tbuckley/cabot-search huggingface dataset:
Error rates in clinical radiotherapy.
Authors: R M Macklis, T Meier, M S Weinhous
Journal: Journal of Clinical Oncology (1998)

PURPOSE Error rates in clinical oncology are undergoing increasing scrutiny. The purpose of this study was to understand error frequency, error patterns, underlying causal links, consequences, and possible prevention strategies in clinical radiotherapy. PATIENTS AND METHODS Treatment information, self-reported error documentation, and retrospective analyses of electronic treatment verification transcripts for 1,925 consecutive patients treated with a total of 93,332 individual radiotherapy fields were reviewed and analyzed. RESULTS A total of 59 separate errors that affected 168 individual treatment fields were detected, which yielded a crude radiation delivery error rate of 0.18%. All 59 errors were judged to be level I (negligible chance of adverse medical outcome) with the most common error category being a minor treatment field block misplacement. A comprehensive quality assurance program and an electronic record-and-verify linear accelerator interlock system seem to have prevented the occurrence of many additional errors. However, nine of the 59 errors were directly related to the use of this system and generally involved the transposition of similar numbers within series of treatment coordinate data-sets. Overall, radiotherapy error rates favorably compare with reported error rates for pharmaceutical administration in large tertiary care hospitals. CONCLUSION When modern automated error-minimization methods are used along with nonpunitive error reporting systems, clinical radiotherapy seems to be highly safe. Formal error analysis studies may allow the rational design of prevention strategies that are attuned to the frequency, seriousness, and antecedent causes of many classes of potential radiotherapy errors.
Effect of inhibition of PARP-1 on mantle cell lymphoma cells with dysfunctional ATM
Authors: C. Williamson, D. G. Bebb, H. Muzik, S. P. Lees-Miller
Journal: Journal of Clinical Oncology (2008)

8584 Background: Mantle Cell Lymphoma (MCL) represents 10% of Non-Hodgkin's Lymphomas (NHL) and has the lowest overall survival at only 3 years. ATM, a large protein kinase activated in response to DNA double strand breaks (dsb), is altered either through mutation or deletion in up to half of all MCL cases. Activated ATM phosphorylates many downstream targets leading to cell cycle arrest, DNA damage repair, or cell death. It has been demonstrated that inhibition of multiple DNA repair pathways in a single cell can be toxic in the absence of additional genotoxic insult (synthetic lethality). In particular, the inhibition of the single strand break repair protein PARP-1 has been shown to be toxic in cell lines with existing dysfunctions in dsb repair. Here, we have examined the cytotoxic effects of the PARP-1 inhibitor, PJ34, on MCL cells with dysfunctional ATM. Methods: Four MCL cell lines were characterized for ATM function function including phosphorylation of downstream targets - p53 and SMC1, cell cycle checkpoint arrest and radiosensitivity. The Granta-519 cell line was shown to lack functional ATM, while the three other MCL cell lines (Z138C, JVM2 and HBL2) possessed normal ATM function. ATM protein levels were stably reduced in Z138C cells, through the incorporation of an shRNA vector targeting ATM mRNA. Xenograft tumors of the ATM proficient Z138C cell line, the ATM deficient Granta-519 and ZC-shATM cell lines were produced in Nude mice and animals treated with PJ34. Results: PJ34 was more cytotoxic in the ATM deficient Grant 519 cells than in any of the other MCL cell lines tested. Reduction of ATM protein levels in Z138C cells rendered them significantly more sensitive to PJ34 than either parental or control cell lines. Preliminary results suggest that PJ34 reduces tumour growth in ATM-deficient tumours in an animal xenograft model. Conclusions: Inhibition of PARP-1 by PJ34 is toxic in ATM deficient MCL cell lines. Preliminary data from animal models suggests that inhibition of PARP-1 may be cytotoxic in ATM-deficient tumours. Since 20–50% of MCL tumors contain alterations to the ATM gene, we speculate that inhibition of PARP-1 may have potential in the management of MCL. No significant financial relationships to disclose.
