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PubMed2025

Clinical, Morphologic, and Molecular Findings in Neurotrophic Tyrosine Receptor Kinase 3 (NTRK3) Fusion Spitz Neoplasms.

Neurotrophic tyrosine receptor kinase 3 (NTRK3) fusions are a relatively common driver of Spitz neoplasms. This subset of Spitz neoplasms may have smaller cells without the typical abundant glassy eosinophilic cytoplasm seen in most Spitz neoplasms. This can make it difficult to recognize them as belonging to the Spitz family and potentially result in misdiagnosis as melanoma. In this study, we assessed the clinical, morphologic, and genomic features of 60 NTRK3 fusion Spitz neoplasms (13 previously reported and 47 new cases) and performed a comprehensive review of the literature. We identified 5 characteristic morphologic patterns: (1) conventional Spitz nevus (SN) or Spitz tumor (ST), (2) spindle cell nevus of Reed, (3) spindle cell tumor of Reed, (4) dysplastic SN, and (5) exclusively spindle cell variant of SN/ST. The most common fusion partners were MYO5A and ETV6. DNA copy number changes were infrequent (18% of cases), with an average of 1 copy number variant per case. Among 54 cases tested for a TERT promoter mutation, all were negative. One case had a homozygous deletion of 9p21. The majority of cases were diagnosed as SN or Reed nevi (n = 37), rather than ST or Reed tumor (n = 23), and none were diagnosed as Spitz melanoma. Among the 30 patients with outcome data, none experienced recurrence following excision (mean follow-up time was 15 months). NTRK3 fusions can produce morphologic variants of Spitz neoplasms that may be difficult to recognize as belonging to the Spitz family. Familiarity with these morphologic patterns can facilitate identification of the NTRK3 fusion, optimizing classification and distinction from melanoma.

Humans↗
PubMed2025

Optical Genome Mapping Is a Powerful Diagnostic Tool in Non-Hodgkin Lymphoma.

Non-Hodgkin lymphoma (NHL) is a diverse and heterogeneous group of hematological malignancies. These lymphomas arise from the clonal proliferation of either B/T or natural killer lymphocytes, and their correct classification relies partly on identifying characteristic structural variants and copy number alterations. Current standard-of-care technologies for detecting these genomic features, chromosome banding analysis (CBA) and fluorescent in situ hybridization (FISH), are labor intensive and have specific limitations. CBA has low resolution and relies on viable cell culture, whereas the targeted approach of FISH does not provide the whole genome view required for comprehensive disease characterization. This highlights the need for higher-resolution nontargeted genomic methods. Previous studies have evaluated optical genome mapping (OGM) as a whole genome alternative for cytogenomic characterization in NHL diagnostics but were restricted in number and to cases with peripheral blood and/or bone marrow invasion. Here, we selected a comprehensive cohort of 110 NHL cases (79 B-NHL and 31 T-NHL/natural killer-NHL) derived from different types of tissue biopsies, all with established histopathological diagnoses. Seventy-eight samples were genomically well characterized at diagnosis by CBA and FISH. The remaining 32 cases were included because of previous CBA failure, although FISH data were available for 20 cases. OGM provided informative results in 94% of the cohort, with a high concordance rate of 97.6% compared with CBA/FISH in detecting clinically relevant aberrations. The 2 variants that were missed were both present at the detection threshold of OGM. In contrast, OGM successfully resolved 26 samples with previous CBA failure and detected 3 additional disease-defining events, resulting in diagnostic reclassification of 1 patient. Finally, OGM identified novel recurrent aberrations that warrant further investigation into their pathogenetic implications. To conclude, OGM robustly detects clinically relevant structural variants and copy number alterations and presents a promising alternative to CBA and FISH in routine diagnostic evaluation of NHL.

Humans↗
PubMed2026

Long-Read Haplotype Phasing Resolves Allelic Configuration as a Missing Layer of Precision Oncology.

Short-read sequencing cannot determine whether co-occurring variants within a cancer gene lie on the same allele (cis) or opposing alleles (trans), a distinction with direct therapeutic consequences: trans configurations confirm biallelic tumor suppressor inactivation, whereas cis configurations generate compound oncogenic alleles with enhanced activity. Among 768 patients with prostate, breast, or ovarian cancers, we used mutational signatures to nominate cryptic genomic instability cases lacking a causative biallelic event on short-read sequencing. Long-read nanopore sequencing resolved 32 of 46 cryptic cases (69.6%) through methylation detection, long insertion resolution, and structural variant characterization, confirming trans inactivation in every resolved tumor suppressor case. Analysis of 4,496 MiOncoSeq samples identified 17,519 multi-hit gene pairs, 78.7% of which exceeded the 500 bp short-read phasing limit, and long-read phasing revealed recurrent compound cis alleles in NOTCH1, PIK3CA, PDGFRB, and KIT. Haplotype phasing addresses an overlooked gap in cancer variant interpretation and warrants integration into precision oncology.

