Citations

Wilms’ tumor is the most common pediatric primary renal cancer and is highly responsive to surgery and chemotherapy. The role of radiotherapy has evolved in the last three decades from the use of stepwise incremental doses in all patients to the current concept of added radiotherapy in advanced cases or in those with unfavorable pathology. To the authors’ knowledge, this is the first case of a young woman with prior history of Wilms’ tumor and significant weight loss due to radiation arteritis involving the abdominal vasculature. A 31-year-old woman presented with a history of weight loss and severe malnutrition. An angiogram revealed that the aorta was occluded below the renal artery. The celiac artery and the superior mesenteric artery were occluded at the origin, and large intercostal collaterals reconstituted the pelvic circulation. She was initially treated with total parenteral nutrition (TPN) and underwent an infrarenal aortic bypass surgery. Histopathology of the aorta revealed intimal fibrocalcific thickening and changes consistent with radiation-induced arteritis. Later, she was readmitted with progressive hepatic insufficiency. Despite intensive medical therapy, she died of multi-organ failure.

Idiopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder characterized by megakaryocyte hyperplasia and bone marrow fibrosis. Biologically, an autonomous megakaryocyte growth and differentiation is noticed, which contributes to the megakaryocyte accumulation. To better understand the molecular mechanisms involved in this spontaneous growth, we searched for genes differentially expressed between normal megakaryocytes requiring cytokines to grow and IMF spontaneously proliferating megakaryocytes. Using a differential display technique, we found that the immunophilin FKBP51 was 2 to 8 times overexpressed in megakaryocytes derived from patients' CD34+ cells in comparison to normal megakaryocytes. Overexpression was moderate and confirmed in 8 of 10 patients, both at the mRNA and protein levels. Overexpression of FKBP51 in a UT-7/Mpl cell line and in normal CD34+ cells induced a resistance to apoptosis mediated by cytokine deprivation with no effect on proliferation. FKBP51 interacts with both calcineurin and heat shock protein (HSP)70/HSP90. However, a mutant FKBP51 deleted in the HSP70/HSP90 binding site kept the antiapoptotic effect, suggesting that the calcineurin pathway was responsible for the FKBP51 effect. Overexpression of FKBP51 in UT-7/Mpl cells induced a marked inhibition of calcineurin activity. Pharmacologic inhibition of calcineurin by cyclosporin A mimicked the effect of FKBP51. The data support the conclusion that FKBP51 inhibits apoptosis through a calcineurin-dependent pathway. In conclusion, FKBP51 is overexpressed in IMF megakaryocytes and this overexpression could be, in part, responsible for the megakaryocytic accumulation observed in this disorder by regulating their apoptotic program.

AbstractThis prospective randomized study examined the acute‐phase response and wound healing, comparing laparoscopic (LA) and open posterior (PA) adrenalectomy in a cushingoid porcine model. Repository corticotropin gel was given to 40 pigs for 21 days. Biochemical and tissue parameters of Cushing syndrome were confirmed. The pigs were randomized to undergo LA or PA. In addition to operating time and morbidity, the acute‐phase response was compared by measuring the postoperative white blood cell count, fasting glucose, C‐reactive protein, and nitrogen balance. Wound healing was assessed by (1) scored (1–4) gross appearance at 48 hours and 1 and 2 weeks; (2) histologic examination; and (3) tensile strength. There was no difference in operating time (mean ± SD) (36 ± 9 minutes open vs. 37 ± 7 minutes laparoscopic), perioperative mortality, degree of leukocytosis, fasting glucose, or C‐reactive protein (p > 0.05). Nitrogen balance, wound scores, and tensile strength at 24 hours and 1 week were more favorable in the LA group than in the PA group (p < 0.05). In the cushingoid porcine model, laparoscopic adrenalectomy was less catabolic and was associated with fewer wound complications than the open posterior adrenalectomy. These findings provide support for continued pursuit of laparoscopic methods for adrenalectomy in the clinical setting.