Reduction of pain as the primary determinant of improved quality of life of cancer patients receiving zoledronic acid (Zol) for bone involvement
Authors: W. Wiktor-Jedrzejczak
Journal: Journal of Clinical Oncology (2005)

8022 Background: Bone metastases/lesions from breast cancer (BC), prostate cancer (PC), and multiple myeloma (MM) cause clinically significant skeletal morbidity and severe bone pain that diminish quality of life (QOL). We conducted an open-label, multicenter study to investigate the effect of Zol on pain and QOL. Methods: Pts with ≥ 1 bone lesion of BC, PC, or MM received Zol (4 mg) every 3–4 wk for up to 6 infusions. Worst pain during the preceding 7 days was assessed at baseline, before each infusion, and 4 wk after last infusion using a 100-mm visual analogue scale (VAS). QOL was assessed at baseline and before infusions 2 and 6 using the Functional Assessment of Cancer Therapy-General (FACT-G) Scale that evaluates physical, social, emotional, and functional well-being. Results: 260 pts with BC (n = 80), PC (n = 104), or MM (n = 76) were treated at 33 centers. At baseline, mean VAS pain score was 44.5 and mean total FACT-G score was 1.5 (on a scale of 0 to 4). Zol consistently reduced pain scores throughout the study, with significant reductions observed beginning at infusion 2. At final visit, mean pain scores were significantly reduced from baseline in all pts (-20.9 ± 2.1 SEM; P < .001), and in each tumor type (BC: -21.5 ± 3.3; PC: -20.9 ± 4.0; MM: -20.6 ± 3.8; all P < .001). Zol also significantly improved mean total FACT-G scores (-0.14 ± 0.04 SEM; P < .001) and physical (-0.34 ± 0.05; P < .001) and emotional (-0.17 ± 0.05; P < .002) well-being compared with baseline in all pts. FACT-G scores at infusion 6 by tumor type showed that, compared with baseline, Zol significantly improved mean total scores in pts with BC (-0.15 ± 0.08; P < .05) or MM (-0.21 ± 0.06; P < .001), emotional well-being in pts with BC (-0.16 ± 0.07; P < .02 [infusion 2]) or PC (-0.16 ± 0.08; P < .05), and physical well-being in all pts (BC: -0.35 ± 0.11; PC: -0.21 ± 0.09; MM: -0.45 ± 0.08; P < .001). Among the parameters of emotional well-being, reduction in pain was most significant and was the primary factor affecting the overall score. Conclusions: These results suggest that Zol significantly reduces bone pain and improves QOL in pts with bone lesions from advanced cancer, and they provide a rationale for further investigating the effect of Zol on bone pain. No significant financial relationships to disclose.
Rituximab induces long-term remissions in patients with HIV-associated multicentric Castleman's disease
Authors: M. Bower, T. Powles, S. Williams, T. Newsom-Davis, M. Atkins, J. Stebbing, S. Montoto, M. Nelson, A. Webb, P. Kelleher
Journal: Journal of Clinical Oncology (2007)

8049 Background: HIV associated multicentric Castlemans (MCD) is rare lympohproliferative disorder and most treatment options to date, have proved largely unsuccessful. This study investigated the efficacy of the anti CD20 monoclonal antibody rituximab in patients with this disease. Methods: Between 2003 and 2006, patients with histological proven HIV related MCD received a course of 4 infusions of rituximab 375mg/m 2 at weekly intervals. Results: Twenty one consecutive patients (18 male) were recruited into this study and the median follow-up is 12 months (range 1–49). The median age was 37 years and all patients were either on highly active antiretroviral therapy (HAART) (62%) or started HAART at the time of MCD diagnosis (38%). The median CD4 cell count at MCD diagnosis was 275/mm 3 (range 77–725). One died within 2 weeks of starting rituximab (not evaluable); 20 evaluable patients all achieved clinical remission of symptoms and 71% achieved a radiological response according to RECIST criteria. Rituximab lead to a significant fall in anaemia, thrombocytopenia, CRP, ESR, serum HHV8 viral load and IL-10. Rituximab caused transitory fall in the CD19 count, but had no effect on the CD4, CD8 and NK cell counts or plasma HIV viral load. The disease free survival at 2 years is 79% (95%CI: 49–100%) and overall survival is 95% (95%CI: 86–100%). Two patients have relapsed after 1.6 &amp; 2.8 years and were successfully retreated with rituximab therapy. Conclusions: Rituximab therapy results in a sustained clinical, radiological and biochemical remission in patients with HIV related MCD. No significant financial relationships to disclose.
