shRNA-induced saturation of the microRNA pathway in the rat brain.

RNA interference (RNAi) is a powerful strategy for unraveling gene function and for drug target validation, but exogenous expression of short hairpin RNAs (shRNAs) has been associated with severe side effects. These may be caused by saturation of the microRNA pathway. This study shows degenerative changes in cell morphology and intrusion of blood vessels after transduction of the ventromedial hypothalamus (VMH) of rats with a shRNA expressing adeno-associated viral (AAV) vector. To investigate whether saturation of the microRNA pathway has a role in the observed side effects, expression of neuronal microRNA miR-124 was used as a marker. Neurons transduced with the AAV vector carrying the shRNA displayed a decrease in miR-124 expression. The decreased expression was unrelated to shRNA sequence or target and observed as early as 1 week after injection. In conclusion, this study shows that the tissue response after AAV-directed expression of a shRNA to the VMH is likely to be caused by shRNA-induced saturation of the microRNA pathway. We recommend controlling for miR-124 expression when using RNAi as a tool for studying (loss of) gene function in the brain as phenotypic effects caused by saturation of the RNAi pathway might mask true effects of specific downregulation of the shRNA target.

Follicular and Hürthle cell carcinoma: predicting outcome and directing therapy.

BACKGROUND: Follicular thyroid cancer is a heterogeneous disease including follicular and Hürthle cell and tumors with and without vascular and major capsular invasion. Analyses of prognosis and risk groups have been criticized for not taking these differences into account. METHODS: Retrospective analysis was done of 240 patients treated from 1940 to 1997. RESULTS: Ninety-two patients without vascular or major capsular invasion followed up for a median of 14 years had no recurrences or deaths. In the remaining 148 patients, 32 had Hürthle cell and 116 had follicular cell carcinoma. Patients with Hürthle cell carcinoma were significantly older (55 vs 47 years; P = .0014). Lymphatic metastases did not influence outcome. Patients who were at high risk by age and sex, metastases, extent, and size had a 20-year survival rate of 36% for follicular and 35% for Hürthle cell carcinoma; patients at low risk had 20-year survival rates of 94% and 89%, respectively, with no significant difference between follicular and Hürthle cell carcinoma. Recurrences were treated successfully in 33% of patients with follicular carcinoma but never cured in patients with Hürthle cell carcinoma. Bilateral versus unilateral operation or radioiodine for ablation did not alter outcome. CONCLUSIONS: Follicular and Hürthle cell carcinoma with minimal capsular invasion behaved benignly. Age and sex, metastases, extent, and size risk criteria differentiate strongly between patients with high-risk and low-risk follicular and Hürthle cell carcinoma. Controlling for risk factors, Hürthle cell and follicular cell carcinomas have similar prognoses.

Differentiated thyroid cancer: reexamination of risk groups and outcome of treatment.

OBJECTIVE: To reexamine the age, metastases, extent, and size (AMES) risk criteria for well-differentiated thyroid cancer with the effect of therapy on outcome. DESIGN: Review of patient medical records and direct-contact follow-up. SETTING: Two tertiary referral centers. MAIN OUTCOME MEASURES: Recurrence or death. PATIENTS: One thousand nineteen patients with well-differentiated thyroid cancer treated between 1940 and 1990. RESULTS: One thousand nineteen patients with well-differentiated thyroid cancer were treated between 1940 and 1990, with a mean follow-up of 13 years, including a recent group of 264 patients treated from 1980 to 1990 at 2 different institutions with a mean follow-up of 8 years. The AMES criteria were used to designate high- and low-risk patients. The entire group had 229 high- and 790 low-risk patients; the percentage of high-risk patients decreased slightly after 1960. From 1940 to 1960, 1960 to 1979, and 1980 to 1990, the high-risk groups had survival rates of 48%, 62%, and 47%, respectively. For the low-risk patients, survival rates were 96%, 98%, and 98%, respectively. Recurrences occurred in 5% of low-risk patients and were usually curable; in high-risk patients, recurrence was associated with a 75% mortality. In low-risk patients, there was no significant difference in recurrence or death according to type of operation (unilateral or bilateral) or use of radioactive iodine. In high-risk patients, there were trends toward but no significant improvement in survival with bilateral surgery and radioactive iodine therapy; thyroid replacement was associated with a significant improvement in survival. CONCLUSIONS: The AMES risk criteria remain highly valid predictors of risk. They define most low-risk patients for whom radical treatment may add excess morbidity but not improve already excellent prognoses.

