tbuckley/cabot-search huggingface dataset:
Relation between lactate dehydrogenase (LDH) during two first cycles in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib (SU)
Authors: J. Medioni, N. Arakelian, L. Fournier, D. Helley, R. Thiam, E. Banu, C. Cuenod, S. Oudard
Journal: Journal of Clinical Oncology (2007)

14079 Background: LDH is a biomarker of cellular turn over. We evaluated LDH as a surrogate marker of tumor response and tumor necrosis during first cycles of SU. Methods: This is a single center study of immunorefractory patients with mRCC treated in second line with SU (50 mg, 4 weeks on, 2 weeks off). All patients performed CT scan and had serially measured tumor necrosis. Tumor response using the RECIST criteria was evaluated at the end of cycle 2 (C2). Tumor necrosis index was calculated at baseline, at the end of cycle 1 (C1) and C2 by measuring the percent area of the tumor with no enhancement after injection using an electronic calliper. LDH was measured at baseline (D1) and at the end (D28) of C1 and C2 using LD 200 kit on Synchron LX20 (Beckman Coulter). Relations between LDH and tumor response were studied using multivariate analysis of variance (MANOVA) with repeated measures and between LDH and tumor necrosis using Pearson correlation test. Results: Between Feb 2005 and Aug 2006, 56 patients were analyzed (75% men,), 91% Clear Cell Carcinoma. Mean age was 59 years (range: 30–81) and 62% has a performance status ECOG of 0. Median number of metastatic sites was 2 and mean hemoglobin level was 12.7 gr/dl. After C2, 12 (21%) partial responses, 35 (63%) stable diseases and 9 (16%) progressive diseases were noted. Results of LDH are summarized in the table . Mean LDH was statistically different between along time (p &lt; 0.0001). LDH levels were statistically different between responders-stables and progressors patients (p = 0.004). There is a trend for a statistical relation between the index of necrosis and the tumor response measured by RECIST criteria (p = 0.08). No correlation was found between LDH and tumor necrosis. Conclusions: LDH level is higher in progressors compared to responders-stables patients. LDH level is not correlated to tumor necrosis measured by CT scan. [Table: see text] No significant financial relationships to disclose.
Metabolism of pancreatic cancer: paving the way to better anticancer strategies
Authors: Cheng Qin, Gang Yang, Jinshou Yang, Bo Ren, Huanyu Wang, Guangyu Chen, Fangyu Zhao, Lei You, Weibin Wang, Yupei Zhao
Journal: Molecular Cancer (2020)

Abstract Pancreatic cancer is currently one of the most lethal diseases. In recent years, increasing evidence has shown that reprogrammed metabolism may play a critical role in the carcinogenesis, progression, treatment and prognosis of pancreatic cancer. Affected by internal or external factors, pancreatic cancer cells adopt extensively distinct metabolic processes to meet their demand for growth. Rewired glucose, amino acid and lipid metabolism and metabolic crosstalk within the tumor microenvironment contribute to unlimited pancreatic tumor progression. In addition, the metabolic reprogramming involved in pancreatic cancer resistance is also closely related to chemotherapy, radiotherapy and immunotherapy, and results in a poor prognosis. Reflective of the key role of metabolism, the number of preclinical and clinical trials about metabolism-targeted therapies for pancreatic cancer is increasing. The poor prognosis of pancreatic cancer patients might be largely improved after employing therapies that regulate metabolism. Thus, investigations of metabolism not only benefit the understanding of carcinogenesis and cancer progression but also provide new insights for treatments against pancreatic cancer.
Prefrontal-Subthalamic Hyperdirect Pathway Modulates Movement Inhibition in Humans
Authors: Witney Chen, Coralie de Hemptinne, Andrew M. Miller, Michael Leibbrand, Simon J. Little, Daniel A. Lim, Paul S. Larson, Philip A. Starr
Journal: Neuron (2020)

