Monitoring for and Characterizing Crizotinib Progression: A Chart Review of <Emphasis Type="Italic">ALK</Emphasis>-Positive Non-Small Cell Lung Cancer Patients

Introduction

Crizotinib is recommended as first-line therapy for ALK-positive non-small cell lung cancer (NSCLC), but within a year of treatment initiation many patients develop resistance. With the recent approval of second-generation ALK inhibitors, this study assessed how physicians monitor for and diagnose progression and how they alter treatment following progression on crizotinib.

Methods

A panel of oncologists from the United States were surveyed regarding their monitoring practices and criteria for diagnosing progression on crizotinib. The physicians also retrospectively provided data (March–June 2016) from the medical charts of their adult patients with locally advanced or metastatic ALK-positive NSCLC who progressed on crizotinib after the approval (April 2014) of the first second-generation ALK inhibitor, ceritinib.

Results

A total of 28 physicians responded to the survey. Data was abstracted on 74 patients. In the physician survey, most physicians (71%) reported monitoring for radiographic progression every 3–4 months. When new lesions were detected, physician response varied. Following a symptomatic isolated lesion, most physicians (75%) would add local therapy and resume crizotinib. Following multiple symptomatic lesions, 96% and 64% of physicians would switch to a new therapy depending on whether the lesions were extracranial or isolated to the brain, respectively. For the patient cohort, physician-defined progression on crizotinib was diagnosed after a median of 10 months, and within 30 days of diagnosis, 86% of patients discontinued crizotinib. Among all patients who discontinued crizotinib, 77% switched to ceritinib, 14% to chemotherapy, and 1% to alectinib. The remaining 7% did not receive additional systemic antineoplastic therapy.

Conclusion

The findings from this physician survey and retrospective chart review study suggest that physician response to the development of new lesions in crizotinib-treated ALK-positive NSCLC patients varies with location and extent of the lesions. Once patients were considered to have progressed, most of them were immediately switched to ceritinib.

Funding

Novartis Pharmaceuticals Corporation.

     

Delayed open reduction and internal fixation of a neglected fracture dislocation of the ankle

Neglected fracture dislocations of ankle are rare in western countries. Failure to achieve anatomic reduction is associated with a poor prognosis. We present a case of a patient with a neglected Weber B fracture of the fibula with postero-lateral subluxation of the ankle. In theatre, the subluxation could not be reduced, and a posterior and lateral soft tissue release was performed. Granulation tissue was removed from the medial gutter. The fibular fracture was reduced and fixed with a six-hole dynamic compression plate. Post-operative radiographs was satisfactory and the patient was followed up for 12 months with full range of movement and function of the joint. In our case, correction was not obtained by osteotomy of the lateral malleolus alone, and medial and posterior soft tissue release was required. This was due to disruption of the deltoid ligament and posterior tibiofibular ligament and the associated scar tissue. Previous studies have shown that, if anatomic reduction is achieved, results with delayed surgery can be as good as those obtained with immediate surgery. Surgically correcting an old fracture dislocation is a difficult undertaking due to soft-tissue contractures and malunited fractures. It is important to preserve as much soft tissue attachments and periosteum to prevent avascular necrosis.     

A retrospective biochemical,molecular, and neurocognitive review of Saudi patients with argininosuccinic aciduria

A retrospective review was compiled of 54 patients with argininosuccinic aciduria who were either identified through the Saudi National Newborn Screening Program or diagnosed clinically from January 2000 to December 2015. The duration of follow-up is from 2 to 19 years. The majority of patients (65%) originated from the central province of Saudi Arabia. The mean patient age at review was 10 years (2–19 years), 92% received an early diagnosis (<28 days of age) and most were symptomatic at the time of the diagnosis (n?=?34). Normal ammonia at diagnosis was reported in 30% of patients, who were detected under the newborn metabolic screen (n?=?5/16). A very high rate of consanguinity was observed in our cohort (98%). Developmental delay was the most detectable long term neurocognitive consequence followed by seizure disorder; 90.7% (n?=?49) and 62.9% (n = 34) respectively. As expected, the severe neonatal form was the major presentation. The most common variant identified in this cohort was the previously reported founder c.1060C > T; p.(Gln354*) nonsense mutation in the ASL gene. In addition, the frequency of hyperammonemia was higher in patients homozygous for c.1060C > T; p.(Gln354*) compared to the other mutations. Interestingly, frequent thrombocytosis with the mean level of 717 × 10⁹/L (range?=?457–1169?×?10⁹/L) was observed in 96% of the patients with no clear explanation.     

