Derek R. Johnson

Cool, warm, and heat‐pain detection thresholds: Testing methods and inferences about anatomic distribution of receptors

We recently found that vibratory detection threshold is greatly influenced by the algorithm of testing. Here, we study the influence of stimulus characteristics and algorithm of testing and estimating threshold on cool (CDT), warm (WDT), and heat-pain (HPDT) detection thresholds. We show that continuously decreasing (for CDT) or increasing (for WDT) thermode temperature to the point at which cooling or warming is perceived and signaled by depressing a response key (“appearance” threshold) overestimates threshold with rapid rates of thermal change. The mean of the appearance and disappearance thresholds also does not perform well for insensitive sites and patients. Pyramidal (or flat-topped pyramidal) stimuli ranging in magnitude, in 25 steps, from near skin temperature to 9 °C for 10 seconds (for CDT), from near skin temperature to 45 °C for 10 seconds (for WDT), and from near skin temperature to 49 °C for 10 seconds (for HPDT) provide ideal stimuli for use in several algorithms of testing and estimating threshold. Near threshold, only the initial direction of thermal change from skin temperature is perceived, and not its return to baseline. Use of steps of stimulus intensity allows the subject or patient to take the needed time to decide whether the stimulus was felt or not (in 4, 2, and 1 stepping algorithms), or whether it occurred in stimulus interval 1 or 2 (in two-alternative forced-choice testing). Thermal thresholds were generally significantly lower with a large (10 cm2) than with a small (2.7 cm2) thermode. A topographic difference of CDT, WDT, and HPDT was demonstrated, with the face and volar arms having the lowest threshold and legs and feet having the highest threshold. In healthy subjects, warm threshold varied most among different sites, followed by uncomfortably hot, and last by heat-pain threshold. Particularly in older subjects, CDT could be determined on the dorsum of the foot whereas WDT sometimes could not, the first sensation experienced being heat-pain. A low density of warm receptors, especially in the foot and leg of old people, would explain these latter findings.

Cost-Effectiveness of Outpatient Cardiac Monitoring to Detect Atrial Fibrillation After Ischemic Stroke

Background and Purpose— Extending the duration of continuous electrocardiography after ischemic stroke detects more new cases of atrial fibrillation, which is an important and treatable cause of stroke, but the cost-effectiveness of this approach is unknown. Therefore, we performed a cost-utility analysis of outpatient cardiac monitoring after ischemic stroke. Methods— Using a Markov model, we determined the lifetime cost and utility of warfarin therapy in a hypothetical cohort of 70-year-old patients with atrial fibrillation, prior stroke, and no contraindication to warfarin therapy. Meta-analysis was used to determine the yield of outpatient cardiac monitoring. Results— Outpatient cardiac monitoring would detect 44 new cases of atrial fibrillation for every 1000 patients monitored. This would result in a gain of 34 quality-adjusted life-years at a net cost of

Glioblastoma survival in the United States improved after Food and Drug Administration approval of bevacizumab: A population-based analysis

440 000. Therefore, the cost-utility ratio of outpatient cardiac monitoring would be

Distinct germ line polymorphisms underlie glioma morphologic heterogeneity

13 000 per quality-adjusted life-years gained. Outpatient monitoring remained cost-effective throughout a wide range of model inputs in sensitivity analyses, including changes in the cost and yield of monitoring. Conclusions— By identifying patients with paroxysmal atrial fibrillation who will benefit from anticoagulation, outpatient cardiac monitoring is cost-effective after ischemic stroke over a wide range of model inputs. The optimal duration and method of monitoring is unknown.

Conditional probability of long-term survival in glioblastoma: a population-based analysis.

Bevacizumab received US Food and Drug Administration approval for use in recurrent glioblastoma based on promising radiographic response data, but without clear evidence that it prolongs survival. A population‐based analysis was conducted to determine whether bevacizumab approval was associated with improved glioblastoma survival in the United States.

Early measures of cognitive function predict survival in patients with newly diagnosed glioblastoma

Two recent genome-wide association studies reported that single nucleotide polymorphisms (SNPs) in (or near) TERT (5p15), CCDC26 (8q24), CDKN2A/B (9p21), PHLDB1 (11q23), and RTEL1 (20q13) are associated with infiltrating glioma. From these reports, it was not clear whether the single nucleotide polymorphism associations predispose to glioma in general or whether they are specific to certain glioma grades or morphologic subtypes. To identify hypothesized associations between susceptibility loci and tumor subtype, we genotyped two case-control groups composed of the spectrum of infiltrating glioma subtypes and stratified the analyses by type. We report that specific germ line polymorphisms are associated with different glioma subtypes. CCDC26 (8q24) region polymorphisms are strongly associated with oligodendroglial tumor risk (rs4295627, odds ratio [OR] = 2.05, P = 8.3 × 10(-11)) but not glioblastoma risk. The opposite is true of RTEL (20q13) region polymorphisms, which are significantly associated with glioblastoma (rs2297440, OR = 0.56, P = 4.6 × 10(-10)) but not oligodendroglial tumor. The SNPs in or near CCDC26 (8q24) are associated with oligodendroglial tumors regardless of combined 1p and 19q deletion status; however, the association is greatest for those with combined deletion (rs4295627, OR = 2.77, P = 2.6 × 10(-9)). These observations generate hypotheses concerning the possible mechanisms by which specific SNPs (or alterations in linkage disequilibrium with such SNPs) are associated with glioma development.

