tbuckley/cabot-search huggingface dataset:
Heat shock protein: a hot topic in idiopathic pulmonary fibrosis
Authors: Philippe Bonniaud, Pierre-Simon Bellaye, Olivier Burgy, Martin Kolb
Journal: European Respiratory Journal (2017)

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung parenchyma, causing significant morbidity and mortality [1, 2]. The therapeutic options in IPF are limited to only two recently approved drugs, pirfenidone and nintedanib, which have been shown to slow progression but are not able to stop or reverse the disease [3, 4]. Better pathophysiological knowledge is needed to develop new therapeutic strategies in IPF. The current understanding of the disease is that fibroblastic foci, characterised by accumulation of myofibroblasts and overlying "activated" epithelium, represent "hot zones" of the disease and drivers of abnormal extracellular matrix (ECM) accumulation [5]. Transforming growth factor (TGF)-β1 is a key cytokine involved in the process of fibrogenesis. TGF-β1 causes myofibroblast proliferation and differentiation and increases the synthesis of collagen, fibronectin and many other ECM components [5]. The TGF-β1 signalling pathways are complex and occur essentially through serine/threonine kinase receptors, TGF-β receptors type I and II (TGF-βRI and TGF-βRII). TGF-βRII is constitutively active and activates TGF-βRI via phosphorylation upon ligand binding [6]. The cytoplasmic proteins Smad2 and Smad3 predominantly mediate signals from activated TGF-β1 receptors. Activation of Smad2 and Smad3 via phosphorylation makes them bind to Smad4, promoting translocation to the nucleus where numerous TGF-β1-responsive genes are activated. TGF-β1 pathways are undoubtedly very promising but also challenging targets to treat fibrosis and in particular IPF. HSP90 inhibition could be an exciting new treatment strategy for IPF <http://ow.ly/HfKY306uvxw>
Neoadjuvant chemotherapy with gemcitabine-containing regimens in stage I-II non-small cell lung cancer (NSCLC): Initial results of pre-operative pulmonary function testing (PFTs) in the GINEST project
Authors: M. P. Rivera, F. C. Detterbeck, M. A. Socinski, D. Moore, M. J. Edelman, T. M. Jahan, R. H. Ansari, J. D. Luketich, C. K. Obasaju, R. J. Gralla
Journal: Journal of Clinical Oncology (2005)

7227 Background: Several chemotherapy agents including gemcitabine (Gem) and paclitaxel (Tax) have been reported to cause interstitial pneumonitis. The incidence of pulmonary toxicity from the combination of Gem-Tax is reported to be 5–10%. The GINEST Project consists of two similar randomized phase II trials testing platinum and non-platinum regimens preoperatively in patients with Stage I or II NSCLC. This report focuses on PFT analysis; additional study objectives include response and survival outcomes, as well as quality of life. Methods: The regimens in Trial 1 included Gem/carboplatin (GCb)and Gem/paclitaxel (GT); in trial 2, GCb and Gem/cisplatin (GC). PFTs and dyspnea scores were obtained pre and post chemotherapy (chemo) to assess one of several secondary endpoints: drug-induced pulmonary injury and effect on ability to undergo surgical resection. Results: Pre and post chemo PFT data was available in 42/54 pts in trial 1 and in 20/28 pts in trial 2. In this combined group of 62 pts, the diffusing capacity (DLCO) % predicted was reduced by 9% post chemo with a p value of 0.0030 and 0.0012 respectively. The change in FVC, FEV1 and TLC were not statistically significant after chemo. In this same group of pts, 9 (15%)had a >20% reduction in the DLCO (a change considered significant) post chemo. 