Nilima A. Patwardhan

Physician practices in the prevention of venous thromboembolism

OBJECTIVE To determine the rate of use of prophylaxis for venous thromboembolism in high-risk hospital patients. DESIGN A retrospective medical record review. SETTING A community-wide study in 16 short-stay hospitals in central Massachusetts. PATIENTS A total of 2017 patients with multiple risk factors for venous thromboembolism. MEASUREMENTS AND MAIN RESULTS On the basis of age, length of hospitalization, and the presence of at least one additional major risk factor, 17% of 151,349 discharges (25,410 patients) were identified as being at high risk for venous thromboembolism. Eight percent of these discharges were randomly selected for medical record review. Prophylaxis for venous thromboembolism was received by 32% of these high-risk patients. Prophylaxis use among the 16 study hospitals varied widely, ranging from 9% to 56%, and was higher in teaching hospitals than in nonteaching hospitals (44% compared with 19%; P less than 0.001). One or more of the following methods of prophylaxis was used: low-dose heparin (78%), intermittent calf compression (13%), warfarin (12%), and inferior vena caval filter (3%). Use of prophylaxis increased with the number of risk factors identified (P less than 0.001). CONCLUSION Prophylaxis for venous thromboemobolism is underused, particularly in nonteaching hospitals.

The Role of Cell Cycle Regulatory Protein, Cyclin D1, in the Progression of Thyroid Cancer

Cell cycle progression is facilitated by cyclin-dependent kinases that are activated by cyclins including cyclin D1 and inactivated by cyclin-dependent kinase inhibitors (CDKIs) such as p27. Our previous studies have demonstrated decreased p27 expression in both papillary and more aggressive carcinomas of the thyroid compared to thyroid adenoma and almost similar level of cyclin D1 expression between thyroid adenoma and papillary carcinoma. These results indicate that CDKIs may have an important role in the carcinogenesis of the thyroid and that they probably have a limited role in malignant progression of the thyroid cancer. The role of cyclin D1 in malignant progression of thyroid carcinoma has yet to be established. We studied the expression of cyclin D1 by immunohistochemistry in 34 cases of conventional papillary carcinoma (CPC), 10 cases of minimally invasive follicular carcinoma (MIFC), and 32 cases of more aggressive thyroid carcinoma (ATC), which included 11 tall cell variants, one columnar cell variant of papillary carcinoma, seven insular carcinomas, and 13 anaplastic carcinomas. Cyclin D1 staining was classified by staining score as 0, negative; 1+, less than 25%; 2+, 25 to 50%; and 3+, more than 50% tumor cells staining positive. Kruskal-Wallis one-way ANOVA and Wilcoxon Rank Sum/Mann-Whitney U Test was used to assess the difference in the expression of cyclin D1 between the study groups. Twenty-eight out of the 34 CPCs were cyclin D1 positive, 24 (70%) were 1+, 3 (9%) were 2+, and one (3%) were 3+ positive. Seven of 10 MIFCs were cyclin D1 positive, five (71%) were 1+, and the remaining two (29%) were 2+ positive. On the other hand, 28 of 32 ATCs showed cyclin D1 immunostaining. Of these, three (9%) were 1+, five (13%) were 2+, and 20 (63%) were 3+ positive. This study demonstrates a significant overexpression of cyclin D1 in ATC compared CPC (P < .001) and MIFC (P < .005), suggesting that the cyclin D1 expression may play a role in tumor progression and may have prognostic significance in thyroid cancer.

The role of cell cycle regulatory proteins, cyclin D1, cyclin E, and p27 in thyroid carcinogenesis.

The cell cycle is controlled in part by cyclin-dependent kinases (CDKs), which are activated by forming complexes with cyclins. CDKs phosphorylate certain substrates to facilitate the proliferating cells through the cell cycle. CDK inhibitors (CDKIs) such as p27 inhibit cyclin-CDK complexes and function as a negative cell cycle regulator. The overexpression of the positive regulators (cyclins) or the underexpression of the negative regulators including p27 has been seen in a variety of neoplasms, but their role and interaction in thyroid carcinogenesis is yet to be established. We studied the expression of cyclins D1 and E, and the CDKI, p27 by immunohistochemistry in 116 cases, including 59 cases of follicular variant of papillary carcinoma (FVPC) and 57 cases of follicular adenoma (FA). The positive staining was divided into four grades: 1+ if less than 10%, 2+ if 11% to 25%, 3+ if 26% to 50%, and 4+ if greater than 50% of the nuclei of tumor cells stained positively. Cyclin D1 expression was seen in 37 (63%) FVPC and 34 (60%) FA. Cyclin E-positive cells were seen in 51 (86%) FVPC and 47 (82%) FA. No significant differences in the grade of cyclins D1 (P = .261) and E (P = .284) staining was seen between FVPC and FA. Of the 59 FVPC, 53 (89%) showed p27-positive cells; of these, 33 were 1+, nine were 2+, seven were 3+ and only four were 4+ positive. Conversely, all 57 FA were p27 positive, 53 were 4+, and four were 3+ positive. This difference in the grade of p27 staining between FVPC and FA was statistically significant (P < .001). This study shows a significant underexpression of p27 in FVPC compared with FA, suggesting that a decrease in p27 expression plays a more important role than overexpression of cyclins D1 and E alone in thyroid carcinogenesis and that p27 immunostaining may be helpful in the diagnosis of FVPC.