AbstractFunctioning extraadrenal paragangliomas represent more than 10% of all pheochromocytomas, occur at diverse anatomic locations, and are said to have a higher malignancy rate than intraadrenal pheochromocytomas. Sixty‐six patients had surgery for catecholamine‐producing paragangliomas between 1952 and 1992. Median follow‐up was 8.8 years. Median age was 40 years (11–67 years); the male/female ratio was 29:37. Familial disease occurred in 9 patients (13.6%), and 10 patients (15.2%) also developed adrenal pheochromocytoma. Solitary paragangliomas occurred in 52 patients: 46 abdominal, 4 thoracic, and 2 head and neck. Fifty‐three tumors developed in 14 patients with multiple paragangliomas: 38 abdominal and 15 thoracic. Of 28 patients with solitary tumors undergoing localization studies over the past 10 years accurate localization was achieved in 27. There was one operative death; 15 patients had persistent disease; and 50 were cured postoperatively. Of those cured, nine developed recurrence, disease‐free survival being 86%, 80%, and 80% at 5, 10, and 20 years. Metastatic disease was found in 14 patients (21%), 7 of whom have died. An additional 10 patients (15%) had locally invasive disease, of whom 4 have died. Cause‐specific survivals at 5, 10, and 20 years were 90%, 83%, and 72%. Risk factors for death from pheochromocytoma were tumor size > 5 cm (p= 0.0002), metastatic disease (p= 0.001), and tumor invasion (p= 0.0023). Cause‐specific survival for patients with tumors > 5 cm was 59% at 15 years compared to 100% among patients with tumors ≤ 5 cm (p= 0.0003). Functional paragangliomas are frequently malignant and are associated with a high incidence of persistent or recurrent disease. Tumor size > 5 cm and the occurrence of invasive or metastatic disease are strong predictors of outcome. Most tumors are abdominal, and imaging is highly successful for localization.

AbstractIslet cell carcinoma (ICC) of the pancreas is a rare, indolent malignancy associated with higher resectability rate and better survival than ductal carcinoma. This retrospective study presents results of surgical treatment from a single institution. From 1985 through 1993 a total of 64 patients (36 men, 28 women) were surgically treated for ICC. Ages ranged from 22 to 80 years (median 55 years) with a median postoperative follow‐up of 39 months (range 10–97 months). Of the 64 patients, 30 (47%) had functioning and 34 (53%) nonfunctioning tumors. Gastrinoma (n= 11) followed by glucagonoma (n= 6) and insulinoma (n= 4) were the most common functioning tumors. In the patients undergoing a laboratory study, 67% of the nonfunctioning tumors had elevated peptide hormone levels. Potentially curative resections were performed in 17 patients (26%), palliative procedures in 35 (55%), and exploratory laparotomy alone in 12 (19%). One patient (2%) died within 30 days after operation. Symptomatic improvement was achieved in 96% of patients with a mean duration of 22 months. Three‐ and five‐year survivals were 66% and 49%, respectively. In patients with curative resection, the disease‐free survival at 3 years was 53% (95% CI: 32–86%). The presence of diffuse hepatic metastases was a predictor of poor survival at 3 years (74% versus 58%;p= 0.05); there was no statistically significant difference in survival between functioning and nonfunctioning groups (p> 0.1). Although curative resection for ICC is rare, meaningful palliation can be achieved in most patients with rare mortality and acceptable morbidity.

AbstractMultiple endocrine neoplasia type I (MEN‐I) is an autosomal dominant disorder characterized by endocrinopathies involving the anterior pituitary gland, parathyroid glands, and pancreas. The long‐term prognosis for patients affected with this disorder is uncertain. To better characterize this prognosis, we performed a retrospective review of all patients with MEN‐I treated at a single institution during the period 1951–1997. A group of 233 patients served as the study population. Their records were analyzed for confirmation of diagnosis, treatments received, long‐term survival, and cause of death. Altogether, 108 eight male patients (46%) and 125 female patients (54%) were identified. At the conclusion of the study, 164 (70%) were alive and 69 (30%) were deceased, with a median follow‐up for patients alive at last contact of 13.4 years (range < 1 month to 54.3 years). The cause of death was reliably obtained in 60 patients. Of these patients, 17 (28%) died of causes related to MEN‐I, most commonly metastatic islet cell tumors (10 patients). The remaining patients died of causes unrelated to MEN‐I, most commonly coronary artery disease and nonendocrine malignancies (14% each). The overall 20‐year survival of MEN‐I patients was 64% (95% CI was 56–72%), and that of an age‐ and gender‐matched upper Midwest population was 81% (p < 0.001). Patients with MEN‐I appear to be at increased risk of premature death. Earlier diagnosis and treatment of potentially malignant pancreatic islet cell neoplasms may result in a decrease of this premature mortality.