Use of a Foley catheter in the removal of a substernal goiter.

Substernal goiters present a technical challenge to the surgeon. Most substernal goiters may be removed through a cervical incision; however, a median sternotomy may be required in 1% to 2% of patients. To avoid a median sternotomy, many techniques have been described in the literature to facilitate extraction. Special spoons and clamps have been described, and techniques, such as morcellation, the drawer technique, and piecemeal extraction, have been popularized. We describe a method whereby a Foley catheter is used to deliver a large substernal goiter through a cervical incision. It consists of steady traction on the inflated balloon of a Foley catheter placed beyond the substernal component of the goiter. This method has been used successfully and safely on 2 patients and may obviate the need for a sternotomy.

Minimally invasive management of low-grade and benign gastric tumors.

BACKGROUND: Benign gastric tumors and tumors of low-grade malignancy can be safely removed laparoscopically. METHODS: Seven patients were considered candidates for laparoscopic resection of gastric tumors. Inclusion criteria included small tumor size (less than 6 cm), exophytic or endophytic tumor morphology, and benign characteristics. Indications for surgical intervention included bleeding, weight loss, and need for tissue diagnosis. Patients ranged in age from 38 to 70. There were five female and two male patients. All patients underwent preoperative upper GI endoscopy. The procedures were performed using a four- or five-port technique. An Endo-GIA (US Surgical Company, Norwalk, Connecticut) was used to amputate those tumors located on the serosal surface of the stomach. Tumors on the mucosal surface were exposed via a gastrotomy, then likewise amputated using an Endo-GIA. The gastrotomy closure was then either hand sewn or stapled. Operating time ranged from 95 to 225 min. RESULTS: Final pathologic diagnoses included lipoma, lymphoma, leiomyoma, and leiomyosarcoma. There was a 28% conversion rate. There were no complications. Length of postoperative stay ranged from 4 to 7 days. There have been no tumor recurrences in 6-38-month follow-up. CONCLUSIONS: Minimally invasive management of benign and low-grade gastric tumors can be performed safely with excellent short- and long-term results.

Hürthle cell carcinoma of the thyroid gland: prognostic factors and results of surgical treatment.

BACKGROUND: Hürthle cell carcinomas of the thyroid are unusual variants of well-differentiated thyroid cancers. Considered more aggressive tumors, their optimal treatment is controversial. Our institution's half century of experience, the largest series to date, includes 40 patients with Hürthle cell carcinomas of 1000 well-differentiated thyroid cancers. METHODS: A retrospective study was carried out on 40 patients. RESULTS: Seventy-two percent were female, with a median age of 53 years. Median follow-up was 9 years. With the AMES risk stratification (age, distant metastasis, capsular extent, tumor size), among the 21 high-risk patients, 10 (48%) had a recurrence or died, with median time to recurrence 3 years (range, 0.5 to 14 years). Of these 10, 5 died of disease, one died of unrelated causes with disease, and 4 are alive with disease. Five recurrences presented as distant metastases. Extent at operation was the strongest predictor of recurrence, occurring in 66% of those with gross extraglandular involvement. CONCLUSIONS: The AMES criteria are useful in predicting recurrence and death. Although more aggressive surgery is appropriate for high-risk patients, in general their outlook remains grim.

