Pulmonary neuroendocrine neoplasms with well differentiated morphology and high proliferative activity: illustrated by a case series and review of the literature.

OBJECTIVES: Pulmonary neuroendocrine neoplasms (NENs) are subdivided in carcinoids and neuroendocrine carcinomas (small cell lung carcinoma and large cell neuroendocrine carcinoma (LCNEC)), based on the presence of necrosis and mitotic index (MI). However, it is unclear if tumors with well differentiated morphology but high proliferation rate should be regarded as LCNEC or as high grade carcinoids. In previous case series, a longer overall survival then expected in LCNEC has been suggested. We describe 7 of those cases analyzed for pRb expression and overall survival. MATERIAL AND METHODS: Cases with well differentiated morphology, but MI > 10/2mm2 and/or Ki-67 proliferation index >20% were selected based on pathology reports of consecutive NENs in our university medical center (Maastricht UMC+, 2007-2018) and confirmed by pathological review. Immunohistochemistry was performed to assess pRb expression. RESULTS: Seven stage IV cases were included in this study. Median overall survival was 8 months (95% confidence interval 5-11 months). Cases with well differentiated morphology and preserved pRb expression (4/7) had a median overall survival of 45 months. CONCLUSION: A subgroup of pulmonary NENs with well differentiated morphology but high proliferation rate likely exists. pRb staining might be helpful to predict prognosis, but clinical relevance remains to be studied.

Subcutaneous immunotherapy with purified Der p1 and 2 suppresses type 2 immunity in a murine asthma model.

BACKGROUND: Allergen-specific immunotherapy can induce long-term suppression of allergic symptoms, reduce medication use, and prevent exacerbations of allergic rhinitis and asthma. Current treatment is based on crude allergen extracts, which contain immunostimulatory components such as ß-glucans, chitins, and endotoxin. Use of purified or recombinant allergens might therefore increase efficacy of treatment. AIMS: Here, we test application of purified natural group 1 and 2 allergens from Dermatophagoides pteronyssinus (Der p) for subcutaneous immunotherapy (SCIT) treatment in a house dust mite (HDM)-driven mouse model of allergic asthma. MATERIALS AND METHODS: HDM-sensitized mice received SCIT with crude HDM extract, a mixture of purified Der p1 and 2 (DerP1/2), or placebo. Upon challenges, we measured specific immunoglobulin responses, allergen-induced ear swelling response (ESR), airway hyperresponsiveness (AHR), and inflammation in bronchoalveolar lavage fluid (BAL) and lung tissue. RESULTS: ESR measurement shows suppression of early allergic response in HDM-SCIT- and DerP1/2-SCIT-treated mice. Both HDM-SCIT and DerP1/2-SCIT are able to suppress AHR and eosinophilic inflammation. In contrast, only DerP1/2-SCIT is able to significantly suppress type 2 cytokines in lung tissue and BAL fluid. Moreover, DerP1/2-SCIT treatment is uniquely able suppress CCL20 and showed a trend toward suppression of IL-33, CCL17 and eotaxin levels in lung tissue. DISCUSSION: Taken together, these data show that purified DerP1/2-SCIT is able to not only suppress AHR and inflammation, but also has superior activity toward suppression of Th2 cells and HDM-induced activation of lung structural cells including airway epithelium. CONCLUSIONS: We postulate that treatment with purified natural major allergens derived from HDM will likely increase clinical efficacy of SCIT.

5-Aminosalicylates and effects on renal function in patients with Crohn's disease.

BACKGROUND: Case reports concerning irreversible renal failure caused by 5-aminosalicylates (5-ASA) have been published. The aim of this study was to investigate the effect of long-term use of 5-ASA on renal function in patients with Crohn's disease (CD). METHODS: This was a retrospective survey in 200 consecutive outpatients with CD. Endogenous creatinine clearance (ECC) was estimated from serum creatinine with the Cockroft and Gault formula. The first ECC was chosen close to the start of 5-ASA and the second was the most recent ECC available. RESULTS: In 153 patients (59 men and 94 women), sufficient data were available for analysis. The interval between ECCs was 11 years, with a mean exposure to 5-ASA of 8.6 years. The cumulative dose of 5-ASA amounted to 9 kg. The ECC declined 0.3 +/- 5 mL/min/yr (from 100 +/- 25 to 92 +/- 28 mL/min; P < 0.01). In a multiple linear regression model, duration of the interval was a significant predictor for change in ECC (P < 0.0001), but cumulative dose of 5-ASA was not predictive (P = 0.30). No interstitial nephritis was reported, and in the 8 patients with the largest decline in ECC, comorbidity causing renal function impairment was present. CONCLUSIONS: The mean decline in ECC of 0.3 mL/min/yr in patients with CD does not exceed the decline expected from physiologic aging. Furthermore, the cumulative dose of 5-ASA was not a predictor for change in renal function. However, as interstitial nephritis caused by 5-ASA may rarely occur, we still advocate measurements of serum creatinine before and during treatment.