Avapritinib versus Placebo in Indolent Systemic Mastocytosis.

BACKGROUND: Indolent systemic mastocytosis (ISM) is a clonal mast-cell disease driven by the KIT D816V mutation. We assessed the efficacy and safety of avapritinib versus placebo, both with best supportive care, in patients with ISM. METHODS: We randomized patients with moderate to severe ISM (total symptom score [TSS] of ≥28; scores range from 0 to 110, with higher numbers indicating more severe symptoms) two to one to avapritinib 25 mg once daily (n=141) or placebo (n=71). The primary end point was mean change in TSS based on the 14-day average of patient-reported severity of 11 symptoms. Secondary end points included reductions in serum tryptase and blood KIT D816V variant allele fraction (≥50%), reductions in TSS (≥50% and ≥30%), reduction in bone marrow mast cells (≥50%), and quality of life measures. RESULTS: From baseline to week 24, avapritinib-treated patients had a decrease of 15.6 points (95% CI, −18.6 to −12.6) in TSS compared to a decrease of 9.2 points (−13.1 to −5.2) in the placebo group; P<0.003. From baseline to Week 24, 76/141 patients (54%; 45% to 62%) in the avapritinib group compared to 0/71 patients in the placebo group achieved a ≥50% reduction in serum tryptase level; P<0.001. Edema and increases in alkaline phosphatase were more common with avapritinib than placebo; there were few treatment discontinuations because of adverse events. CONCLUSIONS: In this trial, avapritinib was superior to placebo in reducing uncontrolled symptoms and mast-cell burden in patients with ISM. The long-term safety and efficacy of this approach for patients with ISM remain the focus of the ongoing trial. (Funded by Blueprint Medicines Corporation; ClinicalTrials.gov number, NCT03731260.)

Outcomes of older patients with primary central nervous system lymphoma treated in routine clinical practice in the UK: methotrexate dose intensity correlates with response and survival.

Data on older patients with primary central nervous system lymphoma (PCNSL) are scarce. Comorbidities and performance status frequently compromise outcomes in this group. Medical records for consecutive patients ≥65 years (n = 244) with PCNSL diagnosed 2012-2017 from 14 UK centres were retrospectively reviewed. Of these 192 patients received methotrexate (MTX)-based treatment. Patients were categorised based on clinician's treatment choice into 'palliative' (n = 52), 'less intensive: MTX ± rituximab ± alkylators' (n = 74) and 'intensive: MTX/cytarabine combinations' (n = 118) groups. Complete remission (CR) rate, two-year progression-free survival (PFS) and overall survival (OS) rates were 49%, 11% and 24% for the less intensive and 69%, 40% and 50% for the intensive groups. Treatment-related mortality (TRM) was 6·8% for MTX-treated patients. Median MTX cumulative dose was 8·8 g/m2 (range 1·5-21) over a median of three cycles. Higher relative dose intensity of MTX (MTX-RDI) was associated with improved PFS and OS in both groups adjusting for age, Eastern cooperative oncology group (ECOG) score and baseline parameters. Two-year PFS and OS for patients receiving four or more induction cycles followed by consolidation (n = 36) were 65% and 70% respectively. Older patients completing MTX-based induction and consolidation had clinical outcomes similar to those in younger cohorts. These retrospective data suggest that maximising MTX-RDI and delivering consolidation in a subgroup of older patients may improve clinical outcomes.

The Modified Graeb Score: an enhanced tool for intraventricular hemorrhage measurement and prediction of functional outcome.

BACKGROUND AND PURPOSE: Simple and rapid measures of intraventricular hemorrhage (IVH) volume are lacking. We developed and validated a modification of the original Graeb scale to facilitate rapid assessment of IVH over time. METHODS: We explored the relationship between the modified Graeb scale (mGS), original Graeb scale, measured IVH volume, and outcome using data from the Clot Lysis: Evaluating Accelerated Resolution of Hemorrhage with rtPA B (CLEAR B) study. We also explored its reliability. We then evaluated the relationship between mGS and outcome in a large sample of participants with IVH using data contained within the Virtual International Stroke Trials Archive (VISTA). We defined outcome using the modified Rankin scale (>3 signifying poor outcome). RESULTS: The CLEAR B study included 360 scans from 36 subjects. The mGS score and IVH volume were highly correlated (R = 0.80, P<0.0001, R(2) 0.65). Baseline mGS was predictive of poor outcome (area under receiving operating characteristic curve 0.74, 95% confidence interval, 0.57-0.91), whereas the original Graeb scale was not. The VISTA study included 399 participants. Each unit increase in the mGS led to a 12% increase in the odds of a poor outcome (odds ratio, 1.12; 95% confidence interval, 1.05-1.19). Measures of reliability (intra- and inter- reader) were good in both studies. CONCLUSIONS: The mGS, a semiquantitative scale for IVH volume measurement, is a reliable measure with prognostic validity suitable for rapid use in clinical practice and in research.

