tbuckley/cabot-search huggingface dataset:
Clinical management and outcome of childhood lung abscess (LA): A 15-year experience
Authors: Oleksander Katilov, Dmytro Dmytriiev, Oleksander Mazulov
Journal: European Respiratory Journal (2011)

In order to evaluate the clinical manifestations, management and outcome of childhood LA, a retrospective chart review of 35 pediatric with LA from Semtember 1995 to Semtember 2010 was conducted. Among the 37 patients (20 males and 15 females), 51, 4% (18/37) were primary lung abscess and 49,6% (17/35) had underlying chronic diseases (secondary lung abscess). The predisposing factors of the primary group (n = 18) included 16 cases of respiratory tract infection and 2 with laceration wound. The underlying diseases in the secondary group (n = 17) included 11 cases of hematologic disorder (64,7%), 4 of congenital heart disease, and 2 each of hyperimmunoglobulin E syndrome. 14 patients underwent diagnostic tapping, including echo-guided aspiration (11 cases) and computed tomography-guided percutaneous needle aspiration (2 case). Positive yield rate from aspiration of lung abscess was 50% (7/14). Surgical intervention was performed in 10 of the secondary group and in 1 patient from the primary group. The pathogens were identified in 17 patients (49,6%): 5 with oral flora, 4 with Staphylococcus aureus plus other pathogens, 1 with S. aureus alone, 2 with Pseudomonas aeruginosa plus Proteus mirabilis, 4 with P. aeruginosa alone, and 1 with Aspergillus. The average duration of parenteral antibiotic use was 20 days. 2 cases (5.4%) died due to poor control of the underlying diseases, and 4 of the patients (10,8%) had sequelae (3 with bronchiectasis and 1 with lung fibrosis). Early percutaneous aspiration has an important role in identification of pathogens. Oral anaerobes and S. aureus are the core pathogens in primary lung abscess and gram-negative pathogens should also be considered in secondary LA.
Changes in bone metabolism after 2 years’ treatment with exemestane (E) in postmenopausal women with early breast cancer (EBC) at low risk: Follow-up (FU) results of a randomized placebo-controlled study
Authors: P. E. Lonning, J. Geisler, L. E. Krag, L. Ottestad, T. Risberg, A. I. Hagen, E. Schlichting, E. Di Salle, A. Polli, J. Paolini
Journal: Journal of Clinical Oncology (2005)

531 Background: Aromatase inhibitors may increase bone loss. We reported (Proc Am Soc Clin Oncol 2004; 23:6, Abs 518) that a 2-year treatment with E (Aromasin), a steroidal aromatase inactivator, had a non-significant effect on annual rate of bone mineral density (BMD) loss in the lumbar spine (LS) and a small significant effect on the femoral neck (FN) as compared to placebo (P) in EBC patients (pts). E treatment induced a significant increase in all bone turnover markers. Methods: Randomized, double-blind study evaluating the effect of E (25 mg/day p.o.) or P on bone metabolism in 147 pts. BMD in the LS and the FN was measured by dual-absorptiometry before, during (at 6, 12 and 24 months) treatment and at 1-year FU after discontinuation. Bone resorption and formation markers were also assessed. Here we report results for the 57 pts on E and 64 pts on P evaluated for BMD up to 1-year FU. Results: At 1-year FU LS BMD loss in the E group improved as compared to end of treatment (mean % change from baseline at month 24 and 1-year FU: −3.59% and - 2.16%, t-test: p= 0.0003), albeit remaining greater than P (mean % change at 1-year FU: −1.61%). The effects seen in the FN BMD at the end of E therapy extended up to 1-year FU (mean % change at month 24 and 1-year FU: −4.42% and −4.28%, t-test: p= NS) and remained greater than P (mean % change at 1-year FU: −2.73%). Within 6 month of E withdrawal, bone resorption markers returned to or below baseline values and were not significantly different from P, while bone formation markers remained moderately increased. Conclusions: After E withdrawal, the LS BMD tended to normalize while the FN BMD loss stabilized; the effect on bone resorption but not on formation markers faded within 3–6 months after withdrawal. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pharmacia Italia S.p.A./ Pfizer Group AstraZeneca, Novartis, Pfizer
Erlotinib as 2nd and 3rd line monotherapy in patients with metastatic colorectal cancer. Results of a multicenter two-cohort phase II trial
Authors: U. Keilholz, D. Arnold, N. Niederle, W. Freier, R. Porschen, T. Hoehler, F. Lordick, S. Kubicka, E. Kettner, H.-J. Schmoll
Journal: Journal of Clinical Oncology (2005)

