tbuckley/cabot-search huggingface dataset:
A phase II study of aerosolized GM-CSF in the treatment of metastatic melanoma to the lung
Authors: S. N. Markovic, V. J. Suman, R. J. Dalton, J. B. Allred, W. K. Nevala, E. Celis, S. R. Alberts, T. R. Fitch, J. R. Egner, L. P. Ebbert
Journal: Journal of Clinical Oncology (2004)

7571 Background: Metastatic malignant melanoma (MMM) remains a uniformly fatal condition. With the increasing incidence of melanoma worldwide, the need for active therapeutics is urgent. Herein we present the results of a phase II study utilizing aerosolized granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of MMM to the lung. Methods: A two-stage, multicenter, phase II clinical trial was conducted to assess the 2-month progression-free survival (PFS) rate, toxicity profile, and immuno-modulatory effects of aerosolized GM-CSF (250ug twice/day for 7 days of a 14-day treatment cycle) as treatment for MMM. Patients were at least 18 years old with histologically proven metastatic melanoma and radiographic evidence of active involvement of the lung. Results: Twenty-eight patients were accrued from 11/2000 through 9/2001. No patient was declared ineligible. Only one patient achieved a response (complete response) that lasted 12 months. The median PFS time among the 28 patients was 54 days with 8-week PFS rate of 43%. The median survival time was 223 days. Immunological studies comparing pre-treatment to post 4 weeks levels revealed little change in numbers of peripheral blood lymphocyte subsets. However, tetramer analysis of the frequency of melanoma differentiation-antigen peptide-specific cytotoxic T lymphocytes (CTL) in 3 of 4 patients studied, demonstrated evidence of increased CTL frequencies consistent with anti-tumor immunization. Conclusion: Although aerosolized GM-CSF therapy administered in the current regimen was able to demonstrate up-regulation of anti-melanoma T cell responses in 3 of 4 studied patients, beneficial clinical outcomes were not realized. In view of the low treatment-related toxicity and encouraging preliminary immunological evidence of increasing anti-melanoma T cell responses a further dose escalation study of aerosolized GM-CSF may prove more clinically/immunologically effective. No significant financial relationships to disclose.
Erythematous Plaques on the Buttock
Authors: Caroline Z. Tan, Roberto Novoa, Jennifer K. Chen
Journal: JAMA (2016)

A 75-year-old woman with rheumatoid arthritis, treated with long-term prednisone, and genital herpes simplex virus 2 presented with a 1-week history of a painful, pruritic rash on the left buttock. She denied any recent trauma to the area or any new skin exposures. She denied experiencing fevers, lymphadenopathy, and other constitutional symptoms. Of note, she had recently tapered her prednisone dose from 10 mg to 5 mg, with subsequent flare of her rheumatoid arthritis, after which she started pregabalin for pain 3 days before her eruption. Following rash onset, she had also started valacyclovir for 1 week, without benefit. She was not receiving other treatments for rheumatoid arthritis, such as nonsteroidal anti-inflammatory drugs or anti–tumor necrosis factor alpha (anti–TNF-α) therapies. Physical examination revealed warm, indurated, and well-circumscribed erythematous plaques, with subtle vesicles and collarettes of scale, on the left buttock (Figure). Edema, erythema, and pain of the left wrist joint were also noted. The remainder of the physical examination was unremarkable.
Hormone Dependency of Human Breast Neoplasms Cultured in Vitro in the Stem Cell Assay<xref ref-type="fn" rid="FN1">2</xref>
Authors: A Manni, C Wright, M Pontari, P Feil, R Joehl
Journal: JNCI Journal of the National Cancer Institute (1985)

