tbuckley/cabot-search huggingface dataset:
Phase I study of bendamustine and fractionated stereotactic radiotherapy (FSRT) in patients with one to three brain metastases from solid malignancies.
Authors: J. C. Grecula, M. Ammirati, K. L. Kendra, M. Phelps, R. Cavaliere, B. McCracken-Bussa, J. Radawski, L. Wei, E. Mrozek, N. A. Mayr
Journal: Journal of Clinical Oncology (2010)

TPS146 Background: Bendamustine is a multifunctional alkylating agent with a purine-like ring system. It causes formation of intrastrand and interstand crosslinks between DNA bases, induces a concentration-dependent apoptosis as noted by changes in Bcl-2 and Bax expression profiles, downregulates inhibitors of apoptosis proteins, and induces nonapoptotic cell death, termed mitotic catastrophe. These mechanisms of action make it likely to also function as a radiosensitizer, and thus bendamustine is an attractive agent to study in combination with ionizing radiation. Methods: This single-arm phase I study will determine the toxicity of combination therapy with bendamustine and FSRT for treatment of patients with KPS ≥ 70 and 1–3 untreated brain metastases. Metastases ≥ 5 cm or involving leptomeninges, thalamus, basal ganglia, or brainstem are excluded. The primary efficacy endpoint: the recommended phase II dose of bendamustine. Secondary endpoints: 1) bendamustine pharmacokinetics (PK), 2) drug quantitation utilizing high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS) for plasma, brain metastases, brain margin, arachnoid, and cerebral spinal fluid, and 3) assessment of local control of brain metastases. Following consent, eligible patients will undergo treatment with bendamustine (40 mg/m2 IV) on days 1, 2, 3 and surgical resection of the brain metastases on day 3. In patients undergoing surgery, plasma for bendamustine PK will be obtained on day 1 or 2 prior to, during, and up to 2 hours after bendamustine infusion. FSRT will start within 4 weeks after surgery (day 1 if no surgery). Patients will receive 30 Gy in 5 daily fractions (Mon-Fri). Bendamustine IV will be administered over 30 minutes starting 1.5 hours prior to daily FSRT. Patients will be escalated utilizing a phase I design, starting at 40 mg/m2 IV × 5 days. With the standard method of 3 patients per dose level and with 6 at the MTD, we will study a minimum of 6 and a maximum of 18 patients. Two patients have been accrued. Approved and funded by National Comprehensive Cancer Network (NCCN) from general research support provided by Cephalon, Inc; supported in part by NCI P30 CA16058. No significant financial relationships to disclose.
A first-in-human phase I study of BKM120, an oral pan-class I PI3K inhibitor, in patients (pts) with advanced solid tumors.
Authors: J. Baselga, M. J. De Jonge, J. Rodon, H. A. Burris, D. C. Birle, S. S. De Buck, D. Demanse, Q. C. Ru, M. Goldbrunner, J. C. Bendell
Journal: Journal of Clinical Oncology (2010)

