Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data.

BACKGROUND: Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS). METHODS: The integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab. RESULTS: A total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively), Candida infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs. CONCLUSIONS: Secukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions.

Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study.

Background: This is the first trial to directly compare efficacy and safety of alectinib versus standard chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients who have progressed on, or were intolerant to, crizotinib. Patients and methods: ALUR (MO29750; NCT02604342) was a randomized, multicenter, open-label, phase III trial of alectinib versus chemotherapy in advanced/metastatic ALK-positive NSCLC patients previously treated with platinum-based doublet chemotherapy and crizotinib. Patients were randomized 2 : 1 to receive alectinib 600 mg twice daily or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, both every 3 weeks) until disease progression, death, or withdrawal. Primary end point was investigator-assessed progression-free survival (PFS). Results: Altogether, 107 patients were randomized (alectinib, n = 72; chemotherapy, n = 35) in 13 countries across Europe and Asia. Median investigator-assessed PFS was 9.6 months [95% confidence interval (CI): 6.9-12.2] with alectinib and 1.4 months (95% CI: 1.3-1.6) with chemotherapy [hazard ratio (HR) 0.15 (95% CI: 0.08-0.29); P < 0.001]. Independent Review Committee-assessed PFS was also significantly longer with alectinib [HR 0.32 (95% CI: 0.17-0.59); median PFS was 7.1 months (95% CI: 6.3-10.8) with alectinib and 1.6 months (95% CI: 1.3-4.1) with chemotherapy]. In patients with measurable baseline central nervous system (CNS) disease (alectinib, n = 24; chemotherapy, n = 16), CNS objective response rate was significantly higher with alectinib (54.2%) versus chemotherapy (0%; P < 0.001). Grade ≥3 adverse events were more common with chemotherapy (41.2%) than alectinib (27.1%). Incidence of AEs leading to study-drug discontinuation was lower with alectinib (5.7%) than chemotherapy (8.8%), despite alectinib treatment duration being longer (20.1 weeks versus 6.0 weeks). Conclusion: Alectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients, with a favorable safety profile. Trial registration: ClinicalTrials.gov NCT02604342; Roche study MO29750.

Brief report: Aggressive challenging behaviour in adults with intellectual disability following community resettlement.

BACKGROUND: Aggressive challenging behaviour is common in adults with intellectual disability (ID) in long-term care facilities. The government's commitment to the closure of all facilities in England has led to concerns over how to manage this behaviour in the community. The aim of this study was to assess changes in aggressive challenging behaviour and psychotropic drug use in adults with ID following resettlement using a person-centred approach. METHOD: The Modified Overt Aggression Scale was administered to carers of 49 adults with ID prior to discharge from a long-stay hospital and 6 months and 1 year after community resettlement. RESULTS: All areas of aggressive challenging behaviour reduced significantly between baseline and 6 months following resettlement (P < 0.001). This reduction remained (but did not decrease further) at 1-year follow-up. CONCLUSIONS: Further work is needed to evaluate the role of environmental setting on aggressive challenging behaviour in adults with ID.

The theaflavin fraction is responsible for the facilitatory effect of black tea at the skeletal myoneural junction.

The effect of various fractions of black tea [(Camellia Sinensis) (L) O. Kuntze (Theaceae)] on the function of mammalian skeletomotor apparatus was studied. The theaflavin fraction (Tfs) produced a concentration- dependent facilitation of indirect twitch responses of the rat phrenic nerve diaphragm preparation and the facilitation was dependent on the amount of calcium present in the bathing fluid. Nifedipine reduced the facilitatory effect of Tfs as a function of its concentration. Tfs failed to produce facilitation when the twitch height was reduced to about 50% of the control value in presence of magnesium chloride. Tfs completely antagonized the submaximal paralytic effect of d- tubocurarine and decamethonium bromide. Tfs did not have any effect on direct twitch responses or on acetylcholine (Ach) and potassium chloride (KCl) induced contractures of denervated diaphragm. The results revealed that the site of action of Tfs is on the contractile mechanism of the voluntary muscle and point to a critical role of calcium in the mechanism of action of Tfs. N omega-nitro-L-arginine-methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, antagonized both the facilitatory and inhibitory effects on indirect twitch responses of rat diaphragm induced by L-arginine and Tfs when the phrenic nerve was stimulated at 5 Hz and 50 Hz respectively. The thearubigin (Trs) fraction of black tea and the aqueous part which is completely devoid of Tfs, did not potentiate the twitch responses. The findings suggest that Tfs have a potentiating effect on the contractile mechanism of skeletal muscle and that calcium and nitric oxide may modulate this action of Tfs.

Conservation surgery in the management of T1 and T2 oropharyngeal squamous cell carcinoma: the Birmingham UK experience.