12 pts (9 in trial 1 and 3 in trial 2) reported a mild change in their dyspnea scale post chemotherapy, 2 of which were included in the group with a >20% reduction in the post chemo DLCO. No severe respiratory events were reported in any of the patients. 2/62 did not undergo surgery due to a reduction in the FVC and FEV1 after chemo. Conclusion: In the preoperative setting, Gem-based chemotherapy is safe. The most commonly affected PFT parameter post chemo was the DLCO. While 15% of patients had a significant reduction in the DLCO post chemo, it did not correlate with clinical symptoms nor did it impact on ability to undergo surgical resection. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly, Lilly Oncology, Bristol-Myers Squibb Eli Lilly Eli Lilly, Lilly Oncology, Bristol-Myers Squibb, Pfizer, AstraZeneca, Aventis, Amgen Eli Lilly, Aventis, Genentech, Lilly Oncology, Bristol-Myers Squibb, Pfizer, AstraZeneca, Aventis, Amgen Lilly Oncology, Bristol-Myers Squibb
EGFR intron 1 CA dinucleotide repeat as predictor of toxicity and efficacy in lung cancer patients treated with erlotinib
Authors: J. Garcia-Donas, S. Leskelä, J. M. Sanchez, J. C. Camara, N. Rodriguez, S. Hernando, A. Hurtado, M. Robledo, C. Jara, C. Rodríguez-Antona
Journal: Journal of Clinical Oncology (2008)

14566 Background: The length of the CA dinucleotide repeat in epidermal growth factor receptor (EGFR) intron 1 has been proposed to play an important role in the biological effects of tyrosin kinase inhibitors. Thus, we compared this polymorphism with the grade of skin toxicity in non-small cell lung cancer (NSCLC) patients treated with erlotinib. An exploratory analysis of clinical benefit rate and progression-free survival was already planned. Methods: Metastatic or locally advanced unresectable NSCLC patients treated orally with 150 mg/d of erlotinib in our institution were eligible. Rash was assessed according to a modified scale based on the Common Toxicity Criteria v.3.0; clinical benefit rate was defined as the sum of complete response, partial response or stable disease; progression-free survival was the time measured from the treatment start to progression. Only cases without EGFR pathogenic mutations were included in the efficacy analysis. Genomic DNA was isolated from peripheral blood; the length of the EGFR intron 1 CA dinucleotide repeat was evaluated by PCR and analyzed on a capillary sequencer. EGFR mutations were determined in neoplastic tissue. Intron 1 CA alleles were considered “short” if the sum of CA repeats of both alleles was ≤33 (group A), and “long” otherwise (Group B). Results: 23 patients were evaluated (7 retrospectively and 16 prospectively). The most common EGFR genotypes were: 16 and 20 CA repeats (with 46 and 28% frequency, respectively). Rash severity was higher in group A (p=ll seven cases with 0 grade skin toxicity belonged to Group B. 2 cases presented EGFR mutations; thus, 21 were finally included in the efficacy analysis. Clinical benefit rate was 62% (CI 95% 24% to91%) in group A and 33% (CI 95% 7%-70%) in group B. Median progression-free survival was 3.5 months (CI 95% 0–7.2) and 1.3 months (CI 95% 0–2.9) in groups A and B respectively. Conclusions: the length of the CA repeat in EGFR intron 1 accurately predicts skin toxicity of erlotinib in NSCLC. In absence of pathogenic mutations, this polymorphism seems to identify a subgroup of patients that could obtain benefit of this treatment. Larger studies are needed to address this hypothesis. No significant financial relationships to disclose.
A functional assay for the identification of DNA double-strand break repair deficiency in heterozygous carriers of <i>BRCA1/2</i> and <i>RAD51C</i> mutations.