Is hyperglycemia a prognostic factor in pancreatic cancer?
Authors: S. F. Mekan, M. M. Safa, R. S. Komrokji, Z. A. Nahleh, A. R. Jazieh
Journal: Journal of Clinical Oncology (2006)

14078 Background: Pancreatic hyperglycemia is one of the manifestations of pancreatic cancer.The purpose of this study is to explore the prevalence and significance of hyperglycemia at the time of diagnosis of pancreatic cancer. Methods: We reviewed retrospectively cases presenting to our institution with diagnosis of pancreatic carcinoma between 1999–2003. Hyperglycemia was defined as a blood sugar of greater than 140mg/dL. Results: There were 155 cases diagnosed with pancreatic cancer. Out of these, 67 (43.2%) were males and 71(45.8%) were females. The mean age was 63 years. Staging was reported in 134 patients: 19 patients (14%) were stage I, 23 (17%) stage II, 40 (30%) stage III and 52 (39%) stage IV. Median survival time was 8 months. Thirty-four (22%) patients had prior history of diabetes mellitus and were excluded from subsequent analysis. Sixty-four patients out of 121 patients (53%) were found to be hyperglycemic. These patients had no prior history of diabetes mellitus or were diagnosed with diabetes within six months. There was no difference between hyperglycemic patients and normoglycemic patients regarding age, sex, race, tumor location, smoking history, history of pancreatitis and hypertension. Hyperglycemic patients were more likely to have history of alcohol use compared to normoglycemic patients (p value = 0.005, OR = 4.07). Hyperglycemic patients were less likely to present with stage IV disease as compared to normoglycemic patients (25% vs. 55%) (p-value 0.002). The median survival in hyperglycemic patients was significantly longer than in normoglycemic patients (12 vs. 6 months, p-value = 0.02).There was a trend towards better survival among stage IV hyperglycemic patients as compared to normoglycemic patients (13 months vs 3 months) (p-value 0.38). Conclusions: In this retrospective analysis, 53% of pancreatic cancer patients without diabetes had hyperglycemia at presentation. These patients presented at an earlier stage compared to normoglycemic patients and had significantly longer survival. The impact of hyperglycemia on survival could be related to earlier presentation or difference in the tumor biology. The clinical significance of hyperglycemia in pancreatic cancer should be further studied in prospective fashion. No significant financial relationships to disclose.
Trastuzumab-related cardiotoxicity among older breast cancer patients.
