A Tale of Two Histiocytic Disorders

Histiocytosis, including the coexistence of Langerhans'' cell histiocytosis and Erdheim-Chester disease, is discussed.Histiocytosis is a group of rare disorders of unknown etiology characterized by proliferation and accumulation of histiocytes [1]. Histiocytosis is subclassified as Langerhans cell histiocytosis (LCH) and non-LCH. Non-LCH includes Rosai-Dorfman disease, Erdheim-Chester disease (ECD), interdigitating dendritic cell sarcoma, and histiocytic sarcomas [2]. Both LCH and ECD are caused by accumulation and proliferation of histiocytic cells, but each entity has distinct clinical and pathological features, although rarely both diseases can coexist [3, 4]. LCH is associated with accumulation of dendritic cells and typically presents in children, but less often in adults, with an incidence of nine cases per million per year. ECD is a disease of adults, which is associated with xanthogranulomatous infiltration of foamy macrophages. Only about 500 cases have been reported in the literature to date [3, 5]. It remains unclear whether LCH and ECD are neoplastic or reactive, but in many patients they behave like neoplasms. Advances in genome sequencing technologies led to the identification of BRAF V600E mutations in 57% (35 of 61) of patients with LCH and 54% (13 of 24) of patients with ECD [6, 7].Both LCH and ECD can vary in clinical presentation and prognosis depending on the extent of disease and organ involvement [8]. Therapeutic options include surgery, radiation, vinblastine, prednisone, 6-mercaptopurine, cladribine, and cytarabine for LCH and corticosteroids, vinca alkaloids, anthracyclines, cladribine, interferon-α, anakinra, imatinib, and, most recently, infliximab for ECD [3, 5, 8–18]. Whereas the treatment of LCH has been defined based on the results of prospective studies, including randomized trials, ECD is currently treated on the basis of information from published case series, mostly from Europe and North America [8–21].Yin et al. [22] are to be commended for presenting a patient with simultaneous LCH (Hand-Schuller-Christian disease) and ECD and their subsequent retrospective review of an additional 54 patients with LCH and six patients with ECD treated in a single tertiary referral center in China. The coexistence of these two entities is consistent with other previously published reports [4]. The patient presented by Yin et al. [22] had a relatively typical disease course over several years (currently 14 years from diagnosis), with symptoms including central diabetes insipidus, hyperprolactinemia, bone involvement, exophthalmus, and underactive thyroid. The patient had a favorable response to external-beam radiation therapy and systemic therapy with interferon-α. In their analysis of the 54 patients with LCH (eosinophilic granuloma, n = 49; Hand-Schuller-Christian disease, n = 5) and six patients with ECD, they [22] demonstrated that all 35 patients with unifocal eosinophilic granuloma were cured with surgery, and all patients with multifocal eosinophilic granuloma, Hand-Schuller-Christian disease, or ECD were alive, except for one woman who died from unspecified toxicity of chemotherapy.As mentioned, there is some agreement on how LCH should be managed; however, the treatment of patients with ECD remains empiric, based on evidence from case reports and case series [8–21]. The rarity of this entity makes the feasibility of conducting a prospective trial challenging [5]. Traditionally, patients with ECD were deemed to have a poor prognosis, and most patients succumbed to the disease within 3 years. In contrast, our experience suggests that, given the newer therapeutic options, including, but not limited to, interferon-α, imatinib, anakinra, and infliximab, patients can do well for a long period of time [8, 9, 12–14, 16, 17, 23]. These observations are consistent with the experience of Yin et al. [22], and it is also known that interferon-α is associated with a longer survival time than in historical controls [8]. The individual prognosis depends on the degree of organ involvement, infiltration of the central nervous system (CNS) or infiltration of critical visceral organs, and treatment, which can affect outcome [8]. A recent retrospective analysis of 53 patients treated in western European countries and Israel demonstrated 1-year and 5-year survival rates of 96% and 68%, respectively, which is in line with our experience [8, 9, 12]. Factors selected on multivariate analysis that predicted a poor survival outcome included CNS involvement and not being treated with interferon-α [8]. There is no systemic therapy that has been approved by regulatory agencies, and the available treatments are deemed to be not curative; however, they can lead to disease regression accompanied by symptom improvement and, at least for interferon, perhaps even to a longer survival duration. Despite the absence of randomized trials, our treatment options have nevertheless expanded substantially within the last several years. Interferon-α is often used as a frontline therapy for ECD [5, 8, 12]. Unfortunately, patients with ECD can have a poor tolerance to classic doses of interferon-α, such as three million units s.c. three times per week, although doses of one million units s.c. three times per week are usually well tolerated and, in our experience, are effective in about half the patients treated [12]. Interferon-α can be replaced by its pegylated form, which is more costly but has a more convenient weekly dosing schedule [14].Anecdotal reports have also demonstrated therapeutic responses with the BCR-ABL, KIT, and platelet-derived growth factor receptor tyrosine kinase inhibitor imatinib [9, 13, 24–26]. It has been hypothesized that imatinib can inhibit CD34⁺ peripheral blood progenitor cells from differentiating into histiocytes; however, beyond that the mechanistic explanation for the activity of imatinib remains unclear [27]. Because natural interleukin-1 receptor antagonist synthesis is induced after stimulation by interferon-α, anakinra, a recombinant human interleukin-1 receptor antagonist approved for rheumatoid arthritis in Europe and the U.S., was anecdotally tested in ECD patients, with encouraging results reported by several investigators [15, 18]. Anakinra mimics the function of a natural inhibitor of interleukin-1 receptor and is well tolerated, with immunosuppression and injection site tenderness being among its very few side effects. Therefore, anakinra can be a reasonable alternative for patients who cannot tolerate interferon-α or who are at risk for suffering deleterious side effects from interferon. The latest potential addition to the therapeutic armamentarium for ECD is the tumor necrosis factor (TNF)-α antibody infliximab [17]. In ECD patients, TNF-α is deemed to regulate the recruitment of histiocytes, and thus, its blockade can lead to disease control. To date, two patients with severe cardiovascular complications of ECD were treated with infliximab in a single institution setting and both showed improvement, with resolution of pericardial effusion and increased cardiac function [17].Recently, BRAF V600E mutations were found in 57% (35 of 61) and 38% (11 of 29) of patients with LCH and in 54% (13 of 24) of patients with ECD [6, 7, 28]. This mutation predicts a positive response to BRAF kinase inhibitors in patients with advanced melanoma [29, 30]. Recently, we showed that a patient with hairy cell leukemia and a BRAF mutation achieved a remarkable response after only 3 weeks of the BRAF inhibitor vemurafenib [31]. However, treatment of patients with LCH and ECD with BRAF mutations has not been reported.Despite many therapeutic advances, LCH and ECD remain difficult to eradicate. The arrival of new genotyping technologies, such as next-generation sequencing, has the potential to further explicate the molecular background of these disorders. Furthermore, the heterogeneity of these diseases may have biologic and therapeutic implications. It is known that LCH and ECD can coexist, and Yin et al. [22] reported simultaneously occurring Hand-Schuller-Christian disease and ECD. Furthermore, they also described potentially important clinical characteristics to differentiate these entities. Diabetes insipidus and pituitary stalk thickening point to Hand-Schuller-Christian disease; however, diabetes insipidus can also be found in ECD and osteosclerosis may also support an ECD diagnosis. The advent of advanced molecular technologies may help determine if specific molecular aberrations can differentiate these entities and predict therapeutic response.     

