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PubMed1984

Management of locally advanced breast cancer (stage III): a review.

Patients classified as having locally advanced breast cancer constitute a heterogeneous population of patients with variable prognoses among subgroups. Analysis of reported series has been complicated by the use of a wide variety of staging classifications and the inclusion by some (and not by others) of inflammatory carcinoma in reporting of end results. In spite of difficulties in this literature review, certain conclusions are possible: The 1983 AJCC-UICC staging system would appear to be a reasonable system for assuring comparability of results in future clinical trials. Although the precise frequency of LABC among series cannot be determined with certainty, this presentation probably constitutes less than 20% of series in the Western world. Recognizing that axillary lymph node status is the single most important prognostic variable in primary breast cancer, it has been reported that LABC with large local tumors are associated with neoplastic involvement of axillary lymph nodes in 65-80% of cases, thus connoting a poor prognosis. Patients with T3N0 lesions may constitute a subgroup of patients with relatively indolent (possibly receptor-positive) disease who might have a reasonably good prognosis compared with other variants of LABC, with approximately 75% to 82% of patients surviving five years with surgery alone. Surgery alone for the overall category of LABC is associated with a 20-31% ten-year survival rate, with local control varying from 50-75% in two reported series. Most radiation therapy (XRT) series deal with patients considered inoperable; hence five-year survival statistics in most series range between 10-20%. Selected radiation therapy series may yield results comparable to surgical series. Where reported, XRT has been associated with median survivals in the range of 25 months. Local control with XRT is likely a function of radiation dose, and the use of external beam or iridium implant boosts to the primary tumor mass for increased local control is worthy of continued study. The combination of XRT and mastectomy appears to be superior to either modality alone in terms of local control and survival, although this conclusion is based on analysis of retrospective studies. Combined modality therapy with systemic therapeutic modalities (hormonal and/or chemotherapy) plus the local modalities of surgery and radiation therapy appear promising. Prospective controlled trials using a uniformly accepted staging classification coupled with gathering of useful biological data (such as cytokinetic perturbation data, receptor information, marker studies, etc) should lead to improved treatment approaches in the future.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2026

GenProb-PCSM: A Simplified Weighted Germline Score for Prostate Cancer-Specific Mortality.

BACKGROUND: We previously developed a tier-based germline classification using the National Comprehensive Cancer Network (NCCN)-recommended DNA damage repair (DDR) genes and KLK3 I179T to predict prostate cancer (PCa)-specific mortality (PCSM). To provide an easier-to-use single inherited risk score while preserving gene-specific effects, we developed GenProb-PCSM. METHODS: We analyzed 14,644 men with incident PCa from the UK Biobank. The cohort was randomly divided into training (60%) and independent testing (40%) datasets. GenProb-PCSM was developed in the training cohort by integrating pathogenic variants in ten NCCN-recommended DDR genes and the KLK3 I179T variant using gene-specific weights derived from Fine-Gray competing-risk models. Performance was evaluated in the independent testing cohort by discrimination, calibration, and risk stratification. Secondary analyzes evaluated metastatic progression and the composite endpoint of metastatic progression and/or PCSM. RESULTS: Among 14,644 men with incident PCa, 1,581 died from PCa. GenProb-PCSM remained significantly associated with PCSM in the independent testing cohort (HR per SD, 1.18; 95% CI, 1.12-1.24; p&#x2009;<&#x2009;0.001). Using predefined risk thresholds derived from the training cohort, patients in the intermediate- and high-risk groups had significantly increased risks of PCSM compared with the low-risk group (HR 1.49, 95% CI 1.22-1.84; and HR 4.04, 95% CI 2.58-6.33, respectively). GenProb-PCSM also predicted independent metastatic progression and the composite endpoint of metastatic progression and/or PCSM. CONCLUSIONS: GenProb-PCSM transforms complex germline findings into a single inherited risk score for PCSM and metastatic progression. Its simplicity and preservation of gene-specific effects may facilitate clinical implementation of germline prognostic assessment in PCa.