[Handling of thyroid diseases: usefulness and limitations of rapid and fine-needle percutaneous biopsy]. / Manejo de la patología tiroidea: utilidad y limitaciones de la biopsia percutánea con aguja fina y de la biopsia rápida.

Fine needle aspiration biopsy of the thyroid (FNAB) has become an accepted procedure for evaluation of the thyroid nodule, with 899 performed at the Lahey Clinic from 1981 to 1990. We examined them by medical record, pathology, and cytology review, with follow-up by chart or personal communication. Three-hundred-forty-five came to surgery, of which 188 (34%) were malignant; the specificity of the aspirate was 97%, sensitivity 92%, with false negative of 8% and false positive of 3%. By comparison, the frozen section had a false negative rate of 1% and false positive rate of 5%. In combination with frozen section, the fine needle aspirate result improved the accuracy of the intraoperative estimate of malignancy (p = 0.03). When the aspiration was benign but the lesion was clinically suspicious, a cancer was found at surgery in 13% of cases. Of the patients observed for a minimum of 5 years, 1.3% developed a carcinoma. Both cases had a non diagnostic FNAB None of the patients with a clinical and cytological benign lesion developed cancer. The complication rate of FNAB was 1.3% FNAB is a helpful and low risk diagnostic procedure but it needs to be done and read appropriately and its result used within the clinical context. Each medical team needs to monitor their results (continued quality control).

Occult well differentiated thyroid carcinoma presenting as cervical node disease.

Records of 92 patients with differentiated thyroid carcinoma presenting as cervical adenopathy without a palpable mass were reviewed to identify prognostic factors and to evaluate therapy. Patients were treated between 1940 and 1990 and were observed for 3 to 48 years (median 18 years). Follow-up data were obtained by chart review, correspondence, and telephone contact. Among the group, 20 patients had unilateral and 72 bilateral thyroid lobectomy, with node dissection in 77. Thyroid hormone was used in 50 patients and radioactive iodine in 20. Patients were younger than the overall population of patients with differentiated thyroid carcinoma, with more men and more multifocal thyroid disease. Risk group defined by age and sex was the most important determinant of survival. All women 50 years of age or younger and all men 40 or younger (low risk group) survived independent of the type of initial operation or use of thyroid-stimulating hormone suppression or radioactive iodine. Of the low-risk patients, 16% had recurrent disease but were treated successfully with surgery or radioactive iodine; 28% of the older patients (high risk) died of disease. A trend for better survival was noted in high risk patients undergoing bilateral thyroidectomy and in patients receiving thyroid suppression. Of the high risk patients, 26% had recurrent disease, with a 71% mortality rate. Age and sex are the primary determinants of survival. Therapy should be based on risk factors. Low risk patients should have conservative thyroid surgery and modified or limited node dissection.(ABSTRACT TRUNCATED AT 250 WORDS)

Increasing PAs' awareness and understanding of self-help groups. An educational model.

A model for inclusion of information about self-help groups into a PA training program is provided based on the results of a study of 26 PA students enrolled in a patient-counseling class. Interactions with self-help groups yield more positive beliefs and greater intentions to collaborate with self-help groups than training programs that do not address self-help groups. The experiential component is also useful for increasing understanding of appropriate roles for professionals interacting with self-help groups.

Laparoscopic treatment of Meckel's diverticulum. Obstruction and bleeding managed with minimal morbidity.

We present two cases in which complication of a Meckel's diverticulum were dealt with, and in one case diagnosed using the laparoscope. One was a large bleeding diverticulum containing ectopic gastric mucosa, with the diagnosis suggested preoperatively, confirmed laparoscopically, and the pathology resected extracorporeally. The second was a partial intermittent small-bowel obstruction due to torsion around the mesodiverticular band, diagnosed and resected via the laparoscope. The literature of Meckel's diverticula and complications is reviewed, with open and laparoscopic treatment options. Although uncommon, many cases of Meckel's diverticulum may be quite suitable for laparoscopic diagnosis and treatment.