Lot quality assurance sampling (LQAS) for monitoring leprosy elimination in an endemic district in Tamilnadu

This paper examines whether the health administration can use lot quality assurance sampling (LQAS) for identifying high prevalence areas for leprosy for initiating necessary corrective measures. The null hypothesis was that leprosy prevalence in the district was at or above ten per 10,000 and the alternative hypothesis was that it was at or below five per 10,000. A total of 25,500 individuals were to be examined with 17 as an acceptable maximum number of cases (critical value). Two-stage cluster sample design was adopted. The sample size need not be escalated as the estimated design effect was 1. During the first phase, the survey covered a population of 4,837 individuals out of whom 4,329 (89.5%) were examined. Thirty-five cases were detected and this number far exceeded the critical value. It was concluded that leprosy prevalence in the district should be regarded as having prevalence of more than ten per 10,000 and further examination of the population in the sample was discontinued. LQAS may be used as a tool by which one can identify high prevalence districts and target them for necessary strengthening of the programme. It may also be considered for certifying elimination achievement for a given area.     

Thyroid function in children with sepsis and septic shock

AIM: A prospective study was conducted to determine thyroid hormone levels and their relationship to survival in children with septic shock and sepsis. METHODS: We estimated thyroid hormone levels (T3, T4, TSH, fT3 and fT4) in children with septic shock and compared with those in children with sepsis. RESULTS: Twenty-four children (13 boys) with septic shock and 25 children (14 boys) with sepsis were enrolled. The median T3, T4, fT3, fT4 and TSH (95% confidence interval) were 40 (40-40.23) ng/dL, 4.45 (1.9-6.03) microg/dL, 1.85 (1.2-2.37) pg/mL, 0.77 (0.57-0.95) ng/dL, 0.51 (0.26-1.15) microIU/mL, respectively in children with septic shock group compared with 130 (98.28-163.48) ng/dL, 9.3 (7.66-10.63) microg/dL, 3.2 (3-4.27) pg/mL, 1.3 (1.1-1.4) ng/dL, 2.85 (1.07-3.61) microIU/mL, respectively, in children with sepsis. Children with septic shock who died (n = 12) had higher TSH levels compared to those who survived (p = 0.04). There was no difference in hormone levels between children with catecholamine responsive and catecholamine resistant septic shock. CONCLUSION: Children with septic shock had lower levels of T3, T4, fT3, fT4 and TSH compared to those with sepsis. Findings of our study suggest that derangement of thyroid functions in children is not an important factor contributing to the severity of septic shock.     

