Elevated levels of the mismatch repair protein PMS2 are associated with prostate cancer.

BACKGROUND: Defects in mismatch repair (MMR) proteins have been identified in various types of cancer. However, an association with prostate cancer has been controversial. Defective MMR results in genome instability with detrimental consequences that significantly contribute to tumorigenesis. This study determined alterations in key MMR protein levels in prostate cancer with the goal to identify prognostic markers. METHODS: Prostatectomy samples were immunohistochemically stained and the relative presence or absence of key proteins MSH2, MLH1, and PMS2 determined. Cancer tissue of distinct grades was compared with the normal surrounding tissue. Microsatellite instability (MSI) in altered tissues was determined according to NCI guidelines. RESULTS: In contrast to reports that associate a lack of individual MMR proteins with tumorigenesis, a significant increase in PMS2 levels was identified in PIN lesions and prostate cancer tissue. This elevation in PMS2 was independent of changes in levels in its heterodimeric partner, MLH1. Prostate tumors with elevated levels of PMS2 were genetically unstable, which was corrected by MLH1 co-elevation. CONCLUSIONS: This is the first documentation of detrimental consequences associated with the increase in a MMR protein in human cancer. This study recognizes PMS2 elevation as a prognostic marker in pre-neoplastic and prostate cancer lesions. This result has significant implications for future diagnostic and treatment measures.

Efficacy and safety of gemtuzumab ozogamicin in patients with poor-prognosis acute myeloid leukemia.

The objective of this work was to determine the safety and efficacy of gemtuzumab ozogamicin in patients with poor prognosis acute myeloid leukemia (AML). Patients with the following diagnoses/characteristics were treated with 1-3 infusions of gemtuzumab ozogamicin at a dose of 9 mg/m2: (1) relapse of AML < or = 6 months of first complete remission (CR); (2) AML refractory to chemotherapy at initial induction or at first relapse; (3) AML in second or greater relapse; (4) myeloid blast crisis of chronic myeloid leukemia (CML); (5) untreated patients > or = 70 years or > or = 55 years with abnormal cytogenetics (excluding inv 16, t(15;17) and t(8;21)) and/or an antecedent hematologic disorder; (6) refractory anemia with excess blasts in transformation (RAEBT). Forty-three patients, ages 19-84 (mean 62), were treated, including 7 patients with untreated AML age > 70 years, 2 with untreated RAEBT, 14 with AML first salvage (first remission 0-6 months), 15 with AML > or = second salvage and 14 with myeloid blast phase of CML. The overall response rate was 14%, with 4/43 (9%) patients achieving CR and 2/43 (5%) achieving CR without platelet recovery. The most significant toxicity was neutropenic fever, which occurred in 84% of patients. In conclusion, in patients with relapsed/refractory AML, gemtuzumab ozogamicin has a comparable response rate to single-agent chemotherapy and may offer a more favorable toxicity profile.

Bone marrow cytogenetic abnormalities of aplastic anemia.

Cytogenetic abnormalities in association with aplastic anemia have been reported fairly infrequently. Clonal cytogenetic abnormalities at initial diagnosis are uncommon. A retrospective study was performed of the cytogenetic findings in patients with typical morphological and clinical features of severe aplastic anemia from a single institution for the years 1988 through 1998. A total of 30 cases of aplastic anemia, 16 men and 14 women, were identified. The median age was 60 with females being significantly older (67.5 years) in comparison to males (44 years). Bone marrow specimens failed to yield metaphases in 16 cases and normal karyotypes were detected in 11 cases. Cytogenetic abnormalities were detected in 3 cases. Clonal abnormalities, as defined, occurred in only 2 cases (6.7%). A review of the literature identified a total of 24 cases of aplastic anemia with abnormal cytogenetic findings. Overall, the most common chromosome abnormalities are trisomies of 6 and 8 and loss of chromosome 7. Trisomy 6 is more common at diagnosis while loss of chromosome 7 is more common after therapy.

Cell-specific expression of group X and group V secretory phospholipases A(2) in human lung airway epithelial cells.