DNA damage repair genes↗
PubMed1996

Cytogenetic findings in 175 patients indicate that items of the Kiel classification should not be disregarded in the REAL classification of lymphoid neoplasms.

Cytogenetics have proved to be a valuable tool for classifying systemic lymphatic neoplasms, as this technique allows different stem line aberrations and clonal developments to be distinguished. This study was designed to analyze how far groups defined according to common cytogenetic features correlated with their position in either the Kiel (KC) or the REAL classification. Cytogenetic analyses were performed on material from 175 patients with lymphoid neoplasms (LN). Samples were prepared from peripheral blood and bone marrow in acute lymphoblastic leukemia (ALL), from bone marrow in multiple myeloma (MM), and from lymph node biopsies in lymphomas. The results of this study support the inclusion of ALL, MM, and extranodal lymphomas into a comprehensive classification, because their chromosomal aberrations were always characteristic for LN. From the cytogenetic point of view, a subgroup of ALL appears as a leukemic manifestation of lymphoblastic lymphoma. MM have structural aberrations of chromosomes 1, 11, and 14 and secondary aberrations of chromosomes 3, 6, 7, 12, 13, and 18, all of which are characteristic for lymphatic disease. The groups with follicle center cell lymphoma and mantle cell lymphoma correlate well with our results both in the low-grade subtype and in the blastic variant type, the majority of cases demonstrating t(14; 18) and its variants and t(11; 14), respectively. In contrast, the group of diffuse large B-cell (DLB) lymphomas proved to be heterogeneous on the basis of our cytogenetic results. Accordingly, we would suggest keeping the immunoblastic lymphoma (IB) subtype defined by the KC. IB demonstrates no stem line aberration in common with any other group and seems to be characterized by stem line aberrations involving chromosomes 3 and 6. As some DLB lymphomas have a t(14;18) or variant translocations involving chromosome 18, they should either be separated as a subgroup or included into the group of follicle center lymphomas.

Adult↗
PubMed2004

Genomic organization and transcripts of the zebrafish Protocadherin genes.

We have examined the protocadherin (Pcdh) gene clusters of the zebrafish (Danio rerio). At least three sets of the Pcdh gene cluster were found in the zebrafish genome. Here, we describe the complete organization of the DrPcdh2 gene clusters. Classification by phylogenetic and transcript analyses revealed 7 DrPcdh2omicron, 20 DrPcdh2alphaa, 12 DrPcdh2alphab, and 1 DrPcdh2alphac variable exons upstream of the DrPcdh2alpha constant region exons in the DrPcdh2 gene cluster. The constant regions of the DrPcdh1alpha and DrPcdh2alpha genes in zebrafish were orthologs of those of the mammalian Pcdhalpha. These exons all encoded plural PXXP motifs in their cytoplasmic tails. The sequences of the variable exons were highly conserved within each family: DrPcdh2omicron, DrPcdh2alphaa, and DrPcdh2alphab. Transcript analysis revealed that zebrafish Pcdhs had alternatively spliced variants in the constant region that were not found in mammals. More gene clusters, more variable exons, and more alternative splicing variants were found in zebrafish than in mammals. Thus, although the Pcdhalpha families were common to diverse vertebrates, their gene number, structure, and transcripts were different between teleosts and mammals.

Alternative Splicing↗
PubMed1991

Mitochondrial encephalomyopathies in childhood. II. Clinical manifestations and syndromes.

During a 4-year period 1984 to 1988, 20 children referred with manifestations of central nervous system or neuromuscular disease combined with hyperlactatemia were found to have a mitochondrial disease. Each diagnosis was based on the results of thorough biochemical and morphologic investigations. The patients were separated into one series with mainly encephalopathy (n = 14) and another with mainly myopathy (n = 6). The patients with encephalopathy had the following syndromes: Kearns-Sayre (n = 2), MERRF (myoclonus epilepsy and ragged red fibers; n = 2), MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes; n = 3), Alpers (n = 3), Leigh (n = 1), and other variants (n = 3). In patients with myopathy, three had hypertrophic nonobstructive cardiomyopathy. Ultrastructural abnormalities of mitochondria were the most common morphologic changes in the muscle biopsies. Complex I deficiency was most common in the patients with encephalopathy. All of the patients with myopathy had complex IV deficiency. Mutations of mitochondrial DNA were found in six patients with encephalopathy. We conclude that identification of defects at the DNA level and determination of the phenotypic expression with clinical, morphologic, and biochemical methods are fundamental for future rational classification of mitochondrial disorders.