The stem cell soft agar culture system provides a biological tool with which to study tumor clones derived from heterogeneous tumor cell populations. For testing the feasibility of this approach in identifying hormone-responsive clones of mammary tumors, a study was done to determine whether estrogen deprivation or supplementation would alter colony formation in sequential breast neoplasms received in the Cell Kinetics Laboratory, The Pennsylvania State University. Single-cell suspensions obtained from 22 freshly excised breast neoplasms (20 malignant, 2 benign) were plated in soft agar with and without tamoxifen (Tam) (10(-7) M) with the use of serum-supplemented media and with and without 17 beta-estradiol (E2) (10(-8) M] under serum-free medium conditions. Twenty tumors successfully grew, producing 42 +/- 8 (mean +/- SEM) colonies in control dishes in the presence of serum and 27 +/- 5 in its absence (P less than .001). Tam inhibited colony formation in 78% of malignant tumors, whereas a stimulatory effect was observed with E2 in 94%. An increase in colony formation was induced by Tam in 4 tumors (2 benign and 2 malignant). The effects of E2 and Tam on tumor growth were not influenced by the estrogen and progesterone receptor status of the tumor. These preliminary results suggest that all tumors, irrespective of their receptor status, may contain clones of hormone-responsive cells.
Decreased sensitivity to N-Benzyladriamycin-14-valerate (AD 198) in non-dividing LLC-PK1 renal epithelial cells corresponds with decreased PKC-ϵ expression.
Authors: Emily Wolfe, Luydmila Savranskaya, Trevor Sweatman, Leonard Lothstein
Journal: Cancer Research (2007)

3232  In vivo analyses of AD 198 in rats indicate no significant organ toxicity at therapeutic doses, with the dose limiting toxicity of AD 198 being myelosuppression. AD 198 exerts its cytotoxic effect in proliferating cells by binding to the C1b regulatory domain of conventional and novel isoforms of PKC and rapidly triggering apoptosis in a manner that is unaffected by changes in Bcl-2, p53, or NF-κB activity. PKC is active in non-dividing, differentiated cells as well as proliferating cells and, consequently, could provide a cytotoxic target for AD 198. However, we have previously observed ex vivo in rodent hearts that AD 198 has a cardioprotective effect through activation of PKC-ϵ in cardiomyocytes. In this current study, we assessed the cytotoxicity of AD 198 in LLC-PK1 pig renal epithelial cells as they progressed from a proliferative to a non-dividing functionally differentiated state. LLC-PK1 cells grow in monolayer until confluency, whereupon they exhibit typical epithelial functionality: providing a cellular barrier and polarity of fluid transport. These aspects are observed in culture through tight junction formation and transepithelial transport of medium to form fluid-filled epithelial domes. Both functions, in turn, are reported to be modulated by PKCs -α and -δ, with increased expression resulting in tight junction permeability. Confluent and non-dividing LLC-PK1 cells demonstrate a 6-fold decrease in sensitivity to AD 198 compared with proliferating cells. LLC-PK1 cells that have formed tight junctions and produce fluid domes exhibit a 13-fold decreased sensitivity to AD 198. Decreased sensitivity to AD 198 does not correlate with altered drug uptake, since dome-producing cells contain a slightly increased amount of AD 198. PKC-α and PKC-δ protein levels remain unchanged as cells progress from proliferating to dome-producing status, suggesting that changes in AD 198 cytotoxicity do not correspond to modulation of these isoforms. In fact, increased PKC-α and PKC-δ expression at all growth phases from tet-responsive vectors transfected into LLC-PK1 cells failed to alter AD 198 cytotoxicity. By contrast, we observe a 10-fold decrease in the expression of PKC-ϵ protein as cells become confluent, stop proliferating, and form tight junctions. These results suggest that AD 198 targets PKC-ϵ in proliferating LLC-PK1 cells to trigger apoptosis and that loss of drug sensitivity in functionally differentiated cells is due to loss of target protein. (Supported by NCI grant CA100093)
Cut drinking to reduce risk of cancer, says new guidance:
Authors: Jacqui Wise
Journal: BMJ (2016)

New guidelines from all four UK chief medical officers warn that drinking any level of alcohol raises the risk of a range of cancers.1

An expert advisory group examined the evidence from 44 systematic reviews and meta-analyses published since its 1995 Sensible Drinking report and concluded that there was strong evidence that the risk of a range of cancers, particularly breast cancer, increased directly in line with consumption of any amount of alcohol (table⇓).

