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Vascular endothelial growth factor (VEGF) expression and microvessel density were studied in cases of advanced epithelial ovarian carcinoma to evaluate their usefulness as prognostic variables. Tumor samples from 18 patients with advanced stage serous epithelial ovarian cancer were evaluated for VEGF expression by reverse-transcriptase polymerase chain reaction (RT-PCR) analysis. Immunohistochemical study of corresponding archival tissues with an antibody to von Willebrand factor (vWF; FVIII-RA) was used for tumor microvessel count determinations. The correlation of VEGF expression and mean microvessel counts was determined by an unpaired t-test. Survival analysis for known prognostic factors and VEGF expression was performed. Survival distributions were calculated by the product limit of Kaplan and Meier and significant differences between distributions were analyzed with a log rank test. From the RT-PCR analysis of tumor VEGF expression, 12 samples were found to be strongly positive, whereas six samples had low/negative VEGF expression. The median survival was 60 months for the VEGF-low/negative group and 28 months for the VEGF-positive group (P = 0.058). Other prognostic variables had minimal impact on survival, i.e. age < 65 years (P = 0.873), FIGO stage (P = 0.06), grade (P = 0.236) and debulking status (P = 0.842). Fourteen of 18 tumor specimens were suitable for microvessel counting. The mean microvessel counts of the VEGF-positive group and the VEGF-negative group were 27/hpf and 35/hpf, respectively (P = 0.16). In this preliminary analysis, high VEGF expression in epithelial ovarian carcinomas was associated with poor overall survival. Further study will be necessary to elucidate the lack of association of VEGF expression and tumor microvessel counts.

Sex cord-stromal tumors of the pediatric testis present diagnostic and therapeutic challenges. This study examines the clinicopathologic features of 16 testicular sex cord-stromal tumors from children less than 18 years of age. Four juvenile granulosa cell tumors and five tumors of Sertoli or incomplete differentiation in this study had high mitotic rates and/or sarcomatoid areas that suggested malignancy, but none of these children developed recurrence or metastases. Some of these tumors had been initially misdiagnosed as yolk sac tumors or rhabdomyosarcomas because of the presence of areas superficially resembling these neoplasms. These morphologic pitfalls have received little attention in the literature. Even incompletely differentiated sex cord-stromal tumors have at least focal areas characteristic of juvenile granulosa or Sertoli cell differentiation. In addition, immunohistochemical negativity for alpha-fetoprotein, muscle specific actin, and desmin are useful for ruling out yolk sac tumor and rhabdomyosarcoma. Four patients had Leydig cell tumors and three had large cell calcifying Sertoli cell tumors. Children with Leydig cell tumors are not at risk for metastasis, but children with large cell calcifying Sertoli cell tumors are at risk for endocrine syndromes as illustrated by one of our cases. The differential diagnosis of these tumors is also discussed.

Lipoblastoma is an uncommon benign lipomatous soft tissue mass of childhood, occurring most commonly in children less than 3 years of age. We present a case of lipoblastoma occurring in the foot of a 14-year-old boy and review the literature. The appearance of the mass on magnetic resonance imaging (MRI) is illustrated and is correlated with the findings at gross and microscopic pathological examination. A lobulated architecture, the presence of adipose tissue, thin nonenhancing septa, peripheral lobules of more immature and therefore less specific tissue, and a peripheral pseudocapsule were evident on MRI and at pathological examination.

