Kathryn A. Carson

Nonsteroidal anti-inflammatory drugs in Alzheimer's disease

Article abstract-We reviewed the records of 210 patients in the Johns Hopkins Alzheimers Disease Research Center to evaluate the role of nonsteroidal anti-inflammatory drugs (NSAIDs) on clinical features and progression of the disease. We compared patients taking NSAIDs or aspirin on a daily basis (N = 32) to non-NSAID patients (N = 177) on clinical, cognitive, and psychiatric measures. The NSAID group had a significantly shorter duration of illness at study entry. Even after controlling for this difference, the NSAID group performed better on the Mini-Mental State Examination, Boston Naming Test, and the delayed condition of the Benton Visual Retention Test. Furthermore, analysis of longitudinal changes over 1 year revealed less decline among NSAID patients than among non-NSAID patients on measures of verbal fluency, spatial recognition, and orientation. These findings support other recent studies suggesting that NSAIDs may serve a protective role in Alzheimers disease. NEUROLOGY 1995;45: 51-55

Association Between BRAF V600E Mutation and Mortality in Patients With Papillary Thyroid Cancer

IMPORTANCE BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established. OBJECTIVE To investigate the relationship between BRAF V600E mutation and PTC-related mortality. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of 1849 patients (1411 women and 438 men) with a median age of 46 years (interquartile range, 34-58 years) and an overall median follow-up time of 33 months (interquartile range, 13-67 months) after initial treatment at 13 centers in 7 countries between 1978 and 2011. MAIN OUTCOMES AND MEASURES Patient deaths specifically caused by PTC. RESULTS Overall, mortality was 5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) (P < .001) in BRAF V600E-positive vs mutation-negative patients. Deaths per 1000 person-years in the analysis of all PTC were 12.87 (95% CI, 9.61-17.24) vs 2.52 (95% CI, 1.40-4.55) in BRAF V600E-positive vs mutation-negative patients; the hazard ratio (HR) was 2.66 (95% CI, 1.30-5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in the analysis of the conventional variant of PTC were 11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00) in BRAF V600E-positive vs mutation-negative patients; the adjusted HR was 3.53 (95% CI, 1.25-9.98). When lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant (HR, 1.21; 95% CI, 0.53-2.76). A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center. For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]). In patients with distant tumor metastasis, deaths per 1000 person-years were 87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 2.63 [95% CI, 1.21-5.72]; adjusted HR, 0.84 [95% CI, 0.27-2.62]). CONCLUSIONS AND RELEVANCE In this retrospective multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. Because overall mortality in PTC is low and the association was not independent of tumor features, how to use BRAF V600E to manage mortality risk in patients with PTC is unclear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC.

Treatment of Primary CNS Lymphoma With Methotrexate and Deferred Radiotherapy: A Report of NABTT 96–07

PURPOSE A multicenter, phase II study of single-agent, intravenous methotrexate in newly diagnosed non-AIDS-related primary CNS lymphoma was conducted in the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. METHODS Methotrexate (8 g/m(2)) was initially administered every 2 weeks. The primary end point was radiographic CR or PR, as defined by standard radiographic criteria, and secondary end points were survival and drug-related toxicity. RESULTS Twenty-five patients were enrolled with a mean age of 60 years and median Karnofsky Performance Score of 80. Three of 14 patients who underwent lumbar puncture had malignant cells on CSF cytopathology, and five of 25 patients had ocular involvement. Two patients could not be evaluated for the primary end point because of the absence of measurable disease in one and death before radiologic imaging in another. All patients have completed the treatment program or progressed. Among 23 patients, there were 12 CR (52%), five PR (22%), one (4%) with stable disease, and five progressions (22%) while on therapy. Seven patients died of tumor progression, and two died of other causes. Median progression-free survival was 12.8 months. Median overall survival for the entire group had not been reached at 22.8+ months. The toxicity of this regimen was modest, with no grade 3 or 4 toxicity in 13 of 25 patients, grade 3 toxicity in eight of 25 patients, and grade 4 toxicity in four of 25 patients after 287 cycles of chemotherapy. CONCLUSION These results indicate that high-dose methotrexate is associated with modest toxicity and a radiographic response proportion (74%) comparable to more toxic regimens.