View this table:

Estimated lifetime prevalence of cancer (No of cases per 1000), by alcohol consumption



The guidelines came out at the same time as a report from the Committee on Carcinogenicity, a UK non-statutory advisory body, which said that between 4% and 6% of all new cancers in the UK in 2013 were caused by alcohol consumption.2 This report said that research now showed a statistically significant increase in the risk of cancer at low, medium, …
Abstract 16335: S100A1 Prevents SR Ca2+ Leak and Protects Against Arrhythmias in Ventricular Cardiomyocytes
Authors: Julia Ritterhoff, Mirko Volkers, Michelle Blomgren, Joseph E Rabinowitz, Wolfram-Hubertus Zimmermann, Karsten Peppel, Walter J Koch, Hugo A Katus, Patrick Most
Journal: Circulation (2012)

Purpose:  S100A1 exerts its inotropic and therapeutic actions in normal (NCM) and failing (FCM) cardiomyocytes in part through improved sarcoplasmic reticulum (SR) calcium (Ca 2+ ) resequestration. The goal of this study was to determine whether S100A1-mediated SR Ca 2+  content enhancement entails pro-arrhythmogenic diastolic SR Ca 2+  leakage in vitro and in vivo.   Methods and Results:  Adenoviral-mediated S100A1 overexpression (3-4 fold vs. GFP-control) in quiescent NCMs and FCMs decreased SR Ca 2+ -frequency (-50 and -40%) and prevented β-AR-triggered compound Ca 2+ -sparks and Ca 2+  waves (-32% in FCMs) as assessed by epifluorescent and confocal Ca 2+  imaging. Under electrical stimulation (2Hz), S100A1 protected NCMs and FCMs from β-AR-triggered diastolic Ca 2+  waves (-62 and -58%). In multicellular rat engineered heart tissue (EHT), S100A1-overexpression (6-8 fold vs. GFP-control) protected from Ca 2+ - and β-AR-triggered after-contractions (ACs) vs. GFP-control (-50%) with preserved enhancement of isometric twitch force (+40%) at 2Hz and 1.6 mM Ca 2+  extra . S100A1-mediated rescue of contractile failure of endothelin-1-treated EHT (-50% decrease in TF) was associated with protection from Ca 2+ - and β-AR-triggered ACs. Mechanistically, confocal immunofluorescence and co-immunoprecipitation reveals that S100A1 interacts with RyR2 in intact normal myocardium and S100A1/RyR2 binding is decreased in failing hearts (-50%). Enhanced S100A1/ryanodine receptor (RyR2) stoichiometry by S100A1-overexpression changed neither PKA nor CaMKII RyR2 phosphorylation pattern. AAV9/S100A1-mediated cardiac S100A1 restoration eventually protected post-MI failing wild-type as well as S100A1 knock-out mice from epinephrine-induced lethal ventricular fibrillations  in vivo .   Conclusion:  Our data disclose that the cardiac inotropic factor S100A1 exerts profound antiarrhythmic potency  in vitro  and  in vivo . Enhanced binding of S100A1 to RyR2 seems to improve diastolic closure but future work is needed to decipher mutual binding sites and RyR2 conformational changes.
Response rate using conventional criteria is a poor surrogate for clinical benefit on progression-free (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC): A comparative analysis of N9741 and AVF2107
Authors: A. Grothey, E. E. Hedrick, R. D. Mass, S. Sarkar, R. K. Ramanathan, H. Hurwitz, R. M. Goldberg, D. J. Sargent
Journal: Journal of Clinical Oncology (2006)