Adolescent↗
PubMed1999

Neuropathology of prion diseases.

Prion diseases include sporadic forms such as Creutzfeldt-Jakob disease (CJD), familial forms (familial CJD), fatal familial insomnia, Gerstmann-Sträussler-Scheinker disease, and acquired forms (i.e., kuru, iatrogenic CJD). The most frequent of the latter include acquired forms secondary to injections of human cadaveric pituitary-derived growth hormone and the new variant of CJD--probably related to bovine spongiform encephalopathy. The communal lesions are neuronal loss, spongiosis and gliosis and, inconstantly, the presence of amyloid plaques and different kinds of small deposits immunolabeled with anti-prion (PrP) antibodies. Their number and topography are variable. Recent works have shown the role of the host genotype, especially of codon 129, in the susceptibility to these diseases. We have tried to correlate neuropathology with the genotype of codon 129 and the type of PrP to establish a molecular classification.

Animals↗
PubMed2002

A random study of Asian male androgenetic alopecia in Bangkok, Thailand.

BACKGROUND: Androgenetic alopecia remains the most common cause of male pattern baldness (MPB) in all races. The prevalence of MPB in Caucasians is well documented. The prevalence of MPB in Asians is believed to be very low, only one-fourth to one-third on average compared to Caucasians. However, according to my previous study, there is a clear trend indicating that it is approaching that of Caucasians. OBJECTIVE: To assess the prevalence of MPB in the Asian population in Bangkok, Thailand; to compare this prevalence to previous studies conducted on Asians; and to compare the results to previous studies conducted on Caucasian. METHODS: This study was conducted by two physicians and assisted by two registered nurses. The questionnaire included age, sex, Norwood classification, diet, family history of baldness, income, and education. The physicians examined the scalp of each interviewee upon completion of each questionnaire. The ethnic focus group in this study was Thai and Chinese who reside in Bangkok, Thailand. The interviews were conducted in hospitals, nursing homes, classroom, medical meetings, temples, parks, and villages. RESULTS: A total of 1124 men were randomized in this study. The prevalence of cosmetically significant MPB (Norwood III-VII) was 38.52% and steadily increasing with age, approaching that of Caucasians. Variant MPB was found to be 0.67% and other types of androgenetic alopecia was 0.6%. From an ethnic point of view, the majority of the groups were of mixed blood and mostly of Chinese origin, thus we were unable to distinguish between Chinese and Thai. CONCLUSION: This study shows that the prevalence of MPB in Asians is not as low as previously thought. The cause of this increasing prevalence is uncertain. There are no past studies in Thailand for comparison, however, it can be extrapolated that the socioeconomic environment and westernized diet may contribute to this prevalence.

Adolescent↗
PubMedDate not supplied

[Position of ocular amyloidosis among various forms of amyloidosis].

New data, concerning incidence, morphology, clinical manifestations of eye amyloidosis are obtained following its study using modern verification methods. Eye amyloidosis is represented either by its local forms or is associated with a generalized amyloidosis. Local eye amyloidosis predominated and may be isolated and combined. Isolated amyloidosis is represented by two variants: with an involvement of the anterior part of the eye in the form of pseudoexfoliative amyloidosis (PEA) and involvement of the posterior part of the eye with the development of senile macular degeneration (SMD). Local amyloidosis may be associated with senile cerebral amyloidosis, insular amyloidosis of pancreas and both. Predominant involvement of the eye vessels and extraocular structures is an important feature of the ocular amyloidosis as a manifestation of generalized forms. Vitreous body is involved mainly in FAP. New clinico-morpho-pathogenetic classification is suggested.