3003 Background: The PI3K pathway is the most frequently aberrantly hyperactivated pathway in cancer. PI3K pathway inhibition is expected to have a strong impact on tumor survival and proliferation. BKM120 is a potent and highly specific oral pan-class I PI3K inhibitor. Unlike other inhibitors, it does not inhibit the related kinases—mTOR and Vps34. Methods: This was a phase I dose-escalation study of BKM120 given PO QD to adult pts with advanced solid tumors; a Bayesian logistic regression model with overdose control guided dose escalation was used. Results: 30 pts (13 m/17 f) were treated at 6 doses: 12.5 mg (1); 25 mg (2), 50 mg (5), 80 mg (1), 100 mg (17), 150 mg (4). Median age: 53 (37–76). Most common tumor types: colorectal (13) and breast (8 pts). Median duration on trial was 8 weeks (0.4–47+). 7 DLTs occurred: 2 grade (G)4 hyperglycemia at 150 mg, G3 upper abdominal pain, 2 G3 skin rash, and G2 and G3 mood alteration at 100 mg. The MTD was 100 mg. Treatment-related AEs in >10% of pts: rash, hyperglycemia, diarrhea, nausea, anorexia, pruritus, fatigue, mood alteration, malaise, vomiting, and mucositis. Preliminary PK data showed rapid absorption, with Cmax occurring at ∼1.8 h post-dose (0.5–4 h). Total body clearance from plasma (CL/F) was low: ∼4.5 L/h. BKM120 accumulated ∼3-fold in achieving steady-state, consistent with an effective half-life of ∼40 h. Doses ≥50 mg led to steady-state drug exposure (AUC0-24.SS) ≥10,000 ng*h/mL, a target preclinically estimated to be efficacious. BKM120 showed moderate median inter-individual variability (CV%) in systemic (AUC0-24, 28%) and peak (Cmax, 40%) exposure across all cohorts. Downregulation of pS6 in skin (mostly between 50–80%) was seen in all 15 evaluable pts at 100/150 mg. At 100 mg, 8 of 10 evaluable pts showed metabolic PR by FDG-PET, 1 pt had a confirmed partial response (triple negative BrCa) per RECIST, and 5 more pts had minor responses (2 BrCa, 1 CRC, 1 angiosarcoma, 1 lung cancer). In addition, 12 pts (40%) across all doses experienced disease stabilization for ≥4 months. Conclusions: BKM120 was evaluated from 12.5–150 mg. Daily oral dosing at 100 mg (MTD) showed a favorable PK profile, consistent PD changes, and clear signs of clinical activity. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Exelixis, Merck, Novartis, Roche Novartis
Prospective cardiotoxicity screening during tyrosine kinase inhibitor therapy for renal cell carcinoma: An institutional experience
Authors: R. M. Witteles, L. C. Harshman, M. Telli, S. Srinivas
Journal: Journal of Clinical Oncology (2009)

e16003 Background: Tyrosine kinase inhibitors (TKI) can lead to cardiotoxicity either directly by causing left ventricular dysfunction, or indirectly by increasing blood pressure. In light of prior studies at our institution documenting a high rate of symptomatic heart failure in patients with renal cell carcinoma undergoing treatment with sunitinib, we instituted a prospective screening protocol to characterize the incidence and natural history of TKI-associated cardiotoxicity. Methods: From March-December 2008, patients receiving TKI therapy for renal cell carcinoma received cardiac biomarker screening (NT- BNP and Troponin I at baseline and after week 4 of each cycle) and transthoracic echocardiography (baseline, 1 month, 3 months, and every 3 months thereafter). If biomarkers were elevated or a decline in ejection fraction was observed, patients were referred for cardiology evaluation. Results: Twenty-six patients have been included since the protocol's initiation. No elevations in cardiac troponin I have been observed to date. Eight patients (31%) had elevations in NT-BNP (a sensitive marker for heart failure). The TKIs involved included sunitinib (5 patients), sorafenib (2 patients), and bevacizumab (1 patient). One patient who was treated with sunitinib had frank left ventricular systolic dysfunction. Seven of the eight patients with elevated NT-BNP values had baseline hypertension, and five patients had significant increases in blood pressure during TKI treatment. In all patients with follow-up biomarkers, NT-BNP levels fell after initiation of heart failure therapy. TKI treatment appeared to ‘unmask’ previously subclinical cardiac injury, including prior silent myocardial infarction (one patient), left ventricular hypertrophy (four patients), and valvular disease (three patients). Updated data from the ongoing screening protocol will be presented. Conclusions: The Stanford TKI screening protocol identified a high rate of subclinical cardiotoxicity and allowed for early initiation of heart failure therapy. Further studies are needed to determine if this approach can decrease cardiac morbidity and improve oncologic outcomes by preventing discontinuation or dose interruption of TKI therapy. [Table: see text]
Epigenetic regulation of the thioredoxin-interacting protein (TXNIP) gene by hyperglycemia in kidney
Authors: Yang De Marinis, Mengyin Cai, Pradeep Bompada, David Atac, Olga Kotova, Martin E. Johansson, Eliana Garcia-Vaz, Maria F. Gomez, Markku Laakso, Leif Groop
Journal: Kidney International (2016)
C-reactive protein in differentiation between tuberculous and malignant pleural effusions
Authors: Mohamed Sedky, Ibrahim Radwan, Magda Mohamed
Journal: European Respiratory Journal (2011)

