tbuckley/cabot-search huggingface dataset:
A phase I study of the mitochondrial metabolism inhibitor CPI-613 in combination with high-dose ara-C (HDAC) and mitoxantrone for relapsed or refractory acute myeloid leukemia (AML).
Authors: Timothy S. Pardee, Kristin Stadelman, Scott Isom, Leslie R. Ellis, Dmitriy P. Berenzon, Robin Harrelson, Megan Manuel, Sarah Dralle, Susan Lyerly, Bayard L. Powell
Journal: Journal of Clinical Oncology (2014)

7028 Background: Altered metabolism is an emerging hallmark of cancer and a possible therapeutic target. CPI-613 is a first in class agent that targets mitochondrial metabolism.This trial was designed to determine the maximum tolerated dose, safety, and efficacy of CPI-613 given in combination with HDAC and mitoxantrone in patients with relapsed or refractory AML. Methods: CPI-613 was given daily on days 1 through 5 starting at a dose of 500 mg/m2. Beginning on day 3, HDAC at 3,000 mg/m2 (or 1,500 mg/m2 for age ≥60) was given every 12 hours for 5 doses and mitoxantrone at 6 mg/m2 was given daily for 3 doses. The CPI-613 dose was escalated to 2250 mg/m2. If residual disease was present on day 14 re-induction with the same or a three day abbreviated course could be given. Patients who achieved a complete remission (CR) or CR with incomplete count recovery (CRi) could receive additional consolidation cycles. Results: A total of 24 patients were enrolled. The median age was 58 (range 21-76). Four patients had refractory disease and six received two or more previous lines of therapy. In patients with relapsed disease the median duration of CR1 was 7.5 months. Cytogenetics were poor risk in 13 patients, intermediate in 8 and good in 3. The response rate was 54% (11CR+2CRi). In patients ≥60 years old the CR/CRi rate was 55% (6/11). In patients with poor risk cytogenetics the CR/CRi rate was 53% (7/13). In a historical cohort of patients treated with HDAC, mitoxantrone and asparaginase, only 25% (4/16) of patients with poor risk cytogenetics achieved a CR/CRi. Five patients (21%) died on or before day 30. Two patients with circulating blasts had blood samples taken before and after CPI-613 infusion. Samples from a patient who cleared her marrow demonstrated robust phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) consistent with depletion of ATP. This phosphorylation was not seen in a patient with persistent disease. Conclusions: CPI-613 in combination with HDAC and mitoxantrone is a promising salvage regimen, especially in older patients and those with high risk disease. Induction of AMPK phosphorylation may serve as a predictor of response. Clinical trial information: NCT01768897.
Toxicity monitoring in phase I/II clinical trials with applications at James Graham Brown Cancer Center Clinical Trials.
Authors: Shesh Rai, Herman Ray, Jianmin Pan
Journal: Journal of Clinical Oncology (2014)

e14021 Background: Phase II clinical trials are usually designed to measure efficacy but patient safety is also a very important aspect, especially now that combination therapies are becoming increasingly common. In smaller trials, high grade toxicities in a limited subset of enrolled patients may create undue disruption of the trial. Methods: We (Ray and Rai) have developed methods for continuous monitoring of trials that should prevent accrual and treatment delays (Contemporary Clinical Trials, 2011; Pharmaceutical Statistics, 2012 and Statistical Methods in Medicine, 2013). We have further advanced these methods to account for association between response and toxicity rates in formal monitoring for efficacy and toxicity in Phase II clinical trials. Results: Consider a phase II trial which is designed using a Simon’s two stage design with n1=42 (total n=70) to detect 15% increase in response rate at alpha=5% and power=80%. Suppose the new combination treatment is considered not to be safe if grade 3/4 toxicity rate is higher than 33%. Using our systematic approach study will continue treating subjects even though first 4 out of 4 or 5 have developed grade 3/4 toxicity. We have applied the procedures at our institutional studies and will demonstrate the simplicity of the approach with some demonstrations. Conclusions: Our approach is a very systematic approach for monitoring toxicity in addition to monitoring for futility/efficacy in Phase II trials.
Investigation of the role of polycystin-1 and polycystin-2 in colorectal cancer.
Authors: Antonis N. Gargalionis, Penelope Korkolopoulou, Christina Piperi, Georgia Dalagiorgou, Elena Farmaki, Christos Adamopoulos, Georgia Levidou, Adamantia Zizi-Serbetzoglou, Ioannis Karavokyros, Evi Fragkou, Panagiota Tsioli, Angelica Saetta, Kostas Papavassiliou, Michalis Karamouzis, Nicolas Tsavaris, Efthimia K. Basdra, Athanasios G. Papavassiliou
Journal: Journal of Clinical Oncology (2014)