Autosomal recessive otofaciocervical syndrome type 2 with novel homozygous small insertion in PAX1 gene

Otofaciocervical syndrome (OTFCS) is described as a single gene disorder of both autosomal dominant and autosomal recessive inheritance. The major clinical features of OTFCS include ear malformations (external/middle/inner ear), facial dysmorphism, shoulder girdle abnormalities, vertebral anomalies, and mild intellectual disability. The autosomal recessive form of OTFCS syndrome (OTFCS2) has been recently reported to be caused due to homozygous mutations in PAX1 gene. Here we report a third family of OTFCS2 phenotype wherein whole exome sequencing identified a novel homozygous small insertion in PAX1 as the underlying genetic cause.     

Red cell loss following orthopedic surgery: the case against postoperative blood salvage

BACKGROUND: Expensive devices have been developed for the collection and transfusion of blood salvaged after hip or knee arthroplasty. STUDY DESIGN AND METHODS: The volume of salvaged red cells was measured for the first 6 hours after operation. This volume was compared to total red cell loss during hospitalization and to the volume of allogeneic red cells transfused. RESULTS: Mean postoperative red cell loss in 31 patients following hip replacement was 55 +/− 29 mL and that in 20 patients following knee replacement was 121 +/− 50 mL. The 6-hour wound drainage represented 8.7 and 16.8 percent of overall red cell loss during hospitalization for hip and knee replacement, respectively. The transfusion of postoperatively salvaged red cells would have supplanted transfusion of less than one-third of a unit of allogenic blood after hip replacement and two-thirds of a unit after knee replacement. Only three patients (5.9%) lost red cell volume in the drainage equivalent to or in excess of 1 unit of red cells (180 mL). The volume of red cells salvaged postoperatively bore no relationship to perioperative red cell losses as a whole. CONCLUSION: The relatively small red cell loss in the postoperative period in most arthroplasty patients does not appear to justify the routine use of this technique for the recovery of autologous blood.     

Complications of catheter ablation for atrial fibrillation: incidence and predictors

Introduction: Pulmonary vein (PV) isolation by catheter ablation is an increasingly used strategy to treat atrial fibrillation (AF). Complication rates from AF ablation reported in different case series vary widely. We conducted a retrospective analysis of 641 consecutive ablation procedures to assess complication rates, temporal trends, and clinical predictors of adverse outcomes.
Methods: All patients (n = 517) undergoing catheter ablation for AF at Johns Hopkins Hospital between February, 2001 and June, 2007 were prospectively enrolled in a database. Data from 641 consecutive procedures were analyzed and complications considered if they occurred within 30 days of ablation. Major complications were defined as those that required intervention, resulted in long-term disability, or prolonged hospitalization.
Results: Thirty-two major complications occurred in 641 procedures (5%). Among the patients with major complications, seven had cerebrovascular accident (CVA), eight had tamponade, one had PV occlusion with hemoptysis, and 11 had vascular injury requiring surgical repair and/or transfusion. No periprocedural deaths occurred, and no instances of esophageal injury were seen. Complication rates were higher during the first 100 cases (9.0%) than during the subsequent 541 (4.3%). Major adverse clinical events were associated with age > 70 years (P = 0.007; odds ratio 3.7, 95% confidence interval 1.4–9.6) and female gender (P = 0.014; odds ratio 3.0, 95% confidence interval 1.3–7.2). No other clinical or procedural predictors of complication were identified.
Conclusions: Complication rates from AF ablation remain significant, despite improved techniques and increased awareness of procedural risks. Both advanced age and female gender predict major adverse events, suggesting careful consideration of the risk/benefit profile in these patients prior to ablation.     

The role of β-blockers in the management of hypertension: an Asian perspective

Following publication of the National Institute of Clinical Excellence (NICE) Guidelines in 2006, the use of β-blockers as first-line therapy in hypertension has been somewhat controversial. However, a recent reappraisal of the European Society of Hypertension guidelines highlights that these agents exhibit similar BP lowering efficacy to other classes of agents, prompting a re-examination of the utility of these agents in various patient populations. The authors felt that it is important to address this controversy and provide an Asian perspective on the place of β-blockers in current clinical practice and the benefits of β-blockade in selected patient populations. In addition to their use as a potential first-line therapy in uncomplicated hypertension, β-blockers have a particular role in patients with hypertension and comorbidities such as heart failure or coronary artery disease, including those who had a myocardial infarction. One advantage which β-blockers offer is the additional protective effects in patients with prior cardiovascular events. Some of the disadvantages attributed to β-blockers appear more related to the older drugs in this class and further appraisal of the efficacy and safety profile of newer β-blockers will lend support to the current guideline recommendations in Asian countries and encourage increased appropriate use of β-blockade in current clinical practice within Asia.     

Secondary chondrosarcoma in an enchondroma in a proximal phalanx of toe. A diagnostic problem. A case report

The authors present a case of secondary chondrosarcomatous transformation in enchondroma in toe. The authors have discussed the available literature to throw light on differentiation of benign and malignant form.