Circulating tumour DNA is a potential biomarker for disease progression and response to targeted therapy in advanced thyroid cancer.

BACKGROUND: Conventional biomarkers in thyroid cancer are not disease specific and fluctuate in advanced disease, making interpretation difficult. Circulating tumour DNA (ctDNA) has been shown to be a useful biomarker in other solid tumours. This is a multimutational study of ctDNA over multiple timepoints, designed to test the hypothesis that ctDNA is a potential biomarker in patients with advanced thyroid cancer. METHODS: Mutational analysis of archival tumour tissue was performed using NGS with a targeted gene panel. Custom TaqMan assays were designed for plasma ctDNA testing using digital droplet polymerase chain reaction. Concentrations of detected ctDNA were correlated with the conventional biomarker concentration and axial imaging status defined by the Response Evaluation Criteria in Solid Tumours criteria. RESULTS: Tumour tissue from 51 patients was obtained, with the following histologies: 32 differentiated (differentiated thyroid cancer [DTC]), 15 medullary (medullary thyroid cancer [MTC]), three poorly differentiated and one anaplastic. NGS analysis detected variants in 42 (82%) of cases. Plasma was assayed for these patients in 190 samples, and ctDNA was detected in 67% of patients. Earlier detection of disease progression was noted in three patients with MTC. In two cases (PTC and ATC), where conventional biomarkers were not detectable, ctDNA was detected before disease progression. Changes in ctDNA concentration occurred earlier than conventional markers in response to disease progression in multiple patients with DTC receiving targeted therapies. CONCLUSION: The majority of patients with advanced thyroid cancer had detectable ctDNA. ctDNA measurement may offer superiority over conventional markers in several scenarios: earlier detection of progression in MTC; as an alternative biomarker when conventional markers are not available; more rapid assessment of the disease status in response to targeted therapies, thereby potentially allowing prompter discontinuation of futile therapies. These early results support the hypothesis that ctDNA may be a clinically useful biomarker in thyroid cancer.

Coblation® intracapsular tonsillectomy (tonsillotomy) in children: A prospective study of 500 consecutive cases with long-term follow-up.

OBJECTIVES: Intracapsular tonsillectomy (tonsillotomy) has been used internationally, mainly in the management of obstructive sleep apnoea, rather than recurrent tonsillitis, with few published data evaluating its use for this latter indication. We present long-term prospective data from 500 paediatric cases undergoing Coblation® intracapsular tonsillectomy, for both obstructive and infective indications. DESIGN: Prospective case series, March 2013-January 2016, all with completed follow-up. SETTING: Tertiary paediatric otolaryngological practice. PARTICIPANTS: A total of 500 consecutive patients (6 months to 18 years, mean 5.1 years) undergoing Coblation® intracapsular tonsillectomy (with or without adenoidectomy), for obstructive and/ or infective indications, almost exclusively under the care of the senior author (DJT). MAIN OUTCOME MEASURES: Validated parent-reported T-14 tonsil symptom questionnaires were used in all cases pre- and postoperatively, including in the long term. Parents also recorded duration of analgesia, time to return to school, any complications and whether they would recommend the procedure. RESULTS: With a mean follow-up 7.4 months, symptom control has been excellent (mean total T-14 score (/70) 31.01 preoperatively, 2.68 postoperatively, P<.0000001), with similar trends for obstructive and infective domains. Two small secondary haemorrhages required readmission and observation only (0.4%); otherwise, no complications, delayed discharges or readmissions occurred; 12/500 (2.4%) have since undergone revision tonsil surgery, 10 for obstructive and 2 for infective symptoms, the majority in very young children, with revision adenoidectomy at the same time. More than 99% of parents would recommend the surgery. CONCLUSIONS: Our experience of this technique has been very positive, with excellent control of both obstructive and infective symptoms, and exceptionally low rates of complications. Further work will be required to allow conclusive demonstration of its advantages over extracapsular tonsillectomy.

Use of core biopsy in diagnosing cervical lymphadenopathy: a viable alternative to surgical excisional biopsy of lymph nodes?

