Cathepsin B activity and protein levels in thyroid carcinoma, Graves' disease, and multinodular goiters.

Cathepsin B (CB) is involved in the hydrolysis of thyroglobulin (Tg) and thought to be regulated by thyroid stimulating hormone (TSH) in the normal thyroid. Our analyses of 91 thyroid tissues from 71 patients with Graves' disease (GD), multinodular goiter (MNG), papillary carcinoma (PC), or follicular carcinoma (FC), demonstrated a 2-fold increase in expression of CB in GD and an average increase of 1.5-fold in MNG (varying from 10-fold below normal to 6-fold above normal in MNG nodules), as might be predicted by the altered functional status of thyroid follicular cells in those diseases. However, CB activity was not downregulated in conjunction with the known "blocking effect" of malignancy on many thyroid functions, but rather increased on average 9-fold in papillary carcinomas (n = 33), and also showed a marked increase in 2 follicular carcinomas. Activity measurements were confirmed by CB protein detection on Western blot with moderately increased CB protein levels demonstrated in GD, variable expression in nodules of MNG, and markedly increased protein expression in carcinomas. In all diseased states, increased protein was detected primarily as overexpression of the 27 kd heavy chain of 2-chain mature CB and less frequently as overexpression of 31 kd single-chain mature CB. However, an additional 35 kd protein form was noted in 3 of 9 PCs, 1 of 2 FCs, and 1 of 4 GD cases but in none of 10 MNG cases. In conjunction with elevated CB activity plus additional protein bands on Western blots, altered patterns of CB immunohistochemical staining were observed, irrespective of the type of thyroid disease, suggesting certain common changes in CB expression, posttranslational processing, and vesicular trafficking. In summary, GD and MNG thyroid tissues demonstrated altered CB expression in keeping with predicted functional changes in thyroid follicular cells, while increased CB expression in carcinomas indicated a more pathological role for CB in thyroid cancers, possibly related to the processes of invasion or metastasis.

Primary hyperaldosteronism causing posttransplantation hypertension: localization by adrenal vein sampling.

A 58 year-old man with end-stage renal disease who had received a cadaveric renal transplant presented with persistent hypertension and hypokalemia. Allograft renal artery stenosis, rejection, and cyclosporine effects were excluded. Hypokalemia persisted despite potassium supplementation and antihypertensive medications with hyperkalemic effects. The biochemical findings of primary hyperaldosteronism with a normal adrenal anatomy imaged by magnetic resonance imaging (MRI) necessitated adrenal vein sampling to lateralize a left adrenal adenoma. His hypokalemia was cured by the removal of the adenoma, and his blood pressure (BP) control was easily achieved with a less complex regimen of antihypertensives. We suggest that the concomitant existence of resistant hypokalemia and posttransplantation hypertension, especially in the cyclosporine era, should stimulate a search for hyperaldosteronism; once transplant renal artery stenosis has been excluded, the patient should be investigated for primary hyperaldosteronism. When imaging studies fail to show adrenal pathology, adrenal vein sampling will likely do so.

Fine-needle aspiration cytology diagnosis of colloid nodule versus follicular variant of papillary carcinoma of the thyroid.

The cytologic differential diagnosis of colloid nodule (CN) and the follicular variant of papillary carcinoma (FVPC) is difficult with common morphologic features. To assess the utility of 18 cytologic morphometric parameters in the diagnosis of these thyroid lesions we evaluated 31 FNA samples that had histologic confirmation of the diagnoses. These 31 cases included 15 cases of CN, 8 cases of FVPC, and 8 cases of the usual variant of papillary carcinoma (UVPC) for reference values. For the morphometric analysis we used an Optimas 4.0 image analysis system. Comparing the CN group with the UVPC group revealed that eight of the parameters had statistically significant differences. The UVPC specimens were more cellular, less cohesive, had presence of papillary cellular groups more frequently, larger nuclei (UVPC: 109.33 +/- 30.19 microns2; CN: 66.81 +/- 15.02 microns2), higher nuclear to cytoplasmic (N/C) ratio, larger nucleoli, and present nuclear grooves and nuclear pseudoinclusions more frequently. The FVPC group differed from the CN group only in three parameters which included larger nuclei (98.49 +/- 18.24 microns2), higher N/C ratio, and a more frequent presence of nuclear pseudoinclusions. When we compared these two variants of papillary carcinoma, we found that the UVPC specimens had less cellular cohesion, less preservation of the architectural polarity and a more frequent presence of papillary cellular groups than the FVPC. The FVPC can be differentiated from CN based on nuclear changes, which included a larger size, higher N/C ratio, and presence of pseudoinclusions. The absence of cellular cohesion and polarity combined with the presence of papillary groups are useful in separating the UVPC from the FVPC. A cutoff of 75 microns2 should be used in separating benign from malignant nuclei.