3575
Polymorphism in sodium-channel alpha 1-subunit (SCN1A) predicts response, TTP, survival, and toxicity in patients with metastatic colorectal cancer treated with 5-FU/oxaliplatin
Authors: F. Nagashima, W. Zhang, D. Yang, M. Gordon, A. Schultheis, W. Fazzone, M. Azuma, A. El-Khoueiry, S. Iqbal, H. J. Lenz
Journal: Journal of Clinical Oncology (2006)

3533 Background: Genetic polymorphisms in DNA repair and drug metabolism pathways have been shown to be associated with efficacy and toxicity in patients with metastatic colon cancer treated with 5-FU/oxaliplatin. Recent studies demonstrated in in vitro models that the neurotoxicity associated with oxaliplatin may be linked to an effect on neuronal voltage-gated sodium channels (VGSC). In vitro and in vivo models showed that increased VGSC alpha gene expression was associated with metastatic potential, proliferation and progression of breast and prostate cancer indicating a role in predicting toxicity and efficacy to chemotherapy. We tested the hypothesis whether VGSC gene polymorphisms may predict clinical outcome in a phase II study of combination oxaliplatin with 5-FU in patients with colorectal cancer refractory to 5-FU and/or irinotecan based chemotherapy. Methods: 173 patients were enrolled in this phase II study. 152 patients (male/female; 78/74, median age; 60), median follow up of 18.6 months, response rate of 19%, median time to tumor progression 4.2 months and median survival of 10.3 months. Grade 3/4 toxicity was seen in 60% with GI toxicity of 42% and Neurotoxicity of 11%. The dose of oxaliplatin was 130mg/m 2 every 3 weeks and 5-FU was 200mg/m 2 /day CI for 10 weeks followed by 2 weeks rest. We tested the 12 VGSC genes polymorphisms (SCN1A, 1B, 1A1, 1A2, 1A3, 1A4, 1A5, 1A A3169G SNP, 1A C1702T Nonsense Mutation, 1A T1067A SNP, 1A C3637T SNP, SCN8A Ref SNP 303802). Genomic DNA was extracted from peripheral blood samples and polymorphisms were analyzed by PCR-based RFLP technique. Results: Patients with SCN1A T1067A SNP T/T genotype showed a significant better response rate (p=0.02, 21.9% [23/105] vs. 11.3% [5/44]), TTP (p=0.02, 4.6 months vs. 3.4 months), overall survival (p&lt;.001, 12.3 months. vs. 8.0 months.), and frequency of grade 3/4 toxicity (p=.002) compare to patients with T/A genotype. No A/A genotype was observed. Conclusions: SCN1A gene polymorphism may be potential molecular marker for survival and toxicity in patients with colorectal cancer treated with 5-FU/oxaliplatin. In vitro studies are ongoing to identify the mechanism of resistance by SCN1A. [Table: see text]
A phase I study of E7820 in combination with Cetuximab in patients (pts) with advanced solid tumors
Authors: A. B. El-Khoueiry, S. Iqbal, K. Feit, H. J. Lenz, C. Okereke, I. Krivelevich, T. Goldberg, P. Conti, D. Rossignol
Journal: Journal of Clinical Oncology (2008)

3568 Background: In vitro, E7820 inhibits α2-integrin expression, endothelial cell proliferation and vascular tube formation. The maximum tolerated dose (MTD) of E7820 as a single agent is 100mg/day. E7820 and cetuximab demonstrate additive activity in colorectal cancer (CRC) xenograft model studies. Cross-talk between α2-integrin and EGF receptor pathways, provide additional rationale for the combination. Methods: The safety, tolerability and pharmacokinetics were evaluated in a dose escalation phase I study. E7820 was orally administered daily, starting on day 1 of each cycle. Standard dosing of cetuximab was started on day 8 of the first cycle and continued weekly. Secondary objectives included the evaluation of multiple PD markers, and serial FDG-PET imaging. Results: A total of 17 patients (12 males; 5 females; median age 61) were treated and 3 cohorts were assessed with E7820 doses of 40, 70 and 100 mg/day. A total of 46 cycles were administered (range 1–6). A single dose limiting toxicity (DLT) was observed at 70 mg/day (grade 3 transaminitis) while none of the pts at 100 mg E7820 experienced DLT. Grade 3 toxicities were: acneiform rash (2 pts), pruritus, and elevated AST (1 pt each). Grade 1 and 2 toxicities included rash, pruritus, anorexia and fatigue. E7820 attained maximal concentration by ∼4 hours with a half life of 3.6 to 4.9 hr. Cmax and AUC increased dose dependently up to 100 mg. At the 100 mg dose level, α 2-integrin levels in individual pts decreased over the first month to 72% (95% CI = 47.7 - 95.6%) of baseline values. VEGF levels increased at end of cycle 1 to 163 ± 103% in pts treated at the 100 mg E7820/day. There were no significant changes in platelet function assays. One patient with tonsilar cancer achieved an unconfirmed partial response and 5 pts (3 CRC, 1 gastroesophageal, 1 pancreatic cancer) had stable disease. Data from serial FDG-PET scans and other correlates will be presented at the meeting. Conclusions: E7820 can be safely administered at the MTD of 100 mg/day with standard doses of cetuximab. A phase II study of the combination in pts with advanced CRC is on- going. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eisai Medical Research Eisai Medical Research
Primary systemic chemotherapy with carboplatin AUC 6 and docetaxel 75 mg/m<sup>2</sup> (q3w) in triple-negative early breast cancer.
Authors: P. Kern, H. C. Kolberg, F. Stöblen, P. Schmid, S. Kuemmel, D. Pott, R. Kimmig
Journal: Journal of Clinical Oncology (2010)