The ability to dynamically change motor outputs, such as stopping an initiated response, is an important aspect of human behavior. A hyperdirect pathway between the inferior frontal gyrus and subthalamic nucleus is hypothesized to mediate movement inhibition, but there is limited evidence for this in humans. We recorded high spatial and temporal resolution field potentials from both the inferior frontal gyrus and subthalamic nucleus in 21 subjects. Cortical potentials evoked by subthalamic stimulation revealed short latency events indicative of monosynaptic connectivity between the inferior frontal gyrus and ventral subthalamic nucleus. During a stop signal task, stopping-related potentials in the cortex preceded stopping-related activity in the subthalamic nucleus, and synchronization between these task-evoked potentials predicted the stop signal reaction time. Thus, we show that a prefrontal-subthalamic hyperdirect pathway is present in humans and mediates rapid stopping. These findings may inform therapies to treat disorders featuring perturbed movement inhibition.
Cigarette smoking during irinotecan therapy: Effects on pharmacokinetics and neutropenia
Authors: F. A. de Jong, J. M. van der Bol, R. H. Mathijssen, W. J. Loos, L. E. Friberg, R. H. van Schaik, M. J. de Jonge, A. S. Planting, A. Sparreboom, J. Verweij
Journal: Journal of Clinical Oncology (2007)

2506 Background: Irinotecan is mainly metabolized by CYP3A-mediated oxidation to form inactive substances and by esterase- cleavage to form its active metabolite SN-38, which is further conjugated by UGT1A-isozymes. Variability in the pharmacokinetics of irinotecan is extensive and largely unexplained. Several constituents of cigarette smoke are known to interact with drug metabolizing enzymes, e.g. CYPs and UGTs, and potentially affect treatment outcome with substrate drugs. Here, we retrospectively explored the effects of cigarette smoking on the pharmacokinetics and adverse effects of irinotecan. Methods: A total of 190 patients (49 smokers and 141 non-smokers) were eligible and had received irinotecan as a 3-weekly 90-minute infusion. Individual pharmacokinetic parameters were obtained using NONMEM. Complete toxicity data were available in a subset of 134 patients receiving the registered dose of 350 mg/m 2 irinotecan or its flat- fixed dose-equivalent of 600 mg. Results: In smokers, the dose-normalized area under the plasma-concentration versus time curve of irinotecan was significantly lower (15% reduction: median, 28.7 versus 33.9 ng×h/mL/mg; P =.001) compared with non-smokers. In addition, smokers showed an almost 40% lower exposure to SN-38 (median, 0.54 versus 0.87 ng×h/mL/mg; P&lt;.001), and a higher relative extent of glucuronidation of SN-38 into SN-38G (median, 6.6 versus 4.5; P=.006). Smokers experienced considerable less hematological toxicity. In particular, the incidence of grade 3–4 neutropenia was 6% in smokers versus 38% in non-smokers (OR, 0.10; 95%CI, 0.02–0.43; P&lt;.001). There was a non-significant 60% lower incidence of delayed-onset diarrhea in smokers (6% versus 15%; OR, 0.34; 95%CI, 0.07–1.57; P=.149). Conclusions: This study indicates that smoking cigarettes significantly affects both the pharmacokinetic and toxicity profile of irinotecan. Although the underlying mechanism is not entirely clear, modulation of CYP3A and UGT1A may be part of the explanation. The data suggest that further investigation is warranted to determine whether smokers are at increased risk for treatment failure indeed, as is suggested by the lower exposure to the active metabolite SN-38 and by the lower incidence of SN-38 exposure related neutropenia in smokers. No significant financial relationships to disclose.
Abstract 11: Prospective Association of Tet2 Mediated Clonal Hematoopoiesis and Heart Failure and Its Subtypes in Postmenopausal Women
Authors: Chuck Eaton, Laura M Raffield, Alexander Bick, Mary Roberts, Joann E Manson, Alexander Reiner
Journal: Circulation (2020)

