Pediatric Hemophagocytic Lymphohistiocytosis - A Single Center Study.

OBJECTIVE: To describe the epidemiological features, outcomes and prognostic factors in diagnosis of pediatric hemophagocytic lymphohistiocytosis (HLH). METHODS: 118 children fulfilling the inclusion criteria for HLH were identified from review of hospital records for period January, 2010 to December, 2019. RESULT: Median age at diagnosis was 4 years (range13 days-15 years). Presenting features were fever (100%), hepatosplenomegaly (91%), neurological symptoms (23%), bicytopenia (76%), transaminitis (67.3%), increased soluble interleukin-2 receptor) (sIL-2R) (78%) and hemophagocytosis on bone marrow (75%). Median follow-up duration was 13.5 months (3 days to 102 months). Primary HLH was identified in 27 (23%) patients. Etiology of secondary HLH was infections in 53 (45%), rheumatologic illnesses in 21 (18%) and malignancies in 8 (6%) children. Treatment modalities were steroid only (25%), anti-infectious agent (58%), multi-agent chemotherapy (43%) and HSCT (40%); mortality among above treatment groups were 25%, 58%, 43% and 40%, respectively. 15 patients (13%) had relapsed/refractory HLH who were treated with salvage chemotherapy and hematopoietic stem cell transplantation (HSCT). The overall mortality rate was 39%; mortality within 30 days seen in 23%. Estimated overall survival (OS) and event free survival (EFS) at 3 years were 62% and 61%, respectively. CONCLUSION: Pediatric HLH is an aggressive disease with high mortality. Hyponatremia, hyperbilirubinemia, coagulopathy and increased sIL2 receptor level at diagnosis predicts poor outcome.

Clinical Profile and Outcome of Childhood Autoimmune Hemolytic Anemia: A Single Center Study.

OBJECTIVE: To analyze clinical and laboratory parameters, and treatment outcomes of children with autoimmune hemolytic anemia (AIHA). METHODS: Retrospective analysis of 50 children aged 0-18 years. Monospecific direct antiglobulin test (DAT) and investigations for secondary causes were performed. Disease status was categorized based on Cerevance criteria. RESULTS: Median (range) age at diagnosis was 36 (1.5-204) months. AIHA was categorized as cold (IgM+,C3+/cold agglutinin+) (35%), warm (IgG+ with/without C3+) (28%), mixed (IgG+, IgM+, C3+) (15%) and paroxysmal cold hemoglobinuria (4%). Primary AIHA accounted for 64% cases. Treatment modalities included steroid (66%), intravenous immunoglobulin (IVIg) (4%), steroid+IVIg (4%), and steroid+rituximab (4%). Treatment duration was longer for secondary AIHA than primary (11 vs 6.6 months, P<0.02) and in patients needing polytherapy than steroids only (13.3 vs 7.5 months, P<0.006). During median (range) follow-up period of 73 (1-150) months, 29 (58%) remained in continuous complete remission, 16 (32%) remained in complete remission. CONCLUSIONS: Infants with AIHA have a more severe presentation. Monospecific DAT and a thorough search for an underlying cause help optimize therapy in most patients of AIHA.

Predictive blood plasma biomarkers for EGFR inhibitor-induced skin rash.

Epidermal growth factor receptor overexpression in human cancer can be effectively targeted by drugs acting as specific inhibitors of the receptor, like erlotinib, gefitinib, cetuximab and panitumumab. A common adverse effect is a typical papulopustular acneiform rash, whose occurrence and severity are positively correlated with overall survival in several cancer types. We studied molecules involved in epidermal growth factor receptor signaling which are quantifiable in plasma, with the aim of identifying biomarkers for the severity of rash. With a predictive value for the rash these biomarkers may also have a prognostic value for survival and disease outcome.The concentrations of amphiregulin, hepatocyte growth factor (HGF) and calcidiol were determined by specific enzyme-linked immunosorbent assays in plasma samples from 211 patients.We observed a significant inverse correlation between the plasma concentration of HGF and overall survival in patients with an inhibitor-induced rash (p-value = 0.0075; mean overall survival low HGF: 299 days, high HGF: 240 days) but not in patients without rash. The concentration of HGF was also significantly inversely correlated with severity of rash (p-value = 0.00124).High levels of HGF lead to increased signaling via its receptor MET, which can activate numerous pathways which are normally also activated by epidermal growth factor receptor. Increased HGF/MET signaling might compensate the inhibitory effect of epidermal growth factor receptor inhibitors in skin as well as tumor cells, leading to less severe skin rash and decreased efficacy of the anti-tumor therapy, rendering the plasma concentration of HGF a candidate for predictive biomarkers.

[How to individualize drug therapy based on pharmacogenetic information? A systematic review of published guidelines]. / Wie soll die Arzneitherapie auf Grundlage pharmakogenetischer Testergebnisse individuell angepasst werden?