The aim of this paper was to evaluate our experience using conservation surgery in the management of T1 and T2 oropharyngeal squamous cell carcinoma. Eighteen patients underwent conservation surgery between 1993 and 2000 and were analysed retrospectively. The mean age was 54 years and the male to female ratio was 8:1. There were 14 tonsil and 4 tongue base tumours and 83% of cases presented with neck nodes, thereby classifying them as having advanced disease (stages 2-4). All patients received postoperative radiotherapy. All patients were followed up to December 2001. The median follow-up time was 3.8 years (minimum was 1.5 years). The 2-year and 5-year survival rates were 100% and 92% respectively. Approximately 66% of patients returned the EORTC and GHQ/12 quality-of-life questionnaires. Of these, seventy-five percent had a high healthy level of general functioning in accordance with the EORTC general health section. These results show that conservation surgery techniques are effective in the treatment of T1 and T2 oropharyngeal squamous carcinoma associated with significant metastatic neck disease. The techniques are well tolerated, produce minimal functional deficit and do not have a negative impact on the patients quality of life in either the immediate postoperative period or up to 4 years post-treatment.

Mitochondrial myopathy presenting as ataxia with dilated cardiomyopathy.

Mitochondrial disorders are multisystem diseases with very heterogeneous clinical manifestations. Common cardiac features include cardiomyopathy and conduction defects. We report a five-year-old boy who presented with signs of congestive cardiac failure and was diagnosed to have dilated cardiomyopathy. Six months later, he developed progressively worsening ataxia, hypotonia, other cerebellar signs, hearing loss, severe sensory peripheral neuropathy and lactic acidosis. Electronmicroscopy of skeletal muscle biopsy was consistent with mitochondrial myopathy.

Epidemiology of basal cell carcinoma and squamous cell carcinoma of the pinna.

This is a retrospective study designed to compare the incidence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in the head and neck skin area with special reference to the pinna. The results showed 426 patients had 460 cutaneous malignancies in the head and neck area, managed by four specialties (ENT, Dermatology, General Surgery and GPs) over the period 1994-99. The lesions comprised 375 (80.47 per cent) BCC and 85 (18.47 per cent) SCC. In cases of BCC the facial areas were commonly involved (88 per cent), whilst SCC was almost equally distributed between the most (face, forehead and nose) and least exposed areas (pinna and scalp). The overall ratio of BCC to SCC remained four to one in the head and neck area. In 41 patients with 51 lesions over the pinna there were 29 (56.8 per cent) BCC and 22 (43.1 per cent) SCC hence the ratio was 1.3 to 1 for this site. We conclude that in the case of a suspicious lesion over the pinna, the risk of SCC is comparatively much higher. With increasing awareness of early and quick diagnosis of cancer cases, it is recommended that these patients should be referred urgently to prevent the significant morbidity associated with invasive SCC.

Free jejunal patch flaps in oral and oro-pharyngeal reconstruction.

Free jejunum has been commonly tubed to provide a reconstructive pharyngeal conduit following pharyngolaryngectomy. It is also common practice to repair small oral and oro-pharyngeal defects with skin-lined flaps i.e. radial free forearm or pectoralis major myocutaneous flap. Free jejunal patch flaps can provide cover for large defects, secrete mucus, tolerate radiotherapy well and do not contract. The operation is associated with a low morbidity and early return of swallowing is feasible. Here we describe the functional results of free jejunal patch flap reconstruction of extensive oral and oro-pharyngeal defects.

Invasion of the recurrent laryngeal nerve by adenoid cystic carcinoma. An unusual cause of true vocal fold paralysis.

True vocal fold paralysis and goitre are both common problems encountered in ENT practice. Their co-existence, however, should arouse suspicion of the presence of malignant thyroid disease. A rare case of true vocal fold paralysis caused by a clinically occult subglottic adenoid cystic carcinoma, in a 72-year-old, is described. The existence of multinodular goitre in this patient was co-incidental and confounded the diagnostic process.

Changes in parents' mental distress after the violent death of an adolescent or young adult child: a longitudinal prospective analysis.

This study examined changes in bereaved parents' mental distress following the violent deaths of their 12- to 28-year-old children. A community-based sample of 171 bereaved mothers and 90 fathers was recruited by a review of medical examiner records. Data were collected 4, 12, and 24 months post-death. Repeated measures analysis of variance showed significant reductions in 8 of 10 measures of mental distress among mothers and 4 of 10 for fathers, with the most change for both genders occurring between 4 and 12 months post-death. During the 2nd year of bereavement, mothers' symptoms continued to decline, whereas fathers, who started out with less distress than mothers, reported slight increases in 5 of 10 symptom domains. Nonetheless, 2 years after the deaths, mothers' mental distress scores were up to 5 times higher than those of "typical" U.S. women and fathers' scores were up to 4 times higher than "typical" U.S. men. Of the 7 intervening variables examined, higher scores on self-esteem and self-efficacy predicted lower distress for both mothers and fathers 4, 12, and 24 months post-death. Repressive coping was predictive of distress among fathers. It was concluded that violent death bereavement has sustained, distressing consequences on parents of children who die as a result of accidents, homicides, and suicide.