Effect of tonsillectomy on the adult voice.

OBJECTIVES AND HYPOTHESIS: Anecdotal evidence suggests that tonsillectomy has no deleterious consequences on a person's voice under normal vocal demand. However, whether the enlarged dimensions of the oropharynx after tonsillectomy impair the quality of a professional voice user remains unclear. Therefore, we designed a study to determine whether adult tonsillectomy altered the resonance characteristics of the vocal tract in any way and whether these changes were transient or permanent. STUDY DESIGN: This is a prospective observational study with full institutional ethical approval. METHODS: All adult patients presenting for tonsillectomy for recurrent tonsillitis in our institution were recruited. Their voice was recorded preoperatively, postoperatively, and at 4 weeks postoperatively. The values of the first four formants were calculated in all recordings. The oropharyngeal dimensions were measured preoperatively and postoperatively. Tonsillar weights and volumes were also measured. RESULTS: The first formant was noted to rise postoperatively. The average value of F2 and F3 did not alter postoperatively or at 4 weeks. However, it was noted that the fourth formant was not universally present preoperatively but was present in all patients postoperatively and at 4 weeks. CONCLUSIONS: Altering the dimensions of the oropharynx after tonsillectomy causes the first formant to rise but has no effect on the third and fourth formants. However, the fourth formant appears in patients who previously did not demonstrate it. The fourth formant was present in a greater proportion of male patients preoperatively than female patients, but it was universally present postoperatively and at 4 weeks in both sexes. This suggests that increasing the horizontal dimensions of the oropharynx has a nontransient effect on the higher order formants of the voice.

Aspirin resistance and compliance with therapy.

INTRODUCTION: Aspirin resistance is associated with increased cardiovascular risk in aspirin-treated patients. Poor compliance may explain many cases of "resistance," yet few clinical studies have used objective measurement of therapy compliance. We did so in a case-controlled study. METHODS: We enrolled patients within 24 h of ischemic stroke and a group of controls taking aspirin who had never suffered a vascular event on therapy. All claimed to be compliant. We assessed platelet function using platelet function analyser (PFA)-100 and rapid platelet function analyser (RPFA) devices, applying standard definitions of resistance. We used high-performance liquid chromatography for levels of aspirin metabolites in the urine to confirm compliance with therapy. We compared rates of resistance in stroke patients and controls, and performed subgroup analysis restricted to patients with objective confirmation of recent aspirin ingestion. RESULTS: We recruited 90 cases and 90 controls. Complete platelet function tests were available in 177. Resistance rates seen in cases and controls, respectively, were: resistance on one or more test, 30 (34%) versus 21 (25%), P= 0.19; on PFA-100 testing only, 28 (32%) versus 15 (18%), P= 0.031; on RPFA testing only, 16 (18%) versus 12 (14%), P= 0.54; resistance on both tests, 12 (14%) versus 5 (6%), P= 0.037. When only patients with objective evidence of recent aspirin ingestion were considered (n = 71), rates were similar regardless of definition of resistance used. CONCLUSION: Aspirin resistance is common but poor compliance accounted for nearly half of cases of apparent aspirin "failure." Objective measures to assess compliance are essential in studies of aspirin resistance.

Neckties and cerebrovascular reactivity in young healthy males: a pilot randomised crossover trial.