Background | Differences (polymorphisms) in genes encoding drug targets, drug transport proteins, or drug metabolizing enzymes may be responsible, among other factors, for the observed variation in patients' responses to medications. The field of pharmacogenetics aims to identify patients at higher genetically-determined risk of adverse effects or poor response to medication. This information would allow for modification of dosage or substitution with alternative therapy. However, there is a lack of awareness of pharmacogenetic clinical practise guidelines. Methods | A systematic literature review was conducted, using the Medline and PharmGKB databases, which focused on published guidelines for dosage modification or selection of drugs based on germline mutations in genes with pharmacokinetic or pharmacodynamic impact. Prescribing information from the European Medicines Agency, the German Federal Institute for Drugs and Medical Devices, and the US Food and Drug Administration was also screened for pharmacogenetic guidance. Results | The literature review revealed 20 guideline publications elucidating 43 drugs with recommendations for genotype-guided prescribing. Moreover, drug labels for 37 drugs also contained genotype-guided prescribing recommendations, some of which were linked to optional or obligatory pre-therapeutic pharmacogenetic testing. Conclusions | Existing guidelines for genotype-based drug prescribing are rarely derived from prospective, controlled trials; thus, their level of evidence is usually low. Even with low-quality evidence, strong recommendations can be made in favour of pharmacogenetic modification of prescription, such as for abacavir and the HLA-B genotype, if there is a large and certain difference between the benefits and harms. For other drug-gene pairs, such as vitamin K antagonists and CYP2C9/VKORC1, the net benefit from the pharmacogenetic-based dosing strategy is small and matter of debate. Because pharmacogenetics is playing a growing role in drug development and pre-prescription genotyping will become more widespread, specific pharmacogenetic guidance for treating physicians will become increasingly important.

Dosing to rash?--The role of erlotinib metabolic ratio from patient serum in the search of predictive biomarkers for EGFR inhibitor-mediated skin rash.

AIM: The aim of this study was to investigate if biomarkers of individual drug metabolism, respectively, the erlotinib/O-desmethyl-erlotinib metabolic ratio, may be a predictive factor for the severity of erlotinib-mediated skin rash in epidermal growth factor receptor (EGFR) inhibitor-treated patients suffering from epithelial cancers. This is especially important since it is known that the severity of skin rash has a prognostic value on outcome and survival in cancer patients experiencing skin rash under treatment with EGFR inhibitors. METHODS: From 2008 to 2014, 96 patients, n = 63 suffering from histologically confirmed non-small-cell lung cancer and n = 33 from pancreatic adenocarcinoma were observed for the occurrence and severity of skin rash after the onset of treatment with erlotinib. The primary end-points (occurrence and severity of skin rash, progression-free survival [PFS] and overall survival [OS]) were analysed with regard to erlotinib and its metabolite O-desmethyl-erlotinib trough serum concentrations measured at 4 weeks after onset of therapy by the use of correlation, multiple regression and survival analysis. RESULTS: Occurrence of skin rash was associated with PFS (p = 0.0042) and OS (p = 0.017) in the overall cohort of erlotinib-treated cancer patients. Drug-metabolising activity assessed by the erlotinib/O-desmethyl-erlotinib metabolic ratio was correlated with severity of skin rash (p = 0.023) and as well highly associated with both PFS (p = 2.1 × 10(-4)) and OS (p = 5.8 × 10(-5)). CONCLUSION: The erlotinib/O-desmethyl-erlotinib metabolic ratio reflecting the individual metabolic activity of erlotinib correlated with the severity of skin rash and outcome in patients treated with EGFR tyrosine kinase inhibitors. The metabolic ratio determined in serum may be used for therapeutic monitoring in erlotinib treatment and decisions on individual dosing to rash in rash-negative patients.

Gene regulatory biomarker identification for skin toxicities induced by EGFR inhibitor treatment.

1 Federal Institute for Drugs and Medical Devices (BfArM), Research Division, Bonn, 2 Institute of Pharmacology of Natural Products and Clinical Pharmacology, 3 Department of Internal Medicine II, University of Ulm, Ulm, 4 Pneumology, Thoracic Oncology, Sleep- and Respiratory Critical Care Medicine, Clinics Kempten-Oberallgäu, Kempten, and 5 Department of Internal Medicine I, University of Ulm, Ulm, and 4 Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Germany.

Cytokine regulation by epidermal growth factor receptor inhibitors and epidermal growth factor receptor inhibitor associated skin toxicity in cancer patients.