Secretory phospholipase A(2) (sPLA(2)) enzymes contribute to inflammatory injury in human lungs by several mechanisms, including eicosanoid production and hydrolytic damage to surfactant phospholipids. Several distinct sPLA(2) genes have been described in human tissue but little is known regarding their presence, localization, or function(s) within lungs. We hypothesized that sPLA(2)s would have cell-specific distributions within lung. We used reverse transcriptase/polymerase chain reaction to identify sPLA(2) messenger RNAs (mRNAs) in adult human lung tissue. Resulting complementary DNA (cDNA) sequences indicated that total lung extracts contained mRNA for Groups IB, IIA, V, and X sPLA(2). An epithelial cell line, BEAS cells, expressed only Groups IIA, V, and X. We used these cDNAs to clone these enzymes, especially the recently described Group X and Group V enzymes. Digoxigenin-labeled complementary RNA probes were used to determine localization of each sPLA(2) by in situ hybridization of human lung. Hybridization was strongly positive for Group X and Group V in airway epithelial cells, which failed to hybridize Group IB or IIA probes. Although four known mammalian sPLA(2) isotypes were expressed in lung, only Group X and Group V sPLA(2) mRNAs appear uniquely expressed in airway epithelium, suggesting they could provide a mechanism of pulmonary surfactant hydrolysis during lung injury.

Diagnosis and subclassification of primary and recurrent lymphoma. The usefulness and limitations of combined fine-needle aspiration cytomorphology and flow cytometry.

The primary diagnosis of non-Hodgkin lymphoma/leukemia by fine-needle aspiration (FNA) is still controversial and relatively underused. We evaluated our FNA experience with lymphomas using the revised European-American classification of lymphoid neoplasms to determine the reliability of FNA when combined with flow cytometry in the diagnosis of lymphoma, the types of diagnoses made, and the limitations of this technique. Slides and reports from all lymph node and extranodal FNAs performed during the period January 1, 1993, to December 31, 1998, with a diagnosis of lymphoma or benign lymphoid process were reviewed. There were 290 aspirates from 275 patients. These included 158 cases of lymphoma, of which 86 (54.4%) were primary and 72 (45.6%) were recurrent. There were 44 aspirates suggestive of lymphoma and 81 benign/reactive diagnoses. With diagnoses suggestive of lymphoma considered as positive for lymphoma, levels of diagnostic sensitivity and specificity were 95% and 85%, respectively. Specificity was 100% when only definitive diagnoses of lymphoma were considered. Clearly, FNA and immunophenotyping by flow cytometry are complementary and obviate a more invasive open biopsy for many patients with lymphadenopathy.

Prostate cancer diagnosed by the 5 region biopsy method is significant disease.

PURPOSE: The 5 region method of prostate biopsy takes standard sextant biopsies and additional systematic biopsies of the far lateral and middle aspects of the prostate gland. This method has been shown to increase the cancer detection rate of prostate biopsy by 35% over the standard sextant biopsy method, and it is most effective in patients with prostate specific antigen less than 10. Concern has arisen that by taking additional biopsies, cancers are being detected which would otherwise be clinically insignificant. We compare pathological findings of radical prostatectomy specimens detected by the 5 region and sextant biopsy methods to determine if there is a significant difference between tumors diagnosed by each method. MATERIALS AND METHODS: A total of 21 patients enrolled in the 5 region prostate biopsy study with biopsy proved prostate cancer underwent radical prostatectomy. Prostatectomy specimens of 5 zone detected cancers in 11 cases were compared to sextant method detected cancer in 10. Radical prostatectomy specimens were analyzed for tumor volume, ploidy status, Gleason score and TNM pathological stage. Tumor volumes were determined by point counting morphometric analysis using an overlying grid. Tumor ploidy status was determined by deoxyribonucleic acid (DNA) image analysis. RESULTS: Mean tumor volume was 2.4 cc (range 0.10 to 9.6, median 1.4) for 5 region detected cancers versus 1.9 cc (range 0.10 to 6.1, median 1.0) for sextant method detected cancers. This difference was not statistically significant (p = 0.643). Mean DNA index was 1.1 (range 0.93 to 1.64) for 5 region detected cancer compared to 1.4 (range 0.96 to 2.2) for sextant method detected cancer. Overall there were 8 diploid tumors and 3 aneuploid tumors in the 5 region group compared to 4 diploid tumors and 6 aneuploid tumors in the sextant group. Mean Gleason scores were not significantly different for the 5 region (6.5) and sextant (6.7) groups (p = 0.672). Final tumor stage for the 5 region group was 4 pT3 (36%) and 7 pT2 (64%) tumors compared to 2 pT3 (20%) and 8 pT2 (80%) tumors for the sextant group. CONCLUSIONS: Our data demonstrated no significant difference in tumor volume, DNA ploidy status, Gleason score or final pathological tumor stage between tumors diagnosed using the 5 region versus sextant biopsy techniques.

The cytomorphologic features of sclerosing mucoepidermoid carcinoma of the thyroid gland with eosinophilia.

Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a recently described carcinoma of the thyroid gland associated with Hashimoto's thyroiditis and considered to have a relatively indolent clinical course. We describe two patients with SMECE and its aspiration and exfoliative cytologic features. Patient 1 was a 39-year-old woman with a goiter for many years. Examination of the lobectomy specimen revealed SMECE associated with Hashimoto's disease; 4 months later a total thyroidectomy was performed, metastases were found in nine lymph nodes in the neck. Two years later, fine-needle aspiration biopsy (FNAB) of a paritracheal mass revealed recurrent tumor. After 2 more years, two pleural fluid samples contained metastatic carcinoma with eosinophils. Patient 2 was a 61-year-old man with thyromegaly and vocal cord paralysis. The FNAB revealed a poorly differentiated carcinoma. The subsequent thyroidectomy demonstrated SMECE. Two years later, an FNAB of a vertebral mass demonstrated metastatic mucoepidermoid carcinoma. In all specimens, malignant cells with definite glandular and squamoid differentiation were present in small cohesive aggregates; eosinophils associated with the tumor cells were present in all specimens.

Epithelioid hemangioendothelioma of the superior vena cava: computed tomography demonstration and review of the literature.

A case is reported of a 79-year-old man with rapid onset of superior vena cava syndrome caused by an epithelioid hemangioendothelioma. Contrast-enhanced helical computed tomography showed a soft-tissue mass with punctate calcifications obstructing the superior vena cava and infiltrating adjacent fat. Epithelioid hemangioendothelioma is a very rare primary mesenchymal tumor of the superior vena cava that often presents with calcifications. It should to be added to the differential diagnosis of tumors of the anterior mediastinum.

Comparison of puncture versus vasotomy techniques for vasography in an animal model.

PURPOSE: We determine the adverse effects of 2 different techniques of vasography in an animal model. MATERIALS AND METHODS: Unilateral vasography was performed by a direct puncture technique with a lymphangiogram needle or through a partial thickness vasostomy technique in 2 groups of 10 adults Lewis rats using nonionic contrast medium mixed with methylene blue. Each rat had a contralateral vasectomy. A complete vasogram was confirmed by visualization of colored dye in the bladder. An additional group of 5 animals with unilateral vasectomy alone served as controls. The adverse effects of these 2 techniques were assessed by performing mating studies at 2 and 4 months after vasography. In vitro flow through the vas deferens, sperm granuloma formation and histology of the vas deferens at the vasography site were evaluated at sacrifice 5 months after vasography. RESULTS: The fertility of the 3 groups, as measured by the mean number of uterine implantation sites, was not significantly different at the 2 and 4-month breeding periods. In addition, we observed no significant decrease in the fertility of the 3 groups with time. Complete vasal obstruction was noted at sacrifice in 2 rats (20%) in the vasostomy group and none in the puncture or control group (p = 0.476). The mean in vitro flow rates through the vasa of the puncture and vasostomy vasography groups were significantly lower than those in controls (p < 0.05) but not different from each other. The sperm granuloma formation rate was similar among the 3 groups. CONCLUSIONS: Our results demonstrate that both vasography techniques have a measurable adverse effect on vasal flow rates and a potential adverse effect on fertility. The direct puncture method had a slightly lower complication rate than the partial thickness vasostomy method and it may be the preferable technique for the inexperienced microsurgeon.

Primary osteosarcoma of the spermatic cord with synchronous bilateral renal cell carcinoma.

Primary extraskeletal osteosarcoma of the spermatic cord is an extremely rare tumor with only two other cases being reported in the world literature. We describe a patient with this lesion who also had concomitant bilateral renal cell carcinoma. The management of this case and a review of this subject are presented.

Minor salivary gland biopsies in patients investigated for primary Sjögren's syndrome. A review of 187 patients.

OBJECTIVE: To correlate presenting features and indication for biopsy with results in patients undergoing minor salivary gland biopsy for the diagnosis of primary Sjögren's syndrome (SS). METHODS: The charts of 187 patients undergoing minor salivary gland biopsy for primary SS over a 9-year period were reviewed. RESULTS: 76 patients had a focus score > 1, 111 had a focus score < or = 1. No difference between the 2 groups was noted in most features, including frequency of symptomatic dry eyes or mouth, or Schirmer test results. Patients with focus score > 1 had significant increases in frequency of salivary gland swelling (25 vs 9%), antinuclear antibodies > 1:100 (68 vs 32%), rheumatoid factor > 1:160 (63 vs 22%), anti-SSA (46 vs 9%), anti-SSB (32 vs 4%), or any serologic marker (87 vs 46%). Abnormal biopsies were more frequent in those biopsied for serologic abnormalities (53%) than for sicca symptoms (33%) or systemic illness (29%). CONCLUSION: Serologic markers are better predictors of results than clinical features in patients undergoing minor salivary gland biopsy for primary SS. The frequency of a positive biopsy is increased in patients in whom unexplained serologic markers are being evaluated.

