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PubMed2002

Serotonin transporter promoter genotype and illness recurrence in mood disorders.

We tested the hypothesis that allelic variation of 5-HTT linked polymorphic region (5-HTTLPR) could influence illness onset and recurrence in 129 bipolar and 128 unipolar recurrent patients. Among bipolar patients, homozygotes for the short variant showed an earlier age at onset and a lower recurrence rate than heterozygotes and homozygotes for the long variant. Unipolar patients showed a trend toward the same difference. Data support a role for 5-HTTLPR in course of affective illness.

Adult↗
PubMedDate not supplied

Diagnostic and prognostic utility of flow cytometric DNA measurements in follicular thyroid tumors.

Distinguishing cellular follicular adenomas (FA) from minimally invasive follicular carcinomas (FC) continues to plague even experienced thyroid pathologists. DNA ploidy analysis has been promoted as a means of making this differentiation; however, the finding of DNA aneuploidy in FA has caused concern that they may demonstrate potential for malignant behavior or should even be reclassified as low-grade noninvasive cancers. In histologically-proven FC, nuclear DNA content has been claimed to have predictive power equivalent to that of all other prognostic factors combined. The aims of the present study, therefore, were to define the DNA ploidy characteristics of FA and FC, to assess the diagnostic potential of cell-cycle parameters, and, in FC, to investigate the prognostic role of such measurements. We measured DNA content of 124 tumors (60 FA, 64 FC). DNA pattern was normal (diploid) in 75% of FA and 45% of FC, tetraploid/polyploid (T/P) in 13% of FA and 25% of FC, and aneuploid in 12% of FA and 30% of FC. FC was histologically verified in 39% of DNA normal, 67% of T/P, and 73% of aneuploid tumors. DNA index, S-phase, G2M, and S-phase plus G2M were analyzed and were not helpful in differentiating between FA and FC. No patient with FA developed tumor recurrence. In FC (excluding the Hürthle cell variant), no significant differences were found among the 3 DNA ploidy groups with respect to either cancer death or tumor recurrence; however, combining the Hürthle cell variant of follicular carcinomas with pure follicular carcinomas, the presence of distant metastases, DNA aneuploidy, and patient age were the only independently significant prognostic variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1996

Thyroid cancer nodal metastases: biologic significance and therapeutic considerations.

Lymph node metastases at presentation are common in PTC and MTC (about one third of patients at presentation), but are rare in other types of thyroid malignancy, though HCC frequently recurs in lymph nodes. Nodal metastases can be detected by a variety of means, but high resolution ultrasonography may be the method of choice. Unlike other epithelial malignancies, in thyroid cancer neither prognostic significance nor optimal treatment of nodal metastasis are known with certainty. For PTC lymph node metastases at presentation do not seem to adversely affect survival, but do increase the risk of locoregional tumor recurrence. By contrast, in FTC nodal metastases at presentation may adversely affect cause-specific mortality, but because of their rarity definite conclusions are impossible. Except for the oxyphilic variant of FTC (HCC) nodal recurrence in FTC is rare. The most firm evidence of prognostic relevance for nodal metastases in thyroid malignancies exists in medullary thyroid cancer, where most studies suggest that survival and recurrence are both adversely affected by node-positive status at presentation. Primary treatment of nodal metastases is removal of macroscopically affected nodes at initial surgery, optionally supplemented with adjuvant radioiodine treatment in an attempt to reduce recurrence risk. The value, however, of postoperative radioiodine in preventing either nodal recurrence or cancer death in patients with papillary and follicular thyroid cancer remains controversial. Extensive lymph node dissection at presentation offers no advantage (and may cause increased morbidity) in papillary carcinoma, but may be useful in medullary thyroid carcinoma, where nodal metastases seem to increase the risk of cause-specific mortality. In all tumor types postoperative nodal recurrences should primarily be treated surgically.