Authors: Mariana Chavez-Mac Gregor, Ning Zhang, Jiangong Niu, Yufeng Zhang, Thomas A. Buchholz, Linda S. Elting, Gabriel N. Hortobagyi, Sharon Hermes Giordano
Journal: Journal of Clinical Oncology (2012)

135 Background: The use of trastuzumab in the adjuvant setting is associated with reduction in mortality and recurrence. Trastuzumab is extremely well tolerated, but its use is associated with congestive heart failure (CHF). The incidence of this complication in the general population remains largely unknown, especially in older patients. In this study we evaluated the rates and risk factors associated with trastuzumab-related CHF in a large cohort of older breast cancer patients. Methods: Breast cancer patients &gt; 66 years with full Medicare coverage, diagnosed with stage I-III breast cancer between 2005-2007, and treated with chemotherapy were identified in the SEER-Medicare database. Chemotherapy and trastuzumab use, comorbidities and CHF were identified using ICD-9 and HCPCS codes. Analyses included descriptive statistics and Cox proportional hazard model using trastuzumab as a time-dependent variable and logistic regression. Results: From 3,983 patients included, 847 (21.7%) received trastuzumab. Median age of the entire cohort was 71 years old. Among trastuzumab users the rate of CHF was 28.6% compared to 18.1% in non-trastuzumab users (p&lt;.0001). After adjusting for demographic and clinical characteristics, comorbidities, and type of chemotherapy used, trastuzumab users were more likely to develop CHF than non-trastuzumab users (HR 1.74; 95% CI 1.47-2.06). Among trastuzumab users, older age did not further increase the risk, however history of coronary artery disease (OR 2.23; 95%CI 1.56-3.19), heart valve disease (OR 1.41; 95%CI 1.41-2.88) and emphysema -as a proxy for smoking- (OR 2.03; 95% CI 1.13-3.63) significantly increased the risk of CHF. There was a trend for increased risk of CHF associated with anthracycline use (OR 1.36; 95% CI 0.93-2.00). Conclusions: In this large cohort of older breast cancer patients, the risk of CHF among trastuzumab users was 1.74 times higher than non-trastuzumab users, which is higher than what has been reported in younger clinical trial participants. Among older breast cancer patients treated with trastuzumab, cardiac comorbidities, and emphysema may identify high-risk patients.
Is physical function affected by androgen deprivation therapy (ADT) in men with non-metastatic prostate cancer?
Authors: S. Gogov, F. Hussain, G. Naglie, I. Tannock, N. E. Fleshner, M. D. Krahn, S. Duff Canning, P. Warde, S. M. Alibhai
Journal: Journal of Clinical Oncology (2006)

4615 Background: Although prolonged use ofADT is hypothesized to adversely affect physical function, only a few small studies have examined this relationship and it remains unclear if self-reported weakness represents a decline in actual physical performance or is related to fatigue. Loss of physical function may be particularly important to older men who already have limited functional reserves. Methods: Men age 50 or older with non-metastatic prostate cancer who were starting continuous ADT were enrolled in this prospective longitudinal study. Physical function was tested using a Jamar dynamometer (grip strength), the Timed Up and Go (TUG) test, and the six-minute walk test (6MWT), representing upper extremity strength, lower extremity strength, and endurance, respectively. Assessments were done at baseline (prior to ADT), 3 months, 6 months, and 12 months. Results: 42 patients on ADT have been enrolled to date (mean age 74.8 y). There was a gradual but steady decline in grip strength from baseline (39.2 kg) to 3 months (38.1 kg), 6 months (37.9 kg), and 12 months (35.3 kg) (p &lt; 0.05 for all comparisons). On average, patients took 7.3 seconds to complete the TUG and walked 1507 feet during the 6MWT at baseline. TUG and 6MWT scores did not worsen over time (p &gt; 0.05). Conclusions: Preliminary data suggest that 3–12 months of ADT is associated with worsening upper extremity strength but lower extremity strength and endurance are relatively unaffected. A larger sample size is needed to determine if all aspects of physical function or only upper extremity strength deteriorate with ADT use. Additionally, most patients in our study reported excellent health and functional status at baseline and our results may not adequately reflect the impact of ADT in more frail older men. No significant financial relationships to disclose.