Tissue diagnosis of pancreas graft dysfunction is desirable. Bladder-drained pancreaticoduodenal transplants allow tissue diagnosis by cytoscopic biopsy procedures of the pancreas and duodenum. To assess the diagnostic utility of duodenal biopsies, we reviewed all cystoscopically obtained pancreas and duodenal biopsy tissues at our institution (July 1, 1989 through September 30, 1993). Adequate tissue for histologic examination was obtained from 75 biopsies in 58 recipients. Indications for cytoscopic biopsies were relative hypoamylasuria in 85%, hematuria in 6%, hyperamylasemia in 3%, and other causes in 6%. Duodenal specimens were available from 52 biopsies (25 with, and 27 without, concurrent pancreas biopsies). Of the 27 duodenal biopsies alone, 3 were diagnostic of rejection, 15 had features consistent with rejection, 6 were normal, 1 showed fibrosis, 1 showed necrosis, and 1 was ulcerated. Thus, two-thirds of the duodenal biopsies alone yielded clinically relevant information resulting in antirejection treatment. In 25 of the duodenal biopsies, pancreas tissue was also available (11 simultaneous pancreas-kidney, 9 pancreas transplant alone, and 5 pancreas after kidney recipients). Findings in both organs completely agreed in 9 (36%) of the biopsies. In 7 (28%), rejection was suggested or diagnosed in both organs, although the organs were discrepant with regard to the presence of vascular rejection (6 pancreas, 1 duodenum). In 2 (11%), minor nonrejection discrepant findings were present. Therefore, in 18 of 25 (72%) pancreas-duodenal biopsies, treatment would not have been different if only one graft had been biopsied. But in the other 7 (28%), treatment would have been different if only the organ with negative findings had been biopsied. In 6 cases (4 duodenal, 2 pancreas), rejection was seen in one organ but not the other. In 1 case, cytomegalovirus (CMV) inclusions were present in the duodenum, but the pancreas was normal. We conclude that (1) the duodenum and pancreas can reject independently of each other, and a negative biopsy does not preclude rejection of the other organ; (2) duodenal biopsies determined therapeutic decisions one-fifth of the time when both tissues were available for examination, and two-thirds of the time when only duodenal tissue was available; and (3) since cystoscopy allows easy access to the duodenum, both the pancreas and duodenum should be biopsied whenever possible; tissue samples of one organ alone are sufficient only with positive findings.

We assessed the efficacy of 5 dose levels of oral rapamycin for prolonging renal allograft survival in pigs. Untreated and triple therapy groups (cyclosporine, azathioprine, and prednisone) served as controls. Immunosuppression was administered for 28 days posttransplant and then stopped. Rapamycin whole-blood concentrations were followed weekly. Chemistry, hematology, and lipid values were monitored post-transplant. For rapamycin-treated pigs, median survival time (MST) correlated with both dose and trough levels (ng/ml). All kidneys had some degree of rejection seen on necropsy. After rejection, pneumonia was the most common cause of death. No specific end-organ toxicity was noted on histopathologic examination. Triglyceride and cholesterol levels increased in all treated pigs (both rapamycin and triple therapy) vs. untreated controls--however, all values were within normal limits. Mean ALT levels increased in weeks 2 to 4 in the higher-dose rapamycin groups but returned to baseline in pigs surviving after the drug was stopped. ALT levels did not increase above twice normal in any group. Creatinine levels correlated with the degree of rejection seen on biopsy. We noted no other toxicities. We conclude that rapamycin, given as oral monotherapy, is an effective and safe immunosuppressant in our large animal renal allograft model. Outcome correlated with dose and whole-blood levels.

If hyperacute rejection is prevented in the guineapig (GP)-to-Lewis rat (Lew) cardiac xenograft (CXg) model, an accelerated rejection involving cellular infiltration occurs in 3 to 4 days. In previous work using an adoptive transfer model, we found that this accelerated rejection was facilitated by either sensitized splenocytes or sensitized serum. In the current study, in an attempt to determine which splenocyte subset(s) facilitated this process, sensitized splenocytes, with or without subset depletion were injected, into complement- and natural antibody-depleted Lew recipients of GP CXgs. Graft survival was 4.18 +/- 0.75 days with no injection (n = 11), 4.13 +/- 0.99 days with naive splenocytes (n = 8), 1.80 +/- 0.45 days with sensitized splenocytes (n = 5), 2.67 +/- 1.03 days with CD4(W3/25+) depletion of the sensitized splenocytes (n = 6), 3.13 +/- 0.84 days with CD8(OX8+) cell depletion (n = 8), 4.70 +/- 0.68 days with macrophage depletion (n = 10), and 4.22 +/- 0.41 days with B cell depletion (n = 9). Cellular infiltrates, hemorrhage, myocyte necrosis, and endothelial deposition of IgG, IgM, and fibrin were seen in rejected grafts. In most groups, infiltrating cells consisted of CD4 (W3/25+), CD8 (OX8+), IL2R+ cells, macrophages, and natural killer (NK) cells. However, in the macrophages-depleted group, activated (ED2+) macrophages and NK cells were significantly reduced. Total IgM, anti-GP IgM, and anti-GP IgG rebounded in all groups over several days but were not consistent at the time of rejection. Lewis rats rejecting GP CXgs early had lower final titers than those rejecting later. Total IgG titers rebounded to baseline by posttransplant day 1 and were therefore similar in all groups at the time of rejection. These findings suggest that this accelerated rejection requires interaction between macrophages and B cells, since depletion of either significantly alters the rejection tempo. A possible explanation is that xenoreactive IgG antibodies, synthesized by sensitized B cells, bind their target antigens--but also bind sensitized macrophages through their Fc region, thus causing rejection by antibody-dependent cell-mediated cytotoxicity.

