Citations

AbstractThe prediction of outcome in the rare Hürthle cell tumor of the thyroid continues to present a problem to surgeons and pathologists. To better clarify the distinctions between benign and malignant tumors, we have measured DNA content by flow cytometry on isolated cell nuclei derived from archival paraffin‐embedded tissue blocks of 125 Hürthle cell tumors operated from 1943 to 1985 at the Mayo Clinic, Rochester, Minnesota, U.S.A. Nuclear DNA ploidy patterns were divided into 3 groups. A DNA normal (diploid) pattern was found in 55% of 75 Hürthle cell adenomas and in 26% of 50 Hürthle cell cancers; a DNA tetraploid/polyploid pattern was found in 11% of benign, and 14% of malignant tumors. An abnormal DNA stemline was detected in 34% of benign and 60% of malignant tumors. Hürthle cell cancer was the histologic diagnosis in 24% of the DNA normal, 47% of the DNA tetraploid/polyploid, and 54% of the DNA aneuploid tumors. None of the patients with adenomas developed tumor recurrence. However, 20% of the euploid and 40% of the aneuploid tumors developed local or distant recurrences. Survival to thyroid cancer death was significantly correlated with DNA ploidy status (p=0.02) but did not correlate with either tumor size or histologic grade. To date, deaths from thyroid cancer have been confined to patients whose tumors were DNA aneuploid. We would conclude that determination of DNA ploidy status may not aid the surgical pathologist in the diagnosis of Hürthle cell cancer. However, when a patient's Hürthle cell cancer is DNA aneuploid, there is significant risk of death from thyroid cancer.

Background— In case series, mitral regurgitation (MR) increased the risk of death after myocardial infarction (MI), yet the prevalence of MR, its incremental prognostic value over ejection fraction (EF), and its association with heart failure and death after MI in the community is not known. Methods and Results— The prevalence of MR and its association with heart failure and death were examined among 1331 patients within a geographically defined MI incidence cohort between 1988 and 1998. Echocardiography was performed within 30 days after MI in 773 patients (58%), and MR was present in 50% of cases, mild in 38%, and moderate or severe in 12%. Among patients with MR, a murmur was inconsistently detected clinically. After 4.7±3.3 years of follow-up, 109 episodes of heart failure and 335 deaths occurred. There was a graded positive association between the presence and severity of MR and heart failure or death. Moderate or severe MR was associated with a large increase in the risk of heart failure (relative risk 3.44, 95% CI 1.74 to 6.82, P <0.001) and death (relative risk 1.55, 95% CI 1.08 to 2.22, P =0.019) among 30-day survivors independent of age, gender, EF, and Killip class. Conclusions— In the community, MR is frequent and often silent after MI. It carries information to predict heart failure or death among 30-day survivors independently of age, gender, EF, and Killip class. These findings, which are applicable to a large community-based MI cohort, suggest that the assessment of MR should be included in post-MI risk stratification.

Oncology services have been provided by telemedicine from the University of Kansas Medical Center (KUMC) for almost 10 years. We have analysed the costs associated with providing tele-oncology clinics to a rural Kansas town for two fiscal years, 1995 and 2000. The aim was to compare recent tele-oncology costs with those of the first year of tele-oncology practice. A study conducted in 1995 showed that the average cost was $812 per telemedicine consultation. Data from fiscal year 2000 showed that the average cost was $410 per telemedicine consultation, a decrease of almost 50%. As the tele-oncology practice in Kansas continues to grow, it can be expected that the costs associated with providing tele-oncology services will continue to decline.

Background— Coronary bypass surgery (CABG) and angioplasty (PTCA) have been compared in several randomized trials, but data about long-term economic and quality-of-life outcomes are limited. Methods and Results— Cost and quality-of-life data were collected prospectively from 934 patients who were randomized in the Bypass Angioplasty Revascularization Investigation (BARI) and followed up for 10 to12 years. CABG had 53% higher costs initially, but the gap closed to <5% during the first 2 years; after 12 years, the mean cumulative cost of CABG patients was $123 000 versus $120 750 for PTCA, yielding a cost-effectiveness ratio of $14 300/life-year added. CABG patients experienced significantly greater improvement in their physical functioning for the first 3 years but not in later follow-up. Recurrent angina substantially reduced all quality-of-life measures throughout follow-up. Cumulative costs were significantly higher among patients with diabetes, heart failure, and comorbid conditions and among women; costs also were increased by angina, by the number of revascularization procedures, and among patients who died. Conclusion— Early differences between CABG and PTCA in costs and quality of life were no longer significant at 10 to 12 years of follow-up. CABG was cost-effective as compared with PTCA for multivessel disease.

