Expression of neuroendocrine markers: a signature of human undifferentiated carcinoma of the colon and rectum

The frequency and prognostic significance of neuroendocrine marker expression in undifferentiated colorectal cancers has not yet been studied in great detail. Therefore, the survival of 20 patients with small cell undifferentiated colorectal cancers, treated at our institution between 1982 and 1997 (0.8% of all operated colorectal carcinomas), was correlated with the extent of neuroendocrine differentiation. Chromogranin A, synaptophysin, syntaxin1, VAMP2, SNAP25 and alpha/beta-SNAP were used as neuroendocrine markers. Based on the degree of immunoreactivity for these marker proteins, tumors were separated into group 0 (<2% cells stained positive for neuroendocrine markers) and group 1 (>2% cells stained positive). Patients were followed up for at least 5 years or until death. Of 20 (45%) undifferentiated colorectal tumors, 9 expressed neuroendocrine markers (group 1). Only one patient of this group survived for 2 years (11%), whereas the 2-year-survival rate was 45.4% in group 0. Of the 11 patients in group 0, 9 were diagnosed with UICC stages I-III, whereas 8 of 9 tumors with expression of neuroendocrine markers were diagnosed with UICC stage IV ( P=0.002). Our results show that neuroendocrine differentiation is often seen in small cell undifferentiated colorectal cancer. It correlates with a more aggressive course of the disease.     

PharmAdhere: training German community pharmacists with Objective Structured Clinical Examinations

International Journal of Clinical Pharmacy - Background Pharmacists who engage in Pharmaceutical Care need skills to optimise responsible medication use and increase medication adherence....     

Tissue-specific promoters active in CD44+CD24-/low breast cancer cells

It has been proposed that human tumors contain stem cells that have a central role in tumor initiation and posttreatment relapse. Putative breast cancer stem cells may reside in the CD44(+)CD24(-/low) population. Oncolytic adenoviruses are attractive for killing of these cells because they enter through infection and are therefore not susceptible to active and passive mechanisms that render stem cells resistant to many drugs. Although adenoviruses have been quite safe in cancer trials, preclinical work suggests that toxicity may eventually be possible with more active agents. Therefore, restriction of virus replication to target tissues with tissues-specific promoters is appealing for improving safety and can be achieved without loss of efficacy. We extracted CD44(+)CD24(-/low) cells from pleural effusions of breast cancer patients and found that modification of adenovirus type 5 tropism with the serotype 3 knob increased gene delivery to CD44(+)CD24(-/low) cells. alpha-Lactalbumin, cyclo-oxygenase 2, telomerase, and multidrug resistance protein promoters were studied for activity in CD44(+)CD24(-/low) cells, and a panel of oncolytic viruses was subsequently constructed. Each virus featured 5/3 chimerism of the fiber and a promoter controlling expression of E1A, which was also deleted in the Rb binding domain for additional tumor selectivity. Cell killing assays identified Ad5/3-cox2L-d24 and Ad5/3-mdr-d24 as the most active agents, and these viruses were able to completely eradicate CD44(+)CD24(-/low) cells in vitro. In vivo, these viruses had significant antitumor activity in CD44(+)CD24(-/low)-derived tumors. These findings may have relevance for elimination of cancer stem cells in humans.     

Monitoring serum HER2 levels during neoadjuvant trastuzumab treatment within the GeparQuattro trial

In the context of neoadjuvant therapy (NT) for breast cancer patients, different targeted therapy approaches are currently evaluated in clinical trials. Serum markers could help to monitor and optimize such treatment strategies. We investigated human epidermal growth factor receptor 2 serum (sHER2) levels in 175 breast cancer patients participating in the GeparQuattro trial. This study incorporated NT approaches and additional trastuzumab treatment for all patients with HER2-positive tumors. Human epidermal growth factor receptor 2 serum levels were measured by enzyme-linked immunosorbent assay (ELISA) before initiation of NT and after NT (pre-surgery) in a HER2-positive (n = 90) and a HER2-negative patient cohort (n = 85). Median pre-chemotherapy sHER2 levels were higher in patients with positive HER2 status of the primary tumor than in patients with negative HER2 status (14.9 ng/ml vs. 7.7 ng/ml, P < 0.001). A pre-chemotherapy sHER2 cut-off level of 10 ng/ml had the best sensitivity and specificity in discriminating between HER2-positive and HER2-negative primary tumors. In HER2-positive patients, we found a significant positive association between pathological complete remission (pCR) and elevated sHER2 levels (above 15 ng/ml, P = 0.045) and a decrease of sHER2 levels during NT (P = 0.02), which was also significant in multivariate analysis (OR = 3.29, 95% CI 1.001–10.89, P = 0.049). In HER2-negative patients, we observed no association between sHER2 levels and pCR (P > 0.05). Monitoring sHER2 levels in the presence of anti-HER2 treatment might be an adjunct to the clinical evaluation during NT.     

