Practice, efficacy, and costs of thyroid nodule evaluation: a retrospective study in a Dutch university hospital.

Fine-needle aspiration (FNA) of thyroid nodules has markedly reduced the role of thyroid scintigraphy. This is often limited to nondiagnostic or follicular (tumor) FNA classifications. In this study, we evaluated the efficacy and cost of such a strategy in a university center. From 1992-1998, 995 aspirations were done in 667 patients with palpable nodules. FNA was classified as malignant, suspicious, follicular, benign or inadequate. The Gold standard was surgery or extended follow-up, including physical examination, FNA, and/or ultrasound (US) with a time interval of half a year. Cost analysis was limited to operated patients. The first FNA yielded inadequate results in 28%, decreasing to 6% after 4 aspirations (n = 42). The other final classifications were: 76%, benign; 14%, follicular; 2%, suspicious; 1%, malignant (n = 7). Scintigraphy ((99m)Tc) suggested a hyperfunctioning autonomous nodule (adenoma) in 12% and 3% of the inadequate and follicular subset, respectively. Surgery for diagnostic reasons (n = 105) yielded 24 malignancies (23%): in 47% of suspicious, 12% of the follicular, and in all with malignant FNA. Postoperative morbidity occurred in 14 (5 laryngeal nerve paralyses) with benign histology. Major cost drivers were surgery and hospitalization: mean costs per patient amounting to Euro 3.311 in case of benign histology. We conclude that current work-up is still unable to prevent unnecessary surgery for benign thyroid nodules. Thyroid scintigraphy proved most productive in the inadequate FNA category. Improvement of the diagnostic process using immunohistochemistry and/or imaging is needed from the patient's and society's perspective.     

Association of baseline levels of markers of bone and cartilage degradation with long-term progression of joint damage in patients with early rheumatoid arthritis: the COBRA study

OBJECTIVE: The known risk factors for radiologic progression in rheumatoid arthritis (RA) are not optimally discriminative in patients with early disease who do not have evidence of radiologic damage. We sought to determine whether urinary C-terminal crosslinking telopeptide of type I (CTX-I) and type II (CTX-II) collagen (markers of bone and cartilage destruction, respectively) are associated with long-term radiologic progression in patients with early RA. METHODS: This was a prospective study of 110 patients with early RA who were participating in the COBRA (Combinatietherapie Bij Reumato?de Artritis) clinical trial and followup study, a randomized controlled trial comparing the efficacy of oral pulse prednisolone, methotrexate, plus sulfasalazine with sulfasalazine alone. We investigated the relationship between baseline levels of urinary CTX-I and CTX-II and the mean annual progression of joint destruction over a median of 4 years, as measured by changes in the modified Sharp score (average of 2 independent readers). RESULTS: In multivariate logistic regression analysis, baseline urinary CTX-I and CTX-II levels in the highest tertile were the strongest predictors of radiologic progression (Sharp score increase >2 units/year; odds ratio 7.9 and 11.2, respectively), independently of treatment group, erythrocyte sedimentation rate (ESR), Disease Activity Score in 28 joints, rheumatoid factor (RF), and baseline joint damage (Sharp score). The likelihood ratios for a positive test were 3.8 and 8.0 for CTX-I and CTX-II, respectively, which compared favorably with the likelihood ratios for the ESR (3.0), baseline joint damage (1.6), and RF (1.8). When patients were grouped according to the presence (Sharp score >/=4, n = 49) and absence (Sharp score <4, n = 61) of joint damage at baseline, CTX-I and CTX-II levels were predictive only in those without baseline joint damage (odds ratio 14.9 and 25.7, respectively). CONCLUSION: High baseline levels of urinary CTX-I and CTX-II independently predict an increased risk of radiologic progression over 4 years in patients with early RA, especially those without radiologic joint damage. Urinary CTX-I and CTX-II may be useful for identifying individual RA patients at high risk of progression very early in the disease, before erosions can be detected radiographically. Such patients may be in special need of treatments that inhibit bone and cartilage degradation.     

Vascular complications of severe hyperhomocysteinemia in patients with homocystinuria due to cystathionine beta-synthase deficiency: effects of homocysteine-lowering therapy

Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency leads to severe hyperhomocysteinemia (HHcy). Vascular events (VE) remain the major cause of morbidity and mortality in the untreated patients with HCU. The study on the natural history of untreated HCU disclosed that, at the time of maximal risk, in other words beyond 10 years old, there was one event per 25 years. Recent studies from Australia (n = 32), The Netherlands (n = 28), and Ireland (n = 24) have documented the effects of long-term treatment on the vascular outcome of a total of 84 patients with 1314 patient-years of treatment for HCU. The mean (range) age was 27.8 (2.5 to 70) years. Five VE were recorded during treatment; one pulmonary embolism, two myocardial infarctions, and two abdominal aneurysms. All five VE occurred in B6-responsive patients at a mean (range) age of 48.8 (30 to 60) years. In 1314 patient-years of treatment, 53 VE would have been expected if they remained untreated; instead only 5 were documented, relative risk = 0.091 (95% confidence interval [CI] 0.043 to 0.190; p < 0.001). Appropriate homocysteine-lowering therapy for severe HHcy significantly reduced the vascular risk in patients with HCU. VE were rare with treatment despite the fact that the post-treatment homocysteine levels were several times higher than the cutoff point for homocysteine in the normal population. The present findings may have relevance to the current concept of "mild HHcy" as a risk factor for vascular disease, with elevated plasma homocysteine levels considerably lower than that of the post-treatment levels in this group of reported patients.     

