Voriconazole plus terbinafine combination antifungal therapy for invasive Lomentospora prolificans infections: analysis of 41 patients from the FungiScope® registry 2008-2019.

OBJECTIVES: Lomentospora prolificans is an emerging cause of serious invasive fungal infections. Optimal treatment of these infections is unknown, although voriconazole-containing treatment regimens are considered the treatment of choice. The objective of this study was to evaluate the role of combination antifungal therapy for L. prolificans infections. METHODS: We performed a retrospective review of medical records of patients with invasive L. prolificans infection diagnosed between 1 January 2008 and 9 September 2019 that were documented in the FungiScope® registry of rare invasive fungal infections. We compared clinical outcomes between antifungal treatment strategies. RESULTS: Over the study period, 41 individuals with invasive L. prolificans infection from eight different countries were documented in the FungiScope® registry. Overall, 17/40 (43%) had treatment response/stable disease and 21/40 (53%) had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was associated with increased 28-day survival (15/24 survived versus 4/16 receiving monotherapy; p 0.027) and the combination voriconazole plus terbinafine trended to be associated with higher rates of treatment success (10/16, 63%, 95% CI 35%-85%) compared with other antifungal treatment regimens (7/24, 29%, 95% CI 13%-51%, p 0.053). In Kaplan-Meier survival analysis there was a higher survival probability in individuals receiving the voriconazole/terbinafine combination compared with other antifungal regimens (median survival 150 days versus 17 days). CONCLUSIONS: While overall mortality was high, combination antifungal treatment, and in particular combination therapy with voriconazole plus terbinafine may be associated with improved treatment outcomes compared with other antifungal regimens for the treatment of invasive L. prolificans infections.

Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.

The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

Clinical-pathological changes in differentiated thyroid cancer (DTC) over time (1997-2010): data from the University Hospital "Maggiore della Carità" in Novara.

Differentiated thyroid cancer (DTC) is an important clinical entity in our population (Novara, Piedmont, Italy) which is characterized by important environmental influences, as iodine deficiency (ID) and subsequent supplementation, thyroiditis and occupational exposure. To evaluate the features of DTC in our population 20 years after the iodine-prophylaxis pondering the effects of the introduction of the new guidelines for diagnosis and management of DTC after 2005. 322 patients [244 females, age: mean (±SD) 53.8 ± 15.8 years] treated for DTC in a tertiary care center between 1997 and 2010 were retrospectively evaluated. Medical history, demographics, and pathological features were considered. Patients were subdivided into two groups: A (n = 139, diagnosis 1997­2005) and B (n = 183, diagnosis 2006­2010). The population of group A showed a mild ID, while normal iodine status was recorded in group B. A significant increase in histological tumor-associated thyroiditis was found from group A to B (p = 0.021). Recurrent or persistent diseases were found to be correlated with lymph nodes metastases and/or a distant disease at diagnosis, stimulated thyroglobulin levels at the first follow-up and an additional radioiodine therapy. Twenty percent of our patients were females employed in textile industries. The tumor-related inflammation and the occupational exposure should be considered as important factors in the pathogenesis of DTC. Further studies are required in order to confirm our findings.

Distribution of prolactin receptors in the rat forebrain. Immunohistochemical study.

The distribution of prolactin receptors (PRL-R) in the rat brain was investigated for the first time with the immunohistochemical technique using monoclonal antibodies raised against PRL-R purified from rat liver. Granular immunostaining was observed in neurons and along their dendritic processes and fibers. PRL-R like immunoreactive neurons were found in a number of brain areas. There was a very dense labelling in the cerebral cortex (pyramidal cell layer), septal nuclei, amygdaloid complex as well as in the hypothalamus (suprachiasmatic, supraoptic, paraventricular and dorsomedial nuclei). A dense staining was seen in the substantia nigra, habenula and in the paraventricular thalamic nucleus. Immunostaining was also found in the choroid plexus and in the subcommissural organ. Comparison between the present distribution and that of PRL-like immunoreactivity indicates that the density of PRL-R generally corresponds to that of the fibers. However, in some regions densely stained by PRL-R antibody, there are very few PRL-immunoreactive fibers. These results are suggestive of different modes of action of PRL in the brain.

Hypothalamic injection of prolactin or its antibody alters the rat sleep-wake cycle.

Several studies have suggested an interaction between prolactin and the sleep-wake cycle. In this study ovine prolactin (oPRL) and anti-prolactin antibody were microinjected into the rat dorsolateral hypothalamus, which contains prolactin-like immunoreactive neurons. Results indicate that during the light period, prolactin injection induced an increase in paradoxical sleep duration, whereas it caused a decrease when injected during the dark period. Anti-prolactin antibody injection during the dark period also decreased paradoxical sleep duration. There was no effect of oPRL or antibody on slow wave sleep duration irrespective of injection time. These results suggest that prolactin injection may have an inhibitory effect on hypothalamic prolactin neurons.

[Prolactin-secreting neurons in the dorsolateral hypothalamus in Sprague-Dawley rats]. / Neurones à prolactine dans l'hypothalamus dorso-latéral du rat Sprague-Dawley.

By means of immunocytochemical techniques ovine prolactin like immunoreactivity (oPRL-LIR) has been demonstrated in the perikarya located around fornix in the dorso-lateral part of the rat hypothalamus. No PRL-LIR was observed in the arcuate n. perikarya. Immunoreactive fibers were present in the hypothalamus, medial thalamus, accumbens and amygdaloid nuclei.

OKT4/OKT8 ratio and serum beta 2-microglobulin in mycosis fungoides and chronic benign dermatitis.

Pre-treatment Serum Beta 2-microglobulin (S B2-m) and OKT4/OKT8 Ratio (T4/T8 R) were studied in 15 patients with Mycosis Fungoides (MF) and in 10 subjects with Chronic Superficial Benign Dermatitis (CSBD) in order to verify whether these parameters may lend support to an earlier differential diagnosis. S B2-m levels and T4/T8 R showed no significant difference in CSBD as compared to normal controls. MF patients displayed elevated S B2-m and T4/T8 R values in comparison to healthy controls and subjects suffering from CSBD (P less than 0.001). After photochemotherapy (PUVA), markedly decreased S B2-m and T4/T8 R values were observed in all patients but two who proved to be unresponsive to PUVA treatment. On the basis of reported data, S B2-m and T4/T8 R can be regarded as an additional tool to discriminate CSBD and MF when clinical and histological features are not significantly diagnostic. Finally, these parameters seem to provide reliable information in monitoring response to treatment.