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At least 667 records · Page 37Linked to original sources
PubMed1995

Fusion of the EWS gene to a DNA segment from 9q22-31 in a human myxoid chondrosarcoma.

Southern blot analyses revealed a rearrangement of the EWS gene in a skeletal human myxoid chondrosarcoma. Interphase fluorescence in situ hybridization (FISH) studies, using cosmid clones F7 and G9 that flank the EWS locus on 22q12, confirmed the presence of this EWS gene abnormality. Cloning the rearranged EWS DNA fragment and mapping by FISH demonstrated that the EWS gene is joined to DNA sequences localised in 9q22-31. These findings are consistent with previous cytogenetic reports of a recurrent t(9;22)(q22-31;q11-12) in the myxoid variant of chondrosarcoma and reveal involvement of the EWS gene in a fourth type of human sarcoma.

Adult↗
PubMed2006

Influence of gene polymorphisms in ulcer healing process after superficial venous surgery.

OBJECTIVE: Role of superficial venous surgery in reducing the time it takes for ulcers to heal is still controversial, although all studies confirm a significant reduction in ulcer recurrences. Recently, the HFE-C282Y and FXIII-V34L gene variants demonstrated a role in the risk of venous ulceration in primary chronic venous disorder (CVD) and in modulating lesion size in chronic venous ulcer (CVU), respectively. This study was conducted to investigate the role of HFE-C282Y and FXIII (V34L and P564L) gene variants in ulcer healing time after superficial venous surgery, by assessing the outcome of a cohort of homogeneous CVU patients. METHODS: The study selected 91 patients affected by primary CVU (CEAP C6, Ep, Asp, Pr), with the exclusion of any other comorbidity factor involved in delayed healing process, who underwent surgery. We assessed the ulcer area and the healing time. Patients were genotyped by polymerase chain reaction for FXIII (V34L and P564L) and for HFE-C282Y substitutions. RESULTS: Globally, CVU cases had a postoperative mean healing time of 8.5 +/- 5.7 weeks. For the subset of cases above and below the median value (M = 8.0 weeks), FXIII-V34L genotype distribution significantly differed (P < .0001). In addition, Kaplan-Meier analysis yielded specific healing time profiles for the different FXIII-V34L classes of genotype (P = .00001), with an increased risk of delayed healing for the FXIII-VV genotype (hazard ratio, 4.14; 95% confidence interval, 2.1 to 8.2; P = .00005). Although FXIII-P54L genotype distributions did not differ, homozygous 564LL cases (P = .005) and double carriers for both FXIII variants (P < .0001), had a significantly reduced healing time vs wild types. No differences in healing time were observed between carriers and noncarriers of the HFE-C282Y variant, whereas when these cases were stratified by FXIII-V34L genotypes, the L34 carriers had a significantly shorter healing time, irrespective of the HFE genotype. CONCLUSION: The FXIII-34L variant was significantly associated with shorter healing time after superficial venous surgery, suggesting a role in the healing and tissue regeneration phases. Conversely, HFE-C282Y, despite its role in ulcer establishment, did not affect the postoperative healing time. In perspective, the identification of patients with a poor prognosis may give clinicians the opportunity to modify management and to target tailored therapies in the view of a new and alternative concept of treatment based on pharmacogenomics.

Aged↗
PubMed2003

Systemic and primary cutaneous anaplastic large cell lymphomas.

Anaplastic large cell lymphoma (ALCL) is a neoplasm of activated lymphocytes, commonly expressing T-cell antigens and cytotoxic proteins. Histopathology reveals distinctive infiltration of sinuses and paracortical T-cell-rich regions of lymph nodes by tumor cells which have abundant cytoplasm and large irregular/convoluted nuclei, and which are frequently multinucleated with prominent nucleoli. ALCL often presents in advanced clinical stages with B symptoms; extranodal disease occurs in 40% of patients. The pathogenesis of systemic ALCL is linked to phosphorylation of a tyrosine kinase (ALK) resulting in unregulated growth of affected lymphoid cells. ALK is activated through chromosomal translocations/inversions with any of several partner genes, most commonly nucleophosmin (NPM). Downstream signal transduction pathway(s) are not fully defined but appear to involve phospholipase Cgamma, phosphatidylinositol (PI)3K/Akt, and STAT-3 and STAT-5 proteins. Primary cutaneous ALCL appears to have a different pathogenesis and better prognosis than does systemic ALCL, presenting as one or more skin tumors, usually localized. Excision or local irradiation is usually effective treatment. A clinically benign variant of primary cutaneous ALCL is lymphomatoid papulosis (LyP), characterized by recurrent crops of papules/nodules up to 2 cm in diameter which undergo spontaneous regression. LyP is managed by observation, ultraviolet light therapy, or low-dose methotrexate. LyP patients have a predisposition to develop malignant lymphomas, including Hodgkin's lymphoma, mycosis fungoides, and non-Hodgkin's lymphoma, by as yet unknown mechanisms. The prognosis for patients with LyP is otherwise excellent.

