Novel insight into triple-negative breast cancers, the emerging role of angiogenesis, and antiangiogenic therapy.

Triple-negative breast cancer (TNBC) is a heterogeneous group of tumours characterised by lack of expression of oestrogen-, progesterone- and human epidermal growth factor receptors. TNBC, which represents approximately 15% of all mammary tumours, has a poor prognosis because of an aggressive behaviour and the lack of specific treatment. Accordingly, TNBC has become a major focus of research into breast cancer and is now classified into several molecular subtypes, each with a different prognosis. Pathological angiogenesis occurs at a late stage in the proliferation of TNBC and is associated with invasion and metastasis; there is an association with metabolic syndrome. Semaphorins are a versatile family of proteins with multiple roles in angiogenesis, tumour growth and metastasis and may represent a clinically useful focus for therapeutic targeting in this type of breast cancer. Another important field of investigation into the control of pathological angiogenesis is related to the expression of noncoding RNA (ncRNA) - these molecules can be considered as a therapeutic target or as a biomarker. Several molecular agents for intervening in the activity of different signalling pathways are being explored in TNBC, but none has so far proved effective in clinical trials and the disease continues to pose a defining challenge for clinical management as well as innovative cancer research.

Diffuse cutaneous bullous mastocytosis with IgM deposits at dermo-epidermal junction.

Cutaneous mastocytosis is a disease characterized by the infiltration and proliferation of mast cells in the skin. In children, the most common form of presentation is urticaria pigmentosa, while the diffuse cutaneous bullous mastocytosis is one of the rarest subtypes seen. The aim of this paper is to present a case of diffuse bullous mastocytosis with detection of IgM deposits at dermo-epidermal junction using direct immunofluorescence (DIF) microscopy. The diagnosis of diffuse bullous mastocytosis is a challenge, and DIF microscopy is necessary in order to exclude an autoimmune bullous disorder. However, IgM deposits at dermo-epidermal junction can be nonspecific, being found in a variety of skin disorders. A 6-month-old girl presented with bullous lesions and erosions on the scalp and the trunk. During hospitalization, further bullous lesions appeared, along with generalized erythrodermia. Skin biopsy revealed aspects of urticaria pigmentosa. Taking into account the clinical findings, the case was enclosed as bullous mastocytosis. Treatment included the avoidance of trigger factors, and administration of antihistamines along with a short-term course of systemic steroids. The evolution was favorable, with remission of the existing lesions and without occurrence of new ones.

Survival and prognostic factors in bullous pemphigoid: A retrospective cohort study.

Background Bullous pemphigoid is the most common subepidermal autoimmune blistering disease. Till now, the reported prognostic factors in bullous pemphigoid vary considerably. Aims The purpose of this study was to determine the overall survival rate and prognostic factors in bullous pemphigoid. Methods We conducted a retrospective cohort study on newly diagnosed bullous pemphigoid patients between July 2001 and November 2019 in a referral unit for autoimmune blistering skin diseases in Romania. Results One hundred forty-eight patients were included in the study. The Kaplan-Meier overall survival rates at 1, 3, 5 and 10 years were respectively 74.2% (95% confidence interval, 67.5-81.6%), 53.4% (45.7-62.2%), 43.6% (35.9-53%) and 31.3% (23.5-41.7%). The median follow-up among survivors was 48 months (interquartile range: 11-150). Ninety (60.8%) patients died during the follow-up period; of them, 38 (42.2%) had active disease at the time of death. Advanced age, neurological diseases, valvular heart disease, malignancies, use of statins, skin infections and extensive cutaneous involvement were linked to poorer outcomes, while the use of topical corticosteroids was associated with increased overall survival. Limitations This study lacks a control cohort to validate the obtained results. It was conducted in a retrospective manner in a single centre. In addition, indirect immunofluorescence microscopy was not performed in all patients. Conclusion Beyond ageing and neurological comorbidities, the prognosis of bullous pemphigoid patients was significantly influenced by the presence of skin infections, valvular heart disease, use of statins and extensive cutaneous involvement. Topical corticosteroid treatment was associated with increased survival in these patients.

A Recurrent Case of Targetoid Hemosiderotic Hemangioma: A Case Report and a Comprehensive Review of the Literature.