3516 Background: A previous report noted that patients (pts) in the phase III study of IFL ± BV who received BV had significantly longer PFS and OS regardless of whether or not they responded according to RECIST criteria (Mass et al, ASCO 2005). It is unclear if this phenomenon is specific to the addition of a biologic to chemotherapy (CT) or a more general benefit from improved therapy since it has been suggested that stable as well as responding disease is beneficial for pts. We repeated the analysis of Mass et al on pts enrolled in N9741, a study which established the superiority of FOLFOX over IFL and contained no biologic compound. Methods: For this retrospective analysis, pts were defined as ‘responders‘ or ‘nonresponders‘ according to whether criteria for complete or partial response (by RECIST -AVF2107g or WHO criteria -N9741) were either achieved (responders) or not achieved (nonresponders). PFS and OS were estimated from Kaplan-Meier curves; hazard ratios (HR) for progression and death in each subgroup were estimated by Cox regression. Results: In both trials, response was associated with superior outcome. However, statistically significant improvements in PFS and OS were observed in both responders and non-responders treated with either IFL + BV or FOLFOX versus IFL, and the magnitude of improvement was similar regardless of response ( Table ). Conclusions: Analysis of two large recent mCRC phase III trials clearly demonstrate that pts who do not achieve a response according to traditional criteria still have significant benefit from the superior regimen, with a similar magnitude of benefit for responders and non-responders, regardless if the regimen called for CT alone or included the antiangiogenic biologic BV. These data support the conclusion that PFS and the percentage of pts experiencing tumor control may more accurately reflect pt benefit than does response rate in phase III trials in mCRC. [Table: see text] [Table: see text]
Prognostic Value of Nucleolar Protein <i>p120</i> in Patients With Resected Lung Adenocarcinoma
Authors: George Sato, Yasuo Saijo, Bine Uchiyama, Nobuko Kumano, Shun-ichi Sugawara, Shigefumi Fujimura, Masami Sato, Motoyasu Sagawa, Kazuhiro Ohkuda, Kaoru Koike, Yuko Minami, Ken Satoh, Toshihiro Nukiwa
Journal: Journal of Clinical Oncology (1999)

In this study we investigated the prognostic significance of proliferation-associated nucleolar protein p120 in primary resected lung adenocarcinoma because it reflects tumor growth fractions in vitro.Expression levels of p120 in tumors were assessed by immunohistochemistry in 74 patients who underwent radical resection. With clinical follow-up data, the prognostic significance of p120 calculated by labeling indices was evaluated using the Cox proportional hazards model.p120 protein was clearly detected in nucleoli of adenocarcinoma cells. Its expression levels widely varied in each sample from 8.5% to 67. 2%, with a mean +/- SD of 35.2% +/- 15.1%. No significant correlation was found between expression levels of p120 and clinicopathologic factors. However, the expression levels of p120 were negatively correlated with the tumor doubling time calculated with retrospective chest roentgenograms. Using a cutoff value of 35% in the labeling index of p120, patients with high expression of p120 experienced early recurrence and shorter survival compared with those who had low expression of p120. Multivariate analysis showed that p120 served as an independent, as well as the strongest, prognostic factor for resected lung adenocarcinoma.This report provides the first evidence that expression levels of p120 in tumor tissues can be used as an independent and powerful prognostic marker for resected lung adenocarcinoma.
Everolimus plus exemestane in patients with advanced invasive lobular carcinoma: Efficacy and safety results from BOLERO-2.
Authors: Gabriel N. Hortobagyi, Shinzaburo Noguchi, Patrick Neven, Puttisak Puttawibul, Daniel Heng, Thomas Brechenmacher, Francois Philippe Ringeisen, Stephen Saletan, Thomas Denis Bachelot
Journal: Journal of Clinical Oncology (2014)