e11063 Background: Triple-negative early breast cancer (TN BC) is generally associated with a poorer outcome than other subtypes. Clinically, TN BC is a challenge to treat because there is no known target and consequently no role for endocrine or HER2- directed therapy. Phenotypic and molecular similarities between triple-negative breast cancer and BRCA1-associated breast cancers suggest that TN BC may share the same sensitivity to platinum analogues as tumors associated with BRCA1. This pivotal study was initiated to assess the efficacy of platinum-based combination therapy. Patients with primary breast cancer had to be unsuitable for standard anthracycline- based chemotherapy. They received 6 cycles respectively in one case 4 cycles of carboplatin and docetaxel (75 mg/m2) in three week intervals. The primary endpoint was pathological complete response. Methods: 10 patients were enrolled as planned without any dose modifications with carboplatin AUC 6 and docetaxel 75 mg/m2 q3w (with the exception of 1 patient who already experienced clinical complete remission after 4 cycles). Results: 4 out of 10 patients achieved pathological complete remission, 4 patients with minimal residual disease and 2 patients with pT1c. Treatment was comparably well tolerated. Grade 3/4 toxicities was neutropenia in 2 patients, oedema in 2 patients and neurological, joint and muscle pain in 1 patient. Conclusions: The preliminary results demonstrate a high anti-tumour activity of docetaxel and carboplatin as primary chemotherapy for triple negative early breast cancer. The study is ongoing. No significant financial relationships to disclose.
IFCT0401 trial: Phase II study of gefitinib administered as first-line treatment in non-resectable adenocarcinoma with bronchioloalveolar carcinoma features (ADC-BAC): Final results on efficacy and survival
Authors: J. Cadranel, E. Quoix, P. Debove, D. Moro-Sibilot, J. M. Brechot, P. J. Souquet, J. C. Soria, F. Morin, B. Milleron
Journal: Journal of Clinical Oncology (2007)

7560 Background: ADC-BACs are distinguished from other ADCs by epidemiological, clinical and CT scan presentations as well as molecular biology, leading to some responses to EGF receptor tyrosine kinase inhibitors. We therefore conducted a prospective, multicentric, phase II trial to evaluate gefitinib (250 mg/d) as first-line treatment in non-resectable ADC-BAC. Methods: Inclusion criteria were previously untreated, non-resectable cyto/pathologically proven ADC-BAC. Primary objective was disease control rate (DCR) at 3 months. Secondary objectives were progression free survival (PFS), survival, and identification of markers associated with efficacy and survival using multivariate logistic regression and cox model analyses. Results: From 04/04 to 06/05, 88/90 enrolled patients were eligible. All had stage IV disease, with pulmonary (n=86) and/or extra-thoracic metastasis (n=10). All were caucasians, median age 64 yrs (27–84), PS less than 2 in 80.7%, 48 females and 38 never-smokers. Tissue biopsies were centrally reviewed and 85/88 patients evaluable for response by a clinical trial panel. DC was achieved in 25/85 patients (DCR=29.4%, CI=[20–39]). Median PFS was 2.9 months (CI=[2.4–3.2]) and median survival 13.3 months (CI=[13.3–21.8]) with a 1-year survival of 55.7% (CI=[44.4–65.5]). DC was independently associated with age &gt;70 yrs (OR=4.9, p=0.047); never-smoking (OR=8.1, p=0.015); teeter score (clinical pulmonary symptoms score) &lt;9 (OR=18.7, p=0.002); non-mucinous BAC (OR=15.1, p=0.006) and rash (OR=2.1, p=0.02). Shorter PFS and survival were independently associated with teeter clinical score &lt;9 (HR=1.9, p=0.03 and HR=3.3, p=0.006); mucinous BAC (HR=2.7, p=0.008 and HR=2.8, p=0.04), and absence of rash (HR=2.3, p=.004 and HR=2.4, p=0.02). Conclusions: Gefitinib seems active as first-line treatment of non-resectable ADC-BAC. Non-smoking patients, fewer pulmonary symptoms, non-mucinous histological subtype are predicting factors of efficacy and increased survival. Cutaneous rash is associated with efficacy and better survival. In other patients, especially with mucinous BAC, alternative therapies should be offered. No significant financial relationships to disclose.
Incidence of therapy-related leukemia following chemoradiotherapy for esophageal cancer
Authors: H. Tsujimura, N. Mimura, M. Ise, C. Sakai, H. Shimada, M. Nagata, K. Kumagai
Journal: Journal of Clinical Oncology (2009)