Humans↗
PubMed2005

Prognostic impact of BRCA1 pathogenic and BRCA1/BRCA2 unclassified variant mutations in patients with ovarian carcinoma.

BACKGROUND: The clinical relevance of BRCA1/2 alterations in ovarian carcinoma patients is debatable. Our aim was to determine factors influencing the risk of recurrence and death in ovarian carcinoma patients with BRCA pathogenic and unclassified variant mutations. METHODS: A consecutive series of 205 women with primary ovarian carcinoma were screened for mutations in BRCA1 and BRCA2 genes using a conformational sensitive gel electrophoresis and direct sequencing. Data regarding medical and familial history were collected using questionnaires. Clinical and pathologic data were extracted from medical records. RESULTS: Unclassified variant mutations in BRCA1 or BRCA2 genes were found in 16 (8%) patients, and BRCA1 pathogenic mutations were found in 18 (9%) patients. No pathogenic mutation was found in BRCA2 gene. Multivariate analysis showed that BRCA1 pathogenic mutation was an independent predictor of reduced risk of relapse and death (Hazard ratios [HR] 0.52 [confidence interval {CI} 0.28-0.98] and 0.38 [CI 0.10-0.96], respectively). Unclassified variant mutation did not affect recurrence and survival (HR 0.84 [CI 0.43-1.66] and 0.94 [CI 0.48-1.82], respectively). Other factors associated with reduced risk of relapse and death were complete pathologic remission at second-look laparotomy and family history of breast and ovarian carcinoma, respectively. Recurrence and death outcomes among unclassified variant mutation carriers did not differ significantly from those in sporadic cases. CONCLUSIONS: Patients with BRCA1 pathogenic mutation seem to have reduced risk of recurrence and death. These results should be interpreted with caution as they may be influenced by more intensive treatment, better response to cisplatin, and younger age of mutation carriers. Clinical relevance of BRCA1/2 unclassified variant mutations warrants further studies.

Adult↗
PubMedDate not supplied

Differential expression of CD44 variant isoforms by cell lines and tissue specimens of transitional cell carcinomas.

BACKGROUND: Certain splice variants (CD44v) can promote the progressive and metastatic behavior of cancer. We tested whether different CD44v molecules were selectively expressed in transitional cell carcinomas based on the stage and grade. MATERIALS AND METHODS: A panel of 13 TCC cell lines with different degrees of differentiation and biological behavior were tested with monoclonal antibodies to CD44s, CD44v5, v6, v7, v7-8 and v10 by two approaches: immunofluorescence/flow cytometry and immunocytochemistry. In addition, immunohistochemistry was performed on 55 TCC specimens. RESULTS: Immunofluorescence/flow cytometric analysis showed that surface expression of the variant isoforms CD44v5 and v6 were absent in 3/7 high-grade cell lines (MGH-U1, -U1R and CUB III). Immunohistochemistry showing moderate to strong expression of CD44s was found in 46 out of 55 bladder tumor tissues. Expression of CD44v5 was negatively related with tumor grade (p = 0.007), stage (p = 0.030) and recurrence (p = 0.019). Expression of CD44v10 correlated with tumor recurrence (p = 0.008), while that of CD44v6 did not show any correlation with tumor grade, stage or recurrence. CONCLUSION: Among the CD44 variant isoforms on 55 TCC tissue specimens examined, the expression of CD44v5 was inversely related to tumor grade, stage and recurrence, while the expression of CD44v10 was positively related to tumor recurrence. The CD44v10 may have potential to be developed as a specific immunotherapy target for selected urothelial TCCs.

Alternative Splicing↗
PubMed2002

Testicular lymphoma: a literature review and report of a case with a zoster-like cutaneous recurrence.

Testicular lymphoma accounts for approximately 1% of all cases of non-Hodgkin's lymphoma. This distinct clinical entity can have an aggressive course with a high rate of systemic relapse. We describe a unique case of a diffuse large B-cell lymphoma, T-cell-rich variant with cutaneous dermatomal zosteriform recurrence presenting as neuralgia. This case represents a unique pattern of treatment failure in this aggressive extranodal lymphoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Late recurrence of uterine Mullerian adenosarcoma as heterologous sarcoma: Three recurrences in 8 months increasing in number and grade of sarcomatous components.