Journal Article↗
PubMedDate not supplied

The place of cardiac denervation in the surgical treatment of Prinzmetal variant angina.

Coronary artery spasm has been described as occurring frequently in Prinzmetal variant angina. The relatively poorer results obtained after aorto-coronary by pass grafting carried out in patients with Prinzmetal angina may be due to recurrence of spasm despite the grafts. Accordingly it has been our recent policy since February 1973 to carry out cardiac denervation in all patients with Prinzmetal variant angina. The patients fall into two groups depending on the presence or absence of organic disease in the coronary vessel. The technique of cardiac denervation (plexectomy) as described by Arnulf is fully described and the early and late results of this procedure in the two groups are documented and discussed.

Angina Pectoris, Variant↗
PubMed2002

Recurrent evolution of DNA-binding motifs in the Drosophila centromeric histone.

All eukaryotes contain centromere-specific histone H3 variants (CenH3s), which replace H3 in centromeric chromatin. We have previously documented the adaptive evolution of the Drosophila CenH3 (Cid) in comparisons of Drosophila melanogaster and Drosophila simulans, a divergence of approximately 2.5 million years. We have proposed that rapidly changing centromeric DNA may be driving CenH3's altered DNA-binding specificity. Here, we compare Cid sequences from a phylogenetically broader group of Drosophila species to suggest that Cid has been evolving adaptively for at least 25 million years. Our analysis also reveals conserved blocks not only in the histone-fold domain but also in the N-terminal tail. In several lineages, the N-terminal tail of Cid is characterized by subgroup-specific oligopeptide expansions. These expansions resemble minor groove DNA binding motifs found in various histone tails. Remarkably, similar oligopeptides are also found in N-terminal tails of human and mouse CenH3 (Cenp-A). The recurrent evolution of these motifs in CenH3 suggests a packaging function for the N-terminal tail, which results in a unique chromatin organization at the primary constriction, the cytological marker of centromeres.

Amino Acid Sequence↗
PubMed1984

The biological behavior of primary cerebral neuroblastoma: a reappraisal of the clinical course in a series of 70 cases.

The outcome in 70 patients with primary cerebral neuroblastoma was evaluated in light of their age incidence, histological subtypes, and modes of treatment. In more than 80% of the patients, primary cerebral neuroblastoma occurred in the first decade, most often before the age of 2 years (26%). Over half of the tumors were histologically of the classic variant, the remainder showing varying degrees of mesenchymal stromal response (desmoplastic or transitional variants). Patients with a tumor of the desmoplastic or transitional variant without ganglionic differentiation had a lower mean age at the time of diagnosis than those harboring a tumor of the classic variant. Age could not be correlated with the presence of ganglionic differentiation. The overall 3-year survival rate was 60%. At least 30% of patients have a 5-year postoperative survival. Eight patients survived 7 years after diagnosis, and 3 for more than 10 years. The period of risk for tumor recurrence or death was a function of the initial age at diagnosis (Collins's law). Most deaths or fatal recurrences occurred within the first 3 years after operation. No correlation could be made between survival times and histological variant of the tumor or the presence of ganglionic differentiation. Our data do not indicate that, overall, postoperative irradiation with or without chemotherapy improved length of survival, but an occasional favorable clinical response to chemotherapy did occur. Because of the high incidence of local recurrence and the relative frequency of cerebrospinal metastasis, prophylactic whole brain and spinal irradiation is probably justified.

Adolescent↗
PubMed2000

Histological features of ocular adnexal lymphoma (REAL classification) and their association with patient morbidity and survival.