Purpose/objective: To report the long-term results of vulvectomy, node dissection, and postoperative nodal irradiation using a midline vulvar block in patients with node positive vulvar cancer., Methods and Materials: From 1971 through 1992, 27 patients with carcinoma of the vulva and histologically involved inguinal lymph nodes were treated postoperatively with radiation therapy after radical vulvectomy and bilateral lymphadenectomy (n = 25), radical vulvectomy and unilateral lymphadenectomy (n = 1), or hemivulvectomy and bilateral lymphadenectomy (n = 1). Federation Internationale de Gynecologic et d'Obstetrique stages were III (n = 14), IVA (n = 8), and IVB (n = 5) squamous cell carcinoma. Inguinal lymph nodes were involved with tumor in all patients (average number positive = 4, range 1-15). Postoperative irradiation was directed at the bilateral groin and pelvic nodes (n = 19), unilateral groin and pelvic nodes (n = 6), or unilateral groin only (n = 1). These 26 patients had the midline blocked. In addition, one patient received irradiation to the entire pelvis and perineum. Doses ranged from 10.8 to 50.7 Gy (median 45.5) with all patients except 1 receiving > or = 42.0 Gy., Results: Actuarial 5-year overall survival and disease-free survival estimates were 40% and 35%, respectively. Recurrences developed in 63% (17/27) of the patients at a median of 9 months from surgery (range 3 months to 6 years) and 15 of these have died; two patients with recurrences are surviving at 24 and 96 months after further surgery and radiation therapy. Central recurrences (under the midline block) were present in 13 of these 17 patients (76%), either as central only (n = 8), central and regional (n = 4), or central and distant (n = 1). Additionally, three patients developed regional recurrences and one patient developed a concurrent regional and distant relapse. One patient developed a squamous cell cancer of the anus under the midline block 54 months after the initial vulvar cancer and an additional patient developed transitional cell carcinoma of the ureter (outside the radiation field) 12 months after diagnosis. Factors associated with a decreased relapse-free survival included increasing Federation Internationale de Gynecologic et d'Obstetrique stage (p = 0.01) and invasion of the tumor into the subcutaneous (SC) fat or deep soft tissue (p = 0.05). Chronic lower extremity edema developed in four patients, but there have been no other complications., Conclusions: Radical vulvectomy has often been considered sufficient central treatment for vulvar carcinoma, with postoperative irradiation directed only to the nodes. Although designed to protect the radiosensitive vulva, use of a midline block in this series resulted in a 48% (13/27) central recurrence rate, much higher than the 8.5% rate previously reported with this technique. Routine use of the midline block should be abandoned and, instead, postoperative irradiation volumes should be tailored to the individual patient.

The interpretation of atypical leukocytes in the cerebrospinal fluid (CSF) poses diagnostic problems. We present a case of a heart transplant patient whose CSF contained highly atypical lymphocytes that were originally interpreted as "suspicious for lymphoma." Because the patient was clinically thought to have disseminated zoster, he was treated with acyclovir, and the atypical infiltrate resolved. This case exemplifies the extreme difficulty of interpreting cerebrospinal fluid in immunosuppressed patients who are at risk of developing posttransplant lymphoproliferative disorders.