Anaplastic Lymphoma Kinase↗
PubMed1999

Generalized lupus erythematosus profundus in a patient with genetic partial deficiency of C4.

Lupus erythematosus profundus (LEP) is an unusual variant of cutaneous lupus erythematosus (CLE)that is characterized by chronic, recurrent inflammation of the subcutaneous tissue leading to fibrosis. It is found in the settings of both discoid and systemic lupus erythematosus. Generalized forms are extremely rare. We present a case of generalized LEP associated with genetic partial C4-deficiency.

Adult↗
PubMed1990

[The importance of preoperative chemotherapy and radiotherapy in 373 children with Wilms' tumor].

Between 1980 and 1988, in a prospective study of 373 children with Wilms' tumour throughout the Federal Republic of Germany, the results of various pre- and postoperative treatment schedules were analysed. There were 184 boys and 189 girls, mean age 3 11/12 (0-27) years. One third each was in group I, II or III-V, respectively. In 52% of cases the tumour volume, measured by ultrasound, was more than 400 ml. 218 of the children were called protocol patients, the remaining 155 served as observation patients, because the latter had histological variants or there had been marked treatment deviations. The stage-adapted treatment always included operation, in 30% of children after pre-operative chemo- or radiotherapy. Radiotherapy was given in selected patients in stage II and always to those in stages III, IV or V. Chemotherapy consisted of Actinomycin D and vincristine, adriamycin was added for stages III-V and cyclophosphamide or ifosfamide for histologically highly malignant variants. Of the 218 protocol patients 196 (90%) were alive without recurrence, after a mean observation time of more than 7 years. Radiotherapy was given to only 105 of the 218 protocol patients. The prognosis of the 155 observation patients differed according to the histology: those with clear-cell type had a better prognosis than previously reported. Among the total group of 373 patients 305 (81.8%) have remained without recurrence after more than 6 years.

Adolescent↗
PubMed2005

Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors.

BACKGROUND: The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. METHODS: We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro. RESULTS: Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly associated with a clinical response (P<0.001; odds ratio, 51; 95 percent confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P=0.001; odds ratio, 40; 95 percent confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib. CONCLUSIONS: Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.

Adult↗
PubMed2003

Low-grade malignant Triton tumor of the oral cavity: a case report.

Malignant Triton tumor (MTT) is a malignant peripheral nerve sheath tumor showing rhabdomyoblastic differentiation. It is considered a high-grade neoplasm with poor outcome. This report describes an MTT appearing in the oral cavity. On histologic examination the encapsulated lesion was composed of interlacing fascicles of spindle cells and scattered, large, strap-like pleomorphic cells with abundant eosinophilic cytoplasm. No cross striations were seen. Examination of levels through the tissue showed a total of only 4 normal mitoses and no necrosis. Immunohistochemistry demonstrated diffuse S100 positivity in the spindle cells. The large pleomorphic cells were weakly positive for alpha-sarcomeric actin and myoglobin, although variably but strongly positive for desmin. Management involved a small en bloc resection of the maxilla. After 33 months there was no sign of recurrence or distant metastasis. It was concluded that low-grade variants of MTT occur that do not have an aggressive clinical course.

Actins↗
PubMed2004

Common and uncommon variants of melanocytic naevi.

Numerous variants of melanocytic naevi have been described. Their main pathological significance lies in their distinction from melanoma, as well as being precursors and risk markers for melanoma. Various degrees of atypia such as cytological atypia, architectural disorder and pagetoid spread (pagetoid melanocytosis) may be present in naevi and need to be recognised as appropriate for the subtype. As well as the distinction from melanoma, naevi must be differentiated from atypical lesions, such as atypical Spitz tumours, which do not fulfil all the criteria of melanoma, may be benign or malignant and have been called 'melanocytic tumours of unknown malignant potential'. The diagnostic grey area also includes a group of benign atypical naevi which are difficult to subclassify into specific entities. In this paper naevi are divided into: firstly, the common acquired group with a brief discussion of junctional, compound and intradermal naevi, minor variants such as halo and balloon naevi and the major variants that may cause problems -- dysplastic naevi, naevi of special sites, recurrent naevi and Spitz naevi; secondly, congenital naevi; thirdly, blue naevi and related lesions (dermal melanocytoses); and finally, combined naevi. The emphasis is on diagnostic pathological features and the differential diagnosis with melanoma.

Diagnosis, Differential↗
PubMed2005

Parathyroid carcinoma: an overview.