BACKGROUND: The histological characteristics of ocular adnexal lymphomas have previously provided only a limited guide to clinical outcome for affected patients. This clinicopathological relation was re-examined using the Revised European American Lymphoma (REAL) system to classify the tumours in a large cohort of patients. METHODS: The biopsies and clinical follow up data for 192 patients with ocular adnexal lymphoma were reviewed, the biopsies being regraded in accordance with the REAL classification. For each of five histological groups, logistic regression analysis was used to determine the odds ratios (OR) for the presence of systemic disease at the time of orbital diagnosis and Cox regression analysis was used to assess the hazard ratios (HR) for disseminated disease and lymphoma related death. For 108 patients in whom extraorbital spread occurred, the histological category of lymphoma was compared with the sites of dissemination. RESULTS: At presentation, the frequency of previous or concurrent extraorbital disease increased from marginal zone lymphoma (OR 1.0), diffuse lymphoplasmacytic/lymphoplasmacytoid lymphoma (OR 2.3), follicle centre lymphoma (OR 3.8), diffuse large B cell lymphoma (OR 4.0) to other histological lymphoma variants (OR 26.8). For all histological types, the estimated risk of extraorbital disease and lymphoma related death continued for many years and the proportion of patients with at least one extraorbital recurrence after 5 years was 47% for MZL, 48% for LPL, 64% for FCL, 81% for DLCL, and 95% for other lymphoma variants. The corresponding estimated rates for 5 year lymphoma related mortality were 12%, 19%, 22%, 48%, and 53% respectively. CONCLUSIONS: Patients with ocular adnexal lymphoma can be classified by REAL into five distinct groups, which show a progressive increase in the risks of extraorbital disease at diagnosis, of disease dissemination with time, and of tumour related death.

Adolescent↗
PubMed2004

Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate.

BACKGROUND: Cleft lip or palate (or the two in combination) is a common birth defect that results from a mixture of genetic and environmental factors. We searched for a specific genetic factor contributing to this complex trait by examining large numbers of affected patients and families and evaluating a specific candidate gene. METHODS: We identified the gene that encodes interferon regulatory factor 6 (IRF6) as a candidate gene on the basis of its involvement in an autosomal dominant form of cleft lip and palate, Van der Woude's syndrome. A single-nucleotide polymorphism in this gene results in either a valine or an isoleucine at amino acid position 274 (V274I). We carried out transmission-disequilibrium testing for V274I in 8003 individual subjects in 1968 families derived from 10 populations with ancestry in Asia, Europe, and South America, haplotype and linkage analyses, and case-control analyses, and determined the risk of cleft lip or palate that is associated with genetic variation in IRF6. RESULTS: Strong evidence of overtransmission of the valine (V) allele was found in the entire population data set (P<10(-9)); moreover, the results for some individual populations from South America and Asia were highly significant. Variation at IRF6 was responsible for 12 percent of the genetic contribution to cleft lip or palate and tripled the risk of recurrence in families that had already had one affected child. CONCLUSIONS: DNA-sequence variants associated with IRF6 are major contributors to cleft lip, with or without cleft palate. The contribution of variants in single genes to cleft lip or palate is an important consideration in genetic counseling.

Cleft Lip↗
PubMed2000

Lipidized fibrous histiocytoma: clinicopathologic analysis of 22 cases.

We report the clinicopathologic analysis of 23 tumors from 22 patients with lipidized fibrous histiocytoma (FH), which has been an underrecognized variant of cutaneous FH. The 16 men and 6 women patients (male/female ratio, 2.7:1) ranged in age from 21 to 82 years (median, 50 years). The location of the tumor was concentrated strikingly in the lower limb, especially around the ankle, hence the alternative informal designation of "ankle-type" FH. The tumors showed relatively large size compared with those of conventional FH, ranging up to 8 cm in greatest dimension (median, 2.5 cm), and tended to be polypoid and yellowish in color. Hyperlipidemia was only a rare and perhaps incidental association in two cases. Histologically, lipidized FH was characterized by accumulation of numerous foam cells, smaller numbers of siderophages, and stromal hyalinization typically appearing "wiry," keloidlike, or osteoidlike, although focal features of ordinary FH almost always coexisted and were identified as a focal storiform or curlicue pattern of spindle tumor cells, epidermal hyperplasia, and peripheral "entrapped" dermal collagen. Although follow-up data are limited, the prognosis appears to be good with no recurrence, even after incomplete excision. These clinicopathologic features highlight lipidized FH as a distinctive variant, which can be distinguished from ordinary or other variants of FH, as well as from other foam cell-rich cutaneous lesions, especially xanthoma.

Adult↗
PubMed2004

A preliminary study of PEFR monitoring in patients with chronic cough.

