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A description of malignant carcinoid of alveolartrabecular structure developing in the edge of chronic progressive gastric ulcer is presented. Granules detectable by argirophilic method of Grimelius, toluidine blue after acid hydrolysis, and lead hemotoxylin were found in the cytoplasm of tumor cells. Changes in the epithelium of the type of cancer in situ as well as marked hyperplasia of argirophilic cells were observed in gastric mucosa in the edges of the ulcer. Although this observation may be interpreted as a peculiar variant of Zollinger-Ellison syndrome, it is more likely that this is a malignized chronic ulcer with carcinoid differentiation of the tumor tissue.
A replaced right hepatic artery, originating from the superior mesenteric artery, was identified on precontrast abdominal computed tomography and confirmed by a postcontrast dynamic study. This normal anatomic variant can be correctly interpreted by the radiologist, and its correct identification is of potential importance in surgical planning.
Female genital tract neoplasms that may have a deceptively benign appearance and selected frankly malignant neoplasms that may be misinterpreted as less aggressive lesions are reviewed. In the uterine cervix, the two major neoplasms in this group are the minimal deviation adenocarcinomas of mucinous and endometrioid types. The latter subtype has only recently been described. Endometrioid adenocarcinomas, usually of the uterine corpus, but occasionally of other sites, may have microglandular patterns that can lead to their misdiagnosis, sometimes as microglandular hyperplasia. Pure squamous cell carcinomas of the uterine corpus frequently are composed of very well differentiated epithelium, so that it is possible to misinterpret them as nonneoplastic, and a similar phenomenon may occur in association with the squamous element in some adenocarcinomas with squamous differentiation. Other uterine entities that may be underdiagnosed are malignant lymphoma of the cervix, placental site trophoblastic tumor, myxoid leiomyosarcoma, endometrial stromal sarcoma with glandular differentiation, and mullerian adenosarcoma. Consideration of a variety of architectural and cytological features should facilitate their interpretation. One recently described variant of adenocarcinoma of the fallopian tube that may be confused with the usually clinically benign female adnexal tumors of probable Wolffian origin is microfollicular endometrioid adenocarcinoma. Ovarian tumors subject to misinterpretation that are reviewed herein include metastatic tumors with deceptively benign foci, endometrioid adenocarcinomas that may be misdiagnosed as sex cord tumors, and cystic granulosa cell tumors that may be misinterpreted as follicle cysts. Finally, rare variants of malignant mesothelioma that may be underdiagnosed are reviewed.
Smooth muscle tumors are the most common type of uterine neoplasm. The vast majority of such tumors are benign leiomyomas. Leiomyosarcomas fortunately are relatively infrequent. A variety of gross and microscopic features may be found in both benign and malignant tumors and great care must be taken not to mistake leiomyomas with atypical or unusual features of leiomyosarcomas. Individual features, such as hypercellularity, necrosis, nuclear atypia, mitotic figures, and intravascular growth, are ominous but must be interpreted with caution because variants of benign leiomyoma may contain such changes.
The majority of thyroid tumors are not homogeneous histologically, this creating difficulties in interpretation of different carcinoma variants. The aim of the study was a complex comparative study of morphogenetic changes in carcinoma, adenoma and surrounding thyroid tissue. Surgical material from 48 patients operated because of nodular (multinodular) euthyroid goiter in Moscow Medical Academy in 1990-1997 was used. It was established that all the observations of early thyroid carcinoma diagnosed clinically as a nodular (multinodular) euthyroid goiter were represented by differentiated forms of thyroid carcinoma. Thyroid carcinoma was characterized by higher values of biomolecular markers as compared to adenomas and surrounding tissue. High values of c-myc expression in adenomas and surrounding tissue may indicate possible genetic rearrangements. A peculiar feature of carcinomas was the fact that deletions and replication errors in malignant tumors in this study were found simultaneously in the three genes investigated. As to different histological types of carcinoma, the most frequent deletions of the genes studied were observed in medullary and papillary-follicular carcinoma. High values of heterozygosity loss were found already in adenomas and surrounding tissues, this indicating the presence of the genetic changes already in the benign tumors and surrounding tissue.
