tbuckley/cabot-search huggingface dataset:
Multicenter experience with imatinib mesylate in 202 newly diagnosed chronic myeloid leukemia (CML) patients
Authors: M. Carella, E. Orlandi, M. Lazzarino, M. Annunziata, F. Ferrara, E. Pungolino, E. Morra, C. Baratè, M. Petrini, M. Miglino, M. Gobbi
Journal: Journal of Clinical Oncology (2008)

14621 Imatinib mesylate (IM) is a powerful and selective p210 Bcr-Abl tyrosine kinase inhibitor that has been demonstrated to be effective for the treatment of CML. An Italian multicenter study was performed to investigate the safety, efficacy, tolerance and compliance of IM in newly diagnosed CML patients. From February 2000 through February 2007, we collected 339 CML patients in different phases of disease and previously treated with Interferon-alpha and/or other therapies. Two hundred and two untreated Ph+ CML patients received Imatinib at diagnosis at a dose of 400 mg orally per day; 119 were male and 83 female with a median age of 50 (range, 17–84) years. Sokal risk: low 39,6%, intermediate 44,6% and high 15,8%. Complete hematological remission was achieved in 94% of patients. The estimated rate of complete cytogenetic remission (CCR) was 78,7% after 12 months; with a median follow up of 38 months the rate of CCR raised to 86,8%. Levels of Bcr-Abl transcripts had fallen by at least 3 log in 52% of cytogenetic remitters patients at 12 months; after a median follow up of 38 months, 26% of these patients achieved complete molecular remission (CMR). The most commonly reported adverse events after IM were edema (including peripheral and periorbital edema) (50%), muscle cramps (37,7%), diarrhea (40,7%), fatigue (38,8%); moreover in 8 (5,2%) patients grade 3–4 events were observed consisting of pancitopenia and/or elevated liver enzymes. Eight (5,2%) patients died: 2 patients for progressive disease after allografting, 2 patients of cardiac infarction, 1 patient of severe necrotic fascitis, 1 patient of metastatic colon cancer and 2 patients of blastic crisis. In summary, at 84 months 194/202 (96%) patients are alive and 175 (87%) of them are still receiving IM. Nineteen (13%) patients discontinued Imatinib: 7 patients for adverse events grade 3–4 and 12 patients for progressive disease. These data are comparable to those of IRIS study and confirm the safety and efficacy of IM in newly diagnosed patients. No significant financial relationships to disclose.
Toxicity in 1,181 patients with advanced solid tumors treated in phase I clinical trials of predominantly targeted agents: The M. D. Anderson Cancer Center experience.
Authors: J. J. Wheler, A. M. Tsimberidou, S. Wen, A. Naing, D. S. Hong, G. S. Falchook, S. A. Piha-Paul, S. Fu, S. L. Moulder, R. Kurzrock
Journal: Journal of Clinical Oncology (2010)

