Phenotypic and functional analyses of dendritic cells in patients with lymphoproliferative disease of granular lymphocytes (LDGL)

We investigated whether dendritic cells (DCs) play a role in favoring granular lymphocyte (GL) proliferation in patients with lymphoproliferative disease of granular lymphocytes (LDGL). The presence of in vivo circulating DCs was studied in 11 patients (5 CD3+ and 6 CD3- LDGL). Autologous immature (iDCs) and mature (mDCs) DCs generated in vitro were studied for stimulatory activity on cell proliferation of CD3+ and CD3- GLs. The topographic organization of GLs and DCs was also studied in bone marrow (BM) biopsies. Peripheral blood (PB) CD3- GLs from patients showed significant proliferative activity in the presence of iDCs and mDCs. Conversely, monoclonal CD3+ GLs were unresponsive to autologous and allogeneic PB DCs. Analysis of BM biopsies demonstrated a topographic distribution of DCs and GLs that indicates contact between the 2 cell types. On functional assays, DCs obtained from BM were more efficient than PB DCs in stimulating CD3- GLs, and surprisingly, a low but definite stimulatory effect was demonstrated also on CD3+ GLs. The putative contact between DCs and GLs in the BM and, more crucial, the proliferative response of discrete GL populations to DC stimulation suggest the presence of a specific antigen within BM DCs, providing evidence for a role of DCs in the pathogenesis of LDGL.     

Role of gut microbiota-immunity axis in patients undergoing surgery for colorectal cancer: Focus on short and long-term outcomes

Human body is colonized by a huge amount of microorganisms mostly located in the gastrointestinal tract. These dynamic communities, the environment and their metabolites constitute the microbiota. Growing data suggests a causal role of a dysbiotic microbiota in several pathologies, such as metabolic and neurological disorders, immunity dysregulations and cancer, especially the well-studied colorectal cancer development. However, many were preclinical studies and a complete knowledge of the pathogenetic mechanisms in humans is still absent.The gut microbiota can exert direct or indirect effects in different phases of colorectal cancer genesis. For example, Fusobacterium nucleatum promotes cancer through cellular proliferation and some strains of Escherichia coli and Bacteroides fragilis produce genotoxins. However, dysbiosis may also cause a proinflammatory state and the stimulation of a Th17 response with IL-17 and IL-22 secretion that have a pro-oncogenic activity, as demonstrated for Fusobacterium nucleatum. Microbiota has a crucial role in several stages of postoperative course;dysbiosis in fact seems related with surgical site infections and Enterococcus faecalis(and other collagenase-producers microbes) are suggested as a cause of anastomotic leak. Consequently, unbalanced presence of some species, together with altered immune response may also have a prognostic role. Microbiota has also a substantial role in effectiveness of chemotherapy, chemoresistance and in the related side effects. In other words, a complete knowledge of the fine pathological mechanisms of gut microbiota may provide a wide range of new diagnostic tools other than therapeutic targets in the light of tailored medicine.     

Menstrual migraine: what it is and does it matter?

Journal of Neurology - The diagnostic criteria of menstrual migraine (MM), migraine related to menstruation and pure menstrual migraine, are placed in the appendix of the International...     

How I investigate chronic myelomonocytic leukemia

The 2016 revised 4th edition of the World Health Organization classification of hematopoietic neoplasms updated the diagnostic criteria for chronic myelomonocytic leukemia (CMML). Persistent peripheral blood monocytosis of at least 1 × 10⁹/L and a percentage of monocytes ≥10% of the circulating white blood cell count (WBC) are both prerequisite criteria for this diagnosis. CMML represents the prototype of “overlapping” myeloid neoplasms with concurrent myeloproliferative and myelodysplastic features. However, clinical presentation is heterogeneous, with cases showing prevailing “dysplastic” features and others a predominant “proliferative” phenotype. Accounting for this diversity, two variants of CMML are recognized: “dysplastic” CMML defined by WBC < 13 × 10⁹/L and “proliferative” CMML with WBC ≥ 13 × 10⁹/L often showing features mimicking a myeloproliferative neoplasm. Although not an official WHO category, the “oligomonocytic” variant of CMML is defined by relative monocytosis with an absolute monocyte count of 0.5‐0.9 × 10⁹/L. It can be considered a “pre‐phase,” as it frequently anticipates the development of an overt, classic CMML. In an attempt at improving disease prognostication, the blast count based grading system for CMML of the WHO 2008 Classification has been expanded in 2016 to include a new “CMML‐0” category. Lastly, the large body of knowledge on the molecular events occurring in CMML has been used to assist diagnosis and assess prognosis. Despite the step forwards, diagnosis of CMML still remains one of exclusion as no clinical, pathologic or molecular findings are specific for this disease. The current review brings insight into the spectrum of CMML and provides practical advice to approach suspected cases of CMML.     