Background: Recent studies have shown that hematopoietic stems cells can undergo clonal expansion secondary to somatic mutations, termed clonal hematopoiesis of indeterminate potential (CHIP). TET2 is frequently mutated in individuals with CHIP and has been associated with coronary heart disease in humans and Heart Failure in mice models. We investigated whether any of the top three somatic mutations ( DNMT3A,TET2, ASXL1) associated with CHIP were prospectively associated with heart failure (HF), heart failure with preserved ejection fraction (HFPEF) or heart failure with reduced ejection fraction (HFrEF) in post menopausal women. Methods: A subcohort of 5214 postmenopausal women in the Women’s Health Intiative were evaluated for CHIP and HF. CHIP was determined at the Broad Institute via whole genome sequencing using the GATK4 MuTect2 somatic variant caller through the NHLBI TOPMed project. Hospitalized heart failure was based upon trained physician record review. HFpEF was defined as an EF &gt; 50% and HFrEF as EF&lt;50% . Cox proportional hazards model were evaluate adjusting for age, race, income, education, cigarette smoking, body mass index, coronary heart disease, atrial fibrillation, diabetes , hypertension, systolic blood pressure, and stroke. Inverse probability weighting was used to account for selection bias associated with the subcohort selection. Results: Of the 5214 postmenopausal women, 597 developed HF, 283 HFpEF and 204 HFrEF. N=408 had CHIP. The top 3 gene mutations associated with CHIP (N=364) were DNMT3A (4.8%), TET2 (1.7%) and ASXL1 (0.5%). Women with CHIP associated with any of the top 3 mutations and with TET2 were associated with HF, HFpEF but not HFrEF. DNMT3A and ASXL1 CHIP mutations were not associated HF, HFpEF or HFrEF (See Table ). Conclusion: CHIP associated with the top 3 somatic mutations and TET2 were prospectively associated with HF and HFpEF consistent with animal models and the concept of HFpEF being associated with pathologic aging. Replication of these findings in other cohorts is warranted.
Complete Remission of Hypertrophic Discoid Cutaneous Lupus Erythematosus After Treatment of Chronic Hepatitis C With Direct-Acting Antivirals
Authors: Sumeyre Seda Ertekin, Daniel Morgado-Carrasco, Xavier Forns, José M. Mascaró
Journal: JAMA Dermatology (2020)

This case report describes a 42-year-old woman with systemic lupus erythematosus who presented with alopecia, scaly plaques on the face, oral lesions, and verrucous, hyperkeratotic plaques on both hands.
Cetuximab and irinotecan (CPT11) salvage treatment for colorectal cancer (CRC) in progression after two or more chemotherapy (CT) lines: The POLONORD Group experience
Authors: D. Fagnani, A. Bertolini, E. Menatti, M. Duro, G. Luchena, A. Ardizzoia, L. Zavallone, V. Filipazzi
Journal: Journal of Clinical Oncology (2007)

14575 Background: Cetuximab is a monoclonal antibody blocking the Epidermal Growth Factor Receptor (EGFR), that showed activity in advanced CRC. His safety and therapeutic profile in clinical practice is still carefully evaluating. Methods: 7 Italian Oncology Units (PoloNord Group) treated, from December 2004 to December 2006, 72 patients (pts) affected by metastatic (mts) CRC, in progression after two or more previous CT lines, with Cetuximab + CPT11 ± Fluorouracil (5FU). Cetuximab initial dose was 400 mg/m 2 , followed by 250 mg/m 2 as weekly infusion; dose adjustments based on cutaneous toxicity. Median courses: 12 (range 2–59). CPT11 and 5FU was administered according centres favourite schedules. We evaluated pts for safety, objective response (RO), progression free survival (PFS) and overall survival (OS) Results: Pts characteristics: M/F 48/25; median age 64 years (range 39–74); previous chemotherapy lines: 2–6 (Oxaliplatin and CPT11± 5FU); EGFR positive: 72. Mts sites: liver 56%, lung 21%, peritoneum 10%; 13% of pts had two or more mts sites. Safety: 8/72 (11%) pts showed G3–4 toxicity (WHO): cutaneous 5 pts; vomiting 1 pts, and neutropenia 3 pts . No allergic reactions. 4/72 pts stopped therapy to unacceptable toxicity, while 53/72 pts to disease progression. RO in 68/72 pts were: 9 RP (13%), 14 SD (21%) and 45 PD (66%). 6/14 SD pts showed tumor markers (CEA/Ca19.9) reduction. No pts had surgery option after treatment. Median PFS from start of therapy in 58/72 pts was 4 months (range 1–15). Median OS from diagnosis of mts disease in 67/72 pts was 28 months (range 7–81). Conclusions: According to safety and control disease reporting by international trials, our experiences showed that, also in clinical practice, Cetuximab + CPT11 is a valid option for the treatment of advanced, pretreated CRC. No significant financial relationships to disclose.
Celastrol Attenuates Angiotensin II–Induced Cardiac Remodeling by Targeting STAT3
Authors: Shiju Ye, Wu Luo, Zia A. Khan, Gaojun Wu, Lina Xuan, Peiren Shan, Ke Lin, Taiwei Chen, Jingying Wang, Xiang Hu, Shengjie Wang, Weijian Huang, Guang Liang
Journal: Circulation Research (2020)

