An ultrasonographic monitoring of skin condition in patients receiving radiotherapy for head and neck cancers

Radiodermatitis is one of the commonest side effects of radiotherapy. They are usually assessed by semi‐quantitative clinical scores, which are not validated and may be subject to inter‐observer variability. A few previous studies suggested that high‐frequency ultrasonography (HF‐USG) is useful in the assessment of the acute phase of radiation dermatitis in breast cancer patients. (a) To monitor skin changes by HF‐USG during the course of radiotherapy due to head and neck cancers, and (b) to determine whether there is any connection between skin sonograms and the skin scoring criteria. This prospective, observational study includes patients diagnosed with head and neck cancers, treated with radiotherapy or concomitant chemoradiation. The final analysis includes six patients. In every patient, the HF‐USG as well as dermatological assessment (target lesion score—TLS and CACE v. 4.0) were performed 4×: before, in the middle, day after, and 3 months after radiotherapy. There were significant differences between non‐irradiated skin thickness and thickness of skin with clinically obvious radiodermatitis (TLS grade 1‐4; P < .0001), as well as between irradiated, unchanged skin thickness (TLS grade 0) and thickness of skin with clinically obvious radiodermatitis (TLS grade 1‐4; P = .0002). There was no significant difference between non‐irradiated and irradiated, unchanged skin thickness (TLS grade 0; P = .9318). In four patients, we demonstrated subepidermal low echogenic band (SLEB). HF‐USG can be useful tool to noninvasive and objective assessment of skin changes during radiotherapy.     

CTLA4 antagonists in phase I and phase II clinical trials,current status and future perspectives for cancer therapy

Introduction: In cancer, the immune response to tumor antigens is often suppressed by inhibitors and ligands. Checkpoint blockade, considered one of the most promising frontiers for anti-cancer therapy, aims to stimulate the immune anti-cancer response. Agents such as cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) inhibitors offer prolonged survival with manageable side effects.

Areas covered: We summarize the recent clinical successes of CTLA-4 inhibitors and place a strong emphasis on those in early phase clinical trials, often in combination with other immune check-point inhibitors, i.e., programmed cell death protein 1 (PD-1) and BRAF/mitogen-activated protein kinase inhibitors.

Expert opinion: Recent phase I and phase II clinical trials confirm the efficacy of anti-CTLA-4 therapy for treatment of cancers such as renal cell carcinoma. These studies also indicated increased efficacy with combined immune checkpoint blockade with PD-1 or Ras/Raf/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) inhibitors. Researchers must search for new immune targets that may enable more effective and safe immune checkpoint blockade and cancer therapy. This goal may be achieved by next-generation combination therapies to overcome immune checkpoint therapy resistance.     

Aortic pulse wave velocity and carotid-femoral pulse wave velocity: similarities and discrepancies.

The objectives of this study were to determine the relationship between carotid-femoral (cfPWV) and aortic pulse wave velocity (aPWV) and to compare their modulators and association with coronary artery disease (CAD). We studied 107 consecutive patients (68 men) with a mean age of 60.49+/-8.31 years who had stable angina and had been referred for coronary angiography. cfPWV and aPWV were measured simultaneously during cardiac catheterization using the Complior device and aortic pressure waveform recordings, respectively. Based on the presence or absence of significant coronary artery stenosis (CAS) patients were subdivided into a CAS+ or CAS- group. The mean values of cfPWV and aPWV were 10.65+/-2.29 m/s and 8.78+/-2.24 m/s, respectively. They were significantly higher in the CAS+ (n=71) compared with the CAS- (n=36) group and predicted significant CAS independently of cardiovascular risk factors and mean or systolic aortic blood pressure. aPWV and cfPWV were significantly correlated (r=0.70; p<0.001) but the degree of correlation differed significantly (p<0.03) between the CAS+ (r=0.74, p<0.001) and CAS- group (r=0.46, p=0.003). Age and mean aortic blood pressure were independent predictors for aPWV as well as cfPWV. In the receiver operating characteristic (ROC) analysis, aPWV and cfPWV had similar accuracy in identification of significant CAS (AUC [area under the ROC curve]=0.76 and 0.69, respectively; p=0.13). However, neither cfPWV nor aPWV was effective at differentiating the extent of CAD. In conclusion, aPWV and cfPWV are highly correlated parameters with similar determinants and comparable accuracy in predicting significant CAS. The strength of correlation between these two indices differed significantly between subjects with and those without CAS.     