Parathyroid carcinoma is a rare tumor that is responsible for <1% of cases of hyperparathyroidism in most parts of the world. An increased incidence of this tumor has been reported in patients with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome, but the etiology of most other cases is unknown. Parathyroid carcinomas tend to occur a decade earlier than adenomas, and the sex ratio approaches unity in contrast to the female preponderance of adenomas. Most patients with carcinomas present with marked hypercalcemia and are more likely to have associated bone and renal disease than those with adenomas. Although fibrosis and mitotic activity are common in carcinomas, these features are not specific for malignancy. The diagnosis of carcinoma should be restricted to those tumors that show invasion of blood vessels, perineural spaces, soft tissues, thyroid gland, or other adjacent structures or to tumors with documented metastases. Mutations of the HRPT2 gene (1q21-q32), which are responsible for the HPT-JT syndrome, have been implicated in the development of a high proportion of parathyroid carcinomas. A subset of patients with mutation-positive carcinomas have germline mutations of the HRPT2 gene. This finding suggests that some patients with apparent sporadic parathyroid carcinomas may have the HPT-JT syndrome or a variant of this syndrome. Because of the high frequency of local recurrence following incomplete excision, an en bloc resection is the preferred surgical approach for treatment of parathyroid carcinomas.

Carcinoma↗
PubMed2000

Pedunculated melanoma with pulmonary and bony metastases.

We report a patient with pedunculated melanoma. Rounded and epithelioid-type melanoma cells had proliferated in the epidermis and massively into the deep dermis in the pedunculated nodule. At the base of the pedicle, lengtiginous-type melanoma cells formed nests of various sizes in the epidermis extending ten or more rete ridges beyond the site of invasion. Thus, this case shows that a pedunculated melanoma is not necessarily a variant of nodular melanoma. Six years after the primary operation, late recurrence was detected in regional lymph nodes, and nine years after the initial operation, the patient was found to have three large metastatic nodules, up to 8.5 cm in longest diameter, in her lung and bone. Although she died six months after the metastasectomy, prompt surgical excision of the primary tumor and metastasectomy can provide longer survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Partial hepatic resection for hepatocellular carcinoma.

This review summarizes the efficacy of the most common therapeutic option for hepatocellular carcinoma (HCC), partial hepatic resection, taking into account not only its antitumoural effect, but also its consequences on survival. Partial hepatic resection results in 5 year survival rates as high as 45% in more favourable subgroups having: small tumours, well-differentiated tumours, unifocal tumours, a lack of vascular invasions, an absence of cirrhosis, and the fibrolamellar variant. Resection has been limited primarily by low resectability rates and recurrent disease. However, surgical resection in the form of partial hepatectomy is the preferred treatment for HCC. The early detection of tumours by screening high-risk populations is crucial. During the 12 year period between 1983 and 1994, hepatic resections were carried out in 382 patients with HCC. One hundred and fifty-three (40%) had HCC smaller than 5 cm in diameter. There were 294 male and 88 female patients, with an average age of 52.3 years. Among them, 45% had liver cirrhosis and 73% were positive for hepatitis B surface antigen. Two hundred and eighteen (57%) were positive for hepatitis C virus circulating antibodies (since 1991). Operative mortality was 3.9%. The overall survival rates at 1, 3 and 5 years were 71, 52 and 46%, respectively. Sex, cirrhosis, Child's staging, surgical procedure, blood loss, pathological pattern, presence of capsule, surgical margin and DNA ploidy appeared to be factors not related to prognosis. However, alpha-fetoprotein level, size (whether less than or greater than 5 cm), and vascular invasion were factors which significantly affect survival.

Carcinoma, Hepatocellular↗
PubMed1993

Epidermolysis bullosa simplex Dowling-Meara: troublesome blistering and pruritus in an adult patient.

A 46-year-old woman with the Dowling-Meara variant of epidermolysis bullosa simplex (DM-EBS) presented with worsening recurrent, pruritic, circinate crops of clear and haemorrhagic herpetiform blisters affecting her trunk and limbs. Electron microscopy showed tonofilament aggregation and an intra-epidermal level of blister formation confirming a diagnosis of DM-EBS rather than an acquired immunobullous disorder. Antihistamines failed to control the intense pruritus, but dapsone (up to 150 mg daily) was beneficial. Mutations of basal cell keratin genes (K14 and K5) are thought to be of aetiopathological significance in this form of epidermolysis bullosa, but the underlying cellular mechanisms responsible for the clinical deterioration and severe itching in this adult patient are not yet clear.

Blister↗
PubMed2005

A common ancestral glycoprotein (GP) 9 1828A>G (Asn45Ser) gene mutation occurring in European families from Australia and Northern Europe with Bernard-Soulier Syndrome (BSS).