Authors: A. Becker, M. Graeser, C. Landwehr, T. Hilger, W. Baus, R. Weber, B. Wappenschmidt, R. Schmutzler
Journal: Journal of Clinical Oncology (2011)

561 Background: Mutations in breast cancer gene 1 and 2(BRCA1/2) account for 50% of the familial aggregation of breast and ovarian cancer. About one third of the mutations are of unknown pathogenetic relevance (unclassified variants, UCV). We recently identified RAD51C as a third high penetrance gene (Meindl et al., 2010). Like BRCA1/2, RAD51C is also involved in homologous recombination repair (HRR) in response to DNA double strand breaks. It has recently been shown that cells with HRR deficiency are sensitive to synthetic lethality mediated by PARP inhibition. Under the assumption that further high risk genes may exist which acts through the HRR pathway we aimed to develop a reliable functional test system which allows the evaluation of HRR deficiency in heterozygous carriers. Methods: We included eight carriers of a pathogenic BRCA2 mutation, two carriers of a pathogenic RAD51C mutation and nine healthy controls as well as seven BRCA2 UCV carriers. Patient and control lymphocytes were γ-irradiated in G2 phase to introduce DNA-DSB. For the assessment of HRR capacity, metaphase chromosomes were stained by multicolour fluorescence in situ hybridisation (M-FISH). Chromosomal translocations and breakages were counted per mitosis and referred to total chromosomal number. The aberration frequency of BRCA2 and RAD51C carriers versus the controls was compared. Results: Lymphocytes from BRCA2 and RAD51C pathogenic mutation carriers versus controls showed a mean aberration frequency of 2.51±0.36 (standard deviation, SD) and 2.7±0.25 (SD), respectively, versus 1.4±0.44 (SD) chromosomal aberrations per metaphase with no overlap (p-value <0.001; Student’s t-test). Seven patients carrying an UCV in BRCA2 could be allocated to either the pathogenic or the control group. Conclusions: Our test system allows the detection of HRR deficiency in heterozygous lymphocytes of BRCA2 and RAD51C gene mutation carriers and is currently evaluated in BRCA1 positive cases. The assay may enable the identification of HRR deficiency irrespective of the underlying gene defect and may also serve as a biomarker for sensitivity to PARP inhibition.
The assessment value of FLT and FDG PET/CT for lymph node staging in thoracic esophageal squamous cell carcinoma.
Authors: X. Zhong, D. Han, J. Yu, Z. Fu, D. Mu, W. Yang
Journal: Journal of Clinical Oncology (2010)

e14599 Background: We used pathological examination as golden standard to determine whether 3-deoxy-3-18F-fluorothymidine (FLT) PET/CT can accurately assess lymph node staging in untreated thoracic esophageal squamous cell carcinoma, and additionally performed 18F-fluorodeoxyglucose (FDG) PET/CT for direct comparison with that of FLT. Methods: 22 patients with thoracic esophageal squamous cell carcinoma underwent dual-tracer PET/CT examinations before surgery. The results of reviewing CT images and side-by-side FDG PET and FLT PET images for the diagnosis of locoregional lymph node metastasis were compared prospectively in relation to pathologic findings. All patients underwent esophagectomy and lymphadenectomy. Results: Pathologic examination confirmed nodes positive for metastasis in 16 patients and 47 of 424 excised nodes. The uptake of FDG (median SUVmax, 5.4; range, 2.4–10.6) in locoregional lymph nodes metastases was significantly higher than that of FLT (median SUVmax, 2.8; range, 1.3–4.6). There were 14 false positive nodes in FDG PET/CT and only 3 in FLT PET/CT, 8 false negative nodes in FDG PET/CT, while 12 false negative nodes in FLT PET/CT. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of FLT PET/CT were 74.47%, 99.20%, 96.46%, 92.11% and 96.89%, respectively, whereas those of FDG PET/CT were 82.98%, 96.29%, 94.81%, 82.98% and 96.29%, respectively. P values were 0.450, 0.014, 0.313, 0.050 and 0.555, respectively. Conclusions: FLT uptake in regional lymph nodes of esophageal carcinoma is significantly lower compared with FDG uptake. FLT PET/CT has fewer false-positive findings and higher specificity compared with FDG PET/CT. No significant financial relationships to disclose.
The impact of tailored nutrition intervention and dietary counseling on body weight in female cancer cachexia patients in India.