Omalizumab for treatment of refractory severe atopic dermatitis. A pediatric perspective

Omalizumab is a monoclonal antibody, targeting Fc receptor of IgE, approved for the treatment of allergic asthma and chronic spontaneous urticaria. Its utility in atopic dermatitis appears controversial from data in literature since the molecule is well tolerated but it seems less effective than other medications used in adult patients (eg, Dupilumab). At present, the use of Dupilumab is not approved in pediatric patients therefore there are no second level treatments available in this age group. Here we report two clinical cases of patients (15 and 16 years old) suffering from both atopic dermatitis and asthma, treated with Omalizumab. Our experience suggests that atopic eczema of young patients with allergic comorbidities can benefit from asthma treatment with Omalizumab observing improvement on both conditions.     

Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer

Breast cancer is a frequent and treatable disease. However, when recurrent, breast cancer often becomes refractory to therapy and progresses into metastatic forms that are typically incurable. Thus, understanding and targeting the critical pathways underlying breast cancer recurrence is urgently needed to eradicate primary disease and achieve better prognosis. Recently, we have demonstrated that the ribosomal protein p70S6K is activated in residual breast cancer cells as a result of post-surgical inflammation and that interfering with its activity in the peri-operative setting strongly suppresses recurrence in a mouse model. In order to develop clinically-exploitable treatments targeting p70S6K, we have tested a newly generated compound, called FS-115. FS-115 potently inhibited p70S6K1 (IC₅₀ 35nM) with high selectivity over other AGC kinases or PI3K pathway kinases. In vitro, treatment with FS-115 efficiently blocked p70S6K activity in breast cancer cell lines and impaired colony formation and anchorage independent growth. Pharmacokinetic profiling showed that FS-115 exhibited high oral bioavailability, optimal plasma distribution and high brain penetrance. In nude mice, FS-115 strongly suppressed tumor take-rate and primary tumor growth. Oral dosing with FS-115 in a peri-operative schedule was effective in decreasing local recurrence of breast cancer and a long-term treatment schedule was well tolerated and efficiently suppressed distant metastasis formation. Altogether, we propose that FS-115 might be a good candidate for the treatment of breast cancer patients at high risk to relapse.

Summary Statement

Our results confirm that inhibition of p70S6K represents a valuable opportunity for restraining loco-regional relapse and metastasis in breast cancer and identify in FS-115 a promising candidate-inhibitor to move from preclinical to clinical treatments.     

Levothyroxine liquid solution versus tablet form for replacement treatment in pregnant women

Objective: To evaluate the need and the magnitude of levothyroxine (LT4) increase in hypothyroid pregnant women on liquid compared to tablet formulations.

Methods: Patients were recruited by searching our “thyroid patients” database. The selection criteria were as follows: a) pregnant women on treatment for hypothyroidism (both liquid and tablet LT4) who gave birth at our hospital between February 2012 and January 2014; b) thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels obtained at least 3 months before missed menstrual cycle, with a TSH value less than 2.5?mIU/L and c) TSH and FT4 obtained within 12 weeks of pregnancy, and each month subsequently.

Results: During pregnancy, 8/31 (25.5%) of the women had to increase the dosage of LT4. Of these, 7/17 (41.2%) were on LT4 replacement therapy with tablets, and 1/14 (7.1%) with liquid formulation (p?=?0.038). Daily LT4 was significantly increased in the liquid group only (52.9?±?19.5 versus 67.5?±?19.2?mcg/day (p?=?0.013). A logistic regression analysis showed that the treatment with LT4 tablets was the only predictor of LT4 increase (OR: 0.44; 95% CI: 0.04–0.83; p?=?0.031).

Conclusion: Pregnant women on optimal replacement therapy before pregnancy require an increase of LT4 dosage more often when on a tablet than liquid formulation.