Transurethral laser prostatectomy in the canine model.

A technique for performing transurethral prostatectomy was devised using a Neodymium:Yttrium Aluminum Garnet laser in a canine model. Six dogs underwent transurethral laser prostatectomy following establishment of a perineal urethrostomy. The efficacy of the prostatectomies was judged by retrograde urethrography, transrectal prostate ultrasonography, cystoscopy, and histologic examination. The method of applying laser energy while holding the tip of the fiberoptic light guide 2-3 mm away from the prostate was ineffective; with power ranging from 40 to 70 watts, this technique resulted mainly in coagulation necrosis and removal of only a small amount of tissue. However, placing the tip of the light guide in direct contact with the prostate and using power from 70 to 100 watts produced impressively large prostatectomy defects by tissue vaporization. We conclude that this newly devised technique for transurethral prostatectomy in the canine model can be performed safely and effectively using a Neodymium:Yttrium Aluminum Garnet laser (Neodymium:YAG).

Intraoperative renal ultrasonography: a useful adjunct to partial nephrectomy.

Several evolutionary changes in ultrasonographic instrumentation, including miniaturization of transducers and marked improvement in resolution, have made intraoperative renal ultrasonography a valuable adjunct for intrarenal surgery. We investigated its use in 6 patients undergoing partial nephrectomy for treatment of renal cell carcinoma. In addition, 14 kidneys with renal tumors were scanned immediately after radical nephrectomy and the specimens were subjected to simulated partial nephrectomy. Transverse and longitudinal real-time sonographic images were obtained with a 5 MHz. sector scanner or a 7.5 MHz. convex array transducer. With ultrasonography to define tumor extent and location, negative surgical margins were obtained in all 6 individuals undergoing partial nephrectomy. A negative surgical margin was obtained in 13 of the 14 radical nephrectomy specimens subjected to simulated partial nephrectomy. A small satellite lesion was not identified and not resected in 1 of the radical nephrectomy specimens. We found that intraoperative renal ultrasonography helps to identify the location and extent of deep intraparenchymal lesions. It also provides a guide for a more accurate nephrotomy, which facilitates the attainment of negative resection margins during partial nephrectomy.

Bone marrow and peripheral blood findings in patients with extreme thrombocytosis. A report of 63 cases.

Sixty-three bone marrow (BM) and peripheral blood specimens from patients with platelet counts of 1000 x 10(9)/L or greater were examined in an attempt to determine if any BM or peripheral blood findings could be used reliably to distinguish primary thrombocythemia from other myeloproliferative disorders and extreme examples of reactive thrombocytosis. Our results indicated that the BM findings in primary thrombocythemia were quite similar to those in polycythemia vera and chronic granulocytic leukemia with associated extreme thrombocytosis. However, statistically significant differences between the BM findings in myeloproliferative disorders and extreme reactive thrombocytosis were found in the numbers of megakaryocytes, presence or absence of megakaryocyte clusters, stainable iron, cellularity, and reticulin content. We concluded that BM examination is a useful procedure as an aid in determining the cause of extreme thrombocytosis.

The combined effects of shock waves and cisplatin therapy on rat prostate tumors.

The effects of focused high energy shock waves (SW) generated by the Dornier experimental XL-1 lithotripter alone or in combination with cisplatin (CDDP) on the AT-2 prostate tumor were examined. They were assessed by measuring 1) clonogenic cell survival 24 hours after treatment, 2) tumor growth delay, and 3) the number of lung metastases. The survival of clonogenic cells was reduced 38% by exposure to 2000 SW and tumor growth was delayed by 1.5 days. The limb bearing the tumor was excised in all animals when the tumor reached seven cm.3 The subsequent occurrence of lung metastases in three out of 13 unshocked animals and two out of 14 shocked animals indicated that SW did not promote the dissemination of tumor cells. At doses of one to four mg. CDDP/kg. body weight, SW exposure increased the effectiveness of the chemotherapy measured by a clonogenic assay. The fractional survival was 0.62 after 2000 SW alone, 0.23 with four mg. cisplatin/kg. alone and 0.10 after the combination treatment. At higher doses of CDDP, there was no added effect of SW over that of CDDP therapy alone. Tumor growth to one cm.3 was delayed by seven days after treatment with four mg. CDDP/kg., in comparison to untreated controls. SW exposure combined with CDDP treatment delayed the time taken for the tumor to reach one cm.3 by 13 days in comparison with untreated controls. However, the combination treatment increased animal mortality from 9% with CDDP alone to 29%. These results indicate that SW could be used focally to enhance the cell killing effects of CDDP.

