Neuropilin-2 is a novel marker expressed in pancreatic islet cells and endocrine pancreatic tumours

Neuropilin-2 (NP-2) is a cell surface transmembrane protein originally characterized as a receptor for the type 3 semaphorins, and more recently for a number of vascular endothelial growth factor (VEGF) isoforms. NP-2 expression has been recently localized to a subset of neuroendocrine cells in the gastrointestinal tract. The aim of this study was to define the expression pattern of NP-2 in normal pancreatic islets and to determine the utility of NP-2 expression as a diagnostic marker of pancreatic endocrine tumours. Paraffin-embedded tissue sections from 30 endocrine pancreatic tumours (EPTs) and from normal pancreas were immunostained with a rabbit polyclonal antibody generated towards NP-2. Nineteen of the tumours were hormonally functional (nine insulinomas, nine gastrinomas, and one glucagonoma). The NP-2 staining pattern was correlated with islet cell hormone expression. In addition, NP-2 expression was evaluated in other normal neuroendocrine tissues and neuroendocrine neoplasms. In normal pancreas, NP-2 stained a distinct subset of islet cells situated primarily at the islet periphery. Double immunohistochemical staining revealed co-localization with glucagon-expressing cells. Moderate to strong NP-2 staining was present in 27 of 30 EPTs. Serial staining of the pancreatic tumours with insulin, gastrin, glucagon, pancreatic polypeptide (PP) or somatostatin did not reveal a distinct pattern of co-localization. NP-2 expression was not detected in neuroendocrine cells outside the gastroenteropancreatic system, or in their corresponding neoplasms, except for focal staining in one bronchial carcinoid tumour. In conclusion, the vast majority of EPTs examined expressed NP-2, suggesting its utility as a diagnostic marker for these tumours. The function of NP-2 in islet cell biology or tumourigenesis remains to be elucidated.     

Prevalence and risk factors for allergic rhinitis and atopic eczema among schoolchildren in Israel: results from a national study.

BACKGROUND: There is growing evidence that the prevalence rates of asthma and allergic diseases are increasing, especially among children. Several risk factors are under investigation. OBJECTIVE: To evaluate the prevalence and risk factors for allergic diseases, including allergic rhinitis (AR) and atopic eczema (AE), among 13- to 14-year-old schoolchildren in Israel. METHODS: A modified version of the International Study of Asthma and Allergies in Childhood written questionnaire was administered to a national sample of schoolchildren 13 to 14 years old in Israel. The questionnaire was completed by the schoolchildren themselves. RESULTS: There were 10,057 complete questionnaires available for analysis. The prevalence of AR symptoms ever and current AR were 41.6% and 9.4%, respectively. Allergic rhinoconjunctivitis symptoms ever were reported by 15.8% of the children. The prevalence rates of 6 months of itchy rash ever and AE were 5.9% and 7.8%, respectively. After adjustment for demographic and environmental factors, current asthma, parental history of asthma, and population group were the most significant risk factors for current AR (odds ratio [OR], 4.47; 95% confidence interval [CI], 3.70-5.40; OR, 1.30; 95% CI, 1.02-1.66; and OR, 1.75; 95% CI 1.45-2.13; respectively) and AE (OR, 2.30; 95% CI, 1.80-2.90; OR, 1.80; 95% CI, 1.40-2.30; and OR, 1.70; 95% CI, 1.40-2.00; respectively). CONCLUSIONS: Israeli children have a low prevalence rate of current AR and a midrange rate of AE. Arabs have lower prevalence rates of allergic diseases than Jews, and the prominent risk factors for those diseases are current asthma and parental history of asthma.     

A cyclosporine-sensitive psoriasis-like disease produced in Tie2 transgenic mice

Psoriasis is a common, persistent skin disorder characterized by recurrent erythematous lesions thought to arise as a result of inflammatory cell infiltration and activation of keratinocyte proliferation. Unscheduled angiogenic growth has also been proposed to mediate the pathogenesis of psoriasis although the cellular and molecular basis for this response remains unclear. Recently, a role for the angiopoietin signaling system in psoriasis has been suggested by studies that demonstrate an up-regulation of the tyrosine kinase receptor Tie2 (also known as Tek) as well as angiopoietin-1 and angiopoietin-2 in human psoriatic lesions. To examine temporal expression of Tie2, we have developed a binary transgenic approach whereby expression of Tie2 can be conditionally regulated by the presence of tetracycline analogs in double-transgenic mice. A psoriasis-like phenotype developed in double-transgenic animals within 5 days of birth and persisted throughout adulthood. The skin of affected mice exhibited many cardinal features of human psoriasis including epidermal hyperplasia, inflammatory cell accumulation, and altered dermal angiogenesis. These skin abnormalities resolved completely with tetracycline-mediated suppression of transgene expression, thereby illustrating a complete dependence on Tie2 signaling for disease maintenance and progression. Furthermore, the skin lesions in double-transgenic mice markedly improved after administration of the immunosuppressive anti-psoriatic agent cyclosporine, thus demonstrating the clinical significance of this new model.     