BACKGROUND AND OBJECTIVE: In Spain, as in other Mediterranean regions the most common beta-thalassemia mutations are due to point mutations in gene regions that are critical for production of mRNA, such as [IVS-I-nt1 (G-->A), IVS-I-nt6 (T-->C), IVS-I-nt110 (G-->A)] which interrupt normal RNA processing or nonsense mutations [CD39 (C-->T)] which interrupt the translation of mRNA. The frameshift mutation CD8/9 (+G) is a very common allele in Asian Indians but is rare in the Mediterranean regions in which isolated alleles with this mutation have been found in Israel, Greece, Portugal and Turkey. DESIGN AND METHODS: We performed a molecular analysis of 175 chromosomes corresponding to 233 beta-thalassemia patients (221 heterozygous, 10 homozygous and 2 compound heterozygous) who belong to 169 Spanish families. The study of beta-thalassemia was made by PCR-ARMS, the alpha genes by Southern blot, the phenotype of Hb Lepore by enzymatic amplification and the presence of -158 gamma G C-->T mutation by PCR and digestion with the restriction enzyme XmnL. RESULTS: Twenty of these 233 patients showed the beta-thalassemia mutation CD8/9 (+G) (17 were heterozygous, 2 homozygous and in one patient the mutation was associated with a structural variant Hb Lepore Boston). INTERPRETATION AND CONCLUSIONS: These data reveal the heterogeneity of beta-thalassemia in Spain and the relatively high frequency (8.6%) of the frameshift mutation CD8/9 (+G). It is surprising that homozygotes for beta zero-thalassemia due to this mutation with very high Hb F values (around 90%) present a phenotype of intermediate thalassemia.
A new type of spinous process deviation is described. This variant may cause confusion in the interpretation of anteroposterior (AP) radiographs of the lumbar spine. In the literature, two types of lumbar spinous process deviation (SPD) have been described: 1) SPD due to rotation of the entire vertebra (as in rotatory scoliosis and degenerative arthritis), and 2) SPD as a consequence of developmental asymmetries of the neural arch. The present study demonstrates that spinous process deviation in the AP radiograph is not a reliable diagnostic guide. The authors' quantitative morphologic analysis of computed tomographic (CT) sections of over 200 lower lumbar vertebrae in vivo revealed a third type of SPD, namely isolated deviation of the spinous process, ie, deviation without any associated rotation or asymmetry of the vertebral body or arch. Since the oval shadow cast by the spinous process in AP radiographs is caused by its tip, rather than by its base (as was demonstrated by in vitro tests), it is concluded that the position of the spinous process shadow in AP radiographs cannot be used as a reliable landmark to differentiate between the three types of SPD. This is only possible by means of a CT examination.
BACKGROUND: Streptococcus pneumoniae is a major cause of morbidity and mortality in developed and developing countries. No common genetic determinants of susceptibility have been defined. Mannose-binding lectin (MBL) is a key mediator of innate host immunity that activates the complement pathway and directly opsonises some infectious pathogens. Mutations in three codons in the MBL gene have been identified, and individuals homozygous for a mutant genotype have very little or no serum MBL. We did a case-control study in the UK to assess whether these mutant genotypes were associated with invasive pneumococcal disease. METHODS: The frequencies of genotypes defined by the three mutations in codons 52, 54, and 57, and a functional promoter polymorphism at -221, were compared in a two-stage study of 337 patients with invasive pneumococcal disease and 1032 controls. All individuals were recruited from an ethnically homogeneous white population in Oxfordshire, UK. Patients had S pneumoniae isolated from a normally sterile site. FINDINGS: In our initial set of participants, 28 (12%) of 229 patients and 18 (5%) of 353 controls were homozygotes for MBL codon variants (odds ratio 2.59 [95% CI 1.39-4.83], p=0.002). Neither heterozygosity for these codon variants nor the promoter polymorphism was associated with susceptibility. In a confirmatory study, 11 (10%) of 108 patients were MBL homozygotes compared with 36 (5%) of 679 controls (p=0.046). INTERPRETATION: Homozygotes for MBL codon variants, who represent about 5% of north Europeans and north Americans and larger proportions of populations in many developing countries, could be at substantially increased risk of invasive pneumococcal disease.
BACKGROUND: The reasons why meningococcal disease develops in only a small proportion of individuals carrying the causative bacteria are unknown. Differences in host responses to bacterial colonisation are thought to be involved, since people with deficiencies in the terminal components of the complement pathway, or of properdin, are susceptible to meningococcal disease. We postulate that genetic variants of mannose-binding lectin (MBL), a plasma opsonin that initiates another pathway of complement activation, might similarly cause susceptibility to meningococcal disease. METHODS: The frequency of variants of the MBL gene was ascertained in children with meningococcal disease and controls from two independent studies; one hospital-based (194 patients and 272 controls [patients with non-infectious disorders]), and one community-based (72 patients and 110 controls [healthy individuals]), by means of PCR and restriction-enzyme digestion, with confirmation by DNA sequencing. FINDINGS: The proportion of people homozygous for MBL-variant alleles was higher in patients with meningococcal disease than in controls in the hospital study (15 [7.7%] vs four [1.5%]; odds ratio 6.5 [95% CI 2.0-27.2]) and in the community study (six [8.3%] vs three [2.7%]; 4.5 [0.9-29.1]). The population attributable fraction of cases attributable to MBL variants (homozygous and heterozygous) was 32%. INTERPRETATION: The MBL pathway is a critical determinant of meningococcal-disease susceptibility, and genetic variants of MBL might account for a third of all disease cases.