Effect of intermittent hypoxia on the expression of fatty acid binding proteins in human adipocytes and macrophages
Authors: Judith C.W. Mak, Qian Han, Sze Chun Yeung, Mary S.M. Ip
Journal: European Respiratory Journal (2011)

Background:  Intermittent hypoxia (IH) is a hallmark feature in obstructive sleep apnea (OSA), which is increasingly recognized as an independent risk factor of cardiovascular diseases. Different fatty acid binding proteins (FABPs), including adipocyte (A)-FABP (FABP4) and epidermal (E)-FABP (FABP5), are now widely accepted as biomarkers associated with increased cardio-metabolic risks and carotid atherosclerosis. We hypothesize that IH exposure may regulate the expression of FABPs in two major cell types involved in the development of atherosclerosis, namely adipocytes and macrophages.   Methods:  Human preadipocytes and THP-1 cells were cultivated in the differentiation media until reaching final differentiation level of ∼80% before treatment. Differentiated cells were exposed to intermittent normoxia (IN as control) or IH [a 10-min hypoxia (5% O 2 ) followed by a 5-min normoxia (21% O 2 ) for 64 cycles using the BioSpherix OxyCycler C42 system (Redfield, NY)]. FABP4 and FABP5 mRNA expressions were measured by RT-PCR, and protein by Western blot.   Results:  Adipocytes expressed very high levels of FABP4 and low levels of FABP5 while differentiated macrophages expressed high levels of both FABP4 and FABP5, consistent with previous reports. IH exposure resulted in an up-regulation of FABP5 but not FABP4 expression in adipocytes. Macrophage FABP4 and FABP5 levels remained unchanged following IH treatment, suggesting that the two cell types are likely to have distinct functions.   Conclusions:  These data suggest that FABP5 may play a role in atherogenesis in OSA subjects.   Acknowledgement:  This research is supported by Hong Kong Research Grant Council (RGC) Grant (HKU 7667/07M).
Thromboprophylaxis after Orthopaedic Surgery with an Oral, Direct Factor Xa Inhibitor: Pooled Results of Two Phase Iib Clinical Trials.
Authors: Alexander G.G. Turpie, Kenneth Alan Bauer, Lars Borris, Ola E. Dahl, William D. Fisher, Michael Gent, Sylvia Haas, Menno V. Huisman, Ajay K. Kakkar, Peter Kälebo, Louis M. Kwong, Martin Homering, Frank Misselwitz, Bengt I. Eriksson
Journal: Blood (2005)
Lumiliximab in combination with FCR for the treatment of relapsed chronic lymphocytic leukemia (CLL): results from a phase I/II multicenter study
Authors: J. C. Byrd, J. E. Castro, I. W. Flinn, A. Forero-Torres, T. J. Kipps, N. A. Heerema, T. S. Lin, H. Mu, S. Tangri, S. O' Brien
Journal: Journal of Clinical Oncology (2008)

7003 Background: Lumiliximab is an anti-CD23 monoclonal antibody that is being investigated for the treatment of relapsed B-cell CLL (BCLL). CD23 is a glycoprotein expressed on the majority of CLL B cells. In a previous study, lumiliximab monotherapy given weekly was well tolerated, achieved sustainable CD23 receptor occupancy and showed clinical activity. A Phase I/II, multicenter study was conducted to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide, and rituximab (L + FCR) for patients (pts) with relapsed CD23+ BCLL. In addition, CD23 receptor occupancy on BCLL cells with L + FCR and possible effects of elevated serum CD23 were evaluated. Methods: Thirty-one pts with relapsed BCLL received either 375 mg/m2 (n=3) or 500 mg/m2 (n=28) of L+ FCR for up to six 28-day cycles. All pts completed treatment and follow-up is ongoing. A semi-quantitative flow cytometry method was used to measure CD23 receptor occupancy and serum CD23 levels were measured using an enzyme-linked immunosorbent assay. Results: Median age at study entry was 58 yrs, 71% had Rai Stage I/II, and median # of prior regimens was 2 (1- 10). Using NCI-WG criteria, overall response rate was 65%: complete response (CR) 52% and partial response13%. Five of the 8 pts with del(11q22.3) achieved CR. Based on median follow-up of 16.8 mos (1.5 - 37.6), KM estimated median progression-free survival (PFS) for all pts was 19.3 mos. Median PFS for all responders and CR pts were 23.4 mos and 30.4 mos, respectively. Twenty-three pts (74%) reported a Grade 3 or 4 event, similar to what has been previously reported with FCR. L + FCR has a comparable safety profile with no additional toxicity. At lumiliximab schedule used, CD23 receptor occupancy was sustained with no effects by elevated levels of serum CD23. Conclusions: These results suggest that L +FCR is an effective regimen for pts with relapsed B-CLL. L+FCR produced an impressive CR rate, an encouraging PFS and a similar safety profile to that of FCR. Monthly L + FCR achieved sustainable CD23 receptor occupancy on BCLL, which was not affected by elevated levels of serum CD23. A large, randomized, global study of L+ FCR vs FCR (LUCID) is ongoing to further evaluate the safety and efficacy of this regimen. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Biogen Idec Biogen Idec Biogen Idec
Phase II trial of carboplatin in the management of malignant mesothelioma.