BACKGROUND: Uterine Mullerian adenosarcoma (UMA) is a rare and low-grade variant of mixed mesodermal tumor. UMA recurrences including heterologous sarcomatous elements are extremely rare, with only 3 cases reported thus far. CASE: We present a case of UMA recurring as heterologous sarcoma three times in 8 months for 9.4 years after primary treatment. The number and grade of sarcomatous components increased with each recurrence eventually resulting in loss of the patient. CONCLUSION: The presence of multiple sarcomatous elements of high histological grade in the recurrent tumor following UMA may indicate an unfavorable prognosis with common recurrences and fatal outcome. All UMA patients carry risk of late recurrence, therefore, they should receive long-term follow-up.

Adenosarcoma↗
PubMed2006

Association between manganese superoxide dismutase promoter gene polymorphism and breast cancer survival.

BACKGROUND: Manganese superoxide dismutase (MnSOD) plays a critical role in the detoxification of mitochondrial reactive oxygen species, constituting a major cellular defense mechanism against agents that induce oxidative stress. A genetic polymorphism in the mitochondrial targeting sequence of this gene has been associated with increased cancer risk and survival in breast cancer. This base pair transition (-9 T > C) leads to a valine to alanine amino acid change in the mitochondrial targeting sequence. A polymorphism has also been identified in the proximal region of the promoter (-102 C>T) that alters the recognition sequence of the AP-2 transcription factor, leading to a reduction in transcriptional activity. The aim of our study was to investigate possible associations of the -102 C>T polymorphism with overall and relapse-free breast cancer survival in a hospital-based case-only study. MATERIALS AND METHODS: The relationship between the MnSOD -102 C>T polymorphism and survival was examined in a cohort of 291 women who received chemotherapy and/or radiotherapy for incident breast cancer. The MnSOD -102 C>T genotype was determined using a TaqMan allele discrimination assay. Patient survival was evaluated according to the MnSOD genotype using Kaplan-Meier survival functions. Hazard ratios were calculated from adjusted Cox proportional hazards modeling. All statistical tests were two-sided. RESULTS: In an evaluation of all women, there was a borderline significant reduction in recurrence-free survival with either one or both variant alleles (CT + TT) when compared with patients with wild-type alleles (CC) (odds ratio, 0.65; 95% confidence interval, 0.42-1.01). When the analysis was restricted to patients receiving radiation therapy, there was a significant reduction in relapse-free survival in women who were heterozygous for the MnSOD -102 genotype (relative risk, 0.40; 95% confidence interval, 0.18-0.86). Similarly, when the homozygous and heterozygous variant genotypes were combined, there remained a significant reduction in relapse-free survival in this group (hazard ratio, 0.42; 95% confidence interval, 0.20-0.87). CONCLUSION: The MnSOD -102 variant allele appears to be associated with an improved recurrence-free survival in all patients, and more dramatically in subjects who received adjuvant radiation therapy.

Breast Neoplasms↗
PubMed1990

Combination of congenital nonspherocytic haemolytic anaemia and impairment of granulocyte function in severe glucosephosphate isomerase deficiency. A new variant enzyme designated GPI Calden.

In two siblings, children of non-consanguineous parents, glucosephosphate isomerase (GPI) deficiency was found to be the cause of recurrent haemolytic crises. Characterization of the variant enzyme found in both individuals revealed low specific activity in erythrocytes and leucocytes, increased electrophoretic mobility and pronounced thermolability. Evaluation of the electrophoretic data allows the conclusions that these siblings are compound heterozygous carriers of GPI deficiency. The new variant was designated GPI Calden. Further investigations revealed that isolated granulocytes of both siblings show marked reduction of bactericidal activity and decreased production of superoxide anion. With rare exceptions, deficiency of this enzyme was supposed to cause congenital nonspherocytic haemolytic anaemia only. Here we report on two siblings presenting with the characteristic haemolytic anaemia and a significant decrease in granulocyte function, both presumably as the result of GPI deficiency. Our data indicate that impairment of granulocyte function might be a more general feature of severe GPI deficiency than formerly noted.