AIM: Epidermal growth factor receptor inhibitor (EGFRI) induced skin toxicity has a prognostic value suggesting skin toxicity can be a useful surrogate marker for successful epidermal growth factor receptor (EGFR) inhibition, improved response and survival. But the pathophysiology of EGFRI induced skin toxicity remains elusive. However the involvement of immunological mechanisms has been speculated. This study investigates the possible underlying mechanism of EGFR inhibition associated cytokine production in keratinocytes as well as in patients after treatment with epidermal growth factor receptor inhibitors (EGFRIs). METHODS: Normal human epidermal keratinocytes (NHEK) were incubated for 2 and 24h with different concentrations of EGFRI (erlotinib) for Western blot analysis and cytokine expression analysis, respectively. Inhibition of EGFR, extracellular-signal-regulated kinase 1/2 (Erk 1/2) and c-Jun was examined by Western blot analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in the NHEK cell supernatant and also in the serum of 186 cancer patients who are followed up for EGFRI induced skin rash. RESULTS: A significant inhibitory effect of EGFRI was seen on EGFR (Y845), Erk 1/2 and c-Jun in a dose dependent manner. Further downstream, increased CC-chemokine ligand 2 (CCL2), CC-chemokine ligand 5 (CCL5) and decreased interleukin-8 (IL-8) or CXCL8 expression was observed in keratinocytes. In EGFRI treated patients, low levels of serum CXCL8 corresponding to stronger EGFR inhibition were associated with a higher grade of skin toxicity (p=0.0016) and a prolonged overall survival (p=0.018). CONCLUSIONS: The results obtained in this study indicate that EGFRI can regulate cytokines by modulating EGFR signalling pathway in keratinocytes. Moreover, serum levels of CXCL8 in EGFRI treated patients may be important for individual EGFRI induced skin toxicity and patient's survival.

Postgraduate education in nutrition in south Asia: a huge mismatch between investments and needs.

BACKGROUND: Despite decades of nutrition advocacy and programming, the nutrition situation in South Asian countries is alarming. We assume that modern training in nutrition at the post graduate level is an important contributor to building the capacity of individuals to think and act effectively when combating undernutrition. In this context, this paper presents a regional situation analysis of master's level academic initiatives in nutrition with a special focus on the type of programme we think is most likely to be helpful in addressing undernutrition at the population level: Public Health Nutrition (PHN). METHODS: This situational analysis of Masters in nutrition across South Asian countries viz. India, Pakistan, Bangladesh, Sri Lanka, Afghanistan, Maldives, Nepal, Bhutan was conducted using an intensive and systematic Internet search. Further, detailed information was extracted from the individual institute websites and library visits. RESULTS: Of the 131 master's degree programmes we identified one that was in PHN while another 15 had modules in PHN. Most of these universities and institutions were found in India with a few in Bangladesh and Sri Lanka. In the rest of the countries, neither nutrition nor PHN emerged as an academic discipline at the master's level. In terms of eligibility Indian and Sri Lankan programmes were most inclusive, with the remaining countries restricting eligibility to those with health qualifications. On modules, no country had any on nutrition policy or on nutrition's interactions with agriculture, social protection, water and sanitation or women's empowerment. CONCLUSION: If a strong focus on public health nutrition is key to reducing undernutrition, then the poor availability of such courses in the region is cause for concern. Nutrition master's courses in general focus too little on the kinds of strategies highlighted in the recent Lancet series on nutrition. Governments seeking to accelerate declines in undernutrition should incentivize the delivery of postgraduate programmes in nutrition and Public Health Nutrition (PHN) that reflect the modern consensus on priority actions. In the absence of PHN type programmes, the competence to scale up nutrition capacity is likely to be impaired and the human potential of millions of infants will continue to be squandered.

HLA polymorphisms influence the development of skin rash arising from treatment with EGF receptor inhibitors.

AIM: Development of a skin rash under treatment with EGF receptor (EGFR) inhibitors (EGFRIs) has been linked to a favorable prognosis in some studies, suggesting a possible immunological role for EGFRIs in addition to direct antagonistic downstream effects. The present study aimed to investigate whether particular HLA polymorphisms found in cancer patients treated with EGFRIs are associated with the development of skin rash and overall survival rates. PATIENTS & METHODS: HLA typing was performed on 105 cancer patients and the development of skin rash was rated during the first 4 weeks of therapy with EGFRIs. RESULTS: A significantly lower incidence of skin rash was found in patients carrying the HLA-A*02:01 or HLA-A*03:01 alleles (hazard ratio: 0.277; 95% CI: 0.121-0.634; p = 0.002 and hazard ratio: 0.292; 95% CI: 0.113-0.752; p = 0.011, respectively); however, no association with worse survival was seen. CONCLUSION: The chances of developing a skin rash in patients treated with EGFRIs may be lower in patients that carry the HLA-A*02:01 or HLA-A*03:01 alleles, while the antitumor efficacy of EGFRIs does not seem to be significantly impaired in these patients.