Multiple primary malignancies in patients with Merkel cell carcinoma1

Background Merkel cell carcinoma (MCC) is a rare malignant cutaneous tumour, the incidence of which is increasing. Second malignancies have been reported to occur with high incidence in these patients. Objectives We report the rate and nature of multiple malignancies in patients with MCC treated over a 10 year period in Addenbrooke’s Hospital in Cambridge, United Kingdom, as well as the temporal relationship of these additional malignancies to the diagnosis of MCC. Results The 27 patients had an approximately equal sex incidence with a median age at diagnosis of 79 years. Seventy percent (n=19) of patients had a second primary malignant tumour; and 7 of these patients had two or more tumours in addition to the MCC. Eighteen patients had additional cutaneous malignancies: melanoma, squamous cell carcinoma and basal cell carcinoma, and 8 patients presented non‐cutaneous malignancy including colorectal, haematological and breast tumours. Of the 28 additional tumours in our patients, half were diagnosed prior to presentation of MCC, 32% within 6 months of diagnosis, and 18% between 6 months and 3 years after diagnosis. Possible reasons for the high rate of additional tumours in this population are discussed. Conclusions Our figures reflect a higher incidence of multiple malignancies in those with Merkel cell tumour than has previously been reported. This has important implications for the care and surveillance of these patients.     

Age estimation in children by measurement of open apices in teeth: a study in North Indian population

Age estimation is a prerequisite in forensic medicine, paediatric endocrinology and orthodontic treatment. Dental development has been proven to be suitable for age determination in children because of its lower variability. The aim of this study was to evaluate the applicability of using the open apex method proposed by Cameriere et al. for age estimation in Indian children. Digitalized panoramic radiographs were retrieved from the Department of Oral Medicine & Radiology of 558 Indian children (261 girls, 297 boys) with an age range from 5 to 15 years. The seven left permanent mandibular teeth were evaluated for length and open apices. Dental maturity was evaluated using measurements of the seven left permanent mandibular teeth (x_i = A_i/L_i, i = 1,...,7), the sum of the normalized open apices (s) and the number (N₀) of teeth with root development complete. Using a stepwise multiple regression model, a relationship between open apices, N₀ and age was evaluated. Statistical analysis revealed high accuracy with the morphological variables explaining 88.5% of the variations in estimated chronological age. This research suggests an open apex method could be successful for age estimation in Indian children and could be applied in legal issues pertaining to forensic medicine.     

Depletion of CD52‐positive cells inhibits the development of central nervous system autoimmune disease,but deletes an immune‐tolerance promoting CD8 T‐cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis

The objective was to determine whether CD52 lymphocyte depletion can act to promote immunological tolerance induction by way of intravenous antigen administration such that it could be used to either improve efficiency of multiple sclerosis (MS) inhibition or inhibit secondary autoimmunities that may occur following alemtuzumab use in MS. Relapsing experimental autoimmune encephalomyelitis was induced in ABH mice and immune cell depletion was therapeutically applied using mouse CD52 or CD4 (in conjunction with CD8 or CD20) depleting monoclonal antibodies. Immunological unresponsiveness was then subsequently induced using intravenous central nervous system antigens and responses were assessed clinically. A dose–response of CD4 monoclonal antibody depletion indicated that the 60–70% functional CD4 T‐cell depletion achieved in perceived failed trials in MS was perhaps too low to even stop disease in animals. However, more marked (~75–90%) physical depletion of CD4 T cells by CD4 and CD52 depleting antibodies inhibited relapsing disease. Surprisingly, in contrast to CD4 depletion, CD52 depletion blocked robust immunological unresponsiveness through a mechanism involving CD8 T cells. Although efficacy was related to the level of CD4 T‐cell depletion, the observations that CD52 depletion of CD19 B cells was less marked in lymphoid organs than in the blood provides a rationale for the rapid B‐cell hyper‐repopulation that occurs following alemtuzumab administration in MS. That B cells repopulate in the relative absence of T‐cell regulatory mechanisms that promote immune tolerance may account for the secondary B‐cell autoimmunities, which occur following alemtuzumab treatment of MS.     

Multiple trichoepitheliomas – a novel mutation in the CYLD gene

Background Trichoepitheliomas are benign neoplasms with follicular differentiation. They may present as a solitary lesion or as multiple lesions. Multiple trichoepitheliomas are inherited in an autosomal dominant pattern within families, with both variable penetrance and expressivity. Recent investigations support that mutations in CYLD, the gene affected in familial cylindromatosis as well as in Brooke–Spiegler syndrome, are also responsible for multiple trichoepitheliomas. Objective The authors report the case of a 9‐year‐old African girl with multiple facial trichoepitheliomas in whom a mutation in the CYLD gene was hypothesised. Materials and methods After genomic DNA extraction from the peripheral blood, a molecular analysis of the CYLD gene was performed by PCR, DHPLC and automated sequencing. Results A novel heterozygous mutation in exon 18 of the CYLD gene (c.2449delT) was identified, with a deletion of one nucleotide resulting in a premature translational termination codon at amino acid position 831 on the affected allele (p.Cys817Valfs X15). Conclusions The predominating tumours define the classification of these three entities. Nevertheless, studies suggest that they can simply represent phenotypic variations of the same disease spectrum, sharing common genetic mutations.     

Phase 2 study of tabalumab,a human anti‐B‐cell activating factor antibody,with bortezomib and dexamethasone in patients with previously treated multiple myeloma

In this double‐blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N  = 72), tabalumab 100 mg (N  = 74), or tabalumab 300 mg (N  = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1·3 mg/m² on a 21‐day cycle. No significant intergroup differences were observed among primary (median progression‐free survival [mPFS ]) or secondary efficacy outcomes. The mPFS was 6·6, 7·5 and 7·6 months for the tabalumab 100, 300 mg and placebo groups, respectively (tabalumab 100 mg vs. placebo Hazard ratio (HR ) [95% confidence interval (CI )] = 1·13 [0·80–1·59], P  =  0·480; tabalumab 300 mg vs. placebo HR [95% CI ] = 1·03 [0·72–1·45], P  =  0·884). The most commonly‐reported treatment‐emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF 13B) expression (n  = 162) had significantly longer mPFS than those with high BAFF expression (n  = 55), using the 75th percentile cut‐off point (mPFS [95% CI ] = 8·3 [7·0–9·3] months vs. 5·8 [3·7–6·6] months; HR [95% CI ] = 1·59 [1·11–2·29], P  =  0·015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300 mg tabalumab did not improve efficacy compared to the 100 mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma.     

Bewitched,Buried, and Bewildered

This case study recounts the first years of an analysis that began as therapy for depression but rapidly shifted its focus to promoting coconsciousness and cooperation among personalities who were discovered to be comprising a rigidly dissociated sense of self. At first, unusual ways of experiencing the world were only hinted at, but as the treatment progressed, acute pain and confusion surfaced—both during sessions and in the events and artwork brought to them—revealing a perplexing realm in which facts could be invented accidentally and logic was a threat. As time went on, self-states were heard internally more clearly, and there was greater dialogue and engagement both among the patient's self-states and with the therapist's, enhancing self-knowledge and heightening cohesion within both parties.