Authors: D Raghavan, P Gianoutsos, J Bishop, J Lee, I Young, P Corte, P Bye, B McCaughan
Journal: Journal of Clinical Oncology (1990)

Thirty-one patients with advanced malignant mesothelioma, previously untreated or having received only one prior cytotoxic regimen, were treated in a prospective, single-arm phase II trial with carboplatin (NSC 241240) at a dose of 150 mg/m2 per day intravenously (IV) for 3 days (450 mg/m2/course). One complete remission and four partial remissions were achieved, yielding an overall objective response rate of 16% (95% confidence interval [CI], 5.4% to 34%). The median duration of remission was 8 months (range, 5 to 17). Nonhematological toxicity was mild (only 12% with World Health Organization [WHO] grade 3 vomiting); 16% suffered WHO grade 3 to 4 hematological toxicity, but there were no life-threatening episodes and no treatment-related deaths. Carboplatin has modest activity against malignant mesothelioma and, because of its low toxicity, has a role in the management of this disease.
First Interim Efficacy and Safety Analysis of an International Phase III Randomized Trial in Newly Diagnosed Systemic Peripheral T-Cell Lymphoma Treated with Chemotherapy with or without Alemtuzumab and Consolidated by High Dose Therapy
Authors: Francesco d'Amore, Sirpa Leppä, Maria Gomes da Silva, Thomas Relander, Peter De Nully Brown, Eckhart Weidmann, Grete Fossum Lauritzsen, Antonio Pezzutto, Achiel Van Hoof, Michel van Gelder, Jeanette K Doorduijn, Ka Lung Wu, J.C. Kluin-Nelemans, P.J. Lugtenburg, Milada Jankovska, Mats Merup, Unn-Merete Fagerli, Jan Walewski, Hans Hagberg, Jose Mario Mariz, Per Boye Hansen, Thomas Nösslinger, Ann Janssens, Lena Brandefors, Hilde Demuynck, Martyn Ronald Schaafsma, Ilse Christiansen, David Salek, Sirkku Jyrkkiö, Vit Prochazka, Josee Zijlstra, L. Böhmer, Richard Greil, Wendy Stevens, Rob Fijnheer, Marinus van Marwijk Kooy, Matthias Grube, Georg Hopfinger, Eric Van den Neste, Esa Jantunen, Lorenz Trümper, Gerald Wulf, Bettina Altmann, Marita Ziepert, Markus Loeffler, Helle Toldbod
Journal: Blood (2012)
Loss of CD62L Expression in CD4+FoxP3+ Regulatory T Cells Following Freeze-and-Thaw Prevents Protection Against GVHD in Murine Models
Authors: Mareike Florek, Dominik Schneidawind, Jeanette Baker, Antonio Pierini, Dennis B Leveson-Gower, Yuqiong Pan, Robert S. Negrin, Everett H. Meyer
Journal: Blood (2014)