Authors: Neha Kapoor, Ihab Tewfik, Jane Naufahu, Sundus Tewfik, Rakesh Garg, Sushma Bhatnagar
Journal: Journal of Clinical Oncology (2014)

67 Background: The prevalence of malnutrition, amongst cancer palliative patients, is 81%. As cancer progresses, patients’ develop malnutrition owing to metabolic changes and ill-effects of treatment. The aim of this study was to improve nutritional status of female cancer patients and their quality of life by counseling and providing nutrient rich natural food (IAtta). Methods: Female cancer patients (n=45) attending palliative care clinic (AIIMS, New Delhi); with symptoms of cachexia were randomly distributed into control (Group one, n=23) and intervention group (Group two, n=22). Both groups were provided with nutritional counseling while the intervention group also received 100grams of IAtta, to be consumed daily for three months. Anthropometric measurements [weight, muscle mass, percentage body fat (%BF) and mid upper arm circumference (MUAC)], dietary intake (two day dietary recall) and quality of life (European Organisation for Research and Treatment of Cancer-Quality of Life C30 Questionnaire) were assessed at baseline and after three months. Data was analysed using paired t-test and Wilcoxon signed-rank test on the variables assessed. P-value &lt; 0.05 was considered statistically significant at 95% confidence interval. Results: Patients in group one had significantly decreased body weight (p= 0.001), muscle mass (p= 0.021), MUAC (p= 0.005) and %BF (p= 0.001) by end of three months. While patients in group two reported significant improvement in fatigue (p= 0.001) and appetite loss score (p= 0.002) under quality of life domains. Conclusions: Nutritional counseling along with IAtta food supplementation helps in stabilising weight and improves quality of life of cancer cachexia patients undergoing palliative care treatment. Clinical trial information: RP- 02/17.06.2013. [Table: see text]
Dying with breast cancer: An audit
Authors: M. Clemons, L. Zalany, T. Marcus, G. Beaudoin, A. Blair, B. Fitzgerald, J. Sue, J. Fralick, C. Simmons
Journal: Journal of Clinical Oncology (2005)

8154 Background: Most patients dying of metastatic breast cancer (MBC) would prefer to die at home if possible. Unfortunately, significant discordance exists between preferred & actual location of death, with less than 30% of pts dying at home. The low incidence of home death is associated with a low rate of palliative care referral & a high rate of specialist care at the end of life. At our centre coordination of palliative care & supportive care services is facilitated by a dedicated social work (SW) team. The purpose of our study was to review the management of end of life care of MBC pts to determine if it was consistent with their wishes & to identify areas of improvement. Methods: Pts with MBC who died under the care of one oncology team between October 2001 & October 2004 were identified. Pt demographics, place of death, & expressed preference for place of death were recorded. Health care professionals involved with each pt were interviewed. Results: 63 pts died during the audit period. Mean age was 60 yrs (30–92 range). Median time with metastatic disease was 25 months (range 1 week-125 months). 82% had end of life discussions with the oncologist, & this took place a median of 75 days before death (range 2–983 days). While 71% of pts expressed that they wished to die at home, only 33% actually did. 26% died in a palliative care unit, & 40% died in an acute care setting. 85% of pts were seen by SW prior to death. Health care professionals felt earlier referral to SW & earlier discussion of palliative care services may help meet pts needs. Conclusions: Despite the presence of a coordinating supportive care team, there remains a significant discordance between pt wishes & actual place of death. From clinical experience, while many acute hospital admissions at the end of life occur due to poor coordination of palliative resources or primary care-giver distress, earlier referral to SW may help in the coordination of resources to improve pt management. No significant financial relationships to disclose.
A cost model of capecitabine versus continuous infusional 5-fluorouracil (CI5FU) as chemosensitization during long course radiotherapy in the neoadjuvant treatment of rectal cancer: From the perspective of the Australian health care system.