Antigenic reactivity of F.VIII/WF in variants of von Willebrand's disease (vWd) was studied with both fluid-phase and solid-phase immunoradiometric assays. Two different (rabbit and goat) 125I-labeled specific antibodies against purified F.VIII/WF were used in both their divalent (IgG) and their monovalent (Fab fragment) forms. Dose-response curves obtained by reacting a constant amount of antibody with serial dilutions of plasmas from normal or homozygous vWd demonstrated the specificity of the test. The accuracy was significantly higher with 125I-Fab fragments of goat anti-F.VIII/WF antiserum that intact goat IgG or rabbit IgG or Fab fragments. The significant decrease of the slope of the dose-response curves obtained with plasma from variants of vWd has been interpreted as due to the presence of abnormal F.VIII/WF molecules with decreased antigenic reactivity. A similar anomaly was found in cryosupernatant prepared from normal plasma, paralleling similarities demonstrated between variants of vWd and cryosupernatant. Results of experiments performed by reacting constant plasma dilutions from control or variants of confirmed the decreased antigenic reactivity of variant F.VIII/WF.
In our study of sequence variation within the RPGR gene associated with X-linked retinitis pigmentosa, we and others have observed a high rate of new mutation within this gene, as all reported mutations are unique or uncommon. In this article we report the identification in a single family of a complex allele of 7 sequence variants in linkage disequilibrium, of which four result in amino-acid alterations (Arg425Lys, DGlu, Thr533Met and Gly566Glu). This complex allele was initially found in a family with XLRP. However, further study revealed an estimated prevalence of 4.3% (15/344 chromosomes) with this complex allele in the European population indicating the non-pathogenic nature of this allele and, along with previously reported polymorphisms, further supporting a high level of human protein diversity for RPGR. This common complex allele may have been established in the population as a founder effect. Complete gene sequencing identified a potential pathogenic sequence variant in the family described (IVS6+5G>A). This study emphasises the need to create a more complete picture of the allelic variation within a gene, suggests cautious interpretation of a phenotypic association with variant sequences, and highlights the potential problems associated with interpreting genetic studies for diagnostic purposes.
Distinction of normal from disease is one of the principal tenets in magnetic resonance imaging (MRI) interpretation of the foot and ankle. Therefore, familiarity with normal anatomic variants and pitfalls in the foot and ankle is crucial for accurate diagnostic analysis of MR images. This article will focus on outlining variants and MRI interpretation pitfalls of the tendons, muscles, bones, ligaments, and other miscellaneous structures of the foot and ankle.
Sixty patients with paroxysmal progressive schizophrenia were observed. Three variants of paroxysms were identified, viz. acute systematized interpretative delirium states; those with a mild degree of systematization and states with a mixed (interpretative-sensual) nature of delirium formation and a tendency toward delirium systematization. The psychopathological structure of every variant of these conditions was found to correlate with the clinical picture of the disease as a whole.
BACKGROUND: Immune checkpoint inhibitors (ICIs), including anti-programmed cell death protein 1 (anti-PD-1) antibodies, have significantly improved outcomes in patients with metastatic non-small cell lung cancer (mNSCLC). However, substantial heterogeneity exists in clinical benefit, with some patients exhibiting early progression (EP) and others late progression (LP). To date, no biomarkers of EP versus LP disease have been implemented in clinical practice. Circulating tumor DNA (ctDNA) analysis represents a minimally invasive strategy for identifying such biomarkers. In this proof-of-concept study, we evaluated the performance of the TruSight Oncology 500 ctDNA (TSO500 ctDNA) panel and explored its feasibility to identify candidate variants associated with early and late disease progression under anti-PD-1 therapy. METHODS: Baseline ctDNA from eight mNSCLC patients treated with pembrolizumab was extracted and sequenced using the TSO500 ctDNA assay, a 523-gene targeted next-generation sequencing panel. Patients were classified according to their response as LP or EP. Variant calling was performed using the DRAGEN Bio-IT platform, and variants were annotated and clinically interpreted using the Clinical Genomics Workspace (CGW; PierianDx) according to Association for Molecular Pathology (AMP)/American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. Survival outcomes were assessed using Kaplan-Meier and log-rank tests. Performance of ctDNA variants was evaluated using receiver operating characteristic (ROC) curve analysis, and multi-gene models were assessed using leave-one-out cross-validation with penalized logistic regression. RESULTS: All patients harbored detectable variants, including SNVs (100%), MNVs (87.5%), deletions (75%), and insertions (62.5%). Tier I variants were identified in 37.5% of patients, while all cases showed tier II and multiple tier III alterations. TP53 variants were associated with poorer outcomes under anti-PD-1 therapy. Individual gene alterations in TP53, ERBB3, SMC1A or LATS1 showed moderate discriminatory performance between LP and EP patients; however, combination of mutated genes improved apparent discrimination. Notably, specific two-gene combinations (SMC1A + LATS1 or ERBB3 + LATS1) showed the highest discriminatory performance between LP and EP patients in this exploratory cohort. CONCLUSIONS: This study demonstrates the feasibility and analytical performance of the TSO500 ctDNA panel and provides hypothesis-generating evidence that plasma gene variants may be useful to evaluate early versus late disease progression in patients with mNSCLC receiving immunotherapy.