152 Background: In BOLERO-2 (NCT00863655), everolimus plus exemestane (EVE + EXE) more than doubled median progression-free survival (PFS) vs placebo (PBO) + EXE (by local assessment: 7.8 vs 3.2 mo; hazard ratio [HR], 0.45; P &lt; 0.0001; by central assessment: 11.0 vs 4.1 mo; HR, 0.38; P &lt; 0.0001) in patients (pts) with hormone-receptor–positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). This exploratory analysis assessed the efficacy and safety of EVE + EXE in a subset of pts with baseline invasive lobular carcinoma (ILC) (elderly pts with predominantly peritoneal, gastrointestinal, and ovarian metastases [mets]). Methods: Pts with HR+, HER2– ABC recurring or progressing on/after prior nonsteroidal aromatase inhibitor therapy were randomized 2:1 to receive EVE 10 mg/day + EXE 25 mg/day or PBO + EXE. Primary efficacy end point was PFS (by local assessment). Results: Of 724 pts, 77% (n = 556) had ductal carcinoma and 14% (n = 104; EVE + EXE, n = 64; PBO + EXE, n = 40) had ILC. In ILC subset, median age was 63 years, 47.1% had measurable disease, and majority of baseline characteristics were similar to overall study population with exception of main mets sites. In pts with ILC, 36% reported visceral mets (lung, liver, pleural, pleural effusions, peritoneum, and ascites), 10% lung mets, and 23% liver mets when compared with 59% visceral mets, 31% lung mets, and 33% liver mets in overall study population. Median PFS was higher with EVE + EXE vs PBO + EXE (6.9 vs 4.2 mo; HR, 0.59; 95% CI, 0.37-0.95). Objective response rates were 14.1% (EVE + EXE arm) and 0% (PBO + EXE arm) vs 12.6% and 1.7%, respectively, among overall study population. Clinical benefit rates were 45.3% (EVE + EXE arm) and 30.0% (PBO + EXE arm); 51.3% vs 26.4% in overall study population. The safety profile of EVE + EXE in pts with ILC was similar to overall study population. Most common adverse events (all grades) in EVE-treated pts with ILC were stomatitis (50%), diarrhea (41%), nausea (36%), fatigue (34%), and rash (33%). Conclusions: EVE + EXE prolonged PFS in pts with ILC who had different patterns of mets. Other outcomes were similar to those in overall study population. Clinical trial information: NCT00863655.
Effect of panitumumab on autophagy in colon cancer
Authors: H. P. Kalofonos, A. Antonacopoulou, P. Matsouka, E. Giannopoulou
Journal: Journal of Clinical Oncology (2009)

e22151 Background: Panitumumab, a human monoclonal antibody raised against EGFR, has been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of patients with EGFR-expressing mCRC and wild type kras. The ratio of reduced/oxidised form of glutathione (GSH/GSSG) is an indicator of the redox status in cells. The aim of the current study was to investigate the effect of panitumumab on the redox status of colon cancer cell lines Caco-2, DLD-1 and HT-29 regarding proliferation, apoptosis, necrosis, cell cycle arrest and autophagy. Methods: Cell proliferation was measured by MTT assay. Apoptosis and necrosis were detected by annexin v/propidium iodide assay. Cell cycle arrest was estimated by propidium iodide assay. Autophagy was detected by immunobloting and GSH levels were measured by spectrophotometrical analysis. kras mutations were detected by sequencing analysis. Results: Caco-2, DLD-1 and HT-29 cell lines differ in the expression levels of EGFR and HER-2. Kras mutation analysis in previous studies and in the current study showed that DLD-1 cells express mutated kras while Caco-2 and HT-29 cells express wild type of kras. Panitumumab decreased proliferation only in DLD-1 cells 48 h after its application besides the mutated kras. However, panitumumab did not affect DLD-1 cell apoptosis, necrosis or cell cycle progression 24 and 48 h after cells treatment. Interestingly, panitumumab increased protein levels of beclin 1, an indicator of autophagy, 24 h after its addition in cells. Moreover, an increase in GSH levels was noted 48 h after cells treatment with panitumumab. Conclusions: This is the first study to show that panitumumab, an EGFR inhibitor, affects colon cancer cell proliferation independently of kras mutations and EGFR protein levels through the induction of autophagy. The inhibition in cell proliferation was followed by an increase in GSH levels reflecting an imbalance on the redox status of cells. No significant financial relationships to disclose.
Abstract P180: Ten-Year and Lifetime Cardiovascular Risk and Subclinical Cardiovascular Disease in Mexican Women
Authors: Andrea Luviano, Eduardo Ortiz-Panozo, Elsa Yunes, Carlos Cantu-Brito, Fernando Flores, Andrés Catzin-Kuhlmann, Martín Lajous, Ruy Lopez-Ridaura
Journal: Circulation (2015)