Intrahippocampal Injection of Endothelin-1: A New Model of Ischemia-induced Seizures in Immature Rats

Summary:  The goal of this study was to develop a new model of ischemia-induced seizures in immature rats using injection of vasoconstrictor Endothelin-1 (ET-1) into the brain. ET-1 (10, 20, or 40 pmol) was infused into the left dorsal hippocampus of freely moving Wistar rats 12 (P12) and 25 (P25) days old. Animals were then video/EEG-monitored for 100 min and monitoring was repeated 22 h later. Parameters of electrographic seizures (frequency and mean duration) as well as pattern of their behavioral correlates were evaluated. The pattern of behavioral seizures was used to develop model-specific scoring system. Cresyl violet and Fluoro Jade-B-staining were used to evaluate brain damage. Extension of the lesion was correlated with seizure severity. After ET-1-injection, seizures occurred in 83–100% animals of all age-and-dose groups and persisted for 24 h except P12 rats with 10 pmol. There were no differences in average seizure duration (18–40 s) or seizure frequency (3–7 seizures/100 min) among individual dose-groups. Between the 1st and 2nd observation period, total seizure duration decreased in 71% of P12 and 47% of P25 rats. Electrographic seizure activity was most frequently accompanied by clonus, incidence of more severe convulsions (barrel rolling or generalized clonic seizures) increased with dose of ET-1. Morphologic examination did not reveal any dose-related difference in damage severity, hippocampal damage was however more extensive in P12 compared to P25 animals. Seizure severity correlated positively with severity of the damage in both age groups. Our study presents focal injection of ET-1 into the brain as a new and practical model of ischemia-induced seizures in immature rats.     

Immunosuppressive effect of polycyclic aromatic hydrocarbons by induction of apoptosis of pre-B lymphocytes of bone marrow

Polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental pollutants, distinguished by genotoxic, hepatotoxic, nephrotoxic and immunotoxic effects. Especially secondary toxicity after bioactivation by microsomal monooxygenases (dependent on cytochromes P450) is characteristic of them. The immunotoxic effect is the result of very global impact on immunological reactivity of an organism and immunosuppression by induction of apoptosis of pre-B lymphocytes represents one of its particular forms. It has been proved that the effect of PAH is caused mostly by the following mechanisms: enzymatic induction by the way of activation of AhR (Aromatic hydrocarbon Receptor); alteration of cellular DNA; development of oxidative stress; increase in the concentration of intercellular calcium and decline of activity of NF-kappaB (Nuclear Factor-kappa B). Most sensitive to these changes are particularly B-lymphocytic precursors and pre-B lymphocytes. Intensity of entire manifestations is also considerably dependent on the presence and intensity of mechanisms of active or passive resistance of cells.     

Genetic variants of homocysteine metabolizing enzymes and the risk of coronary artery disease

It is unresolved whether elevated homocysteine in coronary artery disease (CAD) is the cause of arteriosclerosis or its consequence. In contrast, genetic variants of enzymes that metabolize homocysteine cannot be altered by arteriosclerosis. Consequently, their association with CAD would permit to imply causality. We modeled by regression analysis the effect of 11 variants in the methionine cycle upon CAD manifestation in 591 controls and 278 CAD patients. Among the examined variants only the carriership for the c.844ins68 in the cystathionine beta-synthase (CBS) gene was associated with a significantly lowered risk of CAD (OR=0.56; 95% CI=0.35-0.90 in the univariable, and OR=0.41, 95% CI=0.19-0.89 for obese people in the multivariable analysis, respectively). Healthy carriers of the c.844ins68 variant exhibited, compared to the wild type controls, significantly higher postload ratios of blood S-adenosylmethionine to S-adenosylhomocysteine (61.4 vs. 54.9, p=0.001) and of plasma total cysteine to homocysteine (8.6 vs. 7.3, p=0.004). The changes in these metabolites are compatible with an improved methylation status and with enhanced activity of homocysteine transsulfuration. In conclusion, the coincidence of clinical and biochemical effects of a common c.844ins68 CBS variant supports the hypothesis that compounds relating to homocysteine metabolism may play role in the development and/or progression of CAD.     