Follicular variant of papillary thyroid carcinoma: a comparative study of histopathologic features and cytology results in 141 patients.

OBJECTIVE To characterize the histopathologic features of follicular variant of papillary thyroid carcinoma (FVPC) and its cytology results on fine-needle aspiration (FNA) biopsy and compare them with those of papillary thyroid carcinoma (PC). METHODS We searched the University of Massachusetts Medical Center pathology database for all surgical specimens associated with a diagnosis of FVPC or PC between January 1992 and February 1998 and reviewed the related pathology reports. In addition, the associated preoperative FNA results were analyzed. RESULTS On initial assessment, FVPC was associated with a significantly lower incidence of cervical lymph node metastatic involvement in comparison with PC (5.6% versus 35.7%; P<0.001). Even though the mean size of FVPC was larger than that of PC (2.57 cm versus 1.75 cm; P<0.05), FVPC showed a lower incidence of thyroid capsule invasion (5.6% versus 11.4%), infiltrative resection margins (2.8% versus 20.0%; P = 0.01), local soft tissue invasion (7.0% versus 25.7%; P<0.005), and multicentricity (25.4% versus 47.1%; P<0.01). Lymphocytic thyroiditis was a common feature of both FVPC (36.6%) and PC (35.7%). FNA biopsy revealed the presence of malignant cells in 9.8% of patients with FVPC in comparison with 67.5% of patients with PC. Most cytology specimens of FVPC (58.8%) were interpreted as suspicious for a malignant lesion or as a follicular neoplasm. CONCLUSION FVPC is associated with a significantly lower incidence of cervical lymph node metastatic lesions and invasive histologic features than is PC. Long-term prospective clinical studies are needed to determine whether these findings translate into a more benign natural history for this variant of PC. Results of FNA biopsy in FVPC are more commonly interpreted as suspicious rather than malignant; this factor has major implications for preoperative planning.

Simplified electrode array for impedance cardiography

Impedance cardiography has enjoyed widespread interest owing to the promise of noninvasive monitoring of cardiac function. In clinical practice, one factor limiting its use has been the need to use circumferential electrodes. These electrodes can be inconvenient to apply, may interfere with chest tubes or intravenous lines, and can cause additional apprehension in critically ill patients. The paper describes a more convenient electrode array. It uses four disposable electrocardiographic electrodes, two on the base of the neck and two on the lower left, anterolateral surface of the thorax. Simultaneous impedance derivative recordings were made with this ‘spot’ electrode array and with the conventional ‘band’ electrode array, at rest and after exercise on ten normal volunteers. On a given individual, the two signals had shapes which were remarkably similar and relative heights which correlated well, exhibiting correlation coefficients (r′) between 0·77 and 0·98. This new array should facilitate impedance cardiographic measurements in the clinical setting.

Expression of Eukaryotic Translation Initiation Factors 4E and 2α Correlates with the Progression of Thyroid Carcinoma

Cell growth and proliferation depend on protein synthesis that is regulated, in part, by two eukaryotic translation initiation factors, eIF-4E and eIF-2alpha. These factors are transiently increased as normal cells respond to growth factors and are constitutively elevated in transformed cells. In cultured cells, eIF-4E facilitates cell cycle progression by increasing the expression of cell cycle promoting proteins including cyclin D1. Our previous study revealed elevated cyclin D1 expression in histologically more aggressive thyroid carcinomas as compared to conventional papillary carcinoma. We hypothesized that the increased cyclin D1 expression might correlate with increased eIF-4E expression. We, therefore studied the expression of eIF-4E by immunohistochemistry in 25 cases of conventional papillary carcinoma (CPC) and 28 cases of aggressive thyroid carcinomas (ATC), the latter included 11 tall cell/columnar cell variant of papillary carcinoma, 5 insular carcinomas, and 12 anaplastic carcinomas. We also analyzed the expression of eIF-2a in the same samples as this factor is usually regulated similarly to eIF-4E in cell culture models. Of the 25 CPC, 13 were eIF-4E positive (11 weakly and 2 strongly), and 19 were eIF-2a positive (14 weakly and 5 strongly). Conversely, of the 28 ATC, 25 were eIF-4E positive (4 weakly and 21 strongly), and 23 were eIF-2alpha positive (4 weakly and 19 strongly). There was a significantly increased expression of both eIF-4E (p < 0.001) and eIF-2alpha (p < 0.001) in ATC compared to CPC, suggesting that these translation initiation factors may play a role in the progression of thyroid cancer.

Bilateral cervical plexus block for thyroidectomy and parathyroidectomy in healthy and high risk patients.