Selective and rapid monitoring of dual platelet inhibition by aspirin and P2Y12 antagonists by using multiple electrode aggregometry

Background

Experimental models of pulmonary embolism (PE) that produce pulmonary hypertension (PH) employ many different methods of inducing acute pulmonary occlusion. Many of these models induce PE with intravenous injection of exogenous impervious objects that may not completely reproduce the physiological properties of autologous thromboembolism. Current literature lacks a simple, well-described rat model of autlogous PE. Objective: Test if moderate-severity autologous PE in Sprague-Dawley (SD) and Copenhagen (Cop) rats can produce persistent PH.

Methods

blood was withdrawn from the jugular vein, treated with thrombin-Ca⁺⁺ and re-injected following pretreatment with tranexamic acid. Hemodynamic values, clot weights and biochemical measurements were performed at 1 and 5 days.

Results

Infusion of clot significantly increased the right ventricular peak systolic pressure to 45-55 mm Hg, followed by normalization within 24 hours in SD rats, and within 5 days in COP rats. Clot lysis was 95% (24 hours) and 97% (5 days) in SD rats and was significantly lower in COP rats (70%, 24 hours; 87% 5 days). Plasma D-dimer was elevated in surgical sham animals and was further increased 8 hours after pulmonary embolism. Neither strain showed a significant increase in bronchoalveolar chemotactic activity, myeloperoxidase activity, leukocyte infiltration, or chemokine accumulation, indicating that there was no significant pulmonary inflammation.

Conclusions

Both SD and COP rats exhibited near complete fibrinolysis of autologous clot PE within 5 days. Neither strain developed persistent PH. Experimental models of PE designed to induce sustained PH and a robust inflammatory response appear to require significant, persistent pulmonary vascular occlusion.     

Update Breast Cancer 2022 Part 6 – Advanced-Stage Breast Cancer

Large-scale study programs on CDK4/6 inhibitors, targeted therapies, and antibody–drug conjugates launched in recent years have yielded results from current studies which are now being published in journals and presented at international conferences. In this context, new results are available from the major CDK4/6 inhibitor studies. Also, an increasing amount of data is being published from large-scale genomic studies on efficacy and resistance mechanisms in patients treated with CDK4/6 inhibitors. These results now form the basis for further research plans to investigate combination therapies and treatment sequencing. Based on the latest published results, sacituzumab govitecan is now available as a second antibody–drug conjugate; this brings an advantage in terms of overall survival for patients with hormone receptor-positive (HRpos)/HER2-negative (HER2neg) breast cancer. In this review article, we summarize the latest developments and place them in context according to the current status of research.Key words: advanced breast cancer, chemotherapy, therapy standard     

Associations of Different Emotion Regulation Strategies with Coping-Efficacy,Rumination and Stress

Cognitive Therapy and Research - In order to investigate the relationship between stress-reactive rumination and the implementation of different emotion-regulation strategies (ERS), the pilot study...     

Antihistamine induced blood oxygenation level dependent response changes related to visual processes during sensori‐motor performance

The histaminergic involvement in selective processes underlying its role in human sensori‐motor performance is largely unknown. Recently, selective effects of central H₁‐inverse agonism on sensory visual processes were observed in electrophysiological—but not behavioral data; a discrepancy suggested to result from speeded response‐choice related processes. This study attempts to establish the effects on visual processes and identify putative compensatory mechanisms related to increased visual and response‐choice task demands by assessing H₁‐inverse agonism induced changes in blood oxygenation level dependent (BOLD) response. Twelve participants received oral doses of dexchlorpheniramine 4 mg, lorazepam 1 mg, and placebo in a three‐way crossover designed study. Brain activity was assessed for choice reaction time task performance in a 3 T magnetic resonance scanner 2 h after drug administration. Participants responded with their left or right hand and index or middle finger as indicated by the laterality of stimulus presentation and identity of the stimulus, respectively. Stimuli were intact or visually degraded and responses were compatible or incompatible with the laterality of stimulus presentation. Both dexchlorpheniramine and lorazepam affected the BOLD response in the occipital cortex indicating affected visual information processing. Dexchlorpheniramine decreased BOLD response in the dorsal precuneus and left precentral gyrus as part of a motor network, which however might not be interpreted as a compensatory mechanism, but may be the upstream consequence of impaired visual processing. Hum Brain Mapp 35:3095–3106, 2014. © 2013 Wiley Periodicals, Inc.