Although several studies have investigated the levels of C-reactive protein (CRP) in various diseases states, few have focused on its role in pleural effusion.  The aim of this study was to evaluate the value of pleural fluid and pleural/serum CRP in segregation between tuberculous and malignant pleural effusions.  CRP was measured in both pleural fluid and serum among 2 groups of patients, the first included 15 with tuberculous effusion diagnosed by Abram9s needle biopsy, while, the second incorporated 15 with malignant effusion diagnosed by either thoracoscopic or Abram9s biopsy.  A highly significant difference was demonstrated between pleural fluid CRP in tuberculous (29.07±9.32) and malignant (19.30±4.35) effusions. Moreover, serum CRP was significantly higher in tuberculous effusion (52.24±8.55) compared to malignant one (30.65±5.08). Furthermore, CRP pleural/serum ratio was significantly higher in malignant effusion.  In conclusion, CRP is a useful and cheap marker for differentiation between tuberculous and malignant pleural effusion.
Increased levels of CD4+CD25high and CD4+FoxP3+ T-regulatory cells (Tregs) in patients with different severity of bronchial asthma (BA)
Authors: Elena Kremer, Natalya Kirillova, Sergey Fedosenko, Ivan Deev, Ludmila Ogorodova
Journal: European Respiratory Journal (2011)

Background:  BA is characterized by persistent inflammation in the airways in response to allergens or other triggers. The intensity of the inflammation determines the severity of asthma. Levels of T-regs are important in balancing immune responses and maintaining peripheral tolerance. Our study sought to determine whether numbers of CD4+CD25high and CD4+FoxP3+ Tregs are related to airway inflammation and disease severity.   Aim and objectives:  To investigate the expression of surface molecules on Tregs in patients with different severity of bronchial asthma compared to healthy persons.   Methods:  Peripheral blood mononuclear cells of control (n=17) and asthmatic patients (mild BA, n=11; severe BA, n=17) were labeled for CD4, CD25 and intracellular FoxP3 and analysed using flow cytometry.   Results:  Numbers of peripheral blood CD4+CD25high was significantly decreased in asthmatic patients compared to healthy control. Patients with severe asthma had increased levels of CD4+CD25high and CD4+FoxP3+ compared to mild BA.   Conclusions:  Our findings suggest that decreased levels of Tregs in peripheral blood might contribute airway inflammation. Increase CD4+CD25high and CD4+FoxP3+ is important in balancing immune responses for prevention the severity of asthma.
Effect of Levamisole on Malignant Experimental Neurinoma Grown Subcutaneously in a Young Rat: Brief Communication2
Authors: S. Aleksic, F. Drnovski, A. Bloom, H. Rappaport, J. Ransohoff
Journal: JNCI Journal of the National Cancer Institute (1977)

Levamisole, a drug that stimulates the immunologic defenses of the host, was tested on the experimental malignant neurinoma grown subcutaneously in young female inbred CDF rats in a 3-month trial. The drug resulted in prevention of tumor growth in 80% of the treated animals, whereas tumors grew in 100% of the controls. After discontinuation of the drug, none of the animals in the treated group showed evidence of tumor growth upon clinical and pathologic examination 1 month after drug treatment was terminated. Treated animals failed to show any side effects related to levamisole upon clinical and pathologic examination.
Relation Between Smoking and Skin Cancer
Authors: Sofie A.E. De Hertog, Christianne A.H. Wensveen, Maarten T. Bastiaens, Christine J. Kielich, Marjo J.P. Berkhout, Rudi G.J. Westendorp, Bert J. Vermeer, Jan N. Bouwes Bavinck
Journal: Journal of Clinical Oncology (2001)