In the field of occupational and/or environmental toxicology, the measurement of specific metabolites in urine may serve to assess exposure to the parent compounds (biological monitoring of exposure). Styrene is one of the chemicals for which biological monitoring programs have been validated and implemented in environmental and occupational medicine. However, inter-individual differences in the urinary excretion exist both for the main end-products (mandelic acid and phenylglyoxylic acid) and for its specific mercapturic acids (phenylhydroxyethylmercapturic acids, PHEMA). This limits to a certain extent the use of these metabolites for an accurate assessment of styrene exposure. In a group of 26 volunteers selected with relevant genotypes, and exposed to styrene vapours (50 mg/m3, 8 h) in an inhalation chamber, we evaluated whether genotyping or phenotyping relevant drug-metabolizing enzymes (CYP2E1, EPHX1, GSTM1, GSTT1 and GSTP1) may help to explain the observed inter-individual variability in the urinary metabolite excretion. Peripheral blood lymphocytes were used for genotyping and as reporter cells for the phenotyping of CYP2E1 and EPHX1. The GSTM1 genotype was clearly the most significant parameter explaining the variance in urinary PHEMA excretion (6-fold lower in GSTM1 null subjects; P < 0.0001) so that systematic GSTM1 genotyping should be recommended routinely for a correct interpretation of PHEMA urinary levels. Variant alleles CYP2E1*6 (7632T>A) and His113EPHX1 were associated with a significant reduction of, respectively, the expression (P = 0.047) and activity (P = 0.022) of the enzyme in peripheral blood lymphocytes. In combination with GSTM1 genotyping, the phenotyping approach also contributed to improve the interpretation of urinary results, as illustrated by the combined effect of CYP2E1 expression and GSTM1 allelic status that explained 77% of the variance in PHEMA excretion and allows the recommendation of mercapturates as specific and reliable biomarkers of exposure to styrene.
We report a case of agminate blue nevus combined with a lentigo patch in a 38-year-old woman. The combination was interpreted as a unique and peculiar variant of speckled lentiginous nevus.
BACKGROUND: In diagnosing cough due to asthma, methacholine chloride inhalation challenge (MIC) interpreted in a traditional fashion has been shown to have positive predictive values from 60% to 82%. OBJECTIVE: To determine whether any features of positive results of an MIC or the results of a 1-week trial of inhaled beta-agonist therapy were helpful in predicting when the cough was due to asthma. METHODS: The study design was a prospective, randomized, double-blind, placebo-controlled, crossover format performed in adult, nonsmoking subjects, who were referred for diagnosis and treatment of chronic cough. The subjects had no other respiratory complaints or medical conditions for which they were taking medications, the results of baseline spirometry and chest roentgenograms were normal, and the results of MIC were positive. After obtaining baseline data, including MICs on 2 separate days, objective cough counting, and self-assessment of cough severity using a visual analog scale, subjects were randomized to receive 2 inhalations (1.3 mg) of metaproterenol sulfate or placebo by metered dose inhaler attached to a spacer device every 4 hours while awake. At 1 week, data identical to baseline were collected, and subjects received the other metered dose inhaler for 7 days. At 1 week, data identical to baseline were collected. After completion of the protocol, subjects were followed up in the clinic to observe the final response of the cough to specific therapy. RESULTS: Based on the disappearance of the cough with specific therapy, the cough was due to asthma in 9 of 15 subjects and nonasthma in 6 of 15 subjects. Baseline data were similar between groups. With respect to MICs, there were no significant differences between groups in the cumulative dose of methacholine that provoked a 20% decrease in forced expiratory volume in 1 second from the postsaline baseline value (PD20 values), slopes of dose-response curves, and maximal-response plateaus. Cough severity significantly improved after 1 week of metaproterenol use compared with the severity of the cough at baseline (P = .03) and with placebo (P = .02) only in subjects with asthma. CONCLUSIONS: No matter how the results are analyzed, positive MIC results, without observing response to therapy, are only consistent with asthma as the cause of the cough. The results are only diagnostic of asthma when they are followed by a favorable response to asthma therapy. After 1 week of inhaled beta-agonist, only the cough due to cough-variant asthma is significantly better.