Background . The diagnostic work-up and treatment of patients with neuroendocrine neoplasms (NENs) has undergone major recent advances and new methods are currently introduced into the clinic. An update of the WHO classifi cation has resulted in a new nomenclature dividing NENs into neuroendocrine tumours (NETs) including G1 (Ki67 index Յ 2%) and G2 (Ki67 index 3 -20%) tumours and neuroendocrine carcinomas (NECs) with Ki67 index Ͼ 20%, G3. Aim . These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group ' s current view on how to diagnose and treat NEN-patients and are meant to be useful in the daily practice for clinicians handling these patients.

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Background:The prognostic impact of tumour-promoting immune cells in cervical cancer is unclear.Methods:Federation of Gynaecology and Obstetrics (FIGO) stage IB and IIA cervical cancer patients (N=101) were assessed for tumour-associated CD66b+ neutrophils and CD163+ macrophages by immunohistochemistry in whole tissue sections using stereology. Results were correlated with previous results on tumour-infiltrating CD3+, CD4+, and CD8+ lymphocytes in the same cohort with recurrence-free survival (RFS) as end point.Results:The highest densities of CD66b+ neutrophils and CD163+ macrophages were observed in the peritumoural compartment (median 53.1 cells mm−2 and 1.3% area fraction, respectively). Above median peritumoural and stromal CD66b+ neutrophils and peritumoural CD163+ macrophages were significantly associated with short RFS. Multivariate analysis identified high peritumoural neutrophils (HR 2.27; 95% CI 1.09–4.75; P=0.03), low peritumoural CD8+ lymphocytes (HR 3.67; 95% CI 1.63–8.25; P=0.002), and lymph node metastases (HR 2.70; 95% CI 1.26–5.76; P=0.01) as independent prognostic factors for short RFS, whereas CD163+ macrophages were not significant. An index of combined intratumoral and peritumoral CD66b+ neutrophils to CD8+ lymphocytes had good discriminatory power for each quartile with 5-year RFS of 92%, 80%, 62%, and 44% (P=0.001).Conclusion:Tumour-associated neutrophil count is an independent prognostic factor for short RFS in localised cervical cancer. Combining CD66b and CD8 may further improve prognostic stratification. These findings require prospective validation.

Flumazenil is used for the reversal of benzodiazepine overdose. Serious adverse events (SAEs) including seizures and cardiac arrhythmias have been reported in patients treated with flumazenil, and the clinical advantage of flumazenil treatment has been questioned. The objective was to assess the risk of (S)AEs associated with the use of flumazenil in patients with impaired consciousness due to known or suspected benzodiazepine overdose. Studies included in the meta-analyses were identified by literature search in Medline, Cochrane Library and Embase using combinations of the words flumazenil, benzodiazepines, antianxiety agents, poisoning, toxicity and overdose. Randomised clinical trials (RCTs) in verified or suspected benzodiazepine overdose patients comparing treatment with flumazenil versus placebo were included. Pre-defined outcome measures were AEs, SAEs and mortality. Thirteen trials with a total of 994 randomised (990 evaluable) patients were included. AEs were significantly more common in the flumazenil group (138/498) compared with the placebo group (47/492) (risk ratio: 2.85; 95% confidence interval: 2.11-3.84; p < 0.00001). SAEs were also significantly more common in the flumazenil group compared with the placebo group (12/498 versus 2/492; risk ratio: 3.81; 95% CI: 1.28-11.39; p = 0.02). The most common AEs in the flumazenil group were agitation and gastrointestinal symptoms, whereas the most common SAEs were supraventricular arrhythmia and convulsions. No patients died during the blinded phase of the RCTs. The use of flumazenil in a population admitted at the emergency department with known or suspected benzodiazepine intoxication is associated with a significantly increased risk of (S)AEs compared with placebo. Flumazenil should not be used routinely, and the harms and benefits should be considered carefully in every patient.

The purpose of this study was to investigate the prognostic value of the primary in situ cellular immune response in cervical squamous cell carcinoma. A study of 102 women treated for stage IB and IIA disease, between 1990 and 2000, was performed. Paraffinembedded cervical tissue processed at the time of diagnosis was immunostained for CD3 þ (T cells), CD4 þ (T helper/regulatory T cells) and CD8 þ (cytotoxic T cells) cells. Immune cell profile densities were estimated using stereology. Both intra-and peritumoural cell densities were estimated. Using Cox's proportional hazards regression modelling we found an increase in cell density to decrease the risk of relapse for all three cell types. The density of peritumoural CD3 þ cells seems to have the strongest potential for predicting relapse. An increase in CD3 þ cell density from 795 to 2043 cells per mm 2 (25 -75 percentile) reduced the hazard ratio to 0.27.

The prognostic value of oncogenic antigen 519 (OA-519) expression and tumour proliferative activity was evaluated in a retrospective series of 118 patients with low-risk breast cancer. Low risk was defined as negative axillary nodes, tumour diameter < or = 50 mm, and no histological evidence of invasion of skin or deep fascia (= T1N0M0 and T2N0M0). The median follow-up time was 104 months (range 5-143 months). Immunohistochemical analysis of OA-519 expression was performed on formalin-fixed, paraffin-embedded tissue. The proliferative activity was estimated using a Ki-67 equivalent monoclonal antibody (MIB-1), which is applicable on formalin-fixed, paraffin-embedded tissue after microwave pretreatment. OA-519 was expressed in about one-third of the tumours and the percentage of proliferating cells (the MIB-1 index) ranged between 1 and 72 per cent (median 17 per cent). Using multivariate Cox analysis, both the MIB-1 index and OA-519 expression were of independent prognostic value (2p < or = 0.01), and the combined immunohistological approach may therefore be useful in selecting patients with node-negative breast cancer who might benefit from adjuvant therapy.

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