Excessive Ang II (angiotensin II) levels lead to a profibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II-induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure.We have examined the potential effect of celastrol-a bioactive compound derived from the Celastraceae family-on Ang II-induced cardiac dysfunction.In rat primary cardiomyocytes and H9C2 (rat cardiomyocyte-like H9C2) cells, celastrol attenuates Ang II-induced cellular hypertrophy and fibrotic responses. Proteome microarrays, surface plasmon resonance, competitive binding assays, and molecular simulation were used to identify the molecular target of celastrol. Our data showed that celastrol directly binds to and inhibits STAT (signal transducer and activator of transcription)-3 phosphorylation and nuclear translocation. Functional tests demonstrated that the protection of celastrol is afforded through targeting STAT3. Overexpression of STAT3 dampens the effect of celastrol by partially rescuing STAT3 activity. Finally, we investigated the in vivo effect of celastrol treatment in mice challenged with Ang II and in the transverse aortic constriction model. We show that celastrol administration protected heart function in Ang II-challenged and transverse aortic constriction-challenged mice by inhibiting cardiac fibrosis and hypertrophy.Our studies show that celastrol inhibits Ang II-induced cardiac dysfunction by inhibiting STAT3 activity.
An association between thyroid disease and breast cancer
Authors: N. J. Karlin, I. Chopra, J. Mirocha, N. Feldman
Journal: Journal of Clinical Oncology (2007)

21063 Background: Anecdotal studies and isolated case reports have observed an association of thyroid disease and breast cancer. This purported association remains controversial. We describe a retrospective case-control study on the prevalence of breast cancer in patients with abnormal thyroid function studies. Age-matched subjects served as controls. Methods: We reviewed 6211 cases of abnormal TSH values between 1/04 and 12/05 and determined the number of cases with breast cancer. We compared those data to 3,151 control subjects with normal TSH seen during the same period. We excluded patients with thyroid cancer from the total number of malignancies in both groups because abnormal TSH would be expected to result from its treatment. We also reviewed the ER, PR, her 2 neu status and free thyroxine of patients with breast cancers. Results: Breast cancer rate of 36% of all cancers (37/102) in the abnormal TSH group was significantly higher than that of 18% (14/77) in the normal TSH group. (p = 0.012). Breast cancers in the study group with abnormal thyroid function were more frequently hormone receptor positive (74% vs. 67%) and her 2 neu negative (67% vs. 50%). Conclusions: The data suggest that there is an increased rate of breast cancer in patients with abnormal thyroid function. The trend of hormone receptor positive disease in the abnormal TSH group suggests that the IGF receptor may play an important role in the relationship between thyroid disease and breast cancer. The IGF receptor may be a potential target for therapeutic drug development for breast cancer prevention and management. Further studies are warranted. No significant financial relationships to disclose.
MEF2c-Dependent Downregulation of Myocilin Mediates Cancer-Induced Muscle Wasting and Associates with Cachexia in Patients with Cancer
Authors: Sarah M. Judge, Michael R. Deyhle, Daria Neyroud, Rachel L. Nosacka, Andrew C. D'Lugos, Miles E. Cameron, Ravneet S. Vohra, Ashley J. Smuder, Brandon M. Roberts, Chandler S. Callaway, Patrick W. Underwood, Stephen M. Chrzanowski, Abhinandan Batra, Meghan E. Murphy, Jonathan D. Heaven, Glenn A. Walter, Jose G. Trevino, Andrew R. Judge
Journal: Cancer Research (2020)

Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer. SIGNIFICANCE: This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia.
Clinical and molecular determinants of survival in pancreatic cancer patients treated with second line chemotherapy: results of an Italian/Swiss multicenter survey
Authors: A. Mancuso, S. Sacchetta, P. Saletti, C. Tronconi, L. Milesi, M. Garassino, O. Martelli, R. Labianca, F. Cavalli, C. N. Sternberg
Journal: Journal of Clinical Oncology (2007)