Adult↗
PubMed1983

[Classification of amyotrophic lateral sclerosis (clinico-electromyographic study)].

On the basis of the clinical electromyographic examination of 117 patients with lateral amyotrophic sclerosis, the relationship was ascertained between the manifestations of this illness and the primary localization of amyotrophies in the distal or proximal regions of the extremities. The first group was characterized by rapid generalization of the pathological process and by the presence of marked symptoms of the involvement of the segmento-nuclear motoneurons and the pyramidal tracts whilst the second group largely manifested impairment of the anterior cornual motor cells and the spinal localization of the process throughout the course of the disease. It is suggested that cervicothoracic and lumbosacral forms of the illness be subdivided into distinctive variants in relation to the primary localization of amyotrophies in the distal or proximal regions of the extremities.

Adolescent↗
PubMed1998

Prion diseases in man.

Prion diseases are uncommon fatal neurodegenerative disorders which have gained scientific and public importance as a result of major advances in the understanding of the nature of the causative agent, and the emergence of new forms of these diseases in both animals and man. The transmissible agent in prion diseases is unique and is closely associated with an abnormal isoform of a widely distributed cell-surface glycoprotein, prion protein. The precise mechanisms of conversion to the abnormal isoform are unknown; changes in protein folding are of major importance. The abnormal isoform of the protein accumulates in the central nervous system in all prion diseases, but the processes involved in protein accumulation and the pathogenesis of neuronal dysfunction and cell death are poorly understood. Human prion diseases occur as sporadic, familial, and acquired disorders, the most recently identified of which is new variant Creutzfeldt-Jakob disease, which has been aetiologically linked to exposure to the bovine spongiform encephalopathy agent through the food chain. Surveillance of human prion diseases will be crucial in the assessment of the impact of this new disease in the United Kingdom and elsewhere. Effective surveillance depends on accurate diagnosis, which in turn places a high priority on autopsy in suspected cases; neuropathology is essential for the diagnosis of human prion diseases. Phenotypic variation is prominent in all forms of human prion disease; future classifications of these disorders are likely to incorporate genetic and biochemical data in addition to clinical and pathological parameters.

Animals↗
PubMed2000

The genetics of mental illness: implications for practice.

Many of the comfortable and relatively simple models of the nature of mental disorders, their causes and their neural substrates now appear quite frayed. Gone is the idea that symptom clusters, course of illness, family history and treatment response would coalesce in a simple way to yield valid diagnoses. Also too simple was the concept, born of early pharmacological successes, that abnormal levels of one or more neurotransmitters would satisfactorily explain the pathogenesis of depression or schizophrenia. Gone is the notion that there is a single gene that causes any mental disorder or determines any behavioural variant. The concept of the causative gene has been replaced by that of genetic complexity, in which multiple genes act in concert with non-genetic factors to produce a risk of mental disorder. Discoveries in genetics and neuroscience can be expected to lead to better models that provide improved representation of the complexity of the brain and behaviour and the development of both. There are likely to be profound implications for clinical practice. The complex genetics of risk should reinvigorate research on the epidemiology and classification of mental disorders and explain the complex patterns of disease transmission within families. Knowledge of the timing of the expression of risk genes during brain development and of their function should not only contribute to an understanding of gene action and the pathophysiology of disease but should also help to direct the search for modifiable environmental risk factors that convert risk into illness. The function of risk genes can only become comprehensible in the context of advances at the molecular, cellular and systems levels in neuroscience and the behavioural sciences. Genetics should yield new therapies aimed not just at symptoms but also at pathogenic processes, thus permitting the targeting of specific therapies to individual patients.

Genetic Predisposition to Disease↗
PubMed2006

The Spitzoid lesion: rethinking Spitz tumors, atypical variants, 'Spitzoid melanoma' and risk assessment.