e15663 Background: The combination of chemotherapy and concurrent radiotherapy (CRT) has recognized as a curative alternative for several stage of esophageal cancer. On the other hands, a sufficiently long survival time has increased treatment-related late toxicities. However, the frequency and the pathogenesis of secondary malignancies that is the most serious late-onset complication are still unclear. Methods: From July 2000 to March 2008, 348 patients with esophageal squamous cell carcinoma underwent CRT. All patients received chemotherapy consisting with nedaplatin (80 mg/m 2 , div day1) and fluorouracil (700 mg/m 2 , ci day 1–5) and concurrent long T field irradiation (2 Gy daily, up to 30 Gy). A hundred patients received a single course as the neoadjuvant setting. Two cycles of CRT as the definitive or palliative setting were administered in 248 patients. Median and average follow-up durations are 8 and 21 months (1 to 92), respectively. Results: Four patients, who achieved CR after CRT, developed leukemia. Case1, 60-yo-male, developed overt acute myeloid leukemia (AML) from myelodysplastic syndrome 48 months after CRT. Cytogenetic analysis showed complicated abnormalities including deletion 5q. Case2, 64-yo-male, developed AML M0 with t(9;22)(q34;q11) 44 months after CRT. Case3, 72-yo-male, developed Burkitt leukemia with t(8;14)(q24;q32) 19 months after CRT. Case4, 65-yo-male, developed myeloid crisis of chronic myelogenous leukemia with complicated abnormalities including t(9;22)(q34;q11) 48 months after CRT. Case 1 and 3 had localized disease and received single course of neoadjuvant CRT. Case 2 and 4 had advance disease and received 2 courses of CRT. All patients eventually died of leukemia. Conclusions: Since platinum and fluorouracil have shown relatively low chance of secondary neoplasm, our data demonstrates that the concurrent radiotherapy which involves massive bone marrow tissue may increase the risk of leukomogenesis. To this end, atypical cytogenetic abnormalities seen in the present cases give a new insight into the biology of therapy-related leukemia. Notably, this is the first report presenting the incidence of secondary leukemia by nedaplatin. No significant financial relationships to disclose.
Prevalence of MGMT methylation in locally advanced head and neck cancer treated by chemoradiation: influence on response rates
Authors: Z. Abou-Chacra, E. Bissada, S. Girard, L. Guertin, B. Fortin, X. Weng, P. Nguyen-Tan, M. Bélair, J. Tabet, D. Soulieres
Journal: Journal of Clinical Oncology (2008)

6014 Background: The O6-methylguanine-DNA methyltransferase (MGMT) gene encodes a specific DNA repair enzyme that protects cells from toxicity of alkylating agents. Thus, MGMT activity is a major mechanism of resistance to alkylating drugs. It has been shown that decreased MGMT gene expression by promoter hypermethylation results in improved survival in patients with certain types of tumors that are treated with alkylating chemotherapeutic agents. Objectives: To determine the prevalence of MGMT methylation in patients with locally advanced HNSCC treated with chemo-radiation therapy with/without surgery and to evaluate the impact of this methylation on loco-regional control, as well as overall and disease free survival. Methods: Out of 428 consecutive patients treated with chemo-radiation therapy in our institution and followed for a median of 37 months, 199 paraffin embedded biopsy or surgical specimens were retrieved. DNA was extracted and subjected to bisulfite treatment. A methylation specific PCR (MSP) was conducted to assess the methylation status of the MGMT gene promoter. Statistical analysis was performed using Fisher's test for categorical data and Kaplan-Meier's curves and log-rank statistics for failure times. Results: From the initial 199 DNA extracts, 177 (89%) were successfully modified with bisulfite. Out of these, 71 (40%) demonstrated hypermethylation of MGMT. For MGMT methylated cases and non-methylated cases, patients characteristics were not statistically different. Response rates were 71% and 73% (p=NS) respectively. LCR was respectively 87% and 77% (p=0.26), DFS was 80% and 60% (p=0.38), distant metastasis free survival was 92% and 78% (p=0.08) and OS was 64% and 62% (p=0.99) at 3 years. Conclusions: MGMT methylation status is highly prevalent and seems to have a beneficial impact when chemoradiation therapy is given to patients with advanced stage HNSCC, although this does not seem to be mediated through a higher response to treatment. More complete results and analysis will be presented at the meeting. No significant financial relationships to disclose.
Serological detection of elastin fragments in COPD and IPF patients
Authors: F. Genovese, H.B. Skjøt-Arkil, R.E. Clausen, F.J. Martinez, C.M. Hogaboam, M. Han, M.A. Karsdal, D.J. Leeming
Journal: European Respiratory Journal (2012)