Comparative evaluation of optical coherence tomography in glaucomatous, ocular hypertensive and normal eyes

BACKGROUND: To correlate the findings of optical coherence tomography (OCT) evaluation of retinal nerve fiber layer (RNFL) thickness with visual field changes in glaucomatous, ocular hypertensive and normal eyes. MATERIALS AND METHODS: Thirty consecutive normal, 30 consecutive ocular hypertensive and 30 consecutive glaucomatous eyes underwent a complete ophthalmic examination, including applanation tonometry, disc evaluation, (30-2) Humphrey field analyzer white on white (W/W) perimetry and short- wavelength automated perimetry. Thickness of the RNFL around the optic disc was determined with 3.4 mm diameter-wide OCT scans. Average and segmental RNFL thickness values were compared among all groups. A correlation was sought between global indices of perimetry and RNFL thickness. RESULTS: Of the 90 eyes enrolled (mean age of patients 52.32+/-10.11 years), the mean RNFL thickness was significantly less in ocular hypertensive (82.87+/-17.21 mm; P =0.008 and glaucomatous eyes (52.95+/-31.10 microm; P < 0.001), than in normals (94.26+/-12.36 microm). The RNFL was significantly thinner inferiorly in glaucomatous eyes (64.41+/-43.68 microm; P<0.001). than in normals (120.15+/-14.32 microm) and ocular hypertensives (107.87+/-25.79 microm; P<0.001). Ocular hypertensives had thinner RNFL in the nasal, inferior and temporal quadrants (P<0.001) when compared to normals. Global indices in ocular hypertensives on SWAP showed Mean Deviation (MD) of 5.32+/-4.49, Pattern Standard Deviation (PSD) 3.83+/-1.59 and Corrected Pattern Standard Deviation (CPSD) 2.84+/-1.85. The RNFL thickness could not be significantly correlated with global indices of visual fields in ocular hypertensives. CONCLUSION: Optical coherence tomography is capable of detecting changes at the level of RNFL in ocular hypertensive eyes with normal appearance of discs and W/W perimetry fields.     

Effect of Age-Hardening Temperature on Mechanical and Wear Behavior of Furnace-Cooled Al7075-Tungsten Carbide Composite

In this study, aluminum alloy (Al7075) composites with a 4% weight fraction of tungsten carbide (WC) were manufactured using a stir casting process and the developed composites were subjected to various ageing temperatures. An attempt has been made to predict the age-hardening temperature with the enhanced mechanical and wear properties of Al7075-WC. The result shows that the composite specimen aged at 250 °C offered maximum tensile strength and the Brinell hardness number was increased by 37.1% and 50.5%, respectively; the maximum impact energy was observed to be 92.2% for the 450 °C aged composites, compared to the non-aged Al7075-WC composites. The strength properties of the Al7075-WC composite decreased to 30.86%, 4.7%, and 24.9% when the composite specimens aged at 350 °C. The mechanical properties of the Al7075-WC composite were increased at the age-hardening temperatures from 150 °C to 250 °C and decreased from 250 °C to 350 °C. The wear testing pin-on-disc setup utilized to determine the wear characteristics of the prepared MMC with wear parameters of load and sliding distance and the wear resistance of the composite specimens increased due to ageing. The fractography analysis of the composite samples carried out by scanning electron microscope (SEM) images revealed that the fracture of the composite during the tensile test is a mixture of ductile and brittle modes.     

Molecular structure of (+/-) 7alpha,8beta-dihydroxy 9beta, 10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene; an X-ray crystallographic study

The molecular structure of 7, 8ß-dihydroxy-9ß,10ß-epoxy-7, 8, 9, 10-tetrahydrobenzo[a]pyrene, anultimate carcinogenic form of benzo[a]pyrene has been determinedby X-ray crystallography. The tetra-hydrobenzene ring has diequatorialhydroxyl sub-stitutents and a C8 half-chair conformation. Theepoxide ring is symmetric and the plane of the epoxide ringis approximately at right angles to the plane of the aromaticsystem. A variety of other geometric parameters are reported.