Cholecystectomy. Open cholecystectomy revisited.

We have presented a basic set of rules to follow in the performance of cholecystectomy. We do not wish to convince the reader that these methods are the only ones, but they are a safe starting point for the novice surgeon working in the right upper quadrant. Each of us takes part of what we are taught, amplifies what we find works best for us, and tries to impart to others the experience we have gained.

Ductal carcinoma in situ of the male breast.

BACKGROUND: Ductal carcinoma in situ (DCIS) of the male breast is an uncommon disease, accounting for approximately 7% of all male breast carcinomas. Compared with invasive carcinomas of the breast, the prognosis associated with DCIS in men is excellent; however, clinical features, pathology, and treatment of this disease are not well defined in the literature. METHODS: Records of 23 men with carcinoma of the breast treated at the Lahey Clinic from 1968 to 1991 were reviewed, revealing 4 patients with pure DCIS (17%). The reported management of DCIS in women is discussed in comparison with that of DCIS in men. RESULTS: Of the four patients with DCIS, the presenting complaint was a retroareolar mass in three patients and a bloody nipple discharge in one patient. The pathologic subtype was papillary in one patient and intracystic papillary in three patients. Two patients were treated with partial mastectomy alone. Disease recurred locally as DCIS in both patients, requiring mastectomy at 30 and 108 months. No lymph node metastases were found in the three patients who underwent axillary dissection. All four patients were alive without disease at 133, 120, 36, and 32 months of follow-up, respectively. CONCLUSIONS: Although the sample size was small, our patients and a review of the literature suggest that most DCIS in men is of the papillary type and that mastectomy without axillary dissection is the preferred treatment.

Bilateral obturator hernias: case report, radiographic characteristics, and brief review of literature.

Obturator hernia is a rare cause of intestinal obstruction, and bilateral obturator hernias are even rarer. Early diagnosis can decrease the morbidity and mortality associated with these lesions. We present the case of a patient with bilateral obturator hernias, discuss the radiographic findings, and briefly review the literature.

Mediastinal goiters. The need for an aggressive approach.

We reviewed the cases of 52 patients with substernal goiters to examine clinical presentation, workup, technique of removal, malignancy, and outcome. Half of the patients were asymptomatic; half had at least one compressive symptom. Chest film was the most used; computed tomography or magnetic resonance imaging was by far the most useful study. Thyroid scans often failed to show the intrathoracic goiter. Fine-needle aspiration was not helpful because of the gland's inaccessibility. Seventeen percent (nine) of the thyroids showed malignancy, 21% (11) including incidental papillary carcinomas. These were not identified by duration of goiter, symptoms, or fine-needle aspiration. Except for lymphomas, prognosis was good after resection. Removal was almost always accomplished via cervical incision, with low morbidity and no deaths. The threat of compression, the substantial chance of malignancy, and the safety of resection mean that the presence of substernal goiter is an indication for surgery.

The value of screening for glaucoma with tonometry.

This paper estimates the value of performing Schiotz tonometry to detect glaucoma in an asymptomatic patient. About 9% of adults over 40 will be found on a single Schiotz tonometry test to have elevated intraocular pressure (IOP). On work-up, about 1 out of 50 of these individuals with high IOP will be found to have glaucoma. Tonometry, however, will miss about half of all patients with glaucoma because they do not have elevated IOPs at the time of the test. Pilocarpine or epinephrine are the most commonly used drugs to treat the disease, but they are not always effective in lowering a patient's IOP or in stopping the progression of field defects. From the available evidence it does not appear that earlier diagnosis makes a substantial difference in the patient's outcome. If all individuals over 40 years of age in a city of 1,000,000 were screened, the total cost of finding and treating about 484 people with chronic simple glaucoma would be on the order of $4,944,866 or about $13,000 per patient potentially benefited. Screening with tonometry does not appear to be warranted.