Is splenectomy more dangerous for massive spleens?

BACKGROUND: Reports vary about whether risks are greater for removal of massive (> or = 1500 g) spleens than for smaller (< 1500 g) spleens. We sought to determine the hazards of splenectomy. METHODS: We reviewed 223 consecutive adults with elective splenectomies for hematologic diseases. Morbidity and mortality rates were combined with published data to create a meta-analysis. RESULTS: Patients with massive spleens are more likely to have postoperative complications (relative risk [RR] 2.1, 95% confidence interval [CI] 1.3 to 3.4; P = 0.003) and death (RR 4.7, 95% CI, 1.5 to 15.1; P = 0.01). However, when the investigation is restricted to comparable diagnoses, patients with massive spleens do not differ from those with smaller spleens regarding complications (RR 1.4, 95% CI, 0.8 to 2.7; P = 0.3) or mortality (RR 2.1, 95% CI, 0.5 to 9.7; P = 0.4). These observations are confirmed by metaanalysis. Furthermore, multivariate analysis indicts age as a critical risk of complications and death. CONCLUSIONS: Increased age and underlying illness are the predominant factors associated with morbidity and mortality following splenectomy for hematologic disease. Adjusting for age and diagnosis, spleen size is not a hazard.

Results of a phase I trial of a recombinant vaccinia virus that expresses carcinoembryonic antigen in patients with advanced colorectal cancer.

BACKGROUND: The inadequacy of systemic treatments of advanced colorectal cancer has aroused interest in biologic therapy. Recent animal models have demonstrated the efficacy and safety of a recombinant vaccine that contains vaccinia and the gene for carcinoembryonic antigen (rV-CEA). METHODS: A phase I clinical trial of rV-CEA was conducted to assess vaccine toxicities, the maximum tolerated dosage, resulting immune activities, and tumour responses. A dose-escalation protocol was devised for three concentrations. Six patients per dosage were each to receive three vaccinations. RESULTS: Seventeen patients with advanced colorectal cancer received a total of 44 vaccinations. Mild local and systemic reactions-comparable to those seen with vaccinia alone-were observed and were typically associated with the first vaccination. No significant complications or deaths were caused by the rV-CEA. In particular, no autoimmune colitis developed, nor did leukopenia occur, despite some homology between CEA and leukocyte antigens. All three vaccine concentrations were equally well tolerated. Most patients demonstrated tumor progression by clinical and radiographic parameters and by CEA levels. Immune assays are pending. CONCLUSIONS: This phase I trial demonstrated the safety of rV-CEA in patients with advanced colorectal cancer. Future clinical studies are warranted and will likely be influenced by investigations of the immune responses to the vaccine.

Factors influencing outcome of surgery for primary aldosteronism.