e14592 Background: Polycystin-1 and polycystin-2 (PC1, PC2) represent a family of proteins, which are expressed in a variety of epithelial cells and contribute to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). Their role in cellular homeostasis and their capacity in mediating cell–cell and cell–matrix interactions imply a potential involvement in tumor invasive and metastatic processes. The aim of this study was to investigate the expression levels of PC1, PC2, and those of downstream activated molecules of the mammalian target of rapamycin (mTOR) pathway in colorectal cancer (CRC), as well as to elucidate further molecular mechanisms engaged in the regulation of the mTOR pathway by the two proteins. Methods: Immunohistochemical detection of PC1, PC2, p(phospho)-mTOR, and p(phospho)-p70S6K expression was performed in paraffin-embedded tissues of 190 patients. The molecular mechanisms were explored after transient transfections in human CRC cell lines (SW480, HCT116, and HT29) by Western immunoblotting, immunofluorescence, and flow cytometry. The mRNA expression of epithelial-to-mesenchymal transition (EMT) markers was detected by quantitative real-time PCR. Results: A positive correlation was observed between PC1 and PC2 expression (R=0.1575, p= 0.0489), but also between PC2 and p-mTOR expression (R=0.01609, p=0.0532). PC1 and PC2 increased expression levels were correlated with grade III (p=0.0319, p=0.06), increased depth of invasion (p= 0.0397, p=0.0311), and mucinous carcinomas (p=0.0001), whereas in multivariate analysis high PC1 expression emerged as an independent negative prognostic factor of recurrence-free survival (HR[hazard ratio]=1.016, p=0.03). PC1 overexpression promoted EMT process in HCT116 dedifferentiated cells, and SW480 cells transfected with PC1 and PC2 genes revealed an induced regulation of the mTOR protein kinase downstream molecules. Conclusions: PC1 and PC2 constitute two novel cancer-related molecules which are associated with the development of an aggressive phenotype in CRC.
Results from REACH1, a Single-Arm Phase 2 Study of Ruxolitinib in Combination with Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Vs-Host Disease
Authors: Madan Jagasia, Miguel-Angel Perales, Mark A Schroeder, Haris Ali, Nirav N Shah, Yi-Bin Chen, Michael C. Arbushites, Fitzroy Dawkins, Chuan Tian, Hanna Jean Khoury
Journal: Blood (2018)
MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage
Authors: Pedro Sousa-Victor, Joana Neves, Wendy Cedron-Craft, P. Britten Ventura, Chen-Yu Liao, Rebeccah R. Riley, Ilya Soifer, Nicholas van Bruggen, Ganesh A. Kolumam, Saul A. Villeda, Deepak A. Lamba, Heinrich Jasper
Journal: Nature Metabolism (2019)
Some indicators of hydrolytic processes in lymphocytes of blood of lung cancer patients.
Authors: Vladislav Legostayev, Oleg Babenkov, Elena Frantsiyants, Svetlana Dmitriyeva, Gennadi Sergostyants, Ekaterina Komarova
Journal: Journal of Clinical Oncology (2014)