Abstract Among 2333 consecutive patients with myelofibrosis with myeloid metaplasia (MMM) seen at our institution, 91 fulfilled the World Health Organization (WHO) criteria for leukemic transformation (LT). All episodes of LT were myeloid in origin (acute myeloid leukemia [AML]) with all French-American-British (FAB) subtypes represented except M3; the most frequent subtypes were M7 (25.4%), M0 (22.4%), and M2 (17.9%). Cytogenetic studies during LT were available in 56 patients and revealed a clonal abnormality in 51 (91%): 30 patients had complex karyotype, 2 had core-binding factor gene lesions, and 18 had abnormalities of chromosome 5 or 7. Karyotypic evolution was documented in the majority of the patients in whom serial analysis was possible. In general, LT was fatal in 98% of the cases after a median of 2.6 months (range, 0-24.2 months). Twenty-four patients received AML-like induction chemotherapy that resulted in no complete remission: 41% reverted into chronic-phase disease and the incidence of treatment-related mortality was 33%. The remaining 67 patients received either supportive care alone (48 patients) or low-intensity chemotherapy (19 patients). Overall, survival was similarly poor in all 3 treatment categories. The outcome of LT in MMM with current therapies is dismal and either supportive care alone or appropriate clinical trials should be considered.

Abstract OBJECTIVE We studied outcome measures after unilateral and bilateral thalamic stimulation to treat disabling tremor resulting from essential tremor and Parkinson's disease. The surgical technique, qualitative and quantitative tremor assessments, stimulation parameters, locations of active electrodes, complications, and side effects are described and analyzed. METHODS Forty-one patients with essential tremor or Parkinson's disease underwent implantation of 56 thalamic stimulators. Preoperative qualitative and quantitative tremor measurements were compared with those obtained after unilateral and bilateral surgery, with activated and deactivated stimulators. Stimulation parameters and stimulation-related side effects were recorded, and outcome measures were statistically analyzed. RESULTS Qualitative measurements demonstrated significant improvement of contralateral upper-limb (P &lt; 0.001), lower-limb (P &lt; 0.01), and midline (P &lt; 0.001) tremors after unilateral surgery. Ipsilateral arm tremor also improved (P &lt; 0.01). No differences were observed with the Purdue pegboard task. Quantitative accelerometer measurements were correlated with qualitative assessments and confirmed improvements in contralateral resting (P &lt; 0.001) and postural (P &lt; 0.01) tremors and ipsilateral postural tremor (P &lt; 0.05). Activities of daily living improved after unilateral surgery (P &lt; 0.001) and additionally after bilateral surgery (P &lt; 0.05). Adjustments of the pulse generator were required more frequently for tremor control than for amelioration of side effects. Bilateral thalamic stimulation caused more dysarthria and dysequilibrium than did unilateral stimulation. Stimulation-related side effects were reversible for all patients. Stimulation parameters did not change significantly with time. A significantly lower voltage and greater pulse width were used for patients with bilateral implants. CONCLUSION Unilateral thalamic stimulation and bilateral thalamic stimulation are safe and effective procedures that produce qualitative and quantitative improvements in resting, postural, and kinetic tremor. Thalamic stimulation-related side effects are mild and reversible.