Tobacco smoking is a risk factor for several cancers. The risk of cutaneous malignancies related to smoking, however, is relatively unknown. We investigated the possible association between smoking and skin cancer.A hospital-based case-control study was performed that included 161 patients with squamous cell carcinoma, 301 with nodular basal cell carcinoma, 153 with superficial multifocal basal cell carcinoma, 125 with malignant melanoma, and 386 controls. Information on smoking history was collected in personal interviews. Relative risks were estimated using exposure odds ratios from cross-tabulation and logistic regression.An association between smoking and squamous cell carcinoma of the skin was found (relative risk, 2.3; 95% confidence interval, 1.5 to 3.6; P: = .0001), with a higher risk for current smokers (relative risk, 3.3; 95% confidence interval, 1.9 to 5.5) than for former smokers (relative risk, 1.9; 95% confidence interval, 1.2 to 3.0). After adjustment for age, sex, and sun exposure, the relative risk of squamous cell carcinoma was 2.0 (95% confidence interval, 1.2 to 3.2; P: = .008). There was a dose-response relationship with number of cigarettes and pipes smoked. No significant association was found between smoking and nodular basal cell carcinoma, superficial multifocal basal cell carcinoma, or malignant melanoma.Tobacco smoking is an independent risk factor for cutaneous squamous cell carcinoma.
Anaphylaxis in children and adolescents: The European Anaphylaxis Registry
Authors: Linus B. Grabenhenrich, Sabine Dölle, Anne Moneret-Vautrin, Alice Köhli, Lars Lange, Thomas Spindler, Franziska Ruëff, Katja Nemat, Ioana Maris, Eirini Roumpedaki, Kathrin Scherer, Hagen Ott, Thomas Reese, Tihomir Mustakov, Roland Lang, Montserrat Fernandez-Rivas, Marek L. Kowalski, Maria B. Bilò, Jonathan O'B. Hourihane, Nikolaos G. Papadopoulos, Kirsten Beyer, Antonella Muraro, Margitta Worm
Journal: Journal of Allergy and Clinical Immunology (2016)
Validation of a new questionnaire to assess the patient perception of cancer-related fatigue (CRF): The Perform Questionnaire (PQ)
Authors: C. Rodríguez, P. Gascón, J. García-Mata, R. Colomer, J. Cassinello, J. Carulla, V. Valentín, E. Baró, J. A. Gasquet, J. Sánchez
Journal: Journal of Clinical Oncology (2007)

19533 Background: CRF is a frequently reported complaint in cancer patients and survivors. There are scales available to measure the intensity, frequency and duration of CRF but there are few scales to assess patient perceptions and beliefs about CRF. The recently developed PQ attempts to fill this need. This study aims to validate the new measure. Methods: An observational and longitudinal multi- centre study was carried out on a sample of cancer patients with CRF. Data were collected at inclusion and 3 months later. The PQ was administered, as well as the FACT-F and Nottingham Health Profile (NHP) health measures, at both visits. Sociodemographic data, key clinical indicators, fatigue intensity (by means of a visual analogue scale) and self-rated stability for patient health status were also collected. Viability, reliability (internal consistency and test-retest) and validity were assessed for the PQ. Results: 431 patients were included in the study: 60.2% women, mean age 58.9 years, mean time since diagnosis 2.21 years 31.0% with breast cancer, 54.9% with metastatic disease, Karnofsky mean score 80.9, 28.8% with anaemia. Answering the PQ was considered moderately easy to very easy for 80.7% of patients. Answering the questionnaire took less than 10 minutes for 76.3% of the sample. Overall and dimension internal consistency were high (Cronbach alpha = 0.93 range 0.80–0.89). Test-retest reliability for overall score (intra-class correlation coefficient (ICC) = 0.81) and dimension scores (range 0.59–0.77) were also good in patients without changes in health status. The PQ had a stronger correlation with FACT (r=0.82) than with NHP (r=0.71), a moderate correlation with fatigue intensity (r=0.43), and low correlation with Karnofsky (r=0.26). Patients requiring third party care had a worse overall score for the PQ than patients who did not (30 vs. 37; p&lt;0.0001), while patients with anaemia showed a worse health- related quality of life than patients without anaemia (31.7 vs. 36.4; p&lt;0.0001). Conclusions: The PQ has demonstrated good reliability and validity for assessing patient perception of CRF in the study sample. Additional research is needed to obtain further insight into how the PQ performs with specific cancer populations. No significant financial relationships to disclose.
Effect of oxaliplatin combined with fever-range whole-body thermal-therapy in a rat mammary adenocarcinoma in vivo
Authors: Frederick R. Strebel, Jesse M. Proett, R. Wanda Rowe, Wanleng Deng, Joan M C Bull
Journal: Cancer Research (2006)