Article Tools Tumor Biology Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/jco.2014.32.15_suppl.e22093 Journal of Clinical Oncology - published online before print May 20, 2014 Some indicators of hydrolytic processes in lymphocytes of blood of lung cancer patients. Vladislav LegostayevxVladislav LegostayevSearch for articles by this author , Oleg BabenkovxOleg BabenkovSearch for articles by this author , Elena FrantsiyantsxElena FrantsiyantsSearch for articles by this author , Svetlana DmitriyevaxSvetlana DmitriyevaSearch for articles by this author , Gennadi SergostyantsxGennadi SergostyantsSearch for articles by this author , Ekaterina KomarovaxEkaterina KomarovaSearch for articles by this author Show More Rostov Scientific Research Institute of Oncology, Rostov-on-Don, Russia Abstract Disclosures https://doi.org/10.1200/jco.2014.32.15_suppl.e22093 Abstract Abstract e22093 Background: It is known that in immune competent cells the ratio "proteinase – inhibitor" determines the efficiency of immune response, while isolated increase of activity of proteases or inhibitors holds back the activation of lymphocytes and production of interleukines by them Methods: The activity of cathepsin D (cat D), acid stable inhibitors (ASI), antitrypsic activity (ATA), and the activity of alkaline (AP) and acid phosphatase (ACP) was determined in the peripheral blood lymphocytes (PBL) as well as in the blood obtained from lung vessels after pneumonectomy (LVL) of men having lung cancer. The peripheral blood of healthy donors was used as the control. Results: The activity of catD in PBL and LVL of patients was 27.4% and 33.3% higher than the norms, respectively. Meanwhile, ASI and ATA in both samples was similarly lower in relation to the donor parameters: on average, 41.7% and 66.3%, respectively. The factor catD/ATA in PBL was 3.8 times higher, and 3.7 times higher in LVL as compared to the control. The activity of AP in PBL exceeded the indicator in healthy donors 5.5 times, and in LVL – 7.2 times, with reduced activity of ACP – 3 and 2.6 times lower, respectively. The factors of AP/ACP ratio were significantly higher than the norm values: 14 times higher in PBL, and 7.1 times as high in LVL. Conclusions: The lymphocytes of all said blood samples were in condition of deep hypoxia. Meanwhile, in the cells of blood taken from lung vessels, the change of activity of proteolysis system indicators was more pronounced, than one in the peripheral blood of the patients, which reflects higher response to stress of the organism and prognostically unfavorable background for the lymphocytes to perform their specific functions. © 2014 by American Society of Clinical Oncology
Interrelationship of primary and secondary mutations in gastrointestinal stromal tumors during TKI therapy.
Authors: Peter Hohenberger, Ming Wang, Carina Heydt, Alexander Marx, Ulrich Ronellenfitsch, Eva Wardelmann
Journal: Journal of Clinical Oncology (2014)

10518 Background: Gastrointestinal stromal tumors (GISTs) show KIT or PDGFRα gain-of-function mutations in 85% as the primary oncogenic drivers. Although the use of tyrosine kinase inhibitors (TKI) like imatinib has greatly improved therapy, the occurrence of secondary resistance to TKIs is a challenging problem. Secondary mutations in KIT/PDGFRα are believed to be the most important mechanism of drug resistance. We analyzed whether this might be a random process or whether these effects could be correlated to primary tumor characteristics and primary drug therapy. Methods: 58 patients undergoing surgery or CT-guided biopsy of progressive GIST lesions while being on TKI therapy and with known mutations from their primary tumor formed the basis of our study. Paraffin-embedded specimens were used to examine the primary and secondary mutations in exons 8, 9, 11, 13, 14, 17 of KIT and exons 12, 14 18 of the PDGFRαby macrodissection, genomic DNA extraction, PCR amplification, designed primers for exons, Sanger-sequenced twice. Results: Point mutation was the most common type of 2ndary mutation (52/58, 89.7%). Codon 654 of KIT exon 13 (n=20) and codons 820 to 822 of KIT exon 17 (n=28) were the predominant regions of 2ndary mutations. Secondary mutations in KIT exon13 were exclusively found in tumors with primary mutations in KIT exon11. GISTs of non-gastric origin had a higher frequency to develop secondary mutation in activation-loop (AL, exon 17) of KIT than those with gastric origin (67.7% vs. 35.7%, P=0.047). Mean duration of TKI treatment did not influence significantly AL vs non-AL mutations. With respect to the TKIs used, secondary mutations in the activation-loop were more often found after multiple TKIs (imatinib, sunitinib, nilotinib, sorafenib) than after just imatinib, but the difference was not quite statistically significant (85.7% vs. 50.0%, P=0.066). Conclusions: The development of secondary tyrosine kinase mutations in advanced GISTs during treatment with TKIs is not a random effect. Correlations between primary vs. secondary mutations and initial tumor site can be demonstarted. Besides, it seems possible that the use of different TKIs itself may impact on the development as well as type of secondary mutations.
HLA Class I Alloimmunization and Platelet Transfusion Support in HLA-Identical Bone Marrow Transplant for Sickle Cell Disease: A Sickle Transplant Alliance for Research Study
Authors: Robert Sheppard Nickel, John T. Horan, Allistair Abraham, Muna Qayed, Ann Haight, Naomi Luban, Jeanne E. Hendrickson
Journal: Blood (2018)
The effect of carcino-embryonic antigen and squamous cell carcinoma antigen in adjuvant diagnosis of conventional and combined small cell lung cancer.
Authors: Hongyang Lu, Weimin Mao, Qiao-Yuan Cheng, Qixun Chen, Bo Chen, Ju-Fen Cai, Xiaojia Wang, CaiJin Lou, Jing Qin, Wei-Wu Ye, Na Han, Lei Lei
Journal: Journal of Clinical Oncology (2014)