Phase I and Correlative Biology Study of Cilengitide in Patients With Recurrent Malignant Glioma

PURPOSE This multi-institutional phase I trial was designed to determine the maximum-tolerated dose (MTD) of cilengitide (EMD 121974) and to evaluate the use of perfusion magnetic resonance imaging (MRI) in patients with recurrent malignant glioma. PATIENTS AND METHODS Patients received cilengitide twice weekly on a continuous basis. A treatment cycle was defined as 4 weeks. Treatment-related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity of any duration. RESULTS A total of 51 patients were enrolled in cohorts of six patients to doses of 120, 240, 360, 480, 600, 1,200, 1,800, and 2,400 mg/m2 administered as a twice weekly intravenous infusion. Three patients progressed early and were inevaluable for toxicity assessment. The DLTs observed were one thrombosis (120 mg/m2), one grade 4 joint and bone pain (480 mg/m2), one thrombocytopenia (600 mg/m2) and one anorexia, hypoglycemia, and hyponatremia (800 mg/m2). The MTD was not reached. Two patients demonstrated complete response, three patients had partial response, and four patients had stable disease. Perfusion MRI revealed a significant relationship between the change in tumor relative cerebral blood flow (rCBF) from baseline and area under the plasma concentration versus time curve after 16 weeks of therapy. CONCLUSION Cilengitide is well tolerated to doses of 2,400 mg/m2, durable complete and partial responses were seen in this phase I study, and clinical response appears related to rCBF changes.

BRAF Mutation Testing of Thyroid Fine-Needle Aspiration Biopsy Specimens for Preoperative Risk Stratification in Papillary Thyroid Cancer

PURPOSE This study investigated the utility of BRAF mutation testing of thyroid fine-needle aspiration biopsy (FNAB) specimens for preoperative risk stratification in papillary thyroid cancer (PTC). PATIENTS AND METHODS We assessed the T1799A BRAF mutation status in thyroid FNAB specimens obtained from 190 patients before thyroidectomy for PTC and its association with clinicopathologic characteristics of the tumor revealed postoperatively. RESULTS We observed a significant association of BRAF mutation in preoperative FNAB specimens with poorer clinicopathologic outcomes of PTC. In comparison with the wild-type allele, BRAF mutation strongly predicted extrathyroidal extension (23% v 11%; P = .039), thyroid capsular invasion (29% v 16%; P = .045), and lymph node metastasis (38% v 18%; P = .002). During a median follow-up of 3 years (range, 0.6 to 10 years), PTC persistence/recurrence was seen in 36% of BRAF mutation-positive patients versus 12% of BRAF mutation-negative patients, with an odds ratio of 4.16 (95% CI, 1.70 to 10.17; P = .002). The positive and negative predictive values for preoperative FNAB-detected BRAF mutation to predict PTC persistence/recurrence were 36% and 88% for overall PTC and 34% and 92% for conventional PTC, respectively. CONCLUSION Preoperative BRAF mutation testing of FNAB specimens provides a novel tool to preoperatively identify PTC patients at higher risk for extensive disease (extrathyroidal extension and lymph node metastases) and those who are more likely to manifest disease persistence/recurrence. BRAF mutation, as a powerful risk prognostic marker, may therefore be useful in appropriately tailoring the initial surgical extent for patients with PTC.

Association Between BRAF V600E Mutation and Recurrence of Papillary Thyroid Cancer

PURPOSE To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC). PATIENTS AND METHODS This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months). RESULTS The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation-positive and 11.6% (125 of 1,082) of BRAF V600E mutation-negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation-positive versus -negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation-positive versus -negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. CONCLUSION This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories.