Background. A necktie may elevate intracranial pressure through compression of venous return. We hypothesised that a tight necktie would deleteriously alter cerebrovascular reactivity. Materials and Methods. A necktie was simulated using bespoke apparatus comprising pneumatic inner-tube with aneroid pressure-gauge. Using a randomised crossover design, cerebrovascular reactivity was measured with the "pseudo-tie" worn inflated or deflated for 5 minutes (simulating tight/loose necktie resp.). Reactivity was calculated using breath hold index (BHI) and paired "t" testing used for comparative analysis. Results. We enrolled 40 healthy male volunteers. There was a reduction in cerebrovascular reactivity of 0.23 units with "tight" pseudotie (BHI loose 1.44 (SD 0.48); BHI tight 1.21 (SD 0.38) P < .001). Conclusion. Impairment in cerebrovascular reactivity was found with inflated pseudo-tie. However, mean BHI is still within a range of considered normal. The situation may differ in patients with vascular risk factors, and confirmatory work is recommended.

Investigation of the impact of thyroid surgery on vocal tract steadiness.

INTRODUCTION: Subjective nonspecific upper aerodigestive symptoms are not uncommon after thyroid surgery. These are postulated to be related to injury of an extrinsic perithyroid nerve plexus that innervates the muscles of the supraglottic and glottic larynx. This plexus is thought to receive contributing branches from both the recurrent and superior laryngeal nerves. PATIENTS AND METHODS: The technique of linear predictive coding was used to estimate the F(2) values from a sustained vowel /a/ in patients before and 48 hours after thyroid or parathyroid surgery. These patients were controlled against a matched pair undergoing surgery without any theoretical effect on the supraglottic musculature. In total, 12 patients were recruited into each group. Each patient had the formant frequency fluctuation (FFF) and the formant frequency fluctuation ratio (FFFR) calculated for F(1) and F(2). RESULTS: Mixed analysis of variance (ANOVA) for all acoustic parameters revealed that the chiF(2)FF showed a significant "time" main effect (F(1,22)=7.196, P=0.014, partial eta(2)=0.246) and a significant "time by group interaction" effect (F(1,22)=8.036, P=0.010, eta(p)(2)=0.268), with changes over time for the thyroid group but not for the controls. Similarly, mean chiF(2)FFR showed a similar significant "time" main effect (F(1,22)=6.488, P=0.018, eta(p)(2)=0.228) and a "time by group interaction" effect (F(1,22)=7.134, P=0.014, eta(p)(2)=0.245). CONCLUSIONS: This work suggests that thyroid surgery produces a significant reduction in vocal tract stability in contrast to the controls. This noninvasive measurement offers a potential instrument to investigate the functional implications of any disturbance that thyroid surgery may have on pharyngeal innervations.

Cone-beam computed tomography on a mobile C-arm: novel intraoperative imaging technology for guidance of head and neck surgery.

OBJECTIVES: A conventional approach to image-guided surgery relies on positional tracking relative to preoperative images. We investigated the performance of intraoperative cone-beam computed tomography (CBCT) on a mobile C-arm for real-time guidance of head and neck surgery. Objectives were as follows: (1) to quantify improvements in surgical performance achieved with intraoperative CBCT and (2) to investigate specific, challenging surgical tasks for which CBCT is essential for total target ablation and critical structure avoidance. METHODS: Surgical performance was evaluated using a phantom model in which a simulated skull base lesion was excised with and without intraoperative CBCT guidance. Performance was quantified by means of statistical decision theory analysis for conservative and radical excision tasks, yielding measures of sensitivity and specificity for each surgical task. Cadaveric specimens were employed to demonstrate the efficacy of CBCT guidance in sinus and skull base surgery. RESULTS: Performance under CBCT guidance was significantly increased in all cases, particularly for radical excision tasks in proximity to critical normal structures. Cadaver studies demonstrated that CBCT-guided procedures yielded higher-quality surgical product and higher conformity to surgical margins with dramatically increased surgical confidence. CONCLUSIONS: Intraoperative CBCT quantifiably improved surgical performance in all excision tasks and significantly increased surgical confidence. CBCT offers an intraoperative three-dimensional imaging technology that provides exquisite, real-time visualization of sinus and skull base anatomy. Such intraoperative imaging in combination with real-time tracking and navigation should be of great benefit in delicate procedures in which excision must be executed in close proximity to critical structures.

Retinoblastoma gene abnormalities in early laryngeal cancer.