Anemia, Hemolytic, Congenital↗
PubMed2006

Role of c-Src and focal adhesion kinase in progression and metastasis of estrogen receptor-positive breast cancer.

The non-receptor tyrosine kinases c-Src and focal adhesion kinase (Fak) mediate signal transduction pathways that regulate cell proliferation, survival, invasion, and metastasis. Here, we investigated whether c-Src and Fak are activated during progression of hormone-dependent breast cancer. Maximally active c-Src was overexpressed in a subset of tamoxifen-resistant variants and in metastases of recurrent hormone-treated breast cancer. Active Fak was also frequently observed in these tumors. We also show that estrogen receptor (ER) can bind to Fak and that estrogen can modulate Fak autophosphorylation supporting a cross-talk between these two pathways. Inhibition of c-Src activity blocked proliferation of all tamoxifen-resistant variants, suggesting that inhibitors of c-Src-Fak activity may delay or prevent progression and metastasis of ER-positive tumors. These studies also raise the possibility that fully active forms of c-Src and Fak in breast tumors may be biomarkers to predict tamoxifen resistance and/or risk of recurrence in ER-positive breast cancer.

Biomarkers, Tumor↗
PubMed2000

Molecular characterization of HHV-8 positive primary effusion lymphoma reveals pathogenetic and histogenetic features of the disease.

BACKGROUND: Primary effusion lymphoma (PEL) associates with HHV-8 infection, preferentially develops in immunodeficient patients and grows in the serous body cavities. PEL derives from post-germinal center, pre-terminally differentiated B-cells. The pathogenesis of PEL is unclear and the sole identified genetic lesions are human herpesvirus type-8 (HHV-8) infection in all cases and EBV infection in 70% of cases. Epstein-Barr virus (EBV) infection in PEL displays a latency I phenotype. OBJECTIVES: To clarify the pathogenesis and histogenesis of PEL by investigating (1) the lymphoma karyotype; (2) the expression status of the Met tyrosine kinase receptor and of its ligand hepatocyte growth factor (HGF); (3) the molecular profile of EBV, with particular focus on mutations of EBNA-1 genes, which are thought to affect viral tumorigenicity in EBV-infected neoplasms displaying the latency I phenotype. STUDY DESIGN: Twenty-four PEL (nine cell lines and 15 primary specimens) formed the basis of the study. Karyotypes were investigated by conventional cytogenetics and fluorescent in situ hybridization (FISH) in selected cases. The expression status of Met and HGF was defined by multiple techniques, including RT-PCR, FACS analysis, immunocytochemistry, Western blot studies and ELISA. The molecular profile of EBNA-1 genes of EBV were investigated by DNA direct sequencing. RESULTS: Trisomy 7, trisomy 12 and breaks at 1q21-q25 are recurrently associated with PEL. PEL consistently co-express Met and HGF both at the mRNA and protein level. Among aggressive B-cell lymphomas, Met/HGF co-expression appears to be relatively specific for PEL. The EBNA-1 gene of EBV displays a high degree of genetic heterogeneity in PEL, with no preferential association with one specific variant. CONCLUSIONS: PEL associates with recurrent chromosomal alterations, suggesting that viral infection is not sufficient for tumor development and that lesions of cellular genes may be required. The expression of Met/HGF by PEL cells may bear implications for the lymphoma proliferation and growth pattern, since Met/HGF interactions influence cell mitogenesis and motogenesis. EBV infection in PEL displays a latency I phenotype and fails to associate with specific EBNA-1 variants, suggesting that the role of EBV in PEL is not mediated by the major transforming pathways currently known in EBV positive lymphomas.