Although much remains to be learned about Spitzoid lesions, there is increasing evidence that these tumors may be a type of melanocytic neoplasm distinct from conventional melanocytic nevi and malignant melanoma. In the current communication, the author has attempted to describe accurately the state-of-the-art surrounding these lesions, their nomenclature, and assessment of risk. Acknowledging the peculiar nature of Spitzoid lesions, the author prefers the term Spitz tumor rather than 'Spitz nevus' (except perhaps for the most typical lesions) and argues against using the term 'Spitzoid melanoma' until more information is available to justify such a term. The author also believes that patients are best served by the comprehensive evaluation of Spitzoid lesions and their classification into three categories: (1) Spitz tumor without significant abnormality, (2) Spitz tumor with one or more atypical features (atypical Spitz tumor), including those judged to have indeterminate biological potential, and (3) malignant melanoma, rather than the two categories of 'Spitz nevus' and melanoma. Only rigorous characterization of sufficient numbers of Spitzoid lesions and long-term follow-up of patients will provide truly objective information for the formulation of optimal guidelines for the management of patients with these lesions.

Diagnosis, Differential↗
PubMed1986

Mitochondrial dysfunction and spinocerebellar degenerations.

A simplified classification of the spinocerebellar degenerations is proposed. Axonal ataxias include Friedreich's ataxia and other conditions involving, primarily, neurons with very long axons. Multiple system degenerations include the various olivopontocerebellar atrophies and related disorders. Ataxic encephalopathies are diffuse diseases of the nervous system in which ataxia is a prominent clinical feature. Several lines of data suggest that mitochondrial damage is a common mechanism in the spinocerebellar degenerations. Reasonable pathophysiological mechanisms can be invoked, linking mitochondrial damage to the observed pathologies (including the many cases of intermediate on variant forms).

Ataxia↗
PubMed2026

A novel missense mutation in tropomyosin 1 gene associated with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a common genetic heart disorder that can lead to heart failure or sudden death. Family-based identification of rare sarcomeric variants can support molecular diagnosis and cascade screening in inherited HCM. This study aimed to identify and evaluate a novel TPM1 variant found in a Vietnamese family with HCM. The proband, a 3-year-old boy diagnosed with HCM, and eight relatives from three generations underwent clinical and genetic evaluation. A candidate variant initially identified by targeted next-generation sequencing was validated by PCR and Sanger sequencing. Familial segregation analysis was performed, and variant pathogenicity was assessed according to ACMG guidelines with support from in silico prediction and structural modeling. Sanger sequencing confirmed a heterozygous missense variant in exon 6 of TPM1 NM_001018005.2:c.576G&#xa0;>&#xa0;C, p.(Glu192Asp), in the proband, his father, and paternal grandfather, all of whom exhibited clinical signs of HCM. The variant was absent in unaffected relatives and in public population databases. Based on ACMG criteria (PM1, PM2, PM5, and PP3), the variant was classified as likely pathogenic. This novel TPM1 variant segregated with HCM in a Vietnamese family, expands the known mutational spectrum of TPM1 in hypertrophic cardiomyopathy, and warrants further functional investigation and familial genetic evaluation.

American College of Medical Genetics and Genomics ↗
PubMed2006

Pseudo-messenger RNA: phantoms of the transcriptome.

The mammalian transcriptome harbours shadowy entities that resist classification and analysis. In analogy with pseudogenes, we define pseudo-messenger RNA to be RNA molecules that resemble protein-coding mRNA, but cannot encode full-length proteins owing to disruptions of the reading frame. Using a rigorous computational pipeline, which rules out sequencing errors, we identify 10,679 pseudo-messenger RNAs (approximately half of which are transposon-associated) among the 102,801 FANTOM3 mouse cDNAs: just over 10% of the FANTOM3 transcriptome. These comprise not only transcribed pseudogenes, but also disrupted splice variants of otherwise protein-coding genes. Some may encode truncated proteins, only a minority of which appear subject to nonsense-mediated decay. The presence of an excess of transcripts whose only disruptions are opal stop codons suggests that there are more selenoproteins than currently estimated. We also describe compensatory frameshifts, where a segment of the gene has changed frame but remains translatable. In summary, we survey a large class of non-standard but potentially functional transcripts that are likely to encode genetic information and effect biological processes in novel ways. Many of these transcripts do not correspond cleanly to any identifiable object in the genome, implying fundamental limits to the goal of annotating all functional elements at the genome sequence level.