3847  BACKGROUND: Enhancement of the anti-cancer activity of several platinum agents when combined with thermal therapy (hyperthermia) is observed in a number of murine tumor models. We have shown in rats that optimal scheduling of platinum anti-tumor drugs with thermal therapy increases the therapeutic index (TI). This study investigated the scheduling effects of oxaliplatin (Ox), a promising new platinum drug, combined with fever-range whole-body thermal-therapy (FR-WB-TT) in vivo, in the clinically relevant MTLn3 rat mammary adenocarcinoma model. METHODS: Female Fischer 344 rats bearing an orthotopically implanted MTLn3 tumor (n = 6/group) were treated with Ox (11 mg/kg i.v.), Ox 24 h before FR-WB-TT (40°C for 6 h), Ox during (at start of) FR-WB-TT, and αx 24 h after FR-WB-ΤΤ. Anti-tumor effect was assessed by relative tumor volume (RTV) compared to control and tumor growth delay (TGD). Response was characterized as RTV
LSC 2012 abstract - Imaging Wnt/beta-catenin signalling in an ex vivo tissue culture model of lung repair
Authors: Franziska Uhl, Melanie Königshoff
Journal: European Respiratory Journal (2012)

Emphysema is a pathophysiological hallmark of COPD and characterized by airspace enlargement and impaired alveolar repair processes. Recently, decreased Wnt/β-catenin signalling has been linked to emphysemateous changes in human disease and animal models thereof. Here, we aim to further decipher the underlying mechanisms and image structural changes involved in lung repair processes.  We applied an ex vivo tissue culture model from wildtype (C57Bl/6) and Wnt reporter mice (Bat-/TopGal) subjected to elastase treatment or PBS. Tissue slices (300 μm) generated using a vibratome were viable in culture for up to 7 days ex vivo (WST-1: d3 211 ± 68 % vs. d7 241 ± 67 %). Structural integrity of control (C) and emphysemateous (E) lung slices was determined by qPCR and immunofluorescence for lung specific cellular markers as well as live tissue imaging. Functional Sftpc was decreased in E lung slices compared with control and further decreased over time shown by ELISA (d1: 135 ± 19 ng/ml C vs. 82 ± 17 ng/ml E). Wnt signalling activation by LiCl led to an increase in Sftpc expression accompanied by increased β-galactosidase staining in alveolar regions and upregulated target gene expression, such as Axin2, Dkk2 or Lef1.  Emphysemateous tissue slices closely reflect COPD-like changes in vivo. Lung slices are viable up to 7 days ex vivo allowing determination of structural changes and cell fate in the diseased lung upon signal pathway modification.
Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: Prognostic impact of clinical observations and laboratory findings at presentation
Authors: W. Siegert, C. Nerl, A. Agthe, M. Engelhard, G. Brittinger, M. Tiemann, K. Lennert, D. Huhn
Journal: Annals of Oncology (1995)
Vinflunine in combination with trastuzumab for treatment of HER2-positive metastatic breast cancer
Authors: R. Paridaens, H. Wildiers, F. Dalenc, O. Rixe, V. Cadic, M. Pinel, H. Roche
Journal: Journal of Clinical Oncology (2007)