Subclinical renal dysfunction in rheumatoid arthritis

We studied renal function in 35 patients with chronic, seropositive rheumatoid arthritis (RA), of whom 7 had vasculitis, 10 had hypergammaglobulinemia, and 18 had neither of these 2 conditions. Findings included a decreased glomerular filtration rate in 8 patients, (micro)proteinuria in 11, a defective urine concentration in 10, and increased urinary tubular enzyme levels in 15. These results indicate that subclinical renal dysfunction is common in patients with chronic, seropositive RA. In addition, vasculitis and hypergammaglobulinemia were not identified as risk factors for renal dysfunction in the RA patients studied.     

Hexokinase III, cyclin A and galectin-3 are overexpressed in malignant follicular thyroid nodules

Background Distinguishing malignant thyroid nodules in patients with follicular cytology by fine‐needle aspiration (FNA) remains problematic. The large majority of thyroid nodules (> 85%) are overtreated. Therefore, a clear need exists to develop more accurate initial diagnostic tests for follicular thyroid nodules. Galectin‐3 is the most recent promising marker to aid discrimination between benign and malignant thyroid lesions; however, this biomarker can be absent in follicular malignancies. Aims This study was undertaken to determine whether additional biomarkers can help to discriminate between benign and malignant thyroid nodules. Methods Surgical specimens of 36 patients with benign (n = 12) and malignant (n = 24) thyroid nodules showing follicular cytology were assessed by immunohistochemistry for the expression of galectin‐3 and novel biomarkers. Results Expression of hexokinase III (HK III) (P = 0·000) cyclin A (P = 0·002) and galectin‐3 (P = 0·003) differed significantly between benign and malignant thyroid nodules. HK III had a sensitivity of 79% [95% confidence interval (CI) 60–91] and a specificity of 100% (95% CI 76–100) in predicting malignancy. Galectin‐3 had a sensitivity of 79% (95% CI 56–91) and a specificity of 75% (95% CI 47–91) in predicting malignancy. Combining HK III, cyclin A and galectin‐3 in a parallel test increased the sensitivity to 96% (95% CI 80–99) while the specificity remained at a high level of 75% (95% CI 47–91). Leave‐one‐out cross‐validation demonstrated a stable predictive validity of a model based on HK III, cyclin A and galectin‐3. Conclusions In this study, we have demonstrated that in addition to galectin‐3, HK III and cyclin A profiles could be important biomarkers in predicting malignancy in follicular thyroid nodules. The use of these biomarkers may allow an accurate preoperative diagnosis of thyroid cancer, which can be cost saving and may avoid serious morbidity such as vocal cord paralysis. The value of the suggested biomarkers warrants further evaluation in a large prospective study on cytological samples of follicular thyroid nodules.     

Impact of undernutrition on the pharmacokinetics of chemotherapy in children with cancer: A systematic review

Objectives

This systematic review provides an overview of the effect of undernutrition on the pharmacokinetics of chemotherapy in children with cancer.

Methods

PubMed, Embase, and Cochrane were searched to identify eligible studies. This study uses the definition for undernutrition from the World Health Organization and the Gomez classification.

Results

Four studies with a total of 668 children with cancer were included and n = 121 (18%) were undernourished. Significant decreased clearance rates were found for vincristine in undernourished children compared to children with a normal nutritional status.

Conclusion

Presenting outcomes only show significant changes in the pharmacokinetics of vincristine in undernourished children with cancer. However, data are scarce, groups were small, and none of the studies included severely undernourished children. In order to improve outcomes for (severely) undernourished children with cancer, more pharmacokinetic research is needed. The ultimate goal would be to develop subgroups, and ultimately individualized drug dosing in order to improve outcomes for children with cancer worldwide.     

Comparison of different definitions to classify remission and sustained remission: 1 year TEMPO results

OBJECTIVE: To assess methods to calculate achieving and sustaining remission in a double blind randomised trial in patients with RA who received etanercept, methotrexate, or an etanercept/methotrexate combination. METHODS: Remission was defined as DAS <1.6, DAS28 <2.6, and ACR70 response. Sustaining remission was analysed in three ways: (a) analysis of sustained DAS remission, DAS28 remission, or ACR70 response continuously for 6 months; (b) analysis of sustained remission appraised through a continuity rewarded scoring system, which is the weighted sum of all intervals in the study in which patients are in DAS or DAS28 remission; or (c) longitudinal modelling of remission odds using generalised estimating equations. RESULTS: Significantly more patients treated with the etanercept/methotrexate combination reached DAS remission (37%) than those treated with either methotrexate (14%) or etanercept (18%) alone (p<0.01). Results for DAS28 and for the ACR70 response were similar. Agreement between DAS remission and DAS28 remission was good, but agreement between either of these and the ACR70 response was less. Patients in DAS or DAS28 remission had a lower level of disease activity (fewer active joints, lower ESR) than those achieving ACR70 response; the converse was seen using pain VAS. The three methods were comparable for sustainability of remission and showed significant advantage for combination therapy, which increased the number and durability of remission periods. CONCLUSIONS: DAS and DAS28 remission results were similar for assessing achieving and sustaining remission in RA, frequently differing from patients classified as ACR70 responders. The three methods of examining duration of remission produced comparable results.