Background and Purpose — Bovine endothelial nitric oxide synthase (eNOS) is phosphorylated directly by the protein kinase Akt at serine 1179. Mutation of this residue to the negatively charged aspartate (S1179DeNOS) increases nitric oxide (NO) production constitutively in the absence of agonist stimulus. The present study was designed to determine the effect of mutant S1179DeNOS gene expression on vasomotor function of canine cerebral arteries. Methods — Isolated basilar and middle cerebral arteries were exposed ex vivo (30 minutes at 37°C) to an adenoviral vector (10 10 plaque-forming units per milliliter) encoding the S1179DeNOS gene (AdCMVS1179DeNOS), the wild-type eNOS gene (AdCMVeNOS), or the green fluorescent protein (GFP) reporter gene (AdCMVGFP). Twenty-four hours after transduction, arteries were suspended in an organ chamber for isometric force recording, and levels of cGMP were measured by radioimmunoassay. Results — Transgene protein expression was detected mainly in the vascular adventitia. In AdCMVS1179DeNOS-transduced arteries, basal levels of cGMP were significantly elevated compared with those in control (nontransduced), AdCMVGFP-, or AdCMVeNOS-transduced vessels (n=8; P <0.01). The elevation of cGMP was abolished by a NOS inhibitor, N G -nitro- l -arginine methyl ester (L-NAME), or by incubation in the calcium-free medium in the presence of calcium chelators. In AdCMVS1179DeNOS-transduced arteries, contractions to endothelin-1 (10 −10 to 10 −8 mol/L) were significantly reduced compared with those in control and AdCMVGFP-transduced arteries (n=7; P <0.05). The vasoconstrictor effect of endothelin-1 was restored in the presence of the NOS inhibitor L-NAME. Conclusions — Our results suggest that in cerebral arteries, expression of recombinant S1179DeNOS increases basal production of NO and inhibits the vasoconstrictor effect of endothelin-1. This effect may have therapeutic application in prevention and treatment of cerebrovascular diseases.

Unlike other leukemia types in which the bone marrow findings are diagnostic, the bone marrow pathology of T-cell granular lymphocytic leukemia (GLL) is subtle and ill-defined. In this study, bone marrow biopsy specimens from 36 patients with T-cell GLL and from 25 control patients with cytopenias and relative or absolute increases in blood large granular lymphocytes were studied by immunohistochemistry using antibodies to the cytolytic lymphocyte antigens CD8, CD56, CD57, TIA-1, and granzyme B. The goals were to clarify the bone marrow pathology of T-cell GLL and to refine the diagnostic criteria for T-cell GLL. Most bone marrow specimens from the T-cell GLL patients contained interstitially distributed clusters of at least 8 CD8+(83%) or TIA-1+ (75%) lymphocytes or clusters of at least 6 granzyme B+ (50%) lymphocytes. Interstitial clusters of CD8+, TIA-1+, or granzyme B+ cells were present in 36%, 12%, and 0%, respectively, of the control bone marrows (all values significantly different, P &lt; .001). An additional T-cell GLL disease-specific finding was the presence of linear arrays of intravascular CD8+, TIA-1+, or granzyme B+ lymphocytes, found in 67% of cases of T-cell GLL and in none of the 25 control samples (P &lt; .001). Staining for CD56 and CD57 was noncontributory. These findings clarify the bone marrow histopathology of T-cell GLL and provide an additional tool by which the discrete, abnormal lymphocyte population required for a diagnosis of T-cell GLL can be identified.