LONG-TERM PAIN AND ACTIVITY DURING RECOVERY FROM MAJOR THORACOTOMY USING THORACIC EPIDURAL ANALGESIA

Background Pain following thoracotomy can persist for years with an undetermined impact on quality of life. Factors hypothesized to modulate this painful experience include analgesic regimen, gender, and type of incision. Methods A total of 157 generally healthy patients of both genders scheduled for segmentectomy, lobectomy, or bilobectomy through a posterolateral or muscle-sparing incision were randomly assigned to receive thoracic epidural analgesia initiated prior to incision or at the time of rib approximation. Pain and activity scores were obtained 4, 8, 12, 24, 36, and 48 weeks after surgery. Results Overall, there were no differences in pain scores between the control and intervention groups during hospitalization (P ≥ 0.165) or after discharge (P ≥ 0.098). The number of patients reporting pain 1 yr following surgery (18 of 85; 21.2%) was not significantly different (P = 0.122) from the number reporting preoperative pain (15 of 120; 12.5%). During hospitalization, women reported greater pain than men (worst pain, P = 0.007; average pain, P = 0.016). Women experienced fewer supraventricular tachydysrhythmias (P = 0.013) and were thus discharged earlier (P = 0.002). After discharge women continued to report greater discomfort than men (P ≤ 0.016), but did not differ from men in their level of physical activity (P = 0.241). Conclusions Initiation of thoracic epidural analgesia prior to incision or the use of a muscle-sparing incision did not significantly impact pain or physical activity. Although women reported significantly greater pain during hospitalization and after discharge, they experienced fewer complications, were more likely to be discharged from the hospital sooner, and were just as active after discharge as men.

BRAF Mutation in Papillary Thyroid Cancer and Its Value in Tailoring Initial Treatment A Systematic Review and Meta-Analysis

AbstractClinicians have long sought to characterize biological markers of neoplasia as objective indicators of tumor presence, pathogenicity, and prognosis. Armed with data that correlate biomarker activity with disease presence and progression, clinicians can develop treatment strategies that address risks of disease recurrence or persistence and progression. The B-type Raf kinase (BRAF V600E) mutation in exon 15 of the BRAF gene has been noted to be a putative prognostic marker of the most prevalent form of thyroid cancer, papillary thyroid cancer (PTC)—a tumor type with high proclivity for recurrence or persistence. There has been a remarkable interest in determining the association of BRAF mutation with PTC recurrence or persistence. Using many new studies that have been published recently, we performed a meta-analysis to investigate correlations of BRAF mutation status with PTC prognosis, focusing on the recurrence or persistence of the disease after initial treatment.The study was based on published studies included in the PubMed and Embase databases addressing the BRAF mutation and the frequency of recurrence of PTC. We selected studies with data that enabled measurement of the risk ratio for recurrent disease. We also analyzed the factors that are classically known to be associated with recurrence. These factors included lymph node metastasis, extrathyroidal extension, distant metastasis, and American Joint Committee on Cancer (AJCC) stages III/IV.We used 14 articles that included an analysis of these factors as well as PTC recurrence data, with a total of 2470 patients from 9 different countries. The overall prevalence of the BRAF mutation was 45%. The risk ratios in BRAF mutation-positive patients were 1.93 (95% confidence interval [CI], 1.61–2.32; Z = 7.01; p < 0.00001) for PTC recurrence, 1.32 (95% CI, 1.20–1.45; Z = 5.73; p < 0.00001) for lymph node metastasis, 1.71 (95% CI, 1.50–1.94; Z = 8.09; p < 0.00001) for extrathyroidal extension, 0.95 (95% CI, 0.63–1.44; Z = 0.23; p = 0.82) for distant metastasis, and 1.70 (95% CI, 1.45–1.99; Z = 6.46; p < 0.00001) for advanced stage AJCC III/IV.Thus, in this meta-analysis, the BRAF mutation in PTC was significantly associated with PTC recurrence, lymph node metastasis, extrathyroidal extension, and advanced stage AJCC III/IV. Patients with PTC harboring mutated BRAF are likely to demonstrate factors that are associated with an increased risk for recurrence of the disease, offering new prospects for optimizing and tailoring initial treatment strategies to prevent recurrence.