Neoadjuvant treatment of stages T2 to T4 bladder cancer with cis-platinum, cyclophosphamide and doxorubicin.

In an ongoing phase II study 17 patients with potentially operable transitional cell carcinoma of the bladder (stages T2 to T4, Nx, Mo) have been treated with intravenous cis-platinum (50 mg.per m.2), cyclophosphamide (400 mg.per m.2) and doxorubicin (40 mg.per m.2). They were to receive 3 treatments at 3-week intervals before cystectomy and 2 treatments at 3-week intervals commencing 5 weeks after cystectomy. Of 17 patients 14 (82 per cent) completed all 3 preoperative treatments but only 7 (41 per cent) continued on to complete the entire 5 treatments. In most cases incomplete therapy was due to patient refusal. Toxicity was low as measured by World Health Organization standards. Of the 17 patients 9 (53 per cent) exhibited objective tumor response (pathological downstaging or greater than 50 per cent reduction of tumor volume determined by either computerized tomography scan and/or endoscopic examination. When the determination was made by endoscopy the changes were dramatic and not borderline.) No patient demonstrated a pathological complete response. All 9 of the responders (100 per cent) remain clinically free of disease at a median follow-up of 19 months (range 4 to 30 months). The 8 nonresponders have done poorly with 5 dead of disease, 1 alive with pelvic recurrence and 2 free of disease at 4 and 12 months. These tumor response rates compare favorably with other cis-platinum-based combination regimens. The response to the chemotherapy appears to be an important prognostic indicator. Phase III trials must be conducted to determine whether this neoadjuvant chemotherapy regimen has a significant effect on long-term patient survival.

Testicular germ cell tumors in HLA-genotype non-twin brothers.

The diagnosis of metastatic testicular carcinoma in a thirty-three-year-old man and his nineteen-year-old brother is reported. Histologically, the tumor of the older brother consisted predominantly of embryonal carcinoma with minor components of seminoma and adult teratoma; the tumor of the younger brother consisted entirely of embryonal carcinoma. Since previous reports suggest the possibility that the HLA genotype may be a factor in the etiology of testicular cancer, we typed the parents and four children of this family. The two affected brothers shared a paternal HLA-A3, Cw-,B7,DR2 haplotype that had not been transmitted to the two other living siblings. Analysis of the distribution of HLA haplotypes of the affected non-twin brothers of this family and those of three other non-twin pairs of brothers that have been reported showed that the affected pairs in each family shared one HLA haplotype. The differences between the expected and the observed distribution of HLA haplotypes in the four sibling pairs is not statistically significant, perhaps because of the small number of patients typed. Two of the four pairs shared a common haplotype. Additional family studies are required to establish a genetic origin of testicular tumors and to determine whether or not a "testicular carcinoma disease" gene is linked to the HLA complex. A large number of multicase families will be required for linkage analysis.

Comparison of parotid and minor salivary gland biopsy specimens in the diagnosis of Sjögren's syndrome.

We conducted a prospective study comparing minor salivary gland and parotid gland biopsy specimens obtained simultaneously from 24 patients who were undergoing evaluation for primary Sjögren's syndrome (SS). Adequate tissue for study was obtained with all minor salivary gland biopsies and 19 of 24 parotid gland biopsies. Parotid inflammation was seen in 6 of 11 patients whose minor salivary gland biopsy results indicated SS, but in none of 8 patients who had normal findings on minor salivary gland biopsy. Patients with parotid inflammation were older and had a higher frequency of dry eyes and mouth, abnormal results on Schirmer's test, serious extraglandular involvement, and serologic abnormalities. We conclude that parotid gland biopsy adds very little to the minor salivary gland biopsy in the diagnosis of primary SS, but that parotid inflammatory changes may reflect disease duration and/or severity.

Primary renal lymphoma. Does it exist?

Although secondary renal involvement from systemic lymphoma is common, primary lymphoma of the kidney is not well recognized. One case is reported and 27 cases purported to be primary tumors are reviewed. From these cases three conclusions have been drawn: it is reasonable to assume that renal lymphoma can be a primary lesion; almost all patients with primary renal lymphoma will develop extrarenal lymphomatous disease shortly after diagnosis of their renal tumor; and survival for more than 1 year after diagnosis is rare.