Phase II study of subcutaneous octreotide in adults with recurrent or progressive meningioma and meningeal hemangiopericytoma

Advances in glioblastoma care have resulted in a larger proportion of patients surviving beyond 2 years after diagnosis. It is not clear how long‐term survivors should be counseled with respect to future prognosis, or what factors influence that prognosis. The conditional probability of survival was evaluated from multiple time points in patients with glioblastoma, using Surveillance, Epidemiology, and End Results (SEER) data.

Risk factors for meningioma in postmenopausal women: results from the Iowa Women's Health Study

Cognitive dysfunction is a common manifestation of primary brain tumors. We evaluated the association between early cognitive dysfunction and prognosis in a cohort of patients with newly diagnosed glioblastoma. Ninety-one patients who completed neuropsychological assessment after tumor resection but before further treatment were identified in the MD Anderson Neuropsychology database. The relationship between performance on cognitive testing and survival was evaluated using not only Cox proportional hazards models that included clinical factors such as age and KPS but also the Kaplan-Meier method. Median survival time from surgery was 20.7 months. Rates of impairment on cognitive testing ranged from 7.1% for Similarities, to 60.0% for Hopkins Verbal Learning Test-Revised Total Recall. As continuous variables, the Clinical Trial Battery Composite, Trail Making Test Part B, and Controlled Oral Word Association test were associated with survival. Impairment on the Trail Making Test Part B, Controlled Oral Word Association, Similarities, and Digit Span were associated with mortality. Kaplan-Meier analysis demonstrated the survival impact of these tests on the group as a whole and in select patient subgroups defined by classification by the Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA). Cognitive impairment as measured by specific neuropsychological tests is independently associated with poor prognosis in patients with newly diagnosed glioblastoma, and this effect remains significant even within patient subgroups defined by RTOG RPA class. Executive function and attention are the cognitive domains most closely associated with prognosis in this analysis.

Incorporation of Prognostic and Predictive Factors Into Glioma Clinical Trials

The objective of this phase II study was to evaluate the efficacy and safety of subcutaneous octreotide therapy for the treatment of recurrent meningioma and meningeal hemangiopericytoma. Octreotide is an agonist of somatostatin receptors, which are frequently expressed in meningioma, and reports have suggested that treatment with somatostatin agonists may lead to objective response in meningioma. Patients with recurrent/progressive meningioma or meningeal hemangiopericytoma were eligible for enrollment; those with atypical/anaplastic meningioma or hemangiopericytoma must have experienced disease progression despite radiotherapy or have had a contraindication to radiation. Patients received subcutaneous octreotide with a goal dose of 500 μg 3 times per day, as tolerated. Imaging was performed every 3 months during therapy. The primary outcome measure was radiographic response rate. Eleven patients with meningioma and 1 with meningeal hemangiopericytoma were enrolled during the period 1992-1998. Side effects included diarrhea (grade 1 in 4 patients and grade 2 in 2), nausea or anorexia (grade 1 in 4 patients), and transaminitis (grade 1 in 1 patient). One patient developed extra hepatic cholangiocarcinoma, which was likely unrelated to octreotide therapy. No radiographic responses were observed. Eleven of the 12 patients experienced progression, with a median time to progression of 17 weeks. Two patients experienced long progression-free intervals (30 months and ≥18 years). Eleven patients have died. Median duration of survival was 2.7 years. Immunohistochemical staining of somatostatin receptor Sstr2a expression in a subset of patients did not reveal a correlation between level of expression and length of progression-free survival. Octreotide was well-tolerated but failed to produce objective tumor response, although 2 patients experienced prolonged stability of previously progressive tumors.

Detection of Atrial Fibrillation After Stroke and the Risk of Recurrent Stroke

Few risk factors for meningioma, aside from increasing age and female sex, have been identified. We investigated risk factors for meningioma in elderly women, a group with a high incidence. We evaluated associations of demographic, lifestyle, medical history, and anthropometric variables with risk of meningioma in the Iowa Womens Health Study (IWHS), a population-based, prospective cohort study. Risk factors were collected via questionnaires mailed in 1986 and 1992. Incident meningiomas were identified via linkages to Medicare. Cox regression models were used to examine the association of risk factors with meningioma incidence. The mean age at baseline of the 27,791 women in the analysis cohort was 69.3 years (range, 65.0-84.6 years). During 291,021 person-years of follow-up, 125 incident meningiomas were identified. After adjusting for age, lower levels of physical activity (relative risk [RR] , 0.68 for high versus low; P for trend = .039), greater body mass index (BMI; RR, 2.14 for ≥35 versus 19.5-24.9 kg/m(2); P for trend = .0019), greater height (RR, 2.04 for >66 versus ≤62 inches; P for trend = .013), and a history of uterine fibroids (RR, 1.72; 95% confidence interval, 1.19, 2.50) were positively associated with meningioma risk in multivariate analysis. BMI at age 18 and 30 years were not associated with risk. There were no associations with menstrual or reproductive factors or other medical history and lifestyle factors. Physical activity, BMI, height, and history of uterine fibroids were associated with meningioma risk in older women. The positive association with height suggests a role for early life influences on risk, whereas the associations with BMI and physical activity suggest a role for modifiable factors later in life.