Animals↗
PubMedDate not supplied

Anatomy of the junction of the inferior petrosal sinus and the internal jugular vein.

PURPOSE: To evaluate the anatomy of the junction of the inferior petrosal sinus and the internal jugular vein. METHODS: Using a previously described classification system, we prospectively classified venous anatomy bilaterally in 135 of 136 persons consecutively undergoing inferior petrosal sinus sampling. RESULTS: Type IV anatomy, with no anastomosis between the inferior petrosal sinus and the internal jugular vein, was significantly less frequent in our series than in a previous series (1 versus 7%; P < .001). Venous anatomy did not differ significantly between the left and the right junctions or between men and women. Venous anatomy was symmetric in only 65% of subjects (86 of 133). We describe an uncommon variant anatomy, incomplete type IV, found in 4.5% of our subjects (six of 133), that may cause incorrect results of petrosal sinus sampling. CONCLUSION: Bilateral sampling of pituitary venous effluent can be accomplished by the methods described, despite the presence of either incomplete or true type IV venous anatomy. Bilateral petrosal sinus sampling is anatomically possible in 99% of persons.

Adolescent↗
PubMedDate not supplied

[New radiologico-clinical classification of changes in stress incontinence in women].

Setting forth their experience in over 800 colpocystographies applied in genital prolapse and stress incontinence, the authors propose an original classification of changes in urinary stress incontinence with a view to unifying clinical and radiological findings. Along with classical, wellknown radiological aspects (urethral vesicalization and the prolapse of the urinary bladder) one new type of changes is described. It is named the slipping prolapse of the urinary bladder and is determined by the deterioration of the urethro-vaginal septum leading to a completely isolated dislocation of the lower urinary organs and the frontal vaginal wall. The combination of these aspects gives the three types and six variants of stress incontinence which, from the clinical point of view, may be manifest, masked, and potential. The pathogenesis of different types of the disease is analysed, as well as the principles of their therapy. The authors plead for the widest possible use of colpocystography in the preoperative preparation on patients, especially in relapses, since the method is simple and harmless, yielding extremely useful informations in the study of the morphotopography of pelvic organs.

Female↗
PubMed2025

Integrating Imaging-Derived Clinical Endotypes with Plasma Proteomics and External Polygenic Risk Scores Enhances Coronary Microvascular Disease Risk Prediction.

Coronary microvascular disease (CMVD) is an underdiagnosed but significant contributor to the burden of ischemic heart disease, characterized by angina and myocardial infarction. The development of risk prediction models such as polygenic risk scores (PRS) for CMVD has been limited by a lack of large-scale genome-wide association studies (GWAS). However, there is significant overlap between CMVD and enrollment criteria for coronary artery disease (CAD) GWAS. In this study, we developed CMVD PRS models by selecting variants identified in a CMVD GWAS and applying weights from an external CAD GWAS, using CMVD-associated loci as proxies for the genetic risk. We integrated plasma proteomics, clinical measures from perfusion PET imaging, and PRS to evaluate their contributions to CMVD risk prediction in comprehensive machine and deep learning models. We then developed a novel unsupervised endotyping framework for CMVD from perfusion PET-derived myocardial blood flow data, revealing distinct patient subgroups beyond traditional case-control definitions. This imaging-based stratification substantially improved classification performance alongside plasma proteomics and PRS, achieving AUROCs between 0.65 and 0.73 per class, significantly outperforming binary classifiers and existing clinical models, highlighting the potential of this stratification approach to enable more precise and personalized diagnosis by capturing the underlying heterogeneity of CMVD. This work represents the first application of imaging-based endotyping and the integration of genetic and proteomic data for CMVD risk prediction, establishing a framework for multimodal modeling in complex diseases.

Cardiovascular Disease↗