OBJECTIVE: To identify factors that influence the outcome of surgery for primary aldosteronism. DESIGN: A retrospective clinical series, with a mean follow-up of 106 months (range, 12-280 months), of 42 patients who underwent adrenalectomy for primary aldosteronism between the years 1970 and 1993. SETTING: All patients were operated on at the Boston University Medical Center Hospital. PATIENTS AND INTERVENTION: We reviewed the records of 22 women and 20 men, ranging in age from 25 to 68 years, who underwent adrenalectomy for primary aldosteronism. Tests performed for preoperative classification of the adrenal pathological abnormalities included adrenal venous sampling, postural stimulation test, iodocholesterol I 131 scintigraphy, and computed tomography. MAIN OUTCOME MEASURES: The surgical outcome was classified as follows: response, normal blood pressure measurement (< 160/95 mm Hg) without medication; incomplete response, normal blood pressure measurement with medication or blood pressure measurement greater than 160/95 mm Hg despite antihypertensive treatment. RESULTS: Twenty-five patients (60%) became normotensive following surgery. The following factors were associated with a complete response to adrenalectomy by univariate analysis: adenoma classification (odds ratio [OR] = 9.6, P = .002); preoperative response to spironolactone (OR = 8.3, P = .007); age younger than 44 years (OR = 6.2, P = .009); and duration of hypertension less than 5 years (OR = 5.1, P = .03). Response to spironolactone was predictive only in cases classified as adenoma (P = .004). Duration of hypertension showed a strong correlation with age (r = 0.62). Using stepwise logistic regression, adenoma pathological classification, response to spironolactone, and duration of hypertension less than 5 years contributed independently to a predictive model. Micronodular hyperplasia alone was associated with incomplete response. The presence of coexisting micronodular hyperplasia in patients with adenoma did not affect the odds for a complete response. Computed tomography for preoperative diagnosis of adenoma showed the same level of accuracy (75%) as that for postural stimulation test and iodocholesterol scintigraphy, but less than that for adrenal venous sampling (91%). CONCLUSIONS: The study showed that the main determinants of a surgical cure of hypertension in primary aldosteronism were presence of adenoma and preoperative response to spironolactone. We favor computed tomography as the initial test to establish preoperative diagnosis of adenoma because of its reproducibility and high specifity.

Risks of synchronous gastrointestinal or biliary surgery with splenectomy for hematologic disease.

BACKGROUND: The addition of splenectomy to a gastrointestinal (GI) operation may have an adverse effect on mortality, morbidity, and even survival. OBJECTIVE: To determine the risks of the converse: synchronous GI surgery appended to splenectomy for hematologic diseases. DESIGN: Retrospective cohort. SETTING: Multiple hospitals comprising an affiliated surgical training program. PATIENTS: Consecutive sample of 207 adults (mean age, 49 years) with splenectomies for hematologic diseases. INTERVENTION: Splenectomy and concomitant GI or biliary surgery (group 1, n=19) and splenectomy alone (group 2, n=188). MAIN OUTCOME MEASURES: Length of hospital or intensive care unit stay, later operations, postoperative infections, postoperative abdominal abscess, major complications, and death. RESULTS: Preoperative and intraoperative factors were similar in both groups. Operative mortality was 3 of 19 in group 1 and 8 of 188 in group 2 (p=.07). The mean number of major complications tended to be higher in group 1 (1.5 vs 0.5, P=07). Despite no difference between the incidences of overall postoperative infections, patients in group 1 were much more likely to develop an abdominal abscess (4 of 19 vs 3 of 188, P=.002). Logistic regression established that patients undergoing splenectomy and synchronous GI or biliary surgery were 25 times more likely to develop an intra-abdominal abscess than were patients with splenectomy alone, even controlling for confounding factors (odds ratio, 24.7; 95% confidence interval, 3.1 to 196; P=.002). CONCLUSIONS: Synchronous GI or biliary surgery with splenectomy for hematologic disease increases the risk of intra-abdominal abscess and should be avoided. Complication and mortality rates may also be increased.

Duodenal leiomyosarcoma.

Two cases of duodenal leiomyosarcoma were encountered, both of which appeared benign by gross and histologic criteria. Both patients suffered recurrences with poor outcomes. We reviewed the literature and found four other such cases and examined the outcomes in the world literature with respect to tumor size and extent of surgical resection. Large size, limited resections, and local recurrence were associated with poor outcomes. A 6% rate of lymphatic metastases was found, and the bearing this has on the extent of resection is discussed.