e18551 Background: Small cell lung cancer (SCLC) includes conventional and combined SCLC. Combined SCLCs are about 28% of SCLCs who were received surgical resection, but it is reported only about 1-3% of SCLCs diagnosed by biopsy or puncture. Less than 5% SCLCs are suitable for surgical treatment. It is significance to seek optional methods to find combined SCLCs. The value of carcino-embryonic antigen (CEA) in lung adenocarcinoma is usually over the normal range, and the value of squamous cell carcinoma antigen (SCC) in lung squamous cell carcinoma is also usually high. To better identify the conventional SCLCs and combined SCLCs, we evaluate the effect of CEA and SCC in adjuvant diagnosis. Methods: Thirty two SCLCs even received surgical resection from 2000 to 2010 in Zhejiang cancer hospital, including 24 cases of conventional SCLCs, five cases of adenocarcinoma combined SCLC, three cases of squamous cell carcinoma combined SCLC, were retrospective collected. The value of CEA and SCC before operation was also retrospective collected. The relationship between the value of CEA or SCC and the classification of SCLC was analyzed. Results: There were five patients with the value of CEA or SCC over the normal range in conventional SCLCs. The values of CEA were over the normal range in two adenocarcinoma carcinoma combined SCLC patients, and the value of SCC was over the normal range in one squamous cell carcinoma combined SCLC patients. The abnornal values of CEA or SCC were more frequency appearance in combined SCLCs than conventional SCLCs. Conclusions: The values of CEA or SCC can be used as reference to identify conventional and combined SCLC. If the SCLCs with abnormal value of CEA or SCC, we should speculate it may be combined SCLC and do more work to make a further definite diagnosis.
Application of biomarkers measured in serum reflecting specific tissue remodeling and dysregulation for lung cancer and other lung pathologies.
Authors: Nicholas Willumsen, Jacob Hull Kristensen, Cecilie Liv Bager, Lise Larsen, Diana Julie Leeming, Morten Asser Karsdal, Anne-Christine Bay-Jensen
Journal: Journal of Clinical Oncology (2014)

e22225 Background: The extracellular matrix (ECM) is an important part of malignant tumors of the lung. The lung ECM consists of several proteins, where important structural proteins are type I collagen and elastin as well as intermediate filament (IMF) proteins such as vimentin, that play an important part of tissue quality and function. The turnover (formation and degradation) of these proteins are dysregulated as part of malignant changes. We investigated whether serum biomarkers reflecting ECM and IMF turnover could be used to differentiate lung cancer patients and other lung pathologies from healthy controls. Methods: Levels of protease generated fragments of type I collagen (C1M), elastin (ELM7/EL-NE) and of citrullinated vimentin (VICM) were measured by competitive ELISAs in serum from patients with lung cancer (squamous cell carcinoma) (n=10), chronic obstructive pulmonary disease (COPD) (n=13), idiopathic pulmonary fibrosis (IPF) (n=10) and age-matched healthy controls (n=10). Results: For all biomarkers measured there was a tendency towards the highest levels being found in lung cancer patients. C1M, VICM, EL-NE and ELM7 were elevated in patients with lung cancer (p<0.01-0.0001), and COPD (p<0.05-0.0001) as compared to controls. For IPF patients only C1M and VICM was different from controls (p<0.0001). Furthermore, in lung cancer, C1M, EL-NE and ELM7 were elevated as compared to IPF (p<0.05-0.01). Conclusions: This study identifies and tests novel biomarkers that reflect ECM and IMF turnover as applicable for lung cancer and other lung pathologies. The highest levels being found in lung cancer patients may be in agreement with COPD and IPF as risk factors for lung cancer. The markers may potentially aid in characterizing and monitoring of lung cancer patients.
Prostate-specific antigen testing and shared decision making for prostate cancer screening.
Authors: Jun Li, Zahava Berkowitz, Thomas B Richards, Ingrid J Hall
Journal: Journal of Clinical Oncology (2014)