We evaluated the benefits of bilateral deep cervical plexus block regional anesthesia in healthy and high risk patients undergoing thyroid and parathyroid surgery and assessed its effects on respiratory function. Twenty-one patients undergoing thyroid and parathyroid operations were studied. Bilateral superficial and deep plexus blocks were performed in all patients except one (who received only superficial plexus block because of a slightly prolonged prothrombin time) with 0.375–0.5% bupivacaine with 1:200,000 epinephrine. Intraoperatively, supplemental intravenous sedatives/narcotics were titrated to achieve patient comfort and cooperation. To allay anxiety, patients were allowed to listen to music via headphones ntraoperatively. Forced vital capacity was measured before block, 10 minutes after the block and in the recovery room in half the patients. Eighteen patients tolerated the procedure well with supplemental sedation. Two patients required supplemental inhalation anesthesia via mask and one required tracheal intubation because of coughing prior to surgery. Three high risk patients tolerated the procedure well requiring only intraarterial line monitoring. Postoperatively, 11 patients had minimal incisional pain, 13 patients had mild pain on swallowing and 2 patients complained of nausea. There were no significant differences in the baseline forced vital capacity vs. forced vital capacity measured after the block and in the recovery room. This study indicates that regional anesthesia is an appropriate alternative to general anesthesia in selected patients undergoing thyroid and parathyroid surgery and did not compromise respiratory function.

Laparoscopic adrenal surgery.

Laparoscopic adrenalectomy (LA) was performed in 6 patients (4 right and 2 left). A transperitoneal approach in a lateral position was used. Pheochromocystoma was present in two patients and Conns syndrome, with a solitary functioning adenoma, was the diagnosis in four. Early vascular control was obtained in the two patients with pheochromocytoma, resulting in very stable intraoperative blood pressure. Operative time for LA was 152±26 min and was associated with a short length of stay (2.0±0.6 days) and minimal intraoperative blood loss (82±30 ml). There were no conversions to laparotomy and one complication was noted. LA is a safe and effective operation for patients requiring adrenalectomy for hormone-secreting tumors.

β-Catenin Expression in Thyroid Follicular Lesions: Potential Role in Nuclear Envelope Changes in Papillary Carcinomas

The morphologic distinction of benign and malignant thyroid follicular lesions can sometimes be challenging, therefore an immunohistochemical marker to aid in this distinction would be useful. β-Catenin is one such potential marker. It is part of a membrane-bound cell growth-signaling complex that plays a role in cell adhesion, as well as in promotion of growth through activation of the Wnt signaling pathway. Oncogenic signaling occurs when β-catenin is released, accumulates in the cytoplasm, translocates into the nucleus, and promotes transcription of genes including bcl-1 (cyclin D1) and c-myc that induce cell proliferation.Paraffin blocks from 133 thyroidectomy specimens were stained with monoclonal antibodies reactive with β-catenin and cyclin D1. These included 53 cases of papillary thyroid carcinoma (PTC), 46 cases of follicular variant of papillary carcinoma (FVPC), 10 cases of follicular carcinoma (FC), and 24 cases of follicular adenoma (FA). Tissue from six normal thyroid specimens served as a control. The malignant lesions (PTC, FC, and FVPC) expressed strong cytoplasmic/nuclear staining and minimal residual membranous staining in 87%, 80%, and 71% of cases, respectively. In contrast, all normal thyroid tissue and 79% of FAs showed strong membranous reactivity with very minimal cytoplasmic staining. Interestingly, in 83% of PTC cases and 20% FVPCs, the intranuclear inclusions were distinctly β-catenin positive. Cyclin D1 over expression correlated with cytoplasmic relocalization of β-catenin in almost all cases, and no evidence of cyclin D1 gene amplification was observed.β-Catenin can be of a diagnostic utility for thyroid lesions, because it highlights intranuclear inclusions in PTC, and shifts from a membranous localization to a cytoplasmic localization in malignant lesions. We speculate that the localization of β-catenin in intranuclear inclusions may reflect a cytoskeletal remodeling activity of β-catenin that is functionally significant for the PTC pathway.

Impedance plethysmography: the origin of electrical impedance changes measured in the human calf

Electrical impedance plethysmography of the lower leg is now a widely used test for detection of deep vein thrombosis. The origin of the impedance signal is difficult to evaluate in the living subject, and experimental animals have important anatomic differences. A controlled study on human cadavers was therefore undertaken. Conductive and nonconductive fluids were injected into the lower legs of cadavers, while electrical impedance changes were recorded utilising a 4-electrode technique. X-ray studies confirmed the localisation of the injections. Results from ten cadavers showed that significant impedance changes occurred only in response to injections of saline in the region between the electrodes. Injections of nonconductive silicone oil caused a small increase in the measured impedance. It is concluded that electrical impedance plethysmography reflects changes in conductivity confined to the region between the electrodes; and that the ratio of deep to superficial impedance sensitivity is a function of the electrode spacing.