2604 Background: The purpose of this study was to assess toxicity associated with investigational agents in patients with advanced solid tumors treated in a phase I clinic that focuses on targeted agents. Methods: An electronic database search/analysis of patients with advanced cancer who presented to the phase I program between 1/1/2006 and 12/31/2008 was performed. Results: Overall, 1,181 patients with advanced tumors were identified: 893 (75.6%) pts were treated on only one phase I clinical trial; 196 (16.6%) on 2; 66 (5.6%) on 3; 16 (1.4%) on 4; and 10 (<1%) on 5 to 9 trials. The median age was 58 (range: 3-89 years) (48% men). The median number of prior therapies was 4 (range, 0 to 17). Patients were accrued on 85 clinical trials (industry-sponsored, 70; non-industry-sponsored, 15 [including 5 sponsored by NCI]); 57 of the studies were with a single agent and 28 with ≥ 2 agents. Overall, 64 (75.3%) trials had only targeted agents; 10 (11.8%), only cytotoxics; 11 (12.9%), both targeted and cytotoxic agents. The median follow-up for surviving patients was 14 months (range, 1–92 months). The median survival was 9.9 months (95% C.I. 9.1–10.9 months). Overall, 86.5% of pts had no drug-related toxicity > grade 2. Rates of grade 3 and 4 drug-related toxicity were 9.0% and 4.5%, respectively. Preliminary analysis suggests that 2 of 1,181 (0.17%) patients died from drug-related toxicity. The most common ≥ grade 3 toxicities were neutropenia, thrombocytopenia, anemia, nausea, fatigue, diarrhea, rash, and transaminitis. Conclusions: Contemporary phase I clinical trials using mainly targeted agents were associated with low rates of drug-related toxicity, with 86.5% of patients experiencing ≤ grade 2 side effects. The drug-related death rate was 0.17%. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Centocor, Johnson & Johnson, Maxygen, Merck & Co. Amgen, AstraZeneca, Center for Biomedical Continuing Education (CBCE), Genentech, Enzon, IDSC, ImClone Systems, Johnson & Johnson, Maxygen, Merck, Pharmion, Roche Abraxis, Amgen, AmpliMed, Antigenics, AstraZeneca, Bayer, BMS, Callisto, Celgene, Centocor, Concordia, Curagen, Eisai, Eli Lilly, EMD Serono, Enzon, Exelixis, Genentech, GlaxoSmithKline, Globomax, Hoffman- La Roche, Kinex, Merck, Metastatix, MGI Pharmaceuticals, Millennium, Myriad, Nereus, NIH, Novartis, Oncothyreon, Pfizer, Pharmacyclics, Pharmion, Phoenix Biotech, Reata, Taiho, Vioquest, Ziopharm
FRACTURE OF THE SPINE OF THE TIBIA
Journal: JAMA (1921)

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Aberrant promoter methylation in serum of prostate cancer patients and controls
Authors: R. Singal, L. Navarro, E. Gordian, K. Ramachandran, I. Reis, M. Manoharan, M. Soloway
Journal: Journal of Clinical Oncology (2009)

e16046 Background: The current screening method for prostate cancer (PC), which is based on prostate specific antigen (PSA) level lacks specificity and sensitivity. Previous studies have reported that increased levels of free circulating DNA (fcDNA) and hypermethylation of genes are associated with several cancers. In this study we evaluated the use of fcDNA level and aberrant promoter methylation of 4 genes in serum as biomarkers for PC. Methods: 89 PC patients, 59 with prostatitis (PT) and 104 with benign prostatic hyperplasia (BPH) were enrolled. Serum DNA was analyzed for methylation of GSTPi, RARB, RASSF1A and ECAD by methylation-specific PCR. FcDNA level was analyzed by quantitative PCR. We examined the effect of methylation and fcDNA on PC risk by fitting two logistic regression models, one comparing PC vs BPH and PT vs BPH and the other comparing PC vs PT+BPH. Models were adjusted for age, race, and log 2 PSA, and tested for variation in effect of methylation by race. Similar analyses assessed the effect of fcDNA as continuous variable, after log2 transformation, and as dichotomous variable with cutpoint near the upper quartile for BPH controls. Results: When adjusted for age and log 2 PSA, positive GSTPi methylation was associated with increased risk of PC in whites (OR = 6.11, p &lt; 0.001, PC vs BPH; OR = 3.93, p = 0.001, PC vs BPH + PT). Methylation of RARB was associated with PT independent of race (OR = 2.85, p = 0.032, PT vs BPH). Patients with fcDNA ≥180ng/ml were at twice the risk of PC compared to those with levels &lt;180ng/ml, and this result did not vary by race. Models including both GSTPi and fcDNA confirmed the independent effect of these two factors in whites (high fcDNA OR = 3.77, p = 0.002, positive GSTPi methylation OR = 5.41, p &lt; 0.001, PC v. BPH + PT). Although high fcDNA also increased risk of PC in blacks, the effect was not statistically significant (OR = 1.91, p = 0.189, PC vs BPH + PT). Conclusions: Our results suggest that aberrant promoter methylation of GSTPi in serum is a potential biomarker for prostate cancer in whites. Level of fcDNA in serum also appears to be an independent diagnostic marker in whites. No significant financial relationships to disclose.
Primary central nervous system lymphoma: An Irish clinical experience
Authors: P. Forde, C. Grant, E. Smith, M. Farrell, F. Brett, C. Bolger, L. Grogan, O. Breathnach
Journal: Journal of Clinical Oncology (2009)