The retinoblastoma gene (Rb) is postulated to be important in carcinoma of the larynx. Its cellular protein (pRb) is involved in regulation of the cell cycle and may be influential in the cells response to irradiation injury. From the University of Liverpool Head and Neck Database we identified 35 patients with a T2 N0 laryngeal squamous carcinoma whom received primary irradiation and had a minimum of 5 years follow up. Laser capture microdissection was performed on paired normal and tumour biopsy material to analyse for loss of heterozygosity (LOH) and microsatellite instability (MI) of the Rb gene and immunohistochemistry (IHC) was carried out to detect pRb expression. Of 35 tumours, 13 were normal, 12 had MI and 5 had LOH of the Rb gene. Abnormalities at the Rb locus did not correlate with loss of pRb expression. There was also no significant difference between the distribution of normal and abnormal gene sequences and whether or not the primary laryngeal tumour recurred after radiotherapy. Rb gene abnormalities occurred in one third of T2 N0 laryngeal carcinomas. These were not in isolation predictive of cure by radiotherapy.

Completion thyroidectomy versus total thyroidectomy: is there a difference in complication rates? An analysis of 350 patients.

BACKGROUND: This study compared our experience with completion thyroidectomy (CT) and total thyroidectomy (TT) in the management of well-differentiated thyroid cancer (WDTC). We compared complication rates and analyzed the implications of the intraoperative management of the parathyroid glands. STUDY DESIGN: We performed a retrospective cohort study comparing outcomes between patients undergoing CT and TT between January 1994 and December 2004. All patients had surgery for either suspected or confirmed WDTC on fine-needle aspiration. RESULTS: There were 201 CTs and 149 TTs. Mean hospital stays were 4.5 and 3.5 days for the CT and TT groups, respectively (p=0.001). Temporary recurrent laryngeal nerve paresis occurred in 2.0% (4 of 201) and 3.3% (5 of 149) of patients in the CT and TT groups, respectively. There was one (0.5%) case of permanent recurrent laryngeal nerve paralysis in the CT group. Permanent hypoparathyroidism rates were 2.5% and 3.3% in the CT and TT groups, respectively. There was no difference between the two groups in terms of total numbers of parathyroid glands autotransplanted (p=0.63) or present in the specimen (p=0.26). CONCLUSIONS: Completion thyroidectomy is a safe and appropriate option in the management of select cases of WDTC in which a definitive preoperative or intraoperative diagnosis is not available. But it requires a longer hospitalization, so it has implications for both hospital resources and the patients involved.

Treatment of squamous cell carcinoma of the tongue base: irradiation, surgery, or palliation?

OBJECTIVES: Squamous cell carcinoma of the tongue base has a poor prognosis, and treatment is accompanied by a number of major problems. In view of this, it is important to recognize which patients will benefit from treatment with curative intent and which treatment method to use. METHODS: One hundred sixty-five patients with squamous cell carcinoma of the tongue base were identified on our database. Eighty-two patients were treated by radical irradiation, and 41 by surgery. A further 42 patients were considered unsuitable for curative treatment. RESULTS: The 5-year cause-specific survival rate was 41% for those treated by irradiation, 58% for those treated by surgery, and 9% for untreated patients. There was no difference in the efficacy of treatment methods (p = .5362), but a highly significant difference was seen in survival rate between treated and untreated patients (p = .0028). The decision regarding administration of curative treatment was based on the extent of locoregional involvement at the primary site (p = .0139; odds ratio, 0.43) and in the neck (p = .0078; odds ratio, 0.23). No factors affected the decision to treat by irradiation or surgery. When the observed survival rate was calculated, there was no significant difference in 5-year survival rate between treated and untreated patients (p = .2762). Those with early (T1-2) disease at the primary site had an improved survival rate from 0.5 to 4 years compared with those who were untreated (T3-4; p = .0081; odds ratio, 2.2). In addition, those with early (T1-2) disease had a better survival rate than those with advanced cancers (p = .0139; odds ratio, 2.09). There was, however, no difference in survival rate at 5 years. Those with early disease compared with those with advanced disease were twice as likely to be alive at 2 years; however, all survival advantages had disappeared by 5 years. CONCLUSIONS: In terms of observed survival, treating tongue base squamous cell carcinoma that is locally advanced (T3-4) at presentation offers no survival advantage over palliation alone. Treating early disease (T1-2) doubles the survival rate for up to 4 years, but by 5 years this survival advantage is lost. The present study finds radiotherapy and surgery to be equivalent at controlling this disease.

Thyroid scintigraphy in the assessment of the solitary thyroid nodule: differences in practice patterns between family physicians and specialists.