Introduction: Elastin plays a critical role in the development of respiratory system disorders including COPD and IPF, whose pathogenesis involves an inflammatory response and tissue turnover mediated by proteases, especially matrix metalloprotease (MMP)-12 secreted by activated macrophages.  Aims and objectives: Our aim was to evaluate whether a novel biochemical marker of elastin degradation mediated by MMP-12 may provide information in relation to lung tissue destruction during pulmonary disease and aid in the diagnosis of respiratory disease.  Methods: Human elastin was in vitro cleaved by different proteases and the resulting peptides were analyzed by LC-MS/MS. Among more than 400 fragments, the MMP-12 generated elastin neoepitope cleaved at the amino acid position 444 (ELN-441/ELM) was chosen as candidate for antibody generation for its uniqueness for human elastin following assay development. This novel marker was assessed in serum collected in a small cohort of COPD (n=10), IPF (n=29) patients and controls (n=11) using a competitive enzyme linked immunosorbent assay (ELISA).  Results: Serum levels of ELM were significantly higher in patients diagnosed with COPD (p  Discussion: Even though these findings need to be validated in larger clinical settings, the ELM marker described showed potential for the separation of controls from COPD or IPF patients.
Evaluation of reported bone pain in patients (pts) receiving chemotherapy in pegfilgrastim clinical trials
Authors: J. Sierra, R. Harms, M. Mo, C. L. Vogel
Journal: Journal of Clinical Oncology (2009)

9621 Background: Bone pain is the most commonly reported treatment-related adverse event (AE) associated with colony-stimulating growth factors. Some authors have suggested that pegfilgrastim-induced bone pain is unpredictable and refractory to analgesics (Kirshner 2007), though that impression may not be uniformly accepted. To better characterize this adverse event we evaluated bone pain across pegfilgrastim clinical trials. Methods: Completed Amgen-sponsored trials that both incorporated pegfilgrastim 6mg administered 24 hours after chemotherapy and utilized MedDRA library coding of AEs were examined. Included were 2 studies comparing pegfilgrastim with placebo (Vogel 2005, Hecht 2007) and 2 studies comparing pegfilgrastim with filgrastim (Sierra 2008, Lopez 2004). The incidence of bone pain was determined by treatment (pegfilgrastim, filgrastim, or placebo), chemotherapy (taxane-containing or not), cycle, severity, age, and body surface area (BSA). Analysis and recoding of studies with preferred AEs coded to nonMedDRA dictionaries is ongoing. Results: 1310 pts (filgrastim=67, pegfilgrastim=665, placebo=578) were analyzed. In studies comparing pegfilgrastim (n=74) and filgrastim (n==7) in pts with AML and NHL, 52% were female, and the mean (SD) age was 50 (15.1) years. Similar proportions (CI) of pts reported bone pain (24.3% [16.1, 35.7] vs 25.4% [15.5, 37.5], respectively), and grade 3/4 bone pain was reported in 3% [0.3, 9] versus 0% [-, -] of pts, respectively. Studies comparing pegfilgrastim (n=591) and placebo (n=578) pts in breast and colorectal cancer are below ( Table ). Conclusions: Bone pain of any grade was commonly reported in all 3 groups (pegfilgrastim, filgrastim, and placebo) and was marginally higher in pts receiving pegfilgrastim compared with placebo. Bone pain was most common in cycle 1. Severe bone pain was infrequently reported. Bone pain was similar in pts receiving pegfilgrastim and filgrastim. Chemotherapy (eg, taxanes) may also contribute to bone pain. [Table: see text] [Table: see text]