Authors: Robin John Paterson, Kelly Randall, Fiona Day
Journal: Journal of Clinical Oncology (2015)

688 Background: Recent phase III clinical trials have shown that the use of capecitabine with long course radiotherapy in the neoadjuvant treatment of rectal cancer provides equivalent outcomes to the traditionally used CI5FU. In the Australian health system the dispensed price of capecitabine is higher; however CI5FU administration requires a peripherally inserted central catheter (PICC). This analysis was designed to test the comparative cost of capecitabine over CI5FU from the perspective of the Australian healthcare system. Methods: We determined fully itemised direct treatment costs for the administration of neoadjuvant long course chemoradiotherapy with each of capecitabine and CI5FU. A decision analytic model was then used to compare potential clinical adverse events with the respective agents. Clinical probabilities were derived from published studies and the management of adverse events costed using Australian refined diagnosis-related group (AR-DRG) coding. The results of the decision analytic model were integrated with the drug administration costs to produce an inclusive discriminating cost for capecitabine versus CI5FU. Results: The total cost to the Australian healthcare system for the administration of CI5FU was $2,110 per patient, compared with $1,170 for capecitabine. The costs of managing treatment complications were similar: mean $174 per patient for CI5FU and $72 for capecitabine. The integrated discriminating cost difference was a mean saving of $1,042 per patient with prescription of capecitabine. The presented base-case model utilised higher capecitabine costs where input data could vary, and hence in all sensitivity analyses capecitabine continued to demonstrate cost savings (minimum $286 and maximum $1,975 per patient) over CI5FU. Conclusions: Capecitabine is a cost effective alternative to CI5FU. Considering also the expected lower indirect costs with oral therapy, use of capecitabine in chemoradiotherapy for rectal cancer is economically superior.
VHL protein (pVHL) and Src expression in metastatic RCC.
Authors: Kyle William Robinson, Yiyi Chen, Jennifer Podolak, Kerri Forquer, Megan Cook, George Thomas, Christopher W. Ryan
Journal: Journal of Clinical Oncology (2013)

457 Background: Rational therapeutic strategies are lacking for RCC with intact pVHL expression. We recently demonstrated that Src signaling output was elevated in RCC cells expressing pVHL (Suwaki Sci Transl Med 2011). We sought to prospectively identify and clinically characterize RCC patients according to tumor expression of pVHL and Src using an immunohistochemical (IHC) assay, including the association of pVHL and Src expression with response to targeted therapies. Methods: Metastatic RCC patients with available archival tumor tissue provided written informed consent. Primary and metastatic tumors were evaluated by IHC staining using the following scale: 0: absent; 1: weak; 2: moderate-strong. We scored the percent of tumor cells staining at these intensities, giving a total possible score of 200. Association of pVHL and Src score was determined using Spearman correlation coefficient. Time to treatment failure (TTF) &gt; 300 days was used to stratify patients as treatment success versus failure. Logistic regression was used to analyze whether there was an association between pVHL and Src staining and clinical outcome, and ROC curve analysis was used to find the predictive ability of pVHL and Src positivity. Results: 27 patients were consented, from which the nephrectomy specimens of 23 patients and 17 metastatic tumor samples were available. 22 patients had received systemic therapy (21 with VEGF TKI, 1 with mTOR-I). Expression of pVHL and Src were positively correlated (p&lt;0.001). Expression of pVHL in primary tumor, but not Src, was associated with fewer treatment failure events (p=0.0384). Those who had TTF &gt; 300 days had a mean pVHL score of 127.3, and Src of 134, while those with TTF &lt; 300 days had mean pVHL of 57.5, and Src 89.5. Performing ROC analysis, the combination of pVHL and Src score displayed a higher area under the curve (c=0.8) in predicting treatment failure or success than pVHL or Src score alone. Conclusions: We have shown a correlation between pVHL and Src expression in tumors from a prospective population of RCC patients. Accrual continues to this study of a novel quantitative IHC profile that could identify patients for whom currently available therapies may not be effective or for whom a clinical trial of a Src inhibitor may be appropriate.