The cytologic appearance of epithelioid sarcoma in fine-needle aspiration biopsy (FNAB) has not been extensively described. The authors report the cytologic findings in one case that metastasized to a lymph node. The cells are characterized by irregular nuclei, nuclear folds, macronucleoli, and a high nucleus-cytoplasm ratio. The cells vary in shape and occur singly and in clusters where intercellular spaces are uncommon. The findings allow the diagnosis of malignancy but are nonspecific. History, immunocytochemistry, and tissue cores are helpful in the differential diagnosis.

The slide centrifuge (cytospin) Gram's-stain technique has been shown in previous studies to be a sensitive technique for detecting bacteriuria when compared to culture. The method concentrates urine sediment in a small defined area on a glass slide for Gram's staining. A positive test provides morphologic information about suspected pathogens. This study evaluated the cytospin technique using 788 urine specimens, on which routine culture was simultaneously performed, and compared both with clinical evidence for urinary tract infection. One hundred twelve of these specimens, which were cytospin positive and had a culture growing more than 100,000 CFU/mL, were assumed, by definition, to represent true urinary tract infection. Five hundred twenty-six specimens had negative cytospin and negative culture results (less than 1,000 CFU/mL) and were assumed, by definition, to rule out the diagnosis of urinary tract infection. Clinical data were evaluated for 56 cytospin-positive specimens in which culture results were less than 100,000 CFU/mL. Of these specimens, 37 were false positive (no clinical evidence of urinary tract infection), 9 had clinical evidence of urinary tract infection, and for the remaining 10, data regarding clinical status could not be interpreted. Seventy-one specimens were cytospin negative, with cultures growing more than 1,000 CFU/mL. Of these, only one patient had clinical evidence of a urinary tract infection, and his culture result was less than 10,000 CFU/mL. The predictive value of a negative cytospin test was 99.8% compared to clinical information, whereas the predictive value of a negative culture (less than 100,000 CFU/mL) was 98.4%.

To determine the reliability of endomyocardial biopsies in the detection of rejection, we took biopsy specimens from 22 autopsied human cardiac allografts by direct visualization. Five specimens were taken from each of four sites: left ventricular free wall, left ventricular septum, right ventricular free wall, and right ventricular septum. The findings in individual biopsy specimens and the summed diagnosis in the five biopsy specimens from each site were graded for rejection by a grading system similar to the Billingham criteria. Grading of the five specimens from each site also was done using criteria recommended by the International Society for Heart and Lung Transplantation. These findings were compared with the rejection grade determined by examination of large tissue sections from the autopsied hearts, used as the standard. Overall, X-Y correlation for single-specimen grading had an r value of 0.792. Grading based on five biopsy specimens from all sites using the modified Billingham criteria grading scheme had an r value of 0.845; the r value was 0.857 for the new grading system. Specificity of findings was high for all grades. Sensitivity of findings, however, was dramatically less for grades 1, 2, and 3. Predictive values for these grades also were less for grades 1, 2, and 3, but to a lesser degree than sensitivity. No difference in detection of rejection was found from specimens taken from different areas of the heart. We conclude that a significant number of hearts with middle grades of rejection may be underestimated by routine biopsies. The criteria for grading of the International Society for Heart and Lung Transplantation had a slight advantage over a more traditional grading system.

A portion of the gyrA gene from amino acid codons 67 to 129 was sequenced in 34 methicillin-resistant Staphylococcus aureus strains (14 isolated in Minnesota, 10 isolated in Indiana, and 10 isolated in Tennessee). Twenty-eight of these strains were ciprofloxacin resistant. Sixteen of the strains contained a Ser----Leu mutation at codon 84; 3 contained strains a Ser----Ala mutation at codon 84; 3 strains contained two mutations, Ser----Leu at codon 84 and Ser----Pro at codon 85; and 6 strains contained a Glu----Lys mutation at codon 88. Six strains were wild type and ciprofloxacin susceptible. Several mutations from amino acid codons 84 through 88 can be associated with high-level quinolone resistance.