Natural mechanisms protecting against cancer

Carcinogenesis is a multistage process. At each step of this process, there are natural mechanisms protecting against development of cancer. The majority of cancers in humans is induced by carcinogenic factors present in our environment including our food. However, some natural substances present in our diet or synthesized in our cells are able to block, trap or decompose reactive oxygen species (ROS) participating in carcinogenesis. Carcinogens can also be removed from our cells. If DNA damage occurs, it is repaired in most of the cases. Unrepaired DNA alterations can be fixed as mutations in proliferating cells only and mutations of very few strategic genes can induce tumor formation, the most relevant are those activating proto-oncogenes and inactivating tumor suppressor genes. A series of mutations and/or epigenetic changes is required to drive transformation of a normal cell into malignant tumor. The apparently unrestricted growth has to be accompanied by a mechanism preserving telomeres which otherwise shorten with succeeding cell divisions leading to growth arrest. Tumor can not develop beyond the size of 1–2 mm in diameter without the induction of angiogenesis which is regulated by natural inhibitors. To invade the surrounding tissues epithelial tumor cells have to lose some adhesion molecules keeping them attached to each other and to produce enzymes able to dissolve the elements of the basement membrane. On the other hand, acquisition of other adhesion molecules enables interaction of circulating tumor cells with endothelial cells facilitating extravasation and metastasis. One of the last barriers protecting against cancer is the activity of the immune system. Both innate and adaptive immunity participates in anti-tumor effects including the activity of natural killer (NK) cells, natural killer T cells, macrophages, neutrophils and eosinophils, complement, various cytokines, specific antibodies, and specific T cytotoxic cells. Upon activation neutrophils and macrophages are able to kill tumor cells but they can also release ROS, angiogenic and immunosuppressive substances. Many cytokines belonging to different families display anti-tumor activity but their role in natural anti-tumor defense remains largely to be established.     

Sensitization to human milk

Background Allergy to milk is one of the earliest manifestations of IgE‐mediated allergies and affects about 2.5% of newborn children. Several reports indicate that milk‐allergic patients may be sensitized also to human milk proteins. Objective To analyse the specificity and possible biological relevance of IgE reactivity to human milk antigens in milk‐allergic patients. Methods The specificity of IgE reactivity to cow's milk and human milk antigens was analysed with sera from milk‐allergic children and adults by IgE immunoblotting. IgE cross‐reactivity between milk antigens was studied by immunoblot inhibition experiments. That IgE reactivity to human milk antigens is not due to alloreactivity or due to the transmission of foreign antigens into mother's milk was demonstrated through the analysis of milk samples from genetically unrelated mothers before and after intake of dietary milk products. The biological relevance of IgE reactivity to human milk was confirmed by skin testing. Results IgE antibodies to human milk were found in more than 80% of the tested milk‐allergic patients. Cross‐reactive IgE‐reactive human antigens such as α‐lactalbumin and non‐cross‐reactive human milk antigens were identified. Immediate‐type skin reactions could be elicited with human milk samples in patients with IgE reactivity to human milk. Conclusion IgE reactivity to human milk in milk‐allergic patients can be due to cross‐ sensitization and genuine sensitization to human milk and may cause allergic symptoms. IgE‐mediated sensitization to human milk is common in milk‐allergic patients and may require diagnostic testing and monitoring.     

Prevalences, genotypes, and risk factors for HIV transmission in South America

HIV cross-sectional studies were conducted among high-risk populations in 9 countries of South America. Enzyme-linked immunosorbent assay screening and Western blot confirmatory testing were performed, and env heteroduplex mobility assay genotyping and DNA sequencing were performed on a subset of HIV-positive subjects. HIV prevalences were highest among men who have sex with men (MSM; 2.0%-27.8%) and were found to be associated with multiple partners, noninjection drug use (non-IDU), and sexually transmitted infections (STIs). By comparison, much lower prevalences were noted among female commercial sex workers (FCSWs; 0%-6.3%) and were associated mainly with a prior IDU and STI history. Env subtype B predominated among MSM throughout the region (more than 90% of strains), whereas env subtype F predominated among FCSWs in Argentina and male commercial sex workers in Uruguay (more than 50% of strains). A renewed effort in controlling STIs, especially among MSM groups, could significantly lessen the impact of the HIV epidemic in South America.     

Recurrent pericarditis: a rare complication of allergen immunotherapy

We report on a 29-year-old woman suffering from hay fever due to grass and olive tree pollens. She developed recurrent pericarditis during her first course of immunotherapy with an alum-adsorbed pollen extract. A causal relationship was established between the allergen injections and the acute pericarditis episodes on two consecutive occasions, which presented with blood eosinophilia. Blood cultures and serological tests for microorganisms were negative. There were no signs of autoimmune disease or systemic vasculitis. To the best of our knowledge, allergen immunotherapy-induced pericarditis has not been previously reported.