OBJECTIVES Lymphoma often presents with a neck mass and while fine-needle aspiration cytology may be suggestive, tissue biopsy is required for reliable diagnosis and classification of a lymphoma that is sufficient to deliver the correct treatment for the patient. Traditionally, excisional biopsy of a lymph node has been the standard method of tissue sampling, providing ample tissue for assessment. However, this requires theatre time, and preceding fine-needle aspiration cytology, which may incur a delay. With careful use of tissue, coupled with advances in immunohistochemical and molecular investigative techniques, core biopsy provides a possible alternative to traditional fine-needle aspiration and excisional biopsy. In this study, we aimed to determine the efficacy of diagnosing neck masses. METHOD A retrospective analysis was performed of patients being investigated for a neck mass who were undergoing ultrasound-guided core biopsies of cervical lymph nodes over a 17-month period. The final histology report was scrutinised to assess whether adequate tissue was obtained to allow for full tissue diagnosis. RESULTS Over the 17-month period analysed, 70 patients with cervical lymphadenopathy underwent core biopsy. Of these, 63 (90%) were diagnostic for either lymphoma or other pathology and did not require further tissue sampling. Overall, 19 patients were diagnosed with lymphoma, of which only 1 required further biopsy due to inconclusive initial core biopsy. CONCLUSIONS Current guidelines for investigating lymphomas require that excisional biopsy be performed to obtain ample tissue to allow full nodal architecture assessment and ancillary investigation to reach an accurate histological classification. Within our head and neck multidisciplinary team, however, it is considered that results from core biopsies can be obtained in a more timely fashion and with histological accuracy equal to those of open biopsy. The results obtained demonstrate that core biopsy is an effective tool for investigation. We believe this should be the first-line investigation of choice, as it reduces the need for patients to undergo surgery, is more cost effective and offers a faster diagnosis.

Laryngopyocoele presenting with acute airway obstruction.

A 66-year-old woman was transferred to the emergency department with a left-sided neck lump and fever. She was stridulous with reduced consciousness level and required immediate intubation to protect her airway. CT imaging showed a fluid-filled and air-filled lesion in the left side of the neck; the diagnosis was later confirmed as an infected laryngocoele. She underwent ultrasound guided drainage of the lesion with successful reduction of the neck lump. Following elective tracheostomy she was weaned from ventilation. Subsequent direct endoscopy and biopsy showed no evidence of malignancy or other lesion. She was discharged with permanent tracheostomy to be sustained until definitive surgical resection of the laryngocoele.

In vivo assessment of hydrocephalus shunt.

OBJECTIVES: Over a 3-year period, we have performed 312 tests in 197 shunted patients. The data have been analyzed retrospectively to: (1) investigate the parameters describing CSF dynamics that correlate with shunt under-drainage and (2) estimate accuracy of this method. METHODS: Constant rate infusion tests into shunt prechamber were performed. RESULTS: In 161 of the 312 infusion tests, results indicated under-draining shunts. Patients in the under-draining group had higher baseline and plateau CSF pressures, higher resistance to CSF outflow and higher levels of baseline pulse amplitude waveform. During the test, a significantly greater vasogenic waves and lower compensatory reserve was noticed in patients with blocked shunts. In 21 patients with suggestion of shunt blockage and who subsequently underwent operative revision of the shunt, reports of intraoperative shunt patency were available. Shunt blockage was confirmed intra-operatively during surgery in 19 cases. CONCLUSIONS: In vivo shunt testing is easy, safe and clinically useful, aiding decision in difficult clinical situations, where shunt malfunction is suspected but not certain. It also has satisfactory positive predictive power.

Gatifloxacin 400 mg as a single shot or 200 mg once daily for 3 days is as effective as ciprofloxacin 250 mg twice daily for the treatment of patients with uncomplicated urinary tract infections.

The efficacy and safety of two oral dosing regimens of gatifloxacin compared with ciprofloxacin for the treatment of acute uncomplicated lower urinary tract infection was investigated in a double-blind, randomised study, in adult female patients who received either gatifloxacin (400 mg as a single shot or 3 days of 200 mg once daily) or ciprofloxacin (250 mg given twice daily for 3 days). Bacteriological and clinical responses were assessed 7-9 days after the end of treatment (EOT), and 4-6 weeks post-treatment (end of study, EOS). One thousand one hundred and two women were treated, 741 (248 in the gatifloxacin 400 mg group, 252 in the gatifloxacin 200 mg group, and 241 in the ciprofloxacin group) presented with bacteriological proof of infection and entered the efficacy analysis. The bacteriological response per patient at EOT in the three groups were 80% (177/220) [95% CI to ciprofloxacin -8.4%; 6.4%], 83% (184/222) [95% CI to ciprofloxacin -5.9%; 8.7%] and 81% (176/216), respectively. At the follow-up assessment they were slightly lower, 75% (167/224), 79% (169/213) and 79% (171/217), respectively. The clinical responses at EOT were 81% (197/243) [95% CI to ciprofloxacin -10.2%; 3.4%], 85% (213/250) [95% CI to ciprofloxacin -5.7%; 7.2%] and 85% (201/238), respectively. At EOS they were 82% (195/239), 88% (212/241) and 86% (200/233), respectively. The eradication rates for all initial pathogens at the EOT were 90.3% in the gatifloxacin 400 mg S.D. group, 90.6% in the gatifloxacin 200 mg group, and 88.3% in the ciprofloxacin group. All treatment groups showed a similar safety profile. The incidence of treatment-related adverse events was comparable, the majority of adverse events were of mild or moderate intensity and the medications were well tolerated. Both the administration of gatifloxacin 200 mg once daily for 3 days, and gatifloxacin 400 mg as a single shot were shown to be equivalent to ciprofloxacin 250 mg twice daily for 3 days for the treatment of acute uncomplicated lower urinary tract infections.