Kikuchi's disease of the neck (histiocytic necrotizing lymphadenitis).

Histocytic necrotizing lymphadenitis (HNL), also known as Kikuchi's disease is a benign self limiting disease of unknown origin. It effects cervical lymph nodes, predominantly in young females. It is well described in the pathology literature, but little is written about this in the ENT literature, as few clinicians are probably aware of this condition. Five cases of cervical Kikuchi's disease are presented with a brief review of the literature.

Broad-spectrum group treatment for parents bereaved by the violent deaths of their 12- to 28-year-old children: a randomized controlled trial.

This study assessed the efficacy of a 10-week broad-spectrum intervention offered to bereaved parents about 4 months after the deaths of their 12--28-year-old children due to accidents, homicide, or suicide. For three outcomes of distress there was a significant interaction between treatment and baseline values for each outcome for mothers both immediately posttreatment and 6 months later. The intervention appeared to be the most beneficial for mothers most distressed at baseline. Fathers showed no immediate benefits of treatment. Further research is needed to investigate these unexpected results for fathers and to further characterize those who benefit from similar programs.

Transferrin receptor expression by blast cells in acute lymphoblastic leukemia correlates with white cell count & immunophenotype.

Transferrin receptor (TR) expression by blast cells in 127 cases of acute lymphoblastic leukemia (ALL) at presentation and 19 cases at relapse was examined using three anti-TR monoclonal antibodies to find its correlation with prognostic features such as the total leucocyte count (TLC), the morphology of blast cells and their cytochemical and immunophenotypic properties, as well as age and sex of the patients. Blasts in 62 per cent of thymic (T) ALL cases at presentation showed significant TR expression as compared to only 10.9 per cent in common ALL (CALL) (P < 0.001). This differential expression of TR was also observed among cases with > 50 x 10(9)/l TLC, while in cases with < 50 x 10(9)/ l TLC no such pattern was observed (30% TR positivity in T-ALL vs 20% TR positivity in non-T-ALL). Furthermore, the percentage of TR positive blasts was significantly higher (P < 0.005) in cases with > 50 x 10(9)/l TLC as compared to those with < 50 x 10(9)/l (48.3-54.4% vs 24.9-28.8%). In contrast to CALL cases at presentation, those at relapse showed a very high TR positivity (54-66%), similar to the T-ALL cases (53-84%). This suggests a high proliferative rate of blast cells in ALL at relapse, irrespective of its immunophenotype. There was no correlation of TR expression with blast cell morphology (FAB L1 vs L2), their cytochemical properties and sex of the patients. However, a significantly higher incidence of TR positivity was observed in patients above 10 yr of age compared to those below 10 yr (47% vs 15%; P < 0.001). The incidence of T-ALL was also significantly higher in the former group (56%) compared to the latter (33%) (P < 0.005). Our data suggest that by virtue of its association with features of poor prognosis, e.g., age above 10 yr, expression of thymic markers, high leucocyte count and disease relapse, TR expression by blast cells in ALL could serve as a biological marker of poor prognosis.

Red cell distribution width as a measure of severity of iron deficiency in iron deficiency anaemia.

Of the various red cell parameters used for distinguishing iron deficiency anaemia (IDA) from beta-thalassaemia trait BTT, red cell distribution width (RDW), which is an objective measure of the degree of anisocytosis, was examined by us for its discriminating value. RDW was measured in 55 patients of IDA and 56 patients of BTT at presentation with the help of an automated haematology analyser. The mean RDWs in IDA and BTT patients were 18.2 +/- 3.8 and 15.1 +/- 1.2 respectively (P < 0.001). In IDA, RDW showed an inverse relationship with the haemoglobin level (r = -0.543; P < 0.001), while no such correlation was observed in BTT patients. An inverse relation was also observed in IDA between RDW and transferrin saturation (TS). Patients with high RDW had low TS and vice versa. The latter finding, although statistically not significant, suggested that the degree of elevation of RDW in IDA could reflect the severity of iron deficiency. Our study revealed that red cell count, which was significantly higher in BTT patients (P < 0.001), the RDW, and the discriminant function (DF) calculated from these two parameters could be useful in distinguishing IDA from BTT. A RDW above 17.1 strongly suggests the presence of IDA. For RDW below 17.1 the DF can be applied for further discrimination. RDW has the advantage of being obtained directly from the analyser, while DF is a calculated value.

Adenocarcinoma arising in an oesophageal colonic interposition graft.

This case report describes the rare complication of an adenocarcinoma developing in a colonic interposition graft 20 years following surgical resection of a postcricoid squamous carcinoma. A free jejunal graft was used for further oesophageal reconstruction following resection of the colonic graft.