Neoadjuvant chemotherapy with gemcitabine-containing regimens in patients with early stage non-small cell lung cancer (NSCLC): Initial results of the GINEST • project
Authors: F. C. Detterbeck, M. A. Socinski, R. J. Gralla, M. J. Edelman, T. M. Jahan, D. M. Loesch, S. A. Limentani, R. Govindan, L. P. Bloss, C. K. Obasaju
Journal: Journal of Clinical Oncology (2005)

7215 Background: Several trials have indicated survival advantages for both neoadjuvant and adjuvant approaches in NSCLC. Controversy continues as to which chemotherapy regimens to use and in which stages of NSCLC benefit occurs. The GINEST Project consists of two similar randomized phase II trials testing platinum and non-platinum regimens preoperatively in patients with Stage I or II disease. This analysis reports on response, survival, and toxicity, additional study objectives include quality of life and PFT evaluation. Methods: 82 patients with clinical stage I (24%) and Stage II (76%) NSCLC were randomized to preoperative chemotherapy with either Gemcitibine 1000mg/m2 D1,8 plus Carboplatin AUC 5.5 D1(GCb) or Gemcitabine 1000mg/m2 D1,8 plus paclitaxel 200mg/m2 D1 (GT) on the first trial (54pts). In the second trial, pts received the same regimen of GCb or G 1000mg/m2 D1,8 plus Cisplatin 75 mg/m2 D1 (GC) (28 pts). Each doublet was given for 3 cycles every 21 days. Patients were stratified by stage between the two arms of each trial. The primary endpoint was pathologic complete response (pCR). Results: Hematologic side effects were the most common toxicity overall; pts with Grade 3,4 leukopenia and thrombocytopenia = 24 (30%) and 8 (10%) respectively. Most frequent Grade 3,4 nonhem toxicities included arthralgias = 4 (5%); neurotoxicity = 3 (4%); diarrhea, fatigue, & cellulitis = 2 (2%) each. To date, the overall complete resection rate is 73% (60), with 9% (7) undergoing an incomplete resection, with no clear difference between the chemo arms. 16 pts (18%) did not undergo surgery due to either PD (5); adverse event (5); not suitable (4); pt decision (2). Surgical procedures were lobectomy 71%; pneumonectomy 17%; bilobectomy 12%. Perioperative mortality rate was 2%. Currently 1 pCR has been validated. To date, survival at 1 yr is 74% overall. Conclusion: Neoadjuvant chemotherapy with G as part of either platinum or non-platinum doublet is feasible and well tolerated. Rates of resectability, response and survival are competitive with other reports of this treatment strategy for this pt population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly, Lilly Oncology, Bristol-Myers Squibb Eli Lilly Eli Lilly, Lilly Oncology, Bristol-Myers Squibb, Pfizer, AstraZeneca, Aventis, Amgen Eli Lilly underwrites US Trial 02099 in breast cancer, Aventis, Genentech, Lilly Oncology, Bristol-Myers Squibb, Pfizer, AstraZeneca, Aventis, Amgen Lilly Oncology, Bristol-Myers Squibb
Immunotherapy of Acute MYELOID LEUKEMIA: ANTI-LEUKEMIC EFFECTS by Unprimed or Primed, Selected or Unselected Effector T-CELLS.
Authors: Helga Schmetzer, Friedhelm R Schuster, Raymund Buhmann, Markus Freudenreich, Georg Doessinger, Anja Liepert, Christine Grabrucker, Brigitte Steger, Susanne Reuther, Andreas Kremser, Julia Loibl, Dorothea Fischbacher, Christoph Schmid, Tanja Kroell, Dirk Busch, Arndt Borkhardt, Hans-Jochem Kolb
Journal: Blood (2009)