Involvement of Crk adapter proteins in regulation of lymphoid cell functions

The Crk adapter proteins consist of Src homology 2 (SH2) SH2 and SH3 domains, which bind tyrosine-phosphorylated peptides and polyproline-rich motives, respectively. They are linked to multiple signaling pathways in different cell types, including lymphocytes, and because of their lack of catalytic activity, many studies on Crk were aimed at the identification of their binding partners and determination of the physiologic meaning of these interactions. Crk proteins were found to be involved in the early steps of lymphocyte activation through their SH2-mediated transient interaction with signal-transducing molecules, such as Cbl, ZAP-70, CasL, and STAT5. In addition, Crk proteins are constitutively associated with effector molecules that mediate cell adhesion and thereby regulate lymphocyte extravasation and recruitment to sites of inflammation. This article describes selected studies of Crk, performed predominantly in lymphocytes, and discusses their potential relevance to the role of Crk in the regulation of lymphocyte functions.     

Neutrophil-to-Lymphocyte Ratio Predicts Recurrence Pattern in Patients with Resectable Colorectal Liver Metastases

Annals of Surgical Oncology - Studies have suggested that neutrophil-to-lymphocyte ratio (NLR) has value as a predictor of long-term outcomes in various cancer types. Its prognostic potential in...     

ASO Visual Abstract: Neutrophil-to-Lymphocyte Ratio Predicts Recurrence Pattern in Patients with Resectable Colorectal Liver Metastases

Annals of Surgical Oncology -     

Post-mastectomy surveillance of BRCA1/BRCA2 mutation carriers: Outcomes from a specialized clinic for high-risk breast cancer patients

Female BRCA1/BRCA2 mutation carriers may elect bilateral risk-reducing mastectomy. There is a paucity of data on yield of imaging surveillance after risk-reducing mastectomy. This retrospective study focused on female BRCA1/BRCA2 mutation carriers who underwent bilateral mastectomy either as primary preventative, or as secondary preventative, after breast cancer diagnosis. All participants underwent breast imaging at 6- to 12-month intervals after mastectomy. Data on subsequent breast cancer diagnosis and timing were collected and compared between the groups. Overall, 184 female mutation carriers (134 BRCA1, 45 BRCA2, 5 both BRCA genes) underwent bilateral mastectomy after initial breast cancer diagnosis, between April 1, 2009 and August 31, 2018. During a mean follow-up of 6.2 ± 4.2 years, 13 (7.06%) were diagnosed with breast cancer; 12 ipsilateral (range: 0.4–28.8 years) and 1 contralateral breast cancer, 15.9 years after surgery. On the contrary, among asymptomatic BRCA1 (n = 40) and BRCA2 (n = 13) mutation carriers who underwent primary risk-reducing mastectomy (mean age at surgery 39.5 ± 8.4 years); none has developed breast cancer after a mean follow-up of 5.4 ± 3.4 years. BRCA1/BRCA2 mutation carriers with prior disease who underwent risk-reducing mastectomy after breast cancer diagnosis are still prone for developing ipsi or contralateral breast cancer, and therefore may benefit from continues clinical and imaging surveillance, unlike BRCA1/BRCA2 mutation carriers who undergo primary preventative bilateral mastectomy.     

The yield of full <Emphasis Type="Italic">BRCA1</Emphasis>/<Emphasis Type="Italic">2</Emphasis> genotyping in Israeli high-risk breast/ovarian cancer patients who do not carry the predominant mutations

Purpose

Patients treated with trastuzumab for HER2-positive metastatic breast cancer (HER2+MBC) are living longer, but there is little information on their outcomes and treatment experience beyond the median survival from clinical trials and real-world observational studies. We aim to describe the real-world treatment patterns and overall survival (OS) for women surviving five or more years from initiation of trastuzumab for HER2+MBC.

Methods

This is a retrospective, whole-of-population cohort study of women initiating trastuzumab for HER2+MBC between 2001 and 2011, followed to 2016. We defined long-term survivors (LTS) as those patients surviving?≥?5 years from trastuzumab initiation. We used dispensing claims to describe timing of cancer treatments used by LTS and to estimate time on and off HER2-targeted therapies, and OS from trastuzumab initiation for HER2+MBC.

Results

Of 4177 women initiating trastuzumab for HER2+MBC, 1082 (26%) survived ≥?5 years. Median age for LTS was 54 years (IQR 46–63). At a median follow-up of 9.4 years, 36% of LTS died; their conditional probability of surviving an additional 5 years was 55%. Median time on trastuzumab and all HER2-targeted therapy was 58.9 months (27.6–88.1) and 69.1 months (35.6–124.5), respectively. 85% of LTS had a period off HER2 therapy, lasting a median of 30.4 months (8.2–NR).

Conclusions

LTS generally receive HER2-targeted therapies for periods of time longer than in clinical trials, but most LTS also had breaks in treatment. More research is needed to understand the effects of long-term treatment and to identify patients who may be able to safely discontinue HER2-targeted therapy.