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.

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.

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.

Possible functional role of substance P on the mammalian motor nerve terminals.

The effect of substance P (sP) on mammalian skeletal myoneural transmission was studied employing innervated and denervated isolated rat diaphragm preparations. sP at a concentration of 3.7 nM facilitated the indirect twitch responses of the rat diaphragm and antagonised the paralytic effect of d-tubocurarine (d-Tc). sP failed to affect the direct twitch responses as well as the contractures induced by acetylcholine (ACh) and potassium chloride (KCl) in the denervated diaphragm. The amount of ACh released into the bathing medium in response to tetanic stimulation of the phrenic nerve was doubled in presence of sP. The study illustrates a presynaptic facilitatory involvement of sP on mammalian myoneural transmission.

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.

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.

Effect of hydroxyurea on foetal haemoglobin in myeloproliferative & myelodysplastic syndromes.

The effect of hydroxyurea on foetal haemoglobin (HbF) levels was evaluated in 36 patients of myeloproliferative and myelodysplastic disorders. In 17 (47.2%) patients, HbF levels increased from 1.40 +/- 1.17 to 3.03 +/- 1.97 per cent after 4 wk therapy with hydroxyurea. In the responders this increase was highly significant (P less than 0.001). The rise in the HbF levels after hydroxyurea therapy was significant in patients with chronic myeloid leukaemia but not in the other groups.

Limitations of the therapeutic regimens for myelodysplastic syndrome.

Thirty patients of myelodysplastic syndrome (MDS) were treated over a period of 2 yr using 3 different treatment regimens. Twelve patients received hydroxyurea, 4 were given low dose cytosine arabinoside and 14 others were treated with an aggressive acute myeloid leukaemia (AML) induction regimen. A low complete remission was obtained in the first 2 groups (17 and 25% respectively), whereas 9 (64%) patients attained complete remission with the AML induction regimen. Remission in the latter group was associated with prolonged and severe pancytopenia requiring intensive support. Patients in all the 3 groups had a short duration of remission culminating in death with progressive marrow failure or evolution to AML, indicating the limitations of the current treatment strategies for MDS and highlighting the need for exploring newer therapeutic approaches.

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.

An endoscopic silastic keel for anterior glottic webs.

The use of a specially designed silastic keel endoscopically inserted into the larynx to prevent restenosis after division of anterior commisure webs of the larynx is described. The treatment of such webs is discussed.

Traumatic neuroma of the internal laryngeal nerve as a cause of severe cough.

We present a case of traumatic neuroma, describing an unusual symptom which may be more common than is recognized, and indeed we think from our search of the literature that this is the first report of such a case. We have briefly reviewed the pathology, clinical presentation and treatment of traumatic neuromas.

Jugulotympanic paraganglioma (glomus jugulare tumour) presenting as a parotid neoplasm (a case report and review of the literature).

A case of glomus jugulare tumour which presented as a parotid swelling, is reported. The patient also had facial palsy, total deafness and a polypoid lesion in the auditory canal. She was treated by surgery and radiotherapy. In this paper we review the literature and discuss the diagnostic problems and significance of long-standing facial palsy.

Pectoralis major flaps: functional aspects of the repair of oral and oropharyngeal resections.

The use of pectoralis major flaps for reconstruction after oral and oropharyngeal resection in a series of seventeen patients is reported. The applications and complications are described. A post-operative assessment of speech, chewing and swallowing in ten of the patients is reported. The functional aspects of such surgery are discussed.

Radiation induced tumours of the pharynx--can they be avoided?

Three patients who developed a post-cricoid carcinoma 5-21 years after radiotherapy for carcinoma of the larynx are presented. These patients received radiotherapy when they were young. It is suggested that alternative forms of treatment, especially partial laryngectomy with the aid of a laser should be considered in the primary management of small tumours of the larynx of young patients.

Post-laryngectomy pharyngo-cutaneous fistulae.

A personal series of 66 total laryngectomy cases is presented with special reference to post-operative fistula formation. The incidence of fistulae was 7.4 per cent. We could not verify previous reports that any specific factors were significantly related to fistula formation and we feel that operative technique and the post-operative drainage of any fluid collection under the flaps, are the most important ways of reducing the complication of a fistula to a minimum.

Radiation-induced antrochoanal fibrosarcoma.

Therapeutic radiation for malignant conditions is known to cause sarcomatous change in an irradiated field after a latent period; equally this change may occur following radiotherapy to benign conditions which may result in a more difficult management problem later. Radiotherapy to benign conditions should be reserved for use after failure of conventional surgery or other interventional techniques.

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.

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.

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.