1058 Background: Vinflunine (VFL) is a microtubule inhibitor of the vinca alkaloid class with high activity in several tumour types especially in second line treatment of metastatic breast cancer (MBC). Over-expression of HER2 is observed in 20–25% of all breast cancers and is associated with a poor prognosis. The development of the anti-HER2 therapy with trastuzumab (T) allowed significant prolonging of the survival in HER2 positive MBC. The combination of these two compounds which are separately active in MBC warranted a combination study. Methods: This phase I was designed to determine the recommended dose (RD) of VFL in combination with T for treatment of first or second line MBC patients (pts), to assess its safety profile, and to determine its antitumour activity. Results: Thirty pts, median age 55 [33–74] years, WHO performance status 0/1: 18/12 pts , respectively were given VFL 280 mg/m 2 (10 pts) or 320 mg/m 2 (20 pts) day 1 every 3 weeks (w) in combination with T (loading dose 4 mg/kg and subsequently 2 mg/kg/w). Six pts were chemonaive and 5 pts received this combination in second line. At the first VFL dose (280 mg/m 2 ), 0/6 pts experienced dose-limiting toxicity. The RD was established at 320 mg/m 2 in the following 6 pts. All 30 pts are evaluable for safety. Haematological toxicities were: anaemia grade (G) 3: 0 and 1 pt; neutropenia G 3/4: 5/17 pts, febrile neutropenia 0/2 pts with VFL 280 and 320 mg/m 2 , respectively. G 3 non-haematological adverse events were only reported in the 20 pts receiving VFL 320 mg/m 2 : fatigue and myalgia: 5 pts; constipation: 4 pts; abdominal pain, neutropenic infection: 2 pts. ileus, hyponatremia, arthralgia: 1 pt. No significant cardiac events were observed. The response rates, 62.5% [95% confidence interval: 24.5–91.5] and 73.7% [95% confidence interval: 48.8–90.9] in pts receiving VFL at 280 mg/m 2 and 320 mg/m 2 respectively, were established by an external radiologist using RECIST in the first 27 evaluable patients. Conclusions: Vinflunine/trastuzumab combination is feasible with encouraging response rates and manageable toxicity in MBC pts. A phase III study comparing VFL + T versus paclitaxel + T has been initiated. No significant financial relationships to disclose.
Abstract 292: Maternal Transfer of Anti-Cardiac Myosin Antibody Induces Dilated Cardiomyopathy and Underdevelopment of Aortic Arch in Newborn Rats
Authors: Giv Heidari-Bateni, Lisa Goessling, Anoop Brar, Madeleine Cunningham, Pirooz Eghtesady
Journal: Circulation Research (2013)

Introduction: Anti-cardiac myosin (CM) antibodies are induced following certain infectious diseases. We evaluated for the first time the effect of maternally-transferred anti-CM antibody on the newborn heart in a rat model. Methods: Female Lewis rats were immunized with 1 µg of emulsified CM and boosters (0.5 µg) were administered every 2 weeks, followed by mating; control rats (n=3) were injected with saline. After birth, pups were continually housed with dams. Echocardiography was performed on pups on day 20. Pups were sacrificed on day 21 and hearts were fixed, sectioned, and analyzed for morphological changes. Trichrome staining was performed to detect fibrotic changes. Results: All the pups in CM group (n=22) showed anti-CM antibody titers of more than 12800. Echocardiographic study revealed that 45.4% (10/22) of pups in the CM group had evidence of decreased left ventricular systolic function. The affected pups had both thinner anterior and inferior left ventricle walls compared with pups in control group (3.43±0.33 vs. 3.82±0.24, p=0.017 and 3.71±0.32 vs. 4.18±0.31, p=0.009 respectively). There were also evidence of underdevelopment of thoracic aorta and aortic arch (3.1±0.16 vs. 3.3±0.16 for ascending aorta diameter, p=0.002 and 2.6±0.14 vs. 2.8±0.25 for descending aorta diameter, p=0.008). Morphological changes consistent with dilated cardiomyopathy (image) and fibrosis were detected. Conclusion: Maternal anti-CM antibodies can cross the placenta and affect the development of the newborn heart; the resulting phenotype is one of dilated cardiomyopathy with associated hypoplasia of vascular structures perhaps secondary to reduced flow.