B Results
Authors: E. Quoix, G. Losonczy, F. Forget, C. Chouaid, Z. Papai, R. Gervais, C. Ottensmeier, A. Szczesna, A. Kazarnowicz, J.T. Beck, V. Westeel, E. Felip, D. Debieuvre, A. Madroszyk, G. Lacoste, A. Tavernaro, B. Bastien, T. Palanche, J. Limacher, H. Lena
Journal: Annals of Oncology (2014)
ELECT: A phase 3 study of efficacy and safety of lanreotide autogel/depot (LAN) treatment for carcinoid syndrome in patients with neuroendocrine tumors (NETs).
Authors: Aaron Vinik, Edward M. Wolin, Helene Audry, Edda L. Gomez-Panzani
Journal: Journal of Clinical Oncology (2014)

268 Background: Somatostatin analogs (SSAs) are the mainstay treatment for carcinoid syndrome. LAN is a long-acting SSA approved for this indication in &gt;50 countries, but not yet in the US. ELECT is a large multinational phase 3 study evaluating rescue therapy use as a novel alternate endpoint for carcinoid symptom control with LAN. Methods: Eligible patients were age ≥ 18 years with histologically-confirmed NET and a history of carcinoid syndrome, and naïve to SSA treatment or responsive to conventional doses of octreotide LAR (≤ 30 mg/4 weeks) or short acting (≤ 600 µg/day SC). Design: a 16-week, randomized (LAN 120 mg [n=59] vs placebo [n=56] every 4 weeks) double-blind phase, followed by a 32-week long-term open label phase on LAN. Patients had access to short acting octreotide as rescue for breakthrough symptoms throughout the study. Primary endpoint: % of days the patient used rescue octreotide during the double-blind phase. The study was designed to have 90% power to detect a treatment difference of 30%. NCT00774930. Results: Among thestudy population, 83 (72%) had symptoms for ≥ 1 year, and51 (44%)had no prior SSA therapy. Mean [95% CI] % of days with rescue medication use was statistically lower with LAN (34% [25, 42%]) vs placebo (49% [40, 57%]), absolute difference –15% [–27, –3%], p=0.02; however, the pre-defined difference was not met. Complete/partial success (≤3 days use) rather than failure (&gt; 3 days use) was more likely with LAN than placebo (OR 2.4 [95% CI 1.1, 5.3]; p=0.04). Treatment emergent AEs: 15 (26%) LAN patients vs 11 (19%) placebo patients; few AEs were serious (2 [3%] vs 5 [9%]) or led to study withdrawal (1 [2%] vs 1 [2%]). Most frequent AEs were GI disorders, 9 (16%) on LAN vs 5 (9%) on placebo. Conclusions: In the ELECT study, LAN significantly reduced need for short acting SSA use with a favorable safety/tolerability profile. This confirms LAN’s positive benefit-risk profile, which is consistent with experience from previous trials and many years of clinical practice in many countries around the world. Clinical trial information: NCT00774930.
원저 : 알코올성 및 바이러스성 간경변증 환자들의 영양 상태
Authors: 이석화(Seok Hwa Lee), 진윤경(Yoon Kyung Jin), 기춘석(Choon Suhk Kee), 장유경(Yu Kyung Chang)
Journal: Clinical and Molecular Hepatology (2000)

Aims : The purpose of this study was to explore the differences of general characteristics and nutritional factors such as anthropometry and dietary intake between alcohol-related cirrhosis and virus-related liver cirrhosis and to assess the nutritional status of both of these groups. Methods : In this study, the nutritional status of 67 patients with liver cirrhosis (25 with alcohol-related and 42 with virus-related) was evaluated by using clinical assessment, anthropometric measurements, dietary intakes, and biochemical indices. Results : Although anthropometric measurements were not significantly different between alcoholic cirrhosis and viral cirrhosis, anthropometry of patients with viral cirrhosis had a higher tendency than that of alcoholic cirrhotic patients. Alcohol intake factors such as amount, duration, and frequency in alcoholic cirrhotic patients were higher than those in patients with viral cirrhosis. Energy excluding alcohol and vitamin C were significantly different between patients with alcoholic and viral cirrhosis. All subjects had lower intake of energy excluding alcohol, protein, vitamin A, thiamin, riboflavin, niacin, calcium, and iron as than recommended by the Recommended Dietary Allowances (RDA) for Koreans. Of special note was the fact that the intakes of energy excluding alcohol, vitamin A, riboflavin, and calcium were less than 75% of RDA for Koreans. Although the glucose and triglyceride levels were significantly different between alcoholic and viral cirrhotic patients, there were within normal range in both groups. There was an interaction effect in triceps skinfold thickness of the subjects according to both etiology and severity of liver disease. Conclusion : These data suggests that nutritional disorders are common in patients with both alcohol-and virus-related cirrhosis. It is necessary to educate patients with cirrhosis about the importance of a balanced dietary intake as well as its pattern, and quality of diet. (Korean J Hepatol 2000;6:59-72)
Correlation of Src activation with epithelial-mesenchymal transformation and aggressive features of head and neck squamous carcinoma
Authors: A. K. El-Naggar, S. M. Lippman, F. M. Johnson, M. Mandal, J. N. Myers, M. D. Williams, D. I. Rosenthal, R. S. Weber, G. Gallick
Journal: Journal of Clinical Oncology (2007)

6026 Background: The role of the epithelial-mesenchymal transition (EMT) is crucial to invasive and progression of several epithelial malignancies. The role of this process in head and neck squamous cell carcinoma (HNSCC) remains poorly defined. Methods: Eleven head and neck squamous cancer cell lines and 50 primary tumor specimens formed the materials for this study. We used Western blotting, immunohistochemistry, RT-PCR cell motility assay to determine the expression and the functional implications of several cell adhesions and singling molecular associated with EMT in these tumors. Results: Our results showed Src and E-Cadherin to be paradoxically overexpressed in the majority of cell lines and in primary tumor tissues relative to normal squamous mucosa. In both cell lines and tumor tissues elevation of activated Src was accompanied by down-regulation of E-Cadherin and vimentin detection. In-vitro inhibition of Src led to the increased E-Cadherin of expression and cell proliferation in squamous carcinoma cell lines. Immunophenotypic analysis of the protein products of these genes in primary tumor tissues demonstrated a spectrum of changes that correlated significantly with the differentiation, invasive patterns, sarcomatoid transformation and lymph node status. Our results show that high activated Src and low E-Cadherin expression were correlated with finger-like invasive pattern, poor differentiation, sarcomatoid transformation and lymph node metastasis in HNSC. Conclusions: Our study indicates that Src and E-Cadherin play a major role in EMT invasion and progression of head and neck squamous carcinoma. These proteins may be targeted in the therapeutic intervention of patients with HNSCC. No significant financial relationships to disclose.