Symptomatic hypogammaglobulinemia in infancy and childhood – clinical outcome and in vitro immune responses

BACKGROUND: Symptomatic hypogammaglobulinemia in infancy and childhood (SHIC), may be an early manifestation of a primary immunodeficiency or a maturational delay in the normal production of immunoglobulins (Ig). We aimed to evaluate the natural course of SHIC and correlate in vitro lymphoproliferative and secretory responses with recovery of immunoglobulin values and clinical resolution. METHODS: Children, older than 1 year of age, referred to our specialist clinic because of recurrent infections and serum immunoglobulin (Ig) levels 2 SD below the mean for age, were followed for a period of 8 years. Patient with any known familial, clinical or laboratory evidence of cellular immunodeficiency or other immunodeficiency syndromes were excluded from this cohort. Evaluation at 6- to 12-months intervals continued up to 1 year after resolution of symptoms. In a subgroup of patients, in vitro lymphocyte proliferation and Ig secretion in response to mitogens was performed. RESULTS: 32 children, 24 (75%) males, 8 (25%) females, mean age 3.4 years fulfilled the inclusion criteria. Clinical presentation: ENT infections 69%, respiratory 81%, diarrhea 12.5%. During follow-up, 17 (53%) normalized serum Ig levels and were diagnosed as transient hypogammaglobulinemia of infancy (THGI). THGI patients did not differ clinically or demographically from non-transient patients, both having a benign clinical outcome. In vitro Ig secretory responses, were lower in hypogammaglobulinemic, compared to normal children and did not normalize concomitantly with serum Ig's in THGI patients. CONCLUSIONS: The majority of children with SHIC in the first decade of life have THGI. Resolution of symptoms as well as normalization of Ig values may be delayed, but overall the clinical outcome is good and the clinical course benign

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Sebaceous Gland Hyperplasia

Sebaceous gland hyperplasia refers to hypertrophic enlargement of the sebaceous glands. Though benign, its predilection for cosmetically sensitive areas such as the face make efficacious treatment options desirable. While multiple therapeutic modalities are available, sebaceous hyperplasia can be treated quickly and successfully with cryosurgery

Drug-Induced Neutrophilic Dermatoses

Medications are substantial underlying contributors to the development of neutrophilic dermatoses. Many different classes of drugs have been shown to induce a variety of neutrophilic dermatoses, with the histopathologic presence of a dermal neutrophilic infiltrate remaining the unifying feature. Identifying a drug-induced neutrophilic dermatosis with certainty can be difficult, as many patients have underlying conditions that may independently contribute to the development of similar cutaneous findings. Diagnosis is therefore based upon the observation of a temporal relationship between drug initiation and appearance of the characteristic dermatosis, coupled with resolution of symptoms upon discontinuation of the drug. Drugs that have been reported to trigger five classic neutrophilic dermatoses are summarized in Table 20.1 and discussed in more detail below

Cryosurgery for Premalignant and Malignant Skin Conditions

Cryosurgery can be used to treat pre-malignant and malignant skin conditions. Actinic keratosis (AK) is a pre-malignant proliferation of keratinocytes manifesting as erythematous, scaly papules or plaques on sun-exposed skin. Two types of therapy are need for AK: lesion directed, to destroy individual AK and field, to destroy perilesional, microscopic changes. Lesion directed therapies include electrodessication and curettage, excision, and laser ablation. Field physical modalities include photodynamic therapy (PDT), peels, and laser resurfacing. Cryosurgery, a lesion directed therapy, is very successful and is one of the most commonly employed treatments for AK. Bowen’s disease presents as a well-defined, hyperkeratotic plaque; therapeutic options include PDT, curettage, topical 5-FU, excision, laser ablation, radiotherapy and cryosurgery. Malignant lesions treatable with cryosurgery include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Excision is the most commonly used therapy for them. Alternatives include electrodessication and curettage, radiation, PDT, topical 5-FU and imiquimod. Cryosurgery for BCC and SCC shows success rates that rival excision when performed by a trained physician

Comparing the Biological Impact of Glatiramer Acetate with the Biological Impact of a Generic

<div><p>For decades, policies regarding generic medicines have sought to provide patients with economical access to safe and effective drugs, while encouraging the development of new therapies. This balance is becoming more challenging for physicians and regulators as biologics and non-biological complex drugs (NBCDs) such as glatiramer acetate demonstrate remarkable efficacy, because generics for these medicines are more difficult to assess. We sought to develop computational methods that use transcriptional profiles to compare branded medicines to generics, robustly characterizing differences in biological impact. We combined multiple computational methods to determine whether differentially expressed genes result from random variation, or point to consistent differences in biological impact of the generic compared to the branded medicine. We applied these methods to analyze gene expression data from mouse splenocytes exposed to either branded glatiramer acetate or a generic. The computational methods identified extensive evidence that branded glatiramer acetate has a more consistent biological impact across batches than the generic, and has a distinct impact on regulatory T cells and myeloid lineage cells. In summary, we developed a computational pipeline that integrates multiple methods to compare two medicines in an innovative way. This pipeline, and the specific findings distinguishing branded glatiramer acetate from a generic, can help physicians and regulators take appropriate steps to ensure safety and efficacy.</p></div