4622 Background: The impact on survival of palliative second-line therapy in pancreatic cancer has not been clarified and clinical/molecular predictive factors are needed in order to decide which therapeutic regimens may be effective. Methods: Clinical records of 160 Gemcitabine resistant/refractory pancreatic cancer patients (pts) treated in 11 medical oncology departments in Italy and Switzerland were reviewed. All pts received a second line regimen from June 1997 to February 2006. There were 99 males, 61 females, median age 62 years (range 34–78) and median ECOG performance status (PS): 1 (range 0–2). 16 different salvage regimens were administered consisting of monotherapy with fluoropyrimidines in 59% of cases and combinations of platinum- salts/fluoropyrimidines in 36%. Fluoropyrimidines combinations with bevacizumab, irinotecan and mitomycin C were administered in the remaining 5%. ERCC-1 expression was examined by performing immunohistochemical staining in pts treated with platinum-salts. Results: Second line chemotherapy produced partial responses (PR) in 16 (10%) and stable disease (SD) in 40 pts (25%) by RECIST criteria. The median progression free survival (PFS) was 2.65 months. Multivariate analysis revealed that the most important prognostic factor for PFS was PS at the beginning of second line therapy (Second line PFS PS=0–1 vs PS=2: 78 days vs 48 days, p&lt;0.05, log-rank test). Pts who had responded (PR) to first-line Gemcitabine were more likely to respond or attain stable disease after second-line treatment, with a PFS of 2.6 vs 1.6 months (p&lt;0.05, log-rank test). The overall survival (OS) for all evaluable pts was 11.5 months and 1-year survival was 45%. Among 57 pts treated with platinum-containing doublets, a low ERCC1 level (28/57 pts) was highly predictive of longer survival (11.9 versus 9.9 months, p&lt;0.05 log-rank test). Conclusions: These results suggest that fluoropyrimidine-based salvage regimens have marginal activity and should be considered only in pts with a good PS who have responded to first line chemotherapy. ERCC-1 expression should be further evaluated as a predictive test to select patients who may benefit from platinum/fluoropyrimidine salvage regimens. No significant financial relationships to disclose.
Abstract P370: Opioid and Gabapentinoid Medication Use and the Risks of Atrial Fibrillation and Supraventricular Ectopy in the Multi-ethnic Study of Atherosclerosis
Authors: Barbara N Harding, Kerri Wiggins, Paul Jensen, Bruce M Psaty, Susan R Heckbert, James Floyd
Journal: Circulation (2020)

Purpose: Opioids and gabapentinoids may have adverse cardiovascular effects. We evaluated whether these medications were associated with incident clinically-detected atrial fibrillation (AF) or monitor-detected supraventricular ectopy (SVE), including premature atrial contractions (PACs) and supraventricular tachycardia (SVT). Methods: We used data from the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study that enrolled 6,814 Americans without clinically-detected cardiovascular disease (CVD) in 2000-2002. At the 2016-2018 examination, a subset of participants received extended ambulatory electrocardiographic (ECG) monitoring with a device that records up to 14 days of continuous data. Longitudinal analyses investigated time-varying medication exposures at 5 exams (through 2012) and the risk of incident clinically-detected AF through 2015 using Cox proportional hazards regression models. Cross-sectional analyses investigated medication exposures at the 2016-2018 examination and the risk of monitor-detected SVE using linear and logistic regression models. Methods: The longitudinal cohort included 6,652 participants. Opioid and gabapentenoid use increased over time (Figure). During 12.4 years of mean follow-up, 961 participants (14.4%) experienced incident AF. Opioid use and gabapentinoid use were not associated with the risk of incident AF compared with no use. The cross-sectional analysis included 1,435 participants with ECG monitoring. Compared with non-use, gabapentinoid use was associated with an 84% greater count of PACs/hour (95% CI, 25%-171%) and with a 44% greater average number of runs of SVT/day (95% CI, 3%-100%) but not with a higher odds of SVT. No associations were found with use of opioids in cross-sectional analyses. Conclusions: In this study, gabapentinoid use was associated with more SVE. Given the rapid increase in gabapentinoid use, additional studies are needed to clarify whether these medications increase the risk of CVD complications.