e13032 Background: North American studies have demonstrated an increase in incidence of primary CNS lymphoma in recent decades. To our knowledge there have been no studies analyzing primary CNS lymphoma in the Irish setting. This prompted a review of cases diagnosed at our institution, the larger of two national neurosurgical/neuro-oncology referral centers. Methods: The records of 78 patients diagnosed with primary CNS lymphoma at our institution between January 1999 and October 2008 were reviewed. Patient's age, sex, and time to diagnosis were noted. Histology and radiology was reviewed for cell of origin, CD20 status, and sites of involvement. HIV serology results were available for 23 patients. Results: The median age was 60 (4–78). There was a slight female preponderance (1.1:1]). Median time from hospital presentation to histological diagnosis was 17 days (4–790). 92% (74) of primary CNS lymphomas were B cell and CD20 positive with 8% (4) being T cell. One-third of patients had multifocal brain involvement by lymphoma. 2 of 23 patients tested were HIV positive. Conclusions: In comparison with international published series primary CNS lymphoma in Ireland is diagnosed at an older median age, has a more even sex distribution and a relatively higher incidence of T cell origin. Multifocal tumor involvement was also more frequent than in other series possibly indicating later clinical presentations. There was a much lower incidence of HIV infection in patients who were tested than in similar North American studies. The wide range in time to diagnosis indicates the difficulties associated with diagnosing this uncommon condition. No significant financial relationships to disclose.
Second primary tumors (SPTs) in patients (PTS) with non-small cell lung cancer (NSCLC): A retrospective cohort study
Authors: J. Wang, W. Wei, J. J. Lee, G. Blumenschein, W. K. Hong, C. Lu
Journal: Journal of Clinical Oncology (2005)

7214 Background: Outcomes of PTS with NSCLC are expected to improve with advances in early detection, adjuvant therapy, multidisciplinary management, and molecular-targeted therapy. Improvements in survival may increase the incidence and clinical relevance of second primary tumors (SPTs) in these patients. Because the few studies examining SPTs in NSCLC PTS have been of limited size, we conducted a retrospective, single-institution study to better define clinical characteristics and outcomes in a large cohort. Methods: Subjects were identified through a search of the M. D. Anderson Cancer Center tumor registry. Among 9230 stage I-III NSCLC PTS registered between 1/90–7/02, PTS who had a subsequent cancer diagnosis (excluding non-melanoma skin cancers) were identified. A total of 359 PTS with available medical records formed our study population. A uniform set of demographic and clinical data were abstracted by chart review. Results: Subject characteristics: 63% male, median age 63 yrs (range 37–93), 50%/44% current/former smokers, NSCLC stage: 65% I, 13% II, 22% III. Median follow-up 7.5 yrs. SPT stage: 35% I, 28% II, 25% III, 12% IV. 20%/80% synchronous/metachronous SPTs. Most frequent SPTs: head & neck 16%, prostate 11%, breast 8%, colorectal 7%, gynecologic 7%. Most frequent female SPTs: breast 19%, gynecologic 16%, head & neck 14%, lymphoma 6%, colorectal 5%. Most frequent male SPTs: prostate 17%, head & neck 16%, colorectal 8%, leukemia 8%, esophagus 7%. Median overall, SPT-free, and survival after SPT were 7.1, 2.9, and 2.3 yrs, respectively. Adjusted multivariate analysis demonstrated that older age (P<0.0001), synchronous (vs. metachronous) SPT (P<0.0001), and advanced stage (P=0.044) were significantly associated with poorer cancer-specific survival, while older age (P=0.0019) was significantly associated with poorer SPT-free survival. Conclusions: This study represents the largest series of SPTs in NSCLC PTS. The distribution of SPTs reflects the prevalence of smoking in this population. The median time to SPT development, 2.9 yrs, may aid in the development of screening strategies for NSCLC PTS. This research was supported by an NCI Oncology Research Faculty Development Award. No significant financial relationships to disclose.
Multi-clinical laboratory validation of a gene expression-based tissue of origin test applied to poorly differentiated and undifferentiated cancers
Authors: F. A. Monzon, C. I. Dumur, M. Lyons-Weiler, C. M. Sciulli, M. Price, L. Buturovic, S. Becker, C. T. Rigl, G. G. Anderson
Journal: Journal of Clinical Oncology (2007)