Comparison of once- and twice-daily clarithromycin in the treatment of adults with severe acute lower respiratory tract infections.

BACKGROUND: Although the modified-release (MR) formulation of clarithromycin has demonstrated bioequivalence to the immediate-release (IR) formulation and thus can be prescribed for lower respiratory tract infections (LRTIs), a MEDLINE search from 1995 through 1998 and information on file with the manufacturer indicate that no data are available on the effectiveness of this new formulation in the treatment of severe LRTIs such as community-acquired pneumonia. OBJECTIVE: This study was designed to compare clinical success rates (percentage of patients with clinical cure or improvement) with once- and twice-daily regimens of clarithromycin in the treatment of patients with severe, acute LRTIs requiring oral antibiotic therapy. METHODS: In this multicenter, investigator-blinded, randomized, parallel-group study, adult patients with clinical evidence suggesting severe, acute LRTI were recruited from 22 general practices in the United Kingdom. Patients were randomly allocated to receive either clarithromycin 500 mg BID (IR tablets) or clarithromycin 1 g OD (two 500-mg MR tablets) for 7 to 14 days. The outcome measures were resolution of or improvement in clinical signs and symptoms (including resolution of cough), unscheduled visits for the same symptom, days to resumption of normal activities, and improvements in quality of life (assessed using the EQ-5D version of the EuroQoL questionnaire). Clinical, microbiologic, and serologic assessments were performed before, during, and after treatment. Efficacy and safety data were analyzed on an intent-to-treat basis. RESULTS: One hundred sixty men (n = 83) and women (n = 77) between the ages of 19 and 88 years took part in the study, 78 receiving clarithromycin 500 mg BID and 82 receiving clarithromycin 1 g OD. At 4 weeks after the start of treatment, the high clinical success rates were comparable between groups: 84.6% with clarithromycin 500 mg BID and 90.2% with clarithromycin 1 g OD. No significant differences in outcome measures were noted between the 2 regimens. Both treatments were well tolerated, with taste disturbance being the most commonly reported adverse event (10.6% vs 6.1% with clarithromycin 500 mg BID and 1 g OD, respectively). CONCLUSIONS: The 2 clarithromycin regimens were equally efficacious and well tolerated in the treatment of severe, acute LRTIs. However, caution should be exercised in applying these results to the general population, because the study excluded certain categories of patients who would normally be treated. In addition, the small sample size may have obscured clinically significant differences between the 2 regimens.

Prevention through parent training: Three preventive parent education programs.

One route to preventing child behavior disorders and adjustment problems is the enhancement of parent competence. This paper reviews three preventive parent education programs conducted at a community mental health center. One program provides child behavior advice in pediatric practices, another is a class that teaches child management skills to parents of preschoolers, and a third is a more specialized behavior management class for parents of children with Attention Deficit-Hyperactivity Disorder (ADHD). Program evaluations indicate that the interventions improve parent skills, child behavior and parent-child interaction. The contribution to the prevention of serious behavior problems is highlighted.

Effects of esmolol on patients with left ventricular dysfunction.