OBJECTIVE: It has been shown that there is considerable variation in the diagnosis and management of the thyroid nodule. The purpose of this study was to investigate the differences in the practice of family physicians and specialists in ordering thyroid scans in the initial workup of patients with thyroid nodules. DESIGN: Retrospective electronic and paper-based chart review. SETTING: University Health Network, Toronto. PARTICIPANTS: All patients who underwent thyroidectomy over a 2-year period. INTERVENTIONS: An audit of their preoperative diagnostic tests was performed, and the specialties of the ordering physicians were identified. RESULTS: One hundred ninety-four patients were assessed. Sixty-three patients (32.5%) were investigated exclusively by their family physician, 63 (32.5%) were investigated exclusively by a specialist, and 68 (35%) were investigated by both. Family physicians ordered thyroid scans in 51% of patients, whereas specialists ordered scans in 29% of patients (p<.001). The medical specialists ordered 36 scans (33.6%) in 107 patients, whereas the surgical specialists ordered 2 (8.3%) scans in 24 patients (p<.001). CONCLUSION: Despite the limited role for thyroid scans in the initial workup of a solitary thyroid nodule, they are still frequently ordered, particularly by family physicians. We recommend publication of Canadian evidence-based guidelines for the management of thyroid nodules, similar to existing American guidelines, which could help reduce the amount of unnecessary testing.

Minimal incision for open thyroidectomy.

OBJECTIVES: To establish the incision length for thyroid surgery that optimizes access and cosmesis. STUDY DESIGN AND SETTING: Prospective study from January 2003 to June 2004. All thyroidectomies were included. Exclusion criteria were concomitant neck dissections, previous surgery, and those performed endoscopically. The first 40 cases were attempted through a 5 cm incision and the second 40 through a 4 cm incision. METHODS: In both groups, the size of the incision was compared with the thyroid's weight and histology. RESULTS: Two subtotal, 22 total, and 56 hemithyroidectomies were performed. In the first group, median gland weight was 39.5 gm and 62.5% of these were removed through a 5 cm incision. In the second group, median gland weight was 34 gm and 75% were removed through a 4 cm incision. CONCLUSION: A 4 cm incision provides adequate access for the majority of thyroidectomies in our cohort. SIGNIFICANCE: The minimal incision thyroidectomy is a useful addition to the thyroid surgeon's armamentarium. EBM RATING: B-3b.

Intraoperative cone-beam CT for guidance of temporal bone surgery.

OBJECTIVES: To describe our preclinical experience with Cone Beam CT (CBCT) in image-guided surgery of the temporal bone. STUDY DESIGN AND SETTINGS: A mobile isocentric C-arm (PowerMobil, Siemens Medical Systems, Erlangen, Germany) modified to include a flat-panel detector (Varian Imaging Products, Palo Alto, CA) and a motorized orbit was developed to acquire multiple projections in rotation about a subject. Initial experiments imaging steel wire in air were used to investigate the system's spatial resolution in 3D image reconstruction. Subsequently temporal bone dissection was performed on five cadaver heads using the modified C-arm as an image guidance system. RESULTS: We obtained a spatial resolution of 0.85 mm. The image acquisition time was 120 seconds and the radiation dose approximately one-tenth of a conventional CT scan. CONCLUSION: CBCT provided submillimeter accuracy at high speed with low radiation dosage to offer utility as an intraoperative imaging system. SIGNIFICANCE: CBCT offers technology that approximates "near-real-time" image guidance. EBM RATING: C-4.

The sternomastoid branch of the occipital artery: a surgical landmark for the spinal accessory nerve in selective neck dissections.

OBJECTIVE: To evaluate the anatomic relationship between the spinal accessory nerve (SAN) and the sternomastoid branch of the occipital artery (SBOA) and its utility as a surgical landmark during a selective neck dissection (SND). STUDY DESIGN AND SETTINGS: Consecutive patients undergoing SND for squamous cancer from October 1, 2004 to February 28, 2005 were enrolled in this study. During surgery the distance between the SBOA and the point of insertion of the SAN into the sternomastoid muscle (SMM) was measured. RESULTS: Twenty-four patients underwent 33 SND. The distance between the SBOA and SAN ranged between 1 and 11 mm, with a mean of 6.2 mm and a median of 6 mm. CONCLUSION: The relationship between these 2 structures has a range and constancy that is acceptable as a landmark. SIGNIFICANCE: This article presents a useful adjunct for location of the SAN in the anterior neck during SND.