21161 Background: This multi-clinical laboratory validation assessed the accuracy, reproducibility and robustness of the Pathwork™ Tissue of Origin Test. We focused on tumor specimens that are poorly differentiated to undifferentiated (G3-G4; high grade) because this type of specimen can consume a disproportionate amount of physician time and diagnostic resources. A subset of this type of specimen ultimately will be categorized as cancer of unknown primary (CUP), which comprises 4–5% of all malignancies. The Test uses proprietary analytics and a companion genomic microarray (Pathchip™) to compare expression levels of poorly differentiated to undifferentiated specimens with 15 types of cancer. Test development involved over 2000 specimens from 14 labs, representing 15 cancers and sixty morphologies. Methods: The studies addressed operability limits, specimen stability, potential interferences and reproducibility, as well as validation in molecular diagnostics and commercial laboratories. In all, over 700 frozen tumor specimens and microarrays were analyzed. Results: Clinical validation data demonstrated that the percent agreement of the Tissue of Origin Test was 88% across all tissue types. Between-lab concordance was 95%. If the quantitative result (Similarity Score) exceeded the recommended threshold, the probability that the indicated tissue is present was 95% across all tissue types. If the Similarity Score was less than 5, the probability that the indicated tissue is absent was 98% across all tissues types. Conclusions: The Pathwork™ Tissue of Origin Test, which is under development, is accurate and highly reproducible across laboratories in this study. The test gave consistent results for different tissue handling and extraction methods and has the potential to be an effective aid in the diagnosis of cancer patients presenting with poorly differentiated and undifferentiated tumors. No significant financial relationships to disclose.
Does detection and treatment of ductal carcinoma in situ prevent invasive cancer?
Authors: J. J. Griggs, M. E. S. Sorbero, K. Sattelberg, A. W. Dick
Journal: Journal of Clinical Oncology (2004)

664 Background: The diagnostic incidence of ductal carcinoma in situ (DCIS) has increased over 500-fold in the last 3 decades. It is not clear whether detection and treatment of DCIS prevents development of invasive breast cancer (IBC). Methods: We identified all cases of DCIS (n = 1,157) and IBC (n = 9,072) in Monroe County, NY from 1985 - 2002 using the Monroe County Tumor Registry. We linearly extrapolated and interpolated zip code level population totals for women age 35 –79 by year from 1990 and 2000 census data. We then generated incidence rates for DCIS and IBC by zip code and year from 1985 - 2002. To investigate the impact of DCIS detection on IBC incidence, we estimated regression models in which IBC rates were specified as flexible functions of time and lagged DCIS rates. We allowed for IBC rates to be affected by lagged DCIS rates (each of the five prior years) because of the possibility that transit time from in situ to invasive disease is heterogeneous. We included zip code-level fixed effects to eliminate spurious correlation due to unobservable zip code factors that may drive both DCIS and invasive cancer rates. Thus, the relationship between invasive cancer and lagged DCIS is identified by intra-zip code variations in DCIS and invasive cancer rates over time. Results: Bivariate analysis shows that DCIS and IBC rates are positively correlated. Multivariate results, however, indicate that there is a strong negative relationship between lagged DCIS diagnosis rates and IBC rates. The model predicts that 33% (p = .014) of diagnosed DCIS cases would have been diagnosed as IBC cases in two years, a total of almost 50% (p = .06) in the first three years combined, and a total of 72% (p = .046) in the first 5 years combined. The sum of the effects of lagged DCIS rates from years 1 through 5 is significantly different from 0 (p = .046). The relationships become stronger when socioeconomic and demographic controls are included in the model. Conclusions: Results indicate that DCIS diagnoses reduce future IBC diagnoses. This suggests that the natural history of DCIS is progression to IBC at high rates within two to five years. Our results underscore the importance of screening for, detection of, and treatment of DCIS. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis
Height as a risk factor in osteosarcoma
Authors: A. Longhi, A. Pasini, N. Baldini, F. Baronio, A. Pellacani, A. Cicognani, G. Bacci
Journal: Journal of Clinical Oncology (2004)