Epstein-Barr Virus Nuclear Antigens↗
PubMed1987

Tolosa-Hunt syndrome versus recurrent cranial neuropathy. Report of two cases with a prolonged follow-up.

Two patients are described who had suffered for 12 years from episodes of painful ophthalmoplegia consistent with a Tolosa-Hunt syndrome (THS) alternating with palsies of cranial nerves other than the oculomotor (fifth motor and seventh on both sides). These two cases, as well as other similar ones previously reported in the literature, suggest that THS may sometimes be a variant of so-called recurrent cranial neuropathy, which is a benign and poorly understood clinical entity on an inflammatory or ischaemic basis.

Aged↗
PubMed2006

E-cadherin promoter polymorphism (C-160A) and risk of recurrence in patients with superficial bladder cancer.

Tumor recurrence is a hallmark of superficial bladder cancer. Currently, a molecular marker for bladder cancer recurrence is lacking. E-cadherin plays an important role in epithelial development and in the establishment and maintenance of cell-cell adhesion and tissue architecture. The purpose of this study is to investigate the association of an E-cadherin promoter polymorphism (CDH1c-160a) with the risk of bladder cancer recurrence. This study included 302 patients with superficial bladder cancer. Genomic DNA was extracted from peripheral blood lymphocytes and genotyping was performed using Taqman assay. Clinical data were collected by medical chart review. Cox proportional hazard model was used to estimate the hazard ratios (HRs) associated with genotypes while adjusting for age, gender, smoking status, tumor stage and grade where appropriate. During a median follow-up of 27.65 months, 151 patients experienced disease recurrence. Subsequent analyses were restricted to Caucasians only due to the small sample size of other ethnic groups (13 in recurrence group and 15 in non-recurrence group). Among the 274 Caucasian patients, 138 developed recurrence during the same length of follow-up time. In Caucasian patients, having at least one variant A allele conferred a 32% reduction in recurrence risk (adjusted HR: 0.68; 95% CI: 0.48-0.96). The median recurrence-free survival for patients carrying at least one variant A allele was significantly longer than that for patients with a homozygous CC genotype (40.4 vs 12.5 months, p=0.04). Our findings suggest that the E-cadherin promoter polymorphism may be a valuable molecular marker for bladder cancer recurrence.

Cadherins↗
PubMed2001

A dominant hepatitis B virus population defective in virus secretion because of several S-gene mutations from a patient with fulminant hepatitis.

There is increasing evidence that certain pathogenic hepatitis B virus (HBV) variants may play a role in the pathogenesis of fulminant hepatitis (FHB). Recently, we isolated from a patient with fulminant recurrent hepatitis B after liver transplantation variants with enhanced replication competence and a possible defect in viral particle secretion. Both viral features may have contributed to the severity of the disease. The aim of this study was to prove the secretion defect of these variants, to analyze the consequences, and to identify the responsible viral mutations. The variant genomes and appropriate wild-type/variant hybrid genomes were functionally characterized after transfection in human hepatoma cells. Two cloned genomes and the polymerase chain reaction (PCR)-amplified mixture of full-length genomes showed a block in viral particle secretion. This was caused by a combination of amino acid changes in the S-protein including the mutation G145R frequently emerging after hyperimmunoglobulin treatment. The mutations induced retention of the surface proteins in an endoplasmic reticulum (ER)-like compartment, but no intracellular accumulation. These data provide evidence for the in vivo existence of a dominant HBV population with a severe defect in viral particle secretion caused by mutations in the S-gene. This viral phenotype in combination with the enhanced replication competence may have contributed to the fulminant clinical course of the infection.

Amino Acid Substitution↗
PubMed1989

Stage II seminoma: results of postorchiectomy irradiation.