Targetoid hemosiderotic hemangioma is an acquired vascular malformation of unknown origin. We report the case of a 31-year-old man with a recurrent and spontaneous regressive targetoid hemosiderotic hemangioma. Diagnosis relied on clinical and histological findings. Physical examination revealed presence of an approximately 2 cm targetoid lesion located on the left arm, and associated with pain after pressure. No trigger agent (trauma, insect sting) was reported. Dermoscopy showed a group of red lacunae centrally, encircled by an intermediate yellow circular homogenous area and a red violaceous homogenous ring in the periphery. The histopathological examination and the immunohistochemical staining of the lesion were characteristic for a hemangioma-like proliferation of vessels in the upper part of the dermis, similar to a targetoid hemosiderotic angioma. We also review epidemiological, clinical, and histopathological findings in 6 similar cases presented in the literature. Spontaneous regression and recurrence have rarely been described in this type of skin lesion.

Complement-Activating Capacity of Autoantibodies Correlates With Disease Activity in Bullous Pemphigoid Patients.

Background: Bullous pemphigoid is a subepidermal blistering skin disease, associated with autoantibodies to hemidesmosomal proteins, complement activation at the dermal-epidermal junction, and dermal granulocyte infiltration. Clinical and experimental laboratory findings support conflicting hypotheses regarding the role of complement activation for the skin blistering induced by pemphigoid autoantibodies. In-depth studies on the pathogenic relevance of autoimmune complement activation in patients are largely lacking. Therefore, the aim of this study was to investigate the pathogenic relevance of complement activation in patients with bullous pemphigoid. Complement activation by autoantibodies in vivo as measured by the intensity of complement C3 deposits in the patients' skin and ex vivo by the complement-fixation assay in serum was correlated with the clinical disease activity, evaluated by Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and Bullous Pemphigoid Disease Area Index (BPDAI), as well as, with further immunopathological findings in patients with bullous pemphigoid. Results: Complement-activation capacity of autoantibodies ex vivo, but not deposition of complement in the perilesional skin of patients, correlates with the extent of skin disease (measured by ABSIS and BPDAI) and with levels of autoantibodies. Conclusions: Our study provides for the first time evidence in patients for a pathogenic role of complement activation in bullous pemphigoid and should greatly facilitate the development of novel diagnostic tools and of more specific therapies for complement-dependent autoimmune injury.

Immunological markers as predictors of developing steroid-induced diabetes mellitus in pemphigus vulgaris patients: An observational study.

The aim of this study was to evaluate the clinical importance of autoantibodies in pemphigus vulgaris patients who developed steroid-induced diabetes mellitus (SID) because of the glucocorticoid therapy of pemphigus.A total of 137 patients with pemphigus vulgaris were studied. Patients with SID and pemphigus were compared with those that had only pemphigus. The variables recorded were: age at diagnosis, sex, body mass index, presence of diabetes mellitus (DM), cumulative cortisone dose, treatment duration, value of anti-desmoglein 1 and 3, and anti-glutamic acid decarboxylase autoantibodies.A total of 31 patients (22.62%) that developed steroid-induced DM were identified. Anti-glutamic acid decarboxylase autoantibodies were positive in 20.75% of patients with pemphigus vulgaris and in 25.75% of patients with pemphigus vulgaris and SID.The overall anti-glutamic acid decarboxylase autoantibodies prevalence in pemphigus patients was high, and the risk of developing DM in patients with pemphigus remains a serious problem, being associated with increased risk of mortality.

Molecular diagnosis of anti-laminin 332 (epiligrin) mucous membrane pemphigoid.

BACKGROUND: Mucous membrane pemphigoid is a group of chronic subepithelial autoimmune blistering diseases that mainly affect mucous membranes. Laminin 332-specific autoantibodies are present in approximately 1/3 of the patients, being associated with an increased risk of malignancy. Because of the severe complications, an early recognition of the disease allowing a timely therapy is essential. The gold standard methods for detection of laminin 332-specific autoantibodies, including the immunoprecipitation and immunoblotting are non-quantitative, laborious and restricted to a few specialized laboratories worldwide. In addition, the use of radioimmunoassays, although highly sensitive and specific, are laborious, expensive and tightly regulated. Therefore, there is a stringent need for a quantitative immunoassay for the routine detection of laminin 332-specific autoantibodies more broadly available to diagnostic laboratories. The aim of this study was to compare different antigenic substrates, including native, recombinant laminin 332 and laminin 332-rich keratinocyte extracellular matrix, for development of an ELISA to detect autoantibodies in mucous membrane pemphigoid. RESULTS: Using a relatively large number of sera from MMP patients with well-characterized autoantibody reactivity we show the suitability of ELISA systems using laminin 332 preparations as adjunct diagnostic tools in MMP. While glycosylation of laminin 332 does not appear to influence its recognition by MMP autoantibodies, ELISA systems using both purified, native and recombinant laminin 332 demonstrated a high sensitivity and good correlation with the detection of autoantibodies by immunoblotting. ELISA systems using different laminin 332 preparations represent a feasible and more accessible alternative for a broad range of laboratories. CONCLUSIONS: Our findings qualify the use of immunoassays with the laminin 332-rich preparations as an ancillary diagnostic tool in mucous membrane pemphigoid.