9042 Background: The highest incidence of osteosarcoma in dogs of large breed suggested that height can play a role in the pathogenesis of this human bone sarcoma typical of childhood and adolescence Methods: A continuous series of 962 patients (560 males and 402 females) with bone osteosarcoma treated at the same institution between 1981 and 2001 were evaluated. 836 had localized disease, whereas 126 were metastatic at diagnosis. The median age at diagnosis was 16.1 years (2.5–60) with a peak at 12.5 years in females (mean 18.9+/-9) and 15 years in males (mean 17.1+/-8.9). All patients underwent surgery and chemotherapy. The following data were retrieved: age, height and pubertal stage at diagnosis, stage of disease, site, chemotherapy protocol. Our patients were subdivided into 4 groups according to age (Table). Heights of this series were compared with the standard of the national population matched for gender, age, and geographic area of origin and secular trend. Heights were expressed as standard deviation scores (SDS). Results: At diagnosis, a high percentage of patients of Groups 1, 2, and 3 were found to be above the 50th percentile for height of the reference population, and their mean SDS height value was significantly higher than the mean SDS Final Height value, as measured at the end of puberty (p<0.0001), both in males and females. On the contrary, the height of patients with osteosarcoma in adulthood did not significantly differ from that of the reference population. Conclusions: The higher incidence during the pubertal spurt, in the anatomic sites of greater growth and in taller individuals, suggests that the GH-IGF axis may play a role in the pathogenesis of osteosarcoma, in agreement with a number of previous experimental studies. The finding that final height of osteosarcoma patients does not differ from that of the standard reference population may reflect the detrimental influence of aggressive multiagent chemotherapy on osteogenesis. No significant financial relationships to disclose.
Primary mediastinal large B-cell lymphoma: Optimal therapy and prognostic factors in 40 consecutive Asian patients.
Authors: W. D. Tai, H. P. Phoon, S. Tan, Y. Koo, R. H. Quek, M. Tao, S. Lim
Journal: Journal of Clinical Oncology (2010)

8074 Background: The prognosis and optimal treatment for primary mediastinal large B-cell lymphoma (PMBCL) a rare and distinct clinico-pathologic entity from diffuse large B-cell lymphoma (DLBCL) is largely uncertain. Although rituximab, a CD20 monoclonal antibody has become a standard component of DLBCL treatment, its role in PMBCL is unknown. This study aims to evaluate the efficacy of rituximab when combined with CHOP chemotherapy in PMBCL and to delineate the prognostic features in progression free survival (PFS) and overall survival (OS) in this group of patients. Methods: Forty consecutive patients with PMBCL treated with curative intent from 1997 to 2009 were included: 14 received CHOP chemotherapy alone; 26 received rituximab with CHOP(R-CHOP) chemotherapy. All patients received mediastinal radiotherapy except for 2 patients who progressed while undergoing chemotherapy. Results: The cohort of patients had a median age of 27 (range 17-48), female/male ratio: 1.2, LDH> normal: 97.5%, stage 1/2 disease: 85% and bulky mediastinal disease: 75%. After median follow up of 24 months, OS and PFS at 3 years for the entire cohort were 75% and 64% respectively (R-CHOP vs CHOP, OS was 88% vs 43% and PFS- 88% vs 38%). In Cox repression analysis, stage of disease was the only factor prognostic of survival with age adjusted IPI (International Prognostic Index) having limited utility. RCHOP resulted in improvement of PFS (HR 0.14 95%CI: 0.04-0.51 p=0.003) with a trend towards significant improvement in OS (HR 0.27 95%CI: 0.09-1.10, p=0.07). Relapse/progression occurred within 12 months from the start of treatment in 92% of patients in the entire cohort. Any recurrence tend to involve extra nodal organs. Two year estimate of survival after relapse/progression was 25%. Conclusions: This is the first report evaluating the role of rituximab in patients with PMBCL. R-CHOP portends a 3-year OS rate of 88% which is comparable with historical survival rates from more intensive chemotherapy regimes with a toxicity profile in favour of R-CHOP. Stage of disease was the only prognostic factor of survival. The role of radiotherapy in the era of rituximab remains uncertain. No significant financial relationships to disclose.