This study examined the effect of esmolol, an ultrashort-acting beta-receptor blocker, in 10 patients with severe left ventricular dysfunction. Simultaneous hemodynamic and radionuclide angiographic measurements were obtained at incremental doses of esmolol (2, 4, 8, 12 and 16 mg/min). At a dose of 4 mg/min, esmolol produced beats blockade: a decrease in heart rate from 91 +/- 4 to 83 +/- 4 beats/min (p less than 0.05) (mean +/- SEM) and a decrease in systolic aortic pressure from 133 +/- 5 to 128 +/- 5 mm Hg (p less than 0.05). At the maximal dose, the heart rate decreased to 79 +/- 3 beats/min (p less than 0.05) and biventricular function was depressed; the left ventricular ejection fraction decreased from 27 +/- 2 to 21 +/- 2% (p less than 0.05) and the right ventricular ejection fraction decreased from 38 +/- 2 to 29 +/- 2% (p less than 0.05). These changes were accompanied by increases in left ventricular end-diastolic volume (p less than 0.05), left ventricular end-systolic volume (p less than 0.05) and pulmonary artery wedge pressure (p less than 0.05), as well as a decrease in cardiac output (p less than 0.05). The hemodynamic abnormalities (which showed considerable interindividual variability) returned to near baseline levels 10 to 30 minutes after infusion was stopped. Thus, esmolol can be administered to patients with severe left ventricular dysfunction. The beneficial effect (beta-adrenergic blockade) is usually achieved with small doses without clinically important hemodynamic changes. At larger doses, however, significant changes in biventricular function may be observed.

Efficacy and safety of esmolol vs propranolol in the treatment of supraventricular tachyarrhythmias: a multicenter double-blind clinical trial.

The efficacy and safety of intravenous esmolol infusion was compared to that of intravenous propranolol injection in patients with supraventricular tachyarrhythmias (SVT) in a multicenter double-blind parallel study. A total of 127 patients were randomized to either the esmolol (n = 64) or propranolol (n = 63) group. Therapeutic response was achieved in 72% of esmolol and 69% of propranolol patients (p = NS). The average dose of esmolol in responders was 115 +/- 11 micrograms/kg/min. Therapeutic response was sustained in the 4-hour maintenance period in 67% of esmolol and 58% of propranolol patients (p = NS). Rate of conversion to normal sinus rhythm was similar in the two treatment groups. After discontinuation, rapid recovery from beta blockade (decrease in heart rate reduction) was observed in esmolol patients (within 10 minutes) compared to propranolol patients (no change in heart rate up to 4.3 hours). The principal adverse effect was hypotension, reported in 23 esmolol (asymptomatic in 19) and four propranolol (asymptomatic in three) patients. In the majority of esmolol patients, hypotension resolved quickly (within 30 minutes) after esmolol was discontinued. It was concluded that esmolol was comparable in efficacy and safety to propranolol in the treatment of patients with SVT. Unlike propranolol, because of the short half-life of esmolol, rapid control of beta blockade is possible with esmolol in clinical conditions when required.

Successful treatment of anxiety with a single night-time dose of chlormezanone: double-blind comparison with diazepam.

A multi-centre, double-blind trial was carried out in general practice in 44 patients with symptoms of neurotic anxiety to compare the effects of treatment with either 400 mg chlormezanone at night or 5 mg diazepam 3-times daily for 4 weeks. The results indicated tht there were similar improvements in anxiety, duration and quality of sleep, and frequency of waking refreshed with both drugs. There was no significant difference in overall effectiveness of the treatments, as rated by both the patients and physicians. It is suggested, therefore, that chlormezanone could serve as a substitute for the benzodiazepine with the advantage of only once-daily dosage.

Chitin biosynthesis during Blastocladiella zoospore germination: evidence that the hexosamine biosynthetic pathway is post-translationally activated during cell differentiation.

De novo construction of a chitinous cell wall accompanies Blastocladiella emersonii zoospore germination. At least an order of magnitude increase in total hexosamine occurs during germination. This increase is into polymer (chitin) and occurs on schedule in the presence of cycloheximide. Uridine-5'-diphospho-N-acetylglucosamine (UDPGlcNAc), both the end product of hexosamine biosynthesis and a substrate for chitin biosynthesis, is a potent inhibitor of the activity of the first pathway-specific enzyme of hexosamine biosynthesis in zoospore extracts. Certain uridine nucleotides, not perceptibly influencing the activity of the first enzyme per se, counteract the inhibitory effects of UDPGlcNAc. The concentration of UDPGlcNAc in the zoospore is sufficient to act as an inhibitor of the enzyme, but the amount of UDPGlcNAc is sufficient, by over an order of magnitude, to account for the chitin synthesized during germination. Both the production of UDPGlcNAc and its utilization for chitin synthesis appear to be post-translationally regulated in zoospores and during zoospore germination.