Oncologic and Reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 Adenocarcinoma: A systematic review

OBJECTIVE The objective of this review was to analyze published contemporary oncologic and reproductive outcomes in women with endometrial hyperplasia or cancer undergoing medical management with progestin therapy. METHODS A systematic review of oncologic and pregnancy outcomes in women with complex atypical hyperplasia or grade 1 adenocarcinoma was performed using a comprehensive search of the MEDLINE literature. English language studies published from 2004 to 2011 which utilized hormonal therapy were identified using key words endometrial hyperplasia, endometrial cancer, fertility preservation, hormone and progestin therapy. Fishers exact test was used to calculate statistical differences. RESULTS Forty-five studies with 391 study subjects were identified. The median age was 31.7 years. Therapies included medroxyprogesterone (49%), megestrol acetate (25%), levonorgestrel intrauterine device (19%), hydroxyprogesterone caproate (0.8%), and unspecified/miscellaneous progestins (13.5%). Overall, 344 women (77.7%) demonstrated a response to hormonal therapy. After a median follow up period of 39 months, a durable complete response was noted in 53.2%. The complete response rate was significantly higher for those with hyperplasia than for women with carcinoma (65.8% vs. 48.2%, p=.002). The median time to complete response was 6 months (range, 1-18 months). Recurrence after an initial response was noted in 23.2% with hyperplasia and 35.4% with carcinoma during the study periods (p=.03). Persistent disease was observed in 14.4% of women with hyperplasia and 25.4% of women with carcinoma (p=.02). During the respective study periods, 41.2% of those with hyperplasia and 34.8% with a history of carcinoma became pregnant (p=.39), with 117 live births reported. CONCLUSION Based on this systematic review of the contemporary literature, endometrial hyperplasia has a significantly higher likelihood of response (66%) to hormonal therapy than grade 1 endometrial carcinoma (48%). Disease persistence is more common in women with carcinoma (25%) compared to hyperplasia (14%). Reproductive outcomes do not seem to differ between the cohorts.

Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer

The role of aberrant tumor suppressor gene methylation in the aggressiveness of papillary thyroid cancer (PTC) has not been documented. By showing promoter methylation‐induced gene silencing in PTC‐derived cell lines, we first demonstrated the functional consequence of methylation of several recently identified tumor suppressor genes, including those for tissue inhibitor of metalloproteinase‐3 (TIMP3), SLC5A8, death‐associated protein kinase (DAPK) and retinoic acid receptor β2 (RARβ2). We then investigated the role of methylation of these genes in the aggressiveness of PTC by examining the relationship of their aberrant methylation to clinicopathological characteristics and BRAF mutation in 231 primary PTC tumors. Methylation of TIMP3, SLC5A8 and DAPK was significantly associated with several aggressive features of PTC, including extrathyroidal invasion, lymph node metastasis, multifocality and advanced tumor stages. Methylation of these genes was also significantly associated with BRAF mutation in PTC, either individually or collectively in various combinations. Methylation of these genes, either individually or collectively, occurred more frequently in more aggressive classical and tall‐cell PTC subtypes than in less aggressive follicular‐variant PTC, with the latter known to infrequently harbor BRAF mutation. Several other tumor suppressor genes investigated were not methylated. These results suggest that aberrant methylation and hence silencing of TIMP3, SLC5A8, DAPK and RARβ2, in association with BRAF mutation, may be an important step in PTC tumorigenesis and progression.