Bernard-Soulier syndrome (BSS) is an extremely rare hereditary bleeding disorder, caused by mutations occurring in the Glycoprotein (GP) Ibalpha, GPIbbeta and GP9 genes that encode for the corresponding subunits of platelet GPIb-V-IX adhesion receptor complex. BSS has been reported in many populations, mostly behaving in an autosomal-recessive manner.While the great majority of BSS mutations are unique to a single individual or family, the GP9 1828A>G Asn45Ser mutation, which we have identified in an undocumented Australian Caucasian, has already been reported in multiple unrelated Caucasian families from various Northern and Central European countries. Haplotype analysis of 19 BSS patients from 15 unrelated Northern European families (including 2 compound heterozygote siblings from a British family previously published, and 17 1828A>G Asn45Ser homozygotes), showed that 14 of these BSS patients from 11 of the 1828A>G Asn45Ser homozygote families share a common haplotype at the chromosomal region 3' to the GP9 gene. Hence, the results suggest that the GP9 1828A>GAsn45Ser mutation in these families is ancient, and its frequent emergence in the European population is the result of a founder effect rather than recurrent mutational events. Association of the 1828A>G Asn45Ser mutation with variant haplotypes in 4 other Northern European BSS families raised the possibility of a second founder event, or rare recombinations in these families. Additional members from these 'atypical' lineages would need to be screened to resolve this question.

Alleles↗
PubMed2026

Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome.

With the increasing use of genetic sequencing to investigate inborn errors of immunity, rare variants are frequently identified, yet their clinical relevance often remains uncertain. Establishing pathogenicity requires a multidisciplinary approach that integrates genetic, structural, functional, and clinical data. Here, we used such a strategy to investigate a previously unreported hemizygous missense variant - alanine (A) to threonine (T) at residue 518 - in Toll-like receptor 8 (TLR8), identified in 2 male siblings with recurrent infections and systemic inflammation, characterized by a proinflammatory immune signature and B cell dysregulation. Functional studies showed that the TLR8 A518T variant enhanced NF-&#x3ba;B activation and increased secretion of proinflammatory cytokines compared with WT TLR8 upon stimulation, consistent with a gain-of-function effect. Protein degradation and turnover assays revealed reduced abundance of the mutant TLR8 protein due to faster turnover and increased proteasomal degradation. Computational modeling predicted enhanced structural stabilization of the active TLR8 homodimer interface via additional water-mediated hydrogen bonds introduced by the A518T substitution. Together, these findings integrating structural modeling with functional assays identify a novel TLR8 ligand-specific gain-of-function mutation resulting in complex immunopathology in 2 siblings.

Humans↗
PubMed2005

Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation.

The two genes mutated in the bone marrow failure syndrome dyskeratosis congenita (DC) both encode components of the telomerase complex responsible for maintaining the ends of chromosomes in stem cells and in the germ line. In reviewing the mutation profile that is found in DC, we describe 9 novel mutations in the DKC1 gene and 3 novel TERC mutations responsible for the X-linked and autosomal dominant forms of the disease, respectively, but find that two thirds of the families do not have mutations in either of these genes. In a significant subset of these uncharacterized families, the index case presents with severe disease previously defined as the Hoyeraal Hreidarsson (HH) syndrome. The diverse clinical phenotype seen in patients with X-linked DC is not explained by the different amino acid substitutions: Presentation of the recurrent A353V substitution ranges from classic DC to the severe HH variant. However, we do see that patients with HH have significantly shorter telomeres than those with a relatively mild presentation. In the new families described with TERC mutations, there is further evidence of disease anticipation associated with shorter telomeres in the younger generations. This study highlights the considerable genetic and phenotypic diversity of DC.

Chromosomes, Human, X↗
PubMed1998

Granular cell ameloblastoma of jaw. A report of rare case and brief review of literature.

Ameloblastoma is an epithelial odontogenic tumour of the jaw and exhibits diverse microscopic patterns which occurs either singly or in combination with other patterns. The rare granular cell variant is seen in combination usually with follicular or plexiform subtypes. The reported case reveals the microscopic patterns characteristic of granular cell variant only, which is uncommon. The tumour was excised and no recurrence has been observed after nineteen months of surgery.

Adult↗
PubMed1989

[Osseous metastasis of an intracranial angioblastic meningioma: report of a case].

A case of multiple bone metastases from an angioblastic meningioma (intracranial hemangiopericytoma) is reported. From the clinical and pathologic point of view, it is essential to be aware that the hemangiopericytic variant of meningioma (angioblastic meningioma) displays a significantly higher rate of recurrence and extracranial metastasis than other forms of meningioma.

Adult↗