e12512 Background: In 2012, the US Preventive Services Task Force expanded its 2008 recommendation against prostate specific antigen (PSA) screening for prostate cancer among men aged ≥75 years to include men of all ages. In this study, we aimed to describe the prevalence of PSA testing over time and assess associations between shared decision-making (SDM) on PSA testing. Methods: We estimated prevalence of PSA testing using data from the 2000, 2003, 2005, 2008, and 2010 National Health Interview Surveys. Changes in the prevalence by age group, race/ethnicity, and year were assessed with logistic regression models and general linear contrasts of the predicted margins. Bivariate analyses were conducted to assess associations between demographic and health-related characteristics and PSA testing. Results: Men aged ≥ 75 years had a small but significant decrease in PSA testing from 2008 to 2010 (50.8% vs. 43.9%, P < 0.05). However, in 2010, they continued to have a significantly higher prevalence of PSA testing (43.9%) than men aged 50–74 (38.4%), and men aged 40–49 (9.7%). Men who had pre-screening discussions about the advantages and disadvantages of PSA testing (54.9%) and about disadvantages alone (44.1%) were more likely to receive PSA testing than men who had no discussion (17.7%), respectively (both P<0.05). Conclusions: Men ≥ 75 years continued to receive more PSA testing than younger men. Pre-screening discussions were positively associated with PSA testing. Additional research is needed on how SDM is being conducted in clinical practice and the role played by patient’s values and preferences in decisions about PSA testing.
Free thyroxine depletion modulated by exogenous l-triiodothyronine and cancer survival: An observational study.
Authors: Aleck Hercbergs, David Garfield, Osnat Asher-Fabian
Journal: Journal of Clinical Oncology (2014)

e22160 Background: L-thyroxine may be a growth factor for various cancers. Methods: Patients with advanced cancers were made L-thyroxine-deficient and given supplemental L-triiodothyronine. Prior pre-clinical and clinical studies have indicated that lowering serum free thyroxine (FT4) was associated with extended survival in patients with advanced cancers. The objectives of this study were to (a) substitute L-tri-iodothyronine [T3] for L-thyroxine [T4] as replacement therapy for pre-existent hypothyroidism or (b) in euthyroid patients, to use methimazole to induce hypothyroxinemia while adding T3 in an effort to maintain eumetabolism and prevent the compensatory rise in TSH. Twenty-three patients from internationally dispersed locations were either self-referred or recommended by attending physicians to the principal investigator. All patients had advanced cancers of the brain, ovary, lung, pancreas, salivary gland, breast, mesothelioma and soft-tissue sarcomas. Serum FT4 and TSH were serially monitored to enable drug adjustments. Survival was measured from the date of initiation of T3 replacement and/or induction of FT4 deficiency. Outcomes were compared to the odds of death based on SEER and AJCC databases as well as literature reports. Overall, given the wide spectrum of cancers, survival time of 87% [19 of 23] patients exceeded the 20% expected 1 year survival for that patient group. The difference between the actual and expected survival was significant at the P < 0.01 level We conclude that although this is an observational study with obvious limitations, our data suggest that consideration should be given to the use of T3 adjuvant therapy to maintain low FT4 in patients with advanced cancers. Results: Patients so-treated seemed to have prolonged survival. Conclusions: Depleting L-thyroxine, because it may be a tumor growth factor, may prolong survival.
Prevalence and outcome of latent tuberculosis in patients receiving ixekizumab: integrated safety analysis from 11 clinical trials of patients with plaque psoriasis
Authors: R. Romiti, F. Valenzuela, E.N. Chouela, W. Xu, B. Pangallo, S.R. Moriarty, S. Gürbüz, E. Riedl
Journal: British Journal of Dermatology (2019)