A complementary role for thallium-201 scintigraphy with mammography in the diagnosis of breast cancer.

Physical examination and mammography are currently the only proven and reliable methods of early detection of breast cancer. Although both procedures are highly sensitive, their limited specificity often requires surgical biopsy in order to differentiate between malignant and benign lesions. The purpose of this prospective study is to investigate the diagnostic specificity of thallium imaging for breast cancer and to determine its efficacy as a complement to mammography. Two groups were studied: Group A: Patients found to have breast abnormalities and scheduled for biopsy or surgery and Group B: Patients who were suspected to have a recurrence of cancer after mastectomies or lumpectomies. In Group A, thallium scans of 32 breasts in 30 patients were performed prior to biopsy or surgery, yielding pathological diagnoses of 31 breasts in 29 patients. Results for Group A included seven true-positive thallium scans, twenty-two true-negative scans, two false-negative scans, and one false-positive scan. In Group B, seven patients were scanned to evaluate subcutaneous nodules for breast cancer following mastectomy or lumpectomy. Results for Group B included five true-positive scans, one true-negative scan, one false-negative scan and no false-positive scans. Thallium breast scanning was shown to have high specificity for cancer (specificity 96% and sensitivity 80%), suggesting that this technique should be evaluated in additional patient studies to determine its role in clinical situations.

Cytogenetic studies of an adrenal cortical carcinoma.

Cytogenetic findings in the third reported case of adrenal cortical carcinoma are described. In contrast to the two previous cases, hypodiploidy characterized almost all cells, which had as many as eight abnormal chromosomes in each cell analyzed.

Reoperative surgery for persistent hyperparathyroidism.

Persistent hyperparathyroidism is an uncommon but recognized sequela of hyperparathyroidectomy that presents difficult diagnostic and surgical challenges. The approach to such patients, particularly in the area of localizing procedures and the conduct of surgery, is reviewed. The successful management of patients with persistent hyperparathyroidism is directly proportional to the surgeon's depth of experience with this entity.

Clinicopathological aspects of high bile duct cancer. Experience with resection and bypass surgical treatments.

This report reviews the experience of the Hepatobiliary Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London with 16 patients having proximal extrahepatic bile duct malignancy who underwent resection and a comparable group of 15 patients who had surgical bypass. The purposes of the review were to evaluate morbidity and mortality in both treatment groups, to assess whether either treatment influenced the natural history of the disease, and to examine the pathological features of the resected lesions, attempting to correlate the macroscopic and microscopic features with radiological and surgical observations and survival. The presenting symptoms, average age, clinical data, and length of hospital stay were similar in both groups. Hospital mortality, despite 12 major liver resections, was less in the resectional than in the bypass group--19% versus 26%. The average survival for resectional patients was 16.5 months with six of the 13 patients who left hospital still alive, one at 5 years. The bypass patients lived an average of 7 months with no patients surviving beyond 11 months. Both resectional and bypass treatments appeared to influence survival in this disease with greater length and quality of survival being associated with resection. While there were a number of distinctive pathological features associated with the resected tumors, none correlated with survival.

Pancreatic cancer.

As a result of increased funding in the past few years, carcinoma of the pancreas has received increased investigative attention. A substantial body of epidemiologic data has been recorded, which may ultimately provide leads that identify an "at risk" population. Current diagnostic techniques enable clinicians to diagnose pancreatic lesions of relatively small size. Combined with further developments in the tumor marker field, it should be feasible to screen the at-risk population for early disease. Until then, only the early pancreatic lesion permits the slightest hope of cure.

Percutaneous needle biopsy for diagnosis of pancreatic cancer.

Percutaneous fine needle aspiration biopsy of the pancreas is a safe procedure, which may be done inexpensively and rapidly accomplished with high diagnostic accuracy. The major drawback of this technique is the need for a competent cytopathologist for specimen interpretation. It is quite possible, as more trained personnel become available, that percutaneous fine needle aspiration biopsy may become the technique of choice for establishing the diagnosis of pancreatic malignancy.