Introduction: Estimates of Lifetime Cardiovascular Risk may identify individuals with different levels of cardiovascular disease (CVD) risk within the low short-term risk (10-year risk) for coronary heart disease (CHD) category defined by the Framingham Risk Score. Evidence of the applicability of this risk stratification in relatively young people is limited, especially among Hispanics. Hypothesis: We assessed the hypothesis that the risk categories from the combination of these two risk stratification scales are positively associated with subclinical CVD in Mexican women. Methods: We calculated 10-year CHD risk using the Framingham Risk Score and lifetime CVD risk based on risk factor burden in 759 women in Southern Mexico from the Mexican Teachers’ Cohort and evaluated the presence of subclinical CVD. We evaluated common carotid intima-media thickness (IMT), ankle-brachial index (ABI), and inter-arm blood pressure difference (IAD) using standard protocols and performed laboratory analyses from a fasting blood draw. We defined three risk strata: Low 10-year (&lt;10%)/Low lifetime risk, Low 10-year (&lt;10%)/High lifetime risk, and High 10-year risk (≥10%). We evaluated outcome measures continuously and estimated the prevalence of subclinical CVD for each risk strata. We defined subclinical CVD as IMT ≥0.8 mm or atheromatous plaque, ABI &lt;0.90, systolic IAD ≥20 mmHg or diastolic IAD ≥10 mmHg. We calculated the sensibility and specificity of the predicted risk categories to detect subclinical CVD. Results: Women evaluated had a mean age of 48.4 years, 22.5% (n=171) were classified as High 10-year CHD Risk, 58.8% (n=446) as Low 10-year/High lifetime risk and 18.7% (n=142) as Low 10-year/Low lifetime risk. We observed significant increase in IMT measurement according to increasing risk categories: 0.656 mm (±0.062), 0.704mm (±0.085), and 0.739mm (±0.089) (p= &lt;0.001). We found similar significant trends in ABI (p= 0.001), systolic IAD (p= &lt;0.001), and diastolic IAD (p= &lt;0.001). We observed a significant higher prevalence of at least one subclinical CVD as the risk category increased: 10.6%, 26.9%, and 45.6% (p= &lt;0.001). The sensitivity and specificity of the combination of these scores to detect subclinical CVD was of 93% and 23%, whereas only considering the high vs. low 10-year risk categories these parameters were 37% and 83% respectively. Conclusion: The combination of these short-term and lifetime risk scores accurately identify differences in objective measurements of subclinical cardiovascular disease in Mexican women. Further calibration of these risk scores is needed to incorporate them in the risk assessment tools to identify individuals at risk for the implementation of preventive strategies in the Mexican population.
Extracorporeal shock wave lithotripsy as rescue for a balloon dilator trapped in the pancreatic duct
Authors: Dan Wang, Jun-Tao Ji, Duo-Wu Zou, Liang-Hao Hu, Zhao-Shen Li
Journal: Endoscopy (2016)

A 71-year-old man was admitted to our department because of intermittent upper abdominal pain of 2 years' duration. Computed tomography revealed a severely dilated pancreatic duct with multiple radiopaque stones, confirming a diagnosis of chronic pancreatitis ([Fig. 1 a]). We performed extracorporeal shock wave lithotripsy (ESWL) at the pancreatic head with a third-generation lithotripter (Compact Delta II; Dornier MedTech, Wessling, Germany) to break up the stones. A total of 5000 shocks were delivered during the therapeutic session at an intensity of 6 on a scale of 1 to 6 (16 000 kV) and a frequency of 120 shocks per minute. A combination of flurbiprofen and remifentanil was administered via intravenous infusion for analgesia. The pancreatic stones were pulverized after ESWL ([Fig. 1 b]) [1].