It is important to make a differential diagnosis of cough variant asthma in patients with chronic cough. To examine whether or not peak expiratory flow rate (PEFR) is useful for the differential diagnosis of cough variant asthma in such patients, diurnal variation rates of PEFR were calculated in 23 patients who presented with dry cough lasting four or more weeks and who showed no abnormalities on chest radiographs. None of the patients had wheezes, and pulmonary function testing at the time of visit to the hospital revealed no abnormalities. During the control period, the mean diurnal variation rate of PEFR in 23 patients was 16.3 +/- 7.9%. Six, nine and eight patients had PEFR diurnal variations rates of <10% (Group 1), 10-19% (Group 2), and > or = 20% (Group 3), respectively. At week 3 of treatment with bronchodilators, only Group 3 showed a significant decrease in PEFR diurnal variation rate from 25.7% to 10.1%. The cough score decreased significantly in Group 3 only. These patients had enhanced bronchial hyperresponsiveness and showed eosinophils in induced sputum, leading to the diagnosis of cough variant asthma (CVA). After making the diagnosis of CVA, an inhaled corticosteroid or a Th2 cytokine production inhibitor suplatast tosilate was administered to patients; consequently, they showed no recurrence of cough. PEFR monitoring allowed the detection of morning dip and was suggested to be potentially useful for the differential diagnosis of cough variant asthma in patients with chronic cough.

Adult↗
PubMedDate not supplied

Successful repair of recurrent coarctation after neonatal heart transplantation.

Neonatal orthotopic heart transplantation is an attractive primary surgical therapy for severe uncorrectable congenital heart defects such as variants of the hypoplastic left heart syndrome. Aortic arch reconstruction is frequently required to repair the hypoplastic aortic arch and the coarctation at the time of graft implantation. Residual coarctation of the aorta after neonatal heart transplantation for such a condition has satisfactorily been treated with percutaneous balloon dilatation. We describe the successful surgical repair of a recurrent coarctation of the aorta via a sternotomy in a 2-year-old patient who had previously undergone neonatal orthotopic heart transplantation. Postoperative periodic investigations have not shown any evidence of obstruction across the site of the primary end-to-end anastomosis.

Anastomosis, Surgical↗
PubMed1999

Ameloblastic fibroma and related lesions: current pathologic concept.

Ameloblastic fibroma (AF) is a true mixed tumor, in which the epithelial and the ectomesenchymal elements are neoplastic. There are two rare variants of AF; granular cell AF and peripheral AF. Ameloblastic fibrosarcoma is a rare tumor, and is regarded as the malignant counterpart of the benign AF. Recent immunohistochemical study using MIB-1 shows labelling indices in the mesenchymal component of the recurrent AF and ameloblastic fibrosarcoma are quite high, in contrast with the conventional AF. Ameloblastic fibrodentinoma is a histologic variant of AF in which dentin or dentinoid tissue has formed, but there is no eveidence that ameloblastic fibrodentinoma exhibit a different biologic behavior than ordinary AF. Ameloblastic fibro-odontoma is a lesion similar to AF, but also showing inductive changes that lead to the formation of both dentin and enamel. Some lesions diagnosed as ameloblastic fibro-odontoma are probably developing odontoma, but the others should not be considered as hamartomatous in nature, since there are rare cases of ameloblastic fibro-odontoma showing true neoplastic behavior, and since the existence of malignant variant is evident. In revised WHO's classification of odontogenic tumors, the terms "ameloblastic fibrodentinoma" and "dentinoma" are used synonymously, however, there are histologic difference between several cases reported previously as "dentinoma" and ameloblastic fibrodentinoma.

Ameloblastoma↗
PubMed2002

Disseminated pagetoid reticulosis (Ketron-Goodman disease): six-year follow-up.

Pagetoid reticulosis consists of 2 types: Woringer-Kolopp and Ketron-Goodman disease (K-G). Compared with the former, K-G may have disseminated lesions and a guarded prognosis. We encountered a case of K-G in a 67-year-old man with disseminated plaques on the neck, the trunk, and both extremities. Histologic specimens demonstrated medium- to large-sized, atypical cells infiltrating in the lower epidermis. The phenotype (CD3(+), CD4(-), CD8(-), CD45RO(-), CD45RA(+)) and ultrastructural findings suggest that these cells were immature T cells. Although PUVA was initially effective, new plaques in which atypical cells are still present histologically, have appeared through a 6-year follow-up. Literature review revealed the high rate of recurrence. These findings suggest that K-G is an epidermotropic or immature T-cell variant of mycosis fungoides. In patients with K-G, therefore, long-term observation is necessary: Disappearance of cutaneous lesions may not mean cure.

Aged↗
PubMed1998

Acquisition of chemoresistance in a human ovarian carcinoma cell is linked to a defect in cell cycle control.