Role of physical factors in the pathogenesis of bullous pemphigoid: Case report series and a comprehensive review of the published work.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease affecting mainly the elderly. The subtype of the disease induced by physical agents represents a rare and, therefore, insufficiently characterized form. In the present study, we aimed to contribute to a better understanding of the pathogenetic mechanisms involved in the onset of BP induced by different trigger factors. We have retrospectively analyzed nine cases of BP. All patients were characterized based on clinical, epidemiological and immunological parameters. For each case, the trigger factor involved was specified. In addition to our retrospective analysis, a comprehensive review of the 59 published cases was conducted, regarding the involvement of trigger factor in BP, and clinical, epidemiological and immunological data were collected. In the local study, conducted on nine patients diagnosed with BP, various trigger factors were identified: contrast substance injection, surgical procedure, mechanical trauma, insect bite, thermal burn, radiotherapy and ultraviolet exposure associated with pre-existing psoriasis. The autoantibodies from all patients were shown to activate granulocytes and induce dermal-epidermal split. Different hypotheses regarding the pathogenetic mechanism involving the trigger factors have been discussed. In regard of the pathogenetic mechanism, we believe that the most reliable hypothesis is that BP patients already have low titers of anti-basement membrane autoantibodies which activate the granulocytes. However, more studies are needed for a better understanding of the pathogenetic mechanism of the intervention of trigger factors.

Prediction of survival for patients with pemphigus vulgaris and pemphigus foliaceus: a retrospective cohort study.

BACKGROUND: Factors associated with survival in pemphigus have not yet been thoroughly addressed. Therefore, in the present study, risk factors for overall mortality in a large group of patients with pemphigus vulgaris and foliaceus were investigated. METHODS: A retrospective hospital-based cohort study was carried out, between October 1998 and November 2012, in the Department of Dermatology of the University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania. The investigated prognostic endpoint was the overall survival of the patients. RESULTS: A total of 130 patients were studied (108 with pemphigus vulgaris and 22 with pemphigus foliaceus). In pemphigus vulgaris group, univariate analysis found a statistically significant association between the age of onset ≥ 65 years (p < 0.001), presence of coronary heart disease (p = 0.006), presence of cardiac arrhythmia (p = 0.004), level of anti-desmoglein1 autoantibodies ≥ 100 U/mL (p = 0.047) at diagnosis and the survival of the patients. An age-adjusted analysis showed significant results for coronary heart disease. Multivariate analysis identified the age of onset ≥ 65 years and the presence of coronary heart disease at diagnosis as independent risk factors associated with overall mortality. In patients with pemphigus foliaceus, age of onset ≥ 65 years (p = 0.021) was associated with poor survival. CONCLUSIONS: In addition to common prognostic factors, including older age and cardiovascular comorbidities, level of autoantibodies was found to be a disease-specific factor associated with overall mortality in pemphigus vulgaris. The newly identified factors have major implications for the stratification of patients and should greatly facilitate further epidemiological studies in pemphigus. In addition, they provide useful information for the design of personalized therapeutic plans in the clinical setting.

Molecular diagnosis of autoimmune skin diseases.

A wide range of skin diseases are associated with autoimmune responses against skin-specific or ubiquitous antigens. In many of these diseases, including autoimmune blistering disorders, collagenoses and vasculitides, extensive clinical and experimental evidence shows that autoreactive T-cells and/or autoantibodies play a major pathogenic role, allowing their classification as autoimmune diseases. The presence of tissue-bound and circulating autoantibodies does not only bear relevance for disease pathogenesis, but also allows developing robust diagnostic tools and molecular therapeutic approaches. Thus, various immunofluorescence methods, as well as molecular immunoassays, including enzyme-linked immunosorbent assay and immunoblotting, belong to the modern diagnostic algorithms for these disorders. This review article describes the immunopathological features of autoimmune skin diseases and the molecular assays currently available for their diagnosis and monitoring.

Quantitative expression of serum biomarkers involved in angiogenesis and inflammation, in patients with glioblastoma multiforme: correlations with clinical data.

