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We report two brothers with the clinical symptoms and neuropathological findings of hereditary sensory and autonomic neuropathy (HSAN) type IV but with normal sweating function and absence of recurrent fever. We propose that our patients may have a lower degree of expression of the genetic defect underlying HSAN type IV or that they represent a separate genetic entity.
Serous cystic tumours of the pancreas are uncommon and are usually classified as microcystic adenomas (MCA). As new types of serous cystic tumours of this organ have been reported we reviewed a series of 14 lesions and from macroscopic findings two groups were distinguished: ten tumours revealed the features of MCA, while four were clearly distinct from MCA. Grossly, the latter tumours showed only few cysts which were irregularly assembled in fibrous stroma. On the cut surface, there was neither a central stellate scar nor a circumscribed tumour border, features characterizing MCA. Microscopically, the cysts were lined by cuboidal, non-mucin-producing cells. Immunocytochemical staining for cytokeratins 7, 8, 18 and 19 revealed a ductal phenotype. All non-MCA were found in the head of the pancreas and three of them occurred in men. There were no tumour recurrences or signs or malignant transformation after resection (mean follow-up, 2.9 years). These results suggest that there are serous cystic tumours distinct from MCA which may represent another variant of the category of serous cystic adenomas of the pancreas. We propose the term serous oligocystic and ill-demarcated adenoma (SOIA) for these tumours. It is possible that the recently described macrocystic sybtype of serous cystadenoma and SOIA and variants of the same tumour.
Guillain-Barrè syndrome (GBS) and Miller-Fisher syndrome (MFS) are variant forms of acquired demyelinating polyradiculoneuropathy. Their concurrence with immune disorders of the thyroid is infrequent. We report on a 7.5-year-old girl in whom a subclinical thyroiditis was concurrently detected to GBS and a 70-year-old woman with Hashimoto's thyroiditis (HT) who had recurrent MFS. Even though autoimmune thyroiditis is associated with many autoimmune disorders more often than would be expected by chance alone, its concurrence with immune disorders of the peripheral nerve is less frequently reported. The calculated coincidental concurrence of acquired demyelinating polyradiculoneuropathy (in both variants, MFS and GBS) and autoimmune thyroiditis (as in the present cases) was extremely low (0.0004%), thus suggesting common pathogenic mediators.
PURPOSE: A single-nucleotide polymorphism (SNP) in codon 655 of HER-2 has been extensively studied with inconclusive results. The purpose of this study was to investigate the association between common variants of HER-2 and breast cancer risk, HER-2 expression, and survival using a haplotype-based stepwise approach. EXPERIMENTAL DESIGN: Twenty-nine SNPs listed in the National Center for Biotechnology Information database were screened to identify novel polymorphisms of HER-2 gene in 90 healthy Korean women. Six of 29 SNPs were polymorphic and had greater than 10% of minor allele frequencies. Using these six SNPs, linkage disequilibrium and haplotype patterns were characterized. We tested association between the haplotypes and breast cancer in a large case-control study (n=1,039 cases and 995 controls). Six-hundred two breast cancer patients with follow-up at least 24 months were analyzed for outcome in relation to haplotype. Expression of HER-2 protein was determined by immunohistochemistry in 1,094 cases of invasive breast cancer. RESULTS: All six SNPs showed a strong linkage disequilibrium pattern and were considered to belong to one haplotype block. Two haplotype-tagging SNPs (I655V and P1170A) for three common haplotypes (>5%) were genotyped in cases and controls. The haplotypes and individual SNPs were not associated with breast cancer risk. In patients with at least one copy of haplotype I (the most common haplotype), HER-2 expression was 1.5 times higher (P = 0.009) and the prognosis was worse (P = 0.032) compared with patients without having that haplotype. CONCLUSIONS: Our results suggest that the currently identified genetic polymorphisms of HER-2 are not associated with an increased risk of breast cancer in Korean women, whereas one haplotype does affect protein expression of the tumor and disease outcome.
Conventional therapy including nitrates, beta blockers, and surgical bypass has proved to be generally unsatisfactory in patients with variant angina of suspected vasospastic etiology. Recent evidence regarding the role of calcium in the pathogenesis of vascular smooth muscle spasm prompted an open study of the clinical effects of verapamil in seven patients with recurrent rest angina refractory to nitrates. The patients studied met strict clinical ECG and angiographic criteria for vasospastic angina. All patients had rapid (within 24 hours) and complete (without recurrence of symptoms) chronic response to oral verapamil therapy. The pharmacology of verapamil relating to the pathogenesis of vasospastic angina is delineated and guidelines for the clinical application of the agent are presented.
We studied two patients with recurrent sensory neuropathy and weakness of extraocular muscles. There was electrophysiologic evidence of multifocal demyelination of sensory nerves, with relative sparing of somatic motor nerves. Sural nerve biopsy in one patient showed segmental demyelination. We believe that these patients had an unusual form of inflammatory polyneuropathy--possibly a relapsing variant of the Miller-Fisher syndrome of acute idiopathