tbuckley/cabot-search huggingface dataset:
Phase I trial of subcutaneous (SQ) alemtuzumab (A) and CHOP in T-cell lymphoma: Preliminary results
Authors: P. Porcu, R. A. Baiocchi, J. Lee, T. S. Lin, K. Blum, T. Grady, M. R. Grever, J. C. Byrd
Journal: Journal of Clinical Oncology (2006)

7594 Background: T-cell lymphomas are highly chemoresistant. Cure rates with combination chemotherapy do not exceed 25–30%. We showed that A, a humanized IgG1 targeting the CD52 antigen expressed on most human leukocytes, is cytotoxic for malignant T-cells in vitro and in vivo, regardless of p53 mutational status (Blood 106, 3380, 2005). Thus, we initiated a Phase I study with A and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in T-cell lymphoma. Methods: Accrual goal: 15–18 patients (pts) with untreated (u) or relapsed (r) peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL), excluding ALK-1-positive anaplastic large cell lymphoma. Primary objective: maximal tolerated dose (MTD). All pts receive single agent SQ A loading (3, 10, 30 mg) over 5 days, followed by one SQ A dose with each CHOP every 21 days for a total of 8 cycles. A dose levels: 3, 10, 20 and 30 mg. All pts receive valacyclovir and trimethoprim-sulfamethoxasole, plus G-CSF and erythropoietin according to guidelines. Results: Eight of the nine enrolled pts on cohort 1 (A=3 mg) and cohort 2 (A=10 mg) are evaluable for toxicity (uPTCL= 4, rPTCL=1, rCTCL=3). All pts completed single agent A loading on time and tolerated well further SQ A. No cycle was delayed due to myelosuppression. There were no opportunistic infections or neutropenic fevers. Four pts completed all planned therapy. Three pts did not complete therapy due to progression (2) or toxicity (1). One pt remains on study after 4 cycles. There were no Grade 4 adverse events (AEs). Grade 3 AEs included fatigue (1), anemia (1), dyspnea (1) and emesis (1). Cohort 1 was expanded due asymptomatic cytomegalovirus [CMV] reactivation requiring hospitalization for thrice daily foscarnet, thus resulting in Grade 3 AE. Protocol was amended and subsequent asymptomatic CMV reactivations (2) were treated with oral valganciclovir. No symptomatic CMV reactivation occurred. Conclusions: At current dose levels, SQ A can be easily and safely administered with CHOP chemotherapy and growth factor support, without excessive myelosuppression or infectious AEs. Asymptomatic CMV reactivation can be managed with oral valganciclovir. Further A dose escalation is in progress. [Table: see text]
Pharmacokinetic/pharmacodynamic (PK/PD) modeling and trial simulations to guide dose selection with CNTO 328, a chimeric anti-IL-6 monoclonal antibody (MAb), in patients with renal cell carcinoma (RCC)
Authors: H. Jang, U. Prabhakar, Q. Jiao, J. Ford, B. E. Miller, H. M. Davis, M. A. Graham
Journal: Journal of Clinical Oncology (2004)

2608 Background: PK/PD modeling and trial simulation were employed to guide dose selection for a Phase I/II clinical study with CNTO 328 in patients with RCC. Methods: Modeling and simulations were conducted using WinNonlin and Trial Simulator software. The PK model was developed using published data from patients with advanced multiple myeloma (van Zaanen, 1996). It was further refined following the availability of single dose PK data from the current study in RCC. The PK properties of CNTO 328 after IV infusion were best described using a two-compartment model. A PK/PD inhibitory effect of sigmoidal Emax model was developed for characterization of the relationship between serum CNTO 328 concentration and the concentration of the biomarker, C-reactive protein (CRP). Trial simulations were performed to guide the selection of a multiple dosing regimen for further clinical evaluation in RCC. Results: The PK/PD modeling and simulations predicted that 3 and 6 mg/kg of CNTO 328 administered at weeks 0, 3, 6, and 9 would suppress the CRP values to below 4 μg/mL (lower limit of quantification) for approximately 9 and 14 weeks, respectively. Conclusions: This PK/PD modeling and trial simulation approach has been used to rationally select an optimal dosing regimen for CNTO 328 to expedite the further clinical evaluation of this agent in the treatment of RCC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Centocor Centocor Centocor
Abstract 14694: Ventricular Fibroblasts Expression of Orai1 and Ca2+ -influx Through ICRAC is Increased in Human Heart Failure
Authors: Gracious R. Ross, Tanvir Bajwa, Kelsey Kraft, Milanka Cosic, Larisa Emelyanova, Farhan Rizvi, Ekhson L. Holmuhamedov, Paul Werner, A. Jamil Tajik, Arshad Jahangir
Journal: Circulation (2015)

Introduction: Increased ventricular fibrosis contributes to the progression of heart failure (HF); interventions that limit fibrosis are proposed to improve cardiovascular outcomes. Intracellular Ca2+-dependent processes like excessive fibroblast (FB) proliferation, activation and secretion of extracellular matrix and cytokines are critical for progression of fibrosis. Defining pathways that increase Ca2+ mobilization in FB from HF patients could identify a novel target to prevent fibrosis and HF progression. Hypothesis: We hypothesized that human ventricular FB (hVF) from a failing heart will have enhanced intracellular Ca2+ release and ICRAC (Ca2+-release activated channel)-mediated Ca2+ influx. Methods: Primary cultures of hVF obtained from HF patients undergoing left ventricular assist device implantation (n = 9) were compared to non-diseased hVF from trauma victims (n = 3). Cytosolic free Ca2+ imaging was performed in FB preloaded with fluo-3 AM (confocal microscopy) and thapsigargin (2.5 μM) was used to release and deplete intracellular Ca2+ stores in Ca2+-free KRH solution followed by addition of CaCl2 (2 mM) to assess Ca2+ influx (ICRAC). Ionomycin (2 μM) was used for normalization. Protein expression of STIM1, Orai1 and GAPDH was performed by immunoblotting. Data were analyzed by unpaired Student’s t-test. Results: Ca2+ release from intracellular stores by thapsigargin was not different (p = 0.7) between control (16 ± 1%) and HF groups (15 ± 1%), but store-operated Ca2+-influx (ICRAC) was significantly (p = 0.05) elevated in HF (43 ± 2%) compared to control group (32 ± 5%). The Ca2+-influx was sensitive to YM-58483 (10 μM), an ICRAC inhibitor (9 ± 2%, n = 4, p &lt;0.01). Immunoblots of the components of ICRAC channel, STIM1 and Orai1, showed significant (p = 0.01) increase in the Orai1 expression in HF group (0.09 ± 0.01 AU, n = 8) compared to control (0.04 ± 0.01 AU, n = 3) but no difference (p = 0.7) in STIM1 expression (control [0.19 ± 0.02 AU, n = 3] vs HF [0.2 ± 0.02 AU, n = 8]). Conclusions: Store-operated Ca2+ influx is significantly increased in hVF from HF patients and may play an important role in the progression of cardiac fibrosis. Selective fibroblast Orai1 inhibition may be a potential therapeutic target to prevent progressive worsening of HF.
Suicide rate of callers to a poison information service
Authors: H S Sudak, G J Sterin, H B Houser
Journal: American Journal of Psychiatry (1975)

The authors assessed the frequency of suicide subsequent to calls to a poison information center in a follow-up study. The 8 confirmed suicides out of 2,177 calls yielded a rate of 66.8 per 100,000 population--significantly higher than that for the general population. In addition, 15 possible or probable suicides were identified. The authors note that poison center callers seem to constitute a pool of significantly suicidal persons and reaffirm the premise that poison centers and suicide centers should coordinate their efforts.
HER-2/neu expression as a predictor of response to neoadjuvant docetaxel in operable breast cancer
Authors: P. A. Learn, I.-T. Yeh, M. McNutt, G. B. Chisholm, B. H. Pollock, D. L. Rousseau, F. E. Sharkey, A. B. Cruz, M. S. Kahlenberg
Journal: Journal of Clinical Oncology (2005)

9569 Background: The use of biologic markers to predict response to neoadjuvant chemotherapy may permit tailoring regimens to achieve maximal tumor response. Taxanes have demonstrated excellent activity in breast cancer, but tumor-specific factors predicting clinical response are not thoroughly characterized. Methods: We performed a historical review evaluating the association of tumor prognostic factors and response to neoadjuvant cyclophosphamide and doxorubicin, with or without docetaxel (AC vs. AC+D), in 121 women previously enrolled in a phase III, randomized, clinical trial. Using pre-treatment biopsies, immunohistochemical studies were performed for estrogen and progesterone receptors (ER and PR), HER-2/neu, p53, and Ki-67. Outcome variables were pathologic complete response (pCR) and positive clinical response (cPOS), defined as ≥50% regression in clinical tumor size prior to surgery. Results: In multivariate analysis controlling for tumor size and node status, improved cPOS rates were observed with the addition of docetaxel in HER-2/neu negative tumors (81% vs. 51%, p<0.05), yielding an adjusted odds ratio of 3.5 (95% confidence interval: 1.2–13.0) favoring the use of docetaxel. HER-2/neu negative tumors appeared to have a lower response rate with AC alone than HER-2/neu positive tumors (51% vs. 75%, p=0.06), but response rates were matched when docetaxel was added (81% vs. 78%, p=0.99). ER, PR, p53, and Ki-67 results were not significantly associated with response rates on multivariate analysis. Conclusions: HER-2/neu status may predict improved clinical response rates from the addition of docetaxel to anthracycline-based neoadjuvant chemotherapy. Docetaxel may “rescue” the response in HER-2/neu negative tumors to match that observed in HER-2/neu positive tumors treated with AC alone. No significant financial relationships to disclose.
A phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma
Authors: J. M. Kirkwood, P. Lorigan, P. Hersey, A. Hauschild, C. Robert, D. F. McDermott, J. Gomez-Navarro, J. Q. Liang, C. A. Bulanhagui
Journal: Journal of Clinical Oncology (2008)

9023 Background: A phase II, open-label, single-arm study was conducted to assess antitumor activity of tremelimumab (CP- 675,206), a fully human, anticytotoxic T lymphocyte-associated antigen 4 monoclonal antibody, in patients with advanced melanoma. Methods: Patients with measurable surgically incurable stage III or IV melanoma who had progressed, relapsed, or could not tolerate previous treatment received 15 mg/kg tremelimumab administered IV every 12 weeks for up to 4 cycles or until progression of disease or intolerable toxicity. Patients with clinical benefit were eligible for ≤ 4 additional doses. The primary study endpoint was proportion of confirmed objective RECIST responses per independent review, and secondary endpoints included safety, duration of response, and overall survival (OS). Results: Of 251 patients enrolled, 246 patients (241 response-evaluable) received a median of 1 dose (range, 1 to 7). Preliminary RECIST objective response rate was 8.3% (20 PRs, of which 5 are pending independent confirmation). In addition, 13/15 (86.7%) confirmed PRs are ongoing (4.0+ to 11.1+ months). The majority of PRs involved target lesions in lung, lymph nodes, and/or liver. Clinical benefit rate was 22.8% (PRs + SDs ≥ 70 days since first dose). In addition, 7 patients (2.9%) with mixed responses (ie, best overall response of PD but PR in target lesion) remain alive on study with censored OS (9.7+ to 13.5+ months). Median OS was 10.0 months. The majority of drug-related adverse events (AEs) were mild to moderate, and grade 3/4 AEs were primarily diarrhea (n=28, 11.4%), fatigue (n=6, 2.4%), and colitis (n=5, 2.0%). There were 2 (0.8%) treatment-related deaths (1 sudden death and 1 diverticular perforation). Conclusions: This study does not demonstrate a second-line response rate exceeding 10% but the duration of response of this regimen suggests a role for tremelimumab in this population. A full assessment of clinical benefit will await survival data from this study and the ongoing, randomized phase III first-line study. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer Pfizer Pfizer
P-274 Nodal status predict pathologic complete response following preoperative chemotherapy for colorectal liver metastases
Authors: L. Calera, I. Pajares, R. Pazo, J. Martinez Trufero, P. Bueso, A. Cebollero, A.M. Comin, I. Torres, R. Jaso, I. Trueba, V. Alvarez, A. Anton, F. Rivera
Journal: Annals of Oncology (2015)
Quantitative multiplex PCR analysis for large rearrangements in the <i>MLH1</i> and <i>MSH2</i> genes for hereditary non- polyposis colorectal cancer
Authors: B. Roa, T. Judkins, B. Hendrickson, K. Eliason, J. Schoenberger, S. Rajamani, T. Scholl, C. Colvin
Journal: Journal of Clinical Oncology (2007)

4109 Background: Hereditary non-polyposis colon cancer (HNPCC) is caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2. HNPCC patients have ∼80% increased risk of colon cancer, and elevated risk for cancers of the endometrium, ovary, stomach, small intestine and upper urinary tract. Molecular genetic testing in HNPCC families showed that ∼90% of cases are due to MLH1 and MSH2, 7–10% to MSH6, and &lt;5% to PMS2. The majority are point mutations detectable by sequencing; however, about 5% and 20% of mutations in MLH1 and MSH2, respectively, are large rearrangements that require other detection techniques such as Southern blot or multiplex ligation-dependent probe amplification (MLPA). Our laboratory had previously developed and implemented a quantitative multiplex PCR (QMPCR) endpoint assay for clinical testing for large rearrangements in the BRCA1 and BRCA2 genes. We have developed a similar assay for the MLH1 and MSH2 genes in HNPCC which we refer to as CART (Colorectal cancer Rearrangement Test). Methods: CART consists of 9 multiplexes of 8–12 amplicons each, with at least 2 amplicons targeting each coding exon, promoter, and 3’UTR of both genes. Copy numbers are normalized against MLH1, MSH2, and two unlinked control genes. Internally developed software provides automated analysis and statistical confidence levels for the presence or absence of large rearrangements. Results: Initial validation of CART has been performed on 14 MLH1 or MSH2 rearrangement-positive and 30 negative DNA samples. Results were 100% concordant with previous Southern blot data, as well as supplemental MLPA studies. CART has greatly improved turnaround time, accuracy, and consistency compared to Southerns and MLPA. Conclusions: QMPCR is a superior diagnostic tool for detecting large rearrangements in disease genes. Validation of CART for MLH1 and MSH2 rearrangements is underway on a larger set of previously genotyped samples in a blinded manner. In conjunction with sequencing of the MLH1 and MSH2 genes, the CART assay is expected to improve molecular diagnostic testing on individuals at risk for HNPCC. No significant financial relationships to disclose.
A dose adjustment in patients with rheumatoid arthritis not optimally responding to a standard dose of infliximab of 3 mg/kg every 8 weeks is effective: A Belgian prospective study
Authors: Rene Westhovens, Patrick Durez, Jean-Pierre Devogelaer, F. Van den Bosch, L Corluy, Emilie Veys, L. De Clerck, A. Peretz, Michel Malaise, N. Vastesaeger
Journal: Annals of the Rheumatic Diseases (2004)
Multidimensional geriatric evaluation in elderly cancer patients and its relationship with age
Authors: M. Molina-Garrido, C. Guillén-Ponce, A. Carrato
Journal: Journal of Clinical Oncology (2007)

19651 Background: Age is the major risk factor for the majority of patients with cancer. More than 50% of cancers occurs after the age of 60. Older patients are not simply old, but are geriatric patients because of interacting psychosocial and physical problems. As a consequence, the health status of old persons cannot be evaluated by merely describing the single disease or the group of age. We tested the performance of a new Comprehensive Geriatric Assessment (CGA) and its relationship with groups of age in cancer patients. Methods: Between June 2006 and December 2006, a total of 64 oncologic patients older than 75 years were approached to enrol in our study to analyze their functional, physical, mental, pharmacotherapeutic and socio-economic status and to correlate them to some groups of age: youngest-old (75 to 80 years-old), old-old (80 and 85 years-old) and oldest-old (older than 85 years). They were analysed Activities of Daily Living (ADL) measured by Barthel Scale, Instrumental Activities of Daily Living (IADL) measured by Lawton-Brody Scale, Grade of Fragility measured by Barber Scale, cognitive evaluation measured by Pfeiffer Test, and medication intake. A Chi Squared test was used for statistical analysis; p-value &lt;0,05 was considered significative. Results: Sixty-four oncologic patients age &gt; or = 75 years were recruited. Median age was 80.24 years (range 73.88 to 86.94). 51.6% female. Breast cancer was the most frequent diagnosis (30.2%), followed by lung cancer (19%). 29 patients (45.3%) were aged between 75 and 80 years old; 27 patients (43.5%) were between 80 and 85 years- old. There were statistic significative association between groups of age and Pfeiffer Test (p=0.037), Barber Scale (p=0.031) and medication intake (p=0.021). However, there was not a significative relationship between groups of age and Barthel Scale (p=0.052), Lawton-Brody Scale (p=0.2425), Cruz-Roja Scale (p=0,1485) or number of geriatric syndromes (p=0.129). Conclusions: This abstract reviews the findings regarding the correlation between a comprehensive geriatric assessment (CGA) and groups of age in older patients with cancer. Age per se must not be the only criterion for medical decision as it is not correlated to the health status of older cancer patients. No significant financial relationships to disclose.
Prognostic factors of survival after radiotherapy for metastases to the spinal column and a scoring system of survival: Review of 530 patients in Shizuoka Cancer Center Hospital
Authors: M. Mizumoto, H. Harada, H. Asakura, T. Hashimoto, K. Furutani, H. Hashii, T. Takagi, H. Katagiri, M. Takahashi, T. Nishimura
Journal: Journal of Clinical Oncology (2008)

9608 Background: The role of radiotherapy (RT) for patients with spine metastases has been well established. Several reports indicated to select optimal RT schedule appropriate for survival was important; standard-course RT for good predicted survival and short-course RT for poor predicted survival. In this report, we retrospectively analyzed prognostic factors of survival and make a scoring system to predict survival of the patients with spine metastases. Methods: Five hundred and thirty patients with spine metastases were irradiated at Shizuoka Cancer Center Hospital between September 2002 and December 2006. The prognostic factors for survival were studied using the Cox proportional hazards model. Based on the regression coefficient of the multivariate analyses, a scoring system was developed. The scoring system is as follows; 3 points were allocated for unfavorable tumor type, and bad performance status (3 or more), 2 points were allocated for hypercalcemia, visceral metastases, and previous chemotherapy and 1 point was allocated for multiple bone metastases, and elderly (65 years or older). Results: The overall survival rates for all cases after 6, 12 and 24 months were 49.1% (95% confidence intervals [CI]: 45% to 53%), 32.5% (95% CI: 28% to 37%), and 18.9% (95% CI: 15% to 23%), respectively. Median overall survival periods were 5.9 months (95% CI: 4.9 to 6.8 months). Of the 530 patients, 489 patients (92.3%) were followed for a minimum of 12 months, unless death supervened, during which time 41 patients were lost to follow-up. The survival curves can be separated into three groups: Group A, with total scores of 0–5; Group B, with total scores of 6–9; Group C, with total scores of 10–14. 32% of patients were in Group A (MST = 21.3 months), 48% were in Group B (MST = 5.1 months), and 20% were in Group C (MST = 1.8 months). The overall survival rates after 6, 12 and 24 months were: 82%, 65% and 45% in Group A; 43%, 21% and 7% in Group B; 6%, 4% and 0% in Group C, respectively (p<0.001). Conclusions: This scoring system would predict survival of the patients with spine metastases. Further prospective investigation is needed to select optimal RT schedule appropriate for survival using this scoring system. No significant financial relationships to disclose.
Course of calcium and magnesium serum levels in cetuximab-treated patients: Relation to concurrent chemotherapy and possible predictive value.
Authors: Sebastian Stintzing, Doris Fischhaber, Dominik Paul Modest, Clemens Albrecht Giessen, Saskia Hendrich, Phillip Aubele, Volker Heinemann
Journal: Journal of Clinical Oncology (2013)

521 Background: Hypomagnesaemia and hypocalcaemia are well known adverse events of cetuximab treated patients. Whether these side effects are of predictive value remains unclear. Methods: Patients receiving cetuximab for antitumoral treatment in the day clinic were investigated. Calcium and magnesium serum levels were analysed weekly during therapy, and tumor response and adverse events were followed. Serum levels were noted in relation to baseline measurements. Evaluable patients should at least be treated over a period of 6 weeks. Results: Between 2008 and 2011, a total of 97 patients were treated with cetuximab and were evaluable for serum levels. 38 patients had metastatic colorectal cancer, 27 suffered from SCCHN, 14 had other neoplastic diseases. During therapy, calcium serum levels decreased to a level of about 97% of baseline measurement and stayed there for the duration of treatment. Magnesium levels, however, showed a time dependent decrease during the whole observation time. When calculating the serum levels in relation to the chemotherapeutic combination partner, serum levels of magnesium were significantly lower when cetuximab was combined to a platin-derivative (oxali-, cis- or carboplatin). After a treatment duration of 12 weeks, magnesium levels dropped to 70% in platinum-treated pts, while they decreased to only 90% of baseline in pts without platinum therapy. In patients treated for metastatic colorectal cancer (mCRC) a decline of serum magnesium below 95% of baseline levels 14 days after initiating treatment separated patients with good outcome from those with poor outcome. While, a significant correlation between lower magnesium serum levels and the occurrence of acneiform exanthema was shown, no correlation of hypomagnesemia with clinical symptoms such as e.g. muscle cramps were documented. Conclusions: Magnesium levels decline in a time dependent manner during cetuximab therapy without occurrence of clinical symptoms. Hypomagnesaemia was more prominent in patients receiving platinum agents and was associated with better outcome.