Glioblastoma multiforme (GBM) represents a very aggressive brain tumor. Angiogenesis is the formation of a network of new blood vessels, from preexisting ones. It plays an important role in the formation of the tumor, as it supplies it with oxygen and nutrients. Angiogenesis and inflammation play essential roles in glioblastoma development. These processes are regulated by the balance of a few molecules, acting as pro- or antiangiogenic and pro- or anti-inflammatory factors. The purpose of our study was to evaluate the expression of 7 markers involved in angiogenesis and inflammation pathways in patients with glioblastoma. VEGF, PDGF-bb, IGF-1, TGF-ß, TNF-α, IL-6 and IL-8 levels were measured using the ELISA method, in the preoperative sera of 14 patients with histopathologically confirmed glioblastoma multiforme and 32 healthy patients. Serum levels of PDGF-bb, IGF-1 and IL-8 were significantly higher in patients with GBM, compared to the control group (p-value < 0.01). A statistically significant correlation has been found between IGF-1 and IL-6 levels (rho= -0.53, p-value < 0.05) and also between TNF-α and IL-6 levels (rho=0.60, p-value < 0.05). Statistically significant associations have been found between the presence of low levels of IL-8 and the development of coagulation necrosis (p-value < 0.05), high levels of VEGF and development of ischemic necrosis (p-value < 0.01) and high levels of IL-8 and the development of endothelial hyperplasia (p-value < 0.05). We have observed no statistically significant associations between the serum levels of the markers and the survival rates.

TIMP-1 expression in human colorectal cancer is associated with SMAD3 gene expression levels: a pilot study.

BACKGROUND AND AIMS: The prognosis of colorectal cancer (CRC) varies considerably, and there is a compelling need to identify novel biomarkers with prognostic significance. The aim of the present study was to evaluate the prognostic value of a panel of six genes (CDH1, SMAD3, TGFß1, ICAM-1, TIMP-1 and MUC12) in CRC patients. METHODS. We evaluated these genes by qRT-PCR in normal and CRC tumor tissue, and correlated the relative gene expression values with clinical, pathological aspects and other biological factors. RESULTS. RNA expression levels of CDH1, SMAD3, TGFß1, ICAM-1, TIMP-1 and MUC12 were measured by qRT-PCR in a set of 39 tumor samples and non-cancer tissue. Statistically significant increases in expression levels were found for ICAM-1 and TIMP-1 when comparing tumor samples to the non-tumor group. CONCLUSIONS. Among the genes which displayed differential expressions between tumor tissue and adjoining normal tissue, the ones that presented statistically significant correlations were TIMP-1 and SMAD3, possibly with prognostic significance.

Another review on triple negative breast cancer. Are we on the right way towards the exit from the labyrinth?

Triple negative breast cancer is a heterogeneous group of tumors, lacking the expression of estrogen, progesterone and HER-2 receptors. As frequency, it accounts about 15-20% of all breast cancers. Although in the last years there was a "boom" in publishing over this issue, multiple molecular classifications being elaborated, "the triple negative breast cancer odyssey " is still far away from ending, as the complicated molecular pathways of pathogenesis and drug resistance mechanisms remain yet insufficiently explored. The aim of this review is presentation of molecular signatures that could predict outcome and drug resistance in triple negative breast cancer.

Quantitative mRNA expression of genes involved in angiogenesis, coagulation and inflammation in multiforme glioblastoma tumoral tissue versus peritumoral brain tissue: lack of correlation with clinical data.

Glioblastoma multiforme is a very aggressive brain tumor. Angiogenesis, the formation of new blood vessels from pre-existing ones, is a process that plays an essential role in cancer development. The evolution of this process depends upon several proangiogenic factors as well as inhibitors of angiogenesis. Coagulation and inflammation also play an important role in tumorigenesis. Their expression is controlled by over- or under-expression of certain genes. The objective of our study was to evaluate the expression, in tissue samples, of a set of six genes involved in tumoral angiogenesis. The study concerned a group of 14 patients with pathologically-confirmed glioblastoma multiforme. Samples of tumoral and peritumoral brain tissue were taken during surgery. We used RT-PCR to evaluate the expression of six genes involved in angiogenesis: VEGF, PDGF, EPCR, TNF, ICAM-1 and CTGF. Gene expression was calculated by comparing the values obtained for the tumoral tissue with those obtained for the peritumoral tissue. Increased transcription of VEGF, PDGF and ICAM-1 genes were observed in glioblastoma tumoral tissues compared with peritumoral brain tissues. Correlations were observed between transcription of the CTGF and TNF genes (rho = 0.54, p-value = 0.05) and PDGF and ICAM-1 genes (rho = 0.54, p-value = 0.05). Under-expression of CTGF, EPCR and TNF genes was observed in glioblastoma tumoral tissue in comparison with peritumoral brain tissue. The association between gene expression and histopathological results (endothelial hyperplasia, coagulation necrosis and ischemic necrosis) was evaluated. No statistically significant associations were observed between gene expression and survival rates.