One hundred forty patients with testicular seminoma were treated at the State University of New York Health Science Center at Syracuse between 1966 and 1985. Disease was classified as stage II in 32 patients (23%): stage IIA in 21 patients and stage IIB in 11 patients. All patients underwent irradiation below the diaphragm after a radical orchiectomy, and 28 underwent planned mediastinal and supraclavicular irradiation. The median follow-up was 8 1/2 years; 24 of 32 patients have been followed up for more than 5 years. Twenty-eight patients remain alive and well; four patients died of intercurrent disease. Two patients developed a recurrent seminoma in the mediastinum; a variant lymphangiographic pattern was shown in these patients, and they were cured. A third patient developed a non-seminomatous "recurrence" in the ipsilateral, unirradiated, inguinal nodes and is well after chemotherapy.

Adult↗
PubMed1992

Seasonal panic disorder: a possible variant of seasonal affective disorder.

The present communication concerns a 30 year-old female patient with panic disorder in whom panic attacks appeared to be seasonally-related. Characteristically, attacks were more frequent and severe during the months of October to May with spontaneous remissions during the months of June to September. Since 70% of patients with seasonal affective disorder (SAD), a variant of affective illness characterized by recurrent winter depressions with remissions in summer, suffer from anxiety disorders, we propose that seasonal panic disorder may be a variant of SAD. Since SAD is associated with phase delay of circadian rhythms, some forms of panic disorder may be related to phase instability of circadian rhythms. Moreover, since administration of artificial bright light therapy is currently the most effective treatment for SAD, it is suggested that patients with panic disorder should be questioned as to whether their symptoms are seasonally related. If a positive association is established, these patients should be offered treatment with light therapy prior to or coincident with the institution of pharmacotherapy.

Adult↗
PubMed2003

Emergence of a teicoplanin-resistant small colony variant of Staphylococcus epidermidis during vancomycin therapy.

Small colony variants of Staphylococcus aureus can cause persistent and recurrent infections. There are only a few reports of small colony variants of coagulase-negative staphylococci. Herein a case of infection with a teicoplanin-resistant small colony variant of Staphylococcus epidermidis is presented. The small colony variant was isolated from blood cultures of a patient with acute leukaemia and therapy-induced neutropenia who was treated with vancomycin for catheter-associated bloodstream infection. Despite removal of the catheter and adequate antibiotic therapy, the infection did not clear and the patient died 20 days after continuous antibiotic therapy.

Aged↗
PubMed2006

Myoid differentiation and EMA expression in fibrosarcomatous dermatofibrosarcoma protuberans.

Dermatofibrosarcoma protuberans (DFSP) is a relatively unusual, locally aggressive cutaneous tumor of intermediate malignancy. Fibrosarcomatous DFSP (FS-DFSP), a rare variant of DFSP, has a higher tendency for recurrence and metastasis. Recently, a small number of cases of another variant of FSDFSB characterized by areas of myoid differentiation have been reported. We present here a 35 yearold female patient with myoid differentiation in FS-DFSP. The tumor on the left scapular region had slowly grown over six years. Examination revealed a domeshaped, firm, nontender, violaceous dermal nodule. Histologically, it was composed of a monotonous spindle cell population arranged predominantly in a storiform pattern and to a lesser extent in a fascicular fibrosarcomatous pattern with a parallel arrangement of the cells. Immunohistochemically, the tumor cells showed diffuse expression for vimentin and CD34. In the center of the tumor areas with frequent mitosis, hypercellular and negative reactive for CD34 were seen. In addition, approximately 10% of the cells were positive for epithelial membrane antigen. Myoid differentiation was found around the blood vessels. The myoid areas were positive for smooth muscle actin and negative for desmin. It is possible that the presence of hyperplastic myofibroblasts is a reactive phenomenon to the proliferation of tumor cells. We believe that this finding around blood vessels may be present in DFSP or FS-DFSP. However, when myoid areas, myoid fascicles and myoid nodules are seen in the stroma, it may be a new morphological variant of DFSP and/or FS-DFSP.

Actins↗