Chemoresistance is a major concern in cancer erradication; it involves various mechanisms, including defects in the apoptosis program induced by anticancer drugs. In order to further explore the mechanisms underlying the development of chemoresistance in ovarian carcinoma after cisplatin treatment, we established an in vitro model, mimicking a clinical protocol of administration of cisplatin. Therefore, IGROV1 ovarian carcinoma cells were exposed for 2 hr to the drug and allowed to recover for several weeks; this way of exposure was reiterated with escalating doses. We followed changes in cytotoxicity of the drug, cell cycle kinetics and long-term survival of cells after cisplatin treatment, and found that resistance to cisplatin was not associated with altered apoptosis pathway, since both cisplatin sensitive and resistant cells underwent apoptosis in a similar way. Acquisition of resistance to cisplatin was associated with the ability of the treated cells to progress through the cell cycle beyond the G1/S checkpoint; although most cells died by apoptosis, a few surviving cells proliferated and recolonized the cultures. Compared to sensitive cells, the chemoresistant variants were able to override the G1/S checkpoint whatever the dose, and the recurrent cells recolonized the cultures much faster. Analysis of alterations in gene expression suggests that the defect in cell cycle regulation could take place at the level of the cdk inhibitor p21(CIP1/WAF1).

Antineoplastic Agents↗
PubMed1992

Sarcomatoid carcinoma of the prostate. A clinicopathologic study of 12 patients.

Sarcomatoid carcinoma of the prostate is a rare tumor that can be difficult to distinguish from a true sarcoma. The authors report 12 patients in whom the typical light microscopic appearance of prostatic adenocarcinoma was accompanied by the appearance of spindled or pleomorphic sarcomatoid areas within the same specimen or in subsequent accessions. Immunostaining or electron microscopic study demonstrated epithelial differentiation within the sarcomatoid area(s) in 6 of the 11 patients in whom special studies were performed. All nine patients for whom follow-up data were available died of disease within 3 to 48 months (median time until death, 12.0 months) after the appearance of the sarcomatoid carcinoma, and the clinical course in each instance was characterized by aggressive local recurrence. Our experience confirms that sarcomatoid carcinoma of the prostate is an aggressive variant of prostatic adenocarcinoma.

Aged↗
PubMed2006

Pilomyxoid astrocytoma in a patient with neurofibromatosis.

Pilomyxoid astrocytoma (PMA), a recently described variant of low-grade astrocytoma is associated with a high rate of recurrence and a propensity for CSF seeding. While cases of PMA have been reported in infants and young children, there has been no report of PMA in patients with neurofibromatosis. The first reportable case of PMA occurring in a child with neurofibromatosis type 1 (NF1) is described. Following presentation with obstructive hydrocephalus, the patient underwent a partial resection of a third ventricular tumor. Histology confirmed the typical features of PMA. The patient demonstrated a partial response to chemotherapy. The authors review the literature on PMA and discuss the specific issues associated with this diagnosis in the context of a child with neurofibromatosis.

Astrocytoma↗
PubMed1991

The molecular genetics of haemophilia A: screening for point mutations in the factor VIII gene using the restriction enzyme TaqI.

A combination of Southern blotting and the analysis of polymerase chain reaction (PCR) amplified DNA fragments was used to screen the factor VIII genes of 527 haemophilia A patients for point mutations within TaqI restriction sites. Since this "directed search" strategy yielded only four gene lesions, it was concluded that its efficacy is less than that originally predicted. One novel point mutation was however found in a moderately severe haemophiliac; a CGA (Arg) to CTA (Leu) transversion at codon 2209, an evolutionarily conserved residue in the C2 domain of the factor VIII protein. The remaining three detected lesions, CGA (Arg)----TGA (Term) transitions at codons 2116, 2147 and 2307, respectively, have been reported before and are consistent with recurrent mutation at these hypermutable sites. A number of TaqI restriction site polymorphisms/rare variants were also noted. These variants appear to be population-specific but are nevertheless potentially useful in individual cases as intragenic markers for carrier detection and antenatal diagnosis.

Base Sequence↗
PubMed1986

Computed tomography in the differential diagnosis of the enlarged retrorectal space.

The value of computed tomography (CT) in the differentiation of an enlarged retrorectal space was analyzed in 132 cases. Classification of barium enema findings into those with simultaneous mucosal alterations and those without any visible lesions of the rectal mucosa seems to be useful. Computed tomography helps in those cases without mucosal changes to differentiate between retrorectal fibrosis, tumorous masses, and inflammatory diseases of the colon. It also demonstrates the lack of pathologic lesions in equivocal cases of pelvic lipomatosis and so-called "normal variants." If simultaneous mucosal involvement on barium enema--especially in rectal carcinoma or recurrent carcinoma of the rectum--is found, CT may show the perirectal extension of tumorous masses and thus help to clarify local operability.

Abscess↗