Purpose A pressing need exists for agents active against anthracycline- or taxane-refractory metastatic breast cancer (MBC), or both. Previous clinical trials suggested that irinotecan might have such activity. We conducted this multicenter phase II study to assess efficacy and tolerability of two irinotecan schedules. Patients and Methods MBC patients who experienced disease progression after one to three chemotherapy regimens, including at least one anthracycline- or taxane-based regimen, were randomly assigned to irinotecan in 6-week cycles comprising 100 mg/m2 weekly for 4 weeks, then a 2-week rest (weekly) or 240 mg/m2 every 3 weeks. Results The weekly arm had 52 assessable patients; the every-3-weeks arm had 51 assessable patients. In the weekly arm, the objective response (complete regression [CR] + partial regression [PR]) rate was 23% (one CR, 11 PR; 95% CI, 13% to 37%). Median response duration was 4.9 months (range, 1.9 to 15.9 months), and median overall survival was 9.7 months (95% CI, 8.0 to 14.2 months). In the every-3-weeks arm, the objective response rate was 14% (nine PR; 95% CI, 6% to 26%), median response duration was 4.2 months (range, 3.1 to 13.9 months), and median overall survival was 8.6 months (95% CI, 7.0 to 12.3 months). Treatment generally was well tolerated, especially in the weekly arm. Grade 3 to 4 adverse events with ≥ 10% incidence included neutropenia (29%) and diarrhea (17%) in the weekly arm and neutropenia (36%), vomiting (20%), dyspnea (18%), nausea (16%), and diarrhea (12%) in the every-3-weeks arm. Conclusion Irinotecan is active with good tolerability in refractory MBC. Irinotecan (especially weekly) warrants additional study as monotherapy and in combination regimens in this setting.

There has been a longstanding debate regarding the role of proteolysis in Huntington's disease. The toxic peptide theory posits that N-terminal cleavage fragments of mutant Huntington's disease protein [mutant huntingtin (mhtt)] enter the nucleus to cause transcriptional dysfunction. However, recent data suggest a second model in which proteolysis of full-length mhtt is inhibited. Importantly, the two competing theories differ with respect to subcellular distribution of mhtt at initiation of toxicity: nuclear if cleaved and cytoplasmic in the absence of cleavage. Using quantitative single-cell analysis and time-lapse imaging, we show here that transcriptional dysfunction is “downstream” of cytoplasmic dysfunction. Primary and reversible toxic events involve destabilization of microtubules mediated by full-length mhtt before cleavage. Restoration of microtubule structure by taxol inhibits nuclear entry and increases cell survival.

Background— In patients with coronary artery disease (CAD), acute thrombosis frequently occurs in coronary arteries with only mild or moderate stenoses. Obesity increases the risk of atherosclerosis, but it is not known whether it also increases the risk of coronary thrombosis. We hypothesized that body mass index (BMI) might be an independent predictor of an acute coronary syndrome in patients with established coronary atherosclerosis. Methods and Results— Of 504 patients undergoing coronary angiography, those with evidence of >10% coronary artery stenoses were divided into 2 groups, with either stable (n=226) or unstable CAD (unstable angina or myocardial infarction; n=156). After adjusting for other risk factors (age, gender, blood pressure, lipid levels, insulin resistance, leptin, fibrinogen, C-reactive protein (CRP), CAD severity on angiography, smoking status, and a history of myocardial infarction or hypertension), BMI had a significant independent association with an acute coronary syndrome, with an odds ratio of 1.49 ( P =0.014). This positive relation between BMI and the risk of acute coronary events was evident for even mildly elevated BMI values. Multivariate analysis also showed that CRP and the number of coronary lesions were independent predictors of risk of an acute coronary event. Conclusions— In patients with established coronary atherosclerosis, BMI, as well as CRP and number of coronary lesions, are independently associated with acute coronary syndromes. There is evidence of increased risk even at mildly elevated BMI levels.

AbstractT-cell anergy is a tolerance mechanism defined as a hyporesponsive status of antigen-specific T cells upon prior antigen encounter and is believed to play a critical role in the evasion of tumor immunity and the amelioration of allogeneic transplant rejection. Molecular mechanisms in controlling T-cell anergy are less known. We show here that administration of an agonistic monoclonal antibody (mAb) to CD137, a member of the tumor necrosis factor receptor superfamily, prevents the induction of CD8+ cytolytic T-lymphocyte (CTL) anergy by soluble antigens. More importantly, CD137 mAb restores the functions of established anergic CTLs upon reencountering their cognate antigen. As a result, infusion of CD137 mAb inhibits progressive tumor growth that is caused by soluble tumor antigen-induced tolerance in a P815R model. CD137 mAb also restores proliferation and effector functions of anergic alloreactive 2C T cells in a bone marrow transplantation model. Our results indicate that ligation of CD137 receptor delivers a regulatory signal for T-cell anergy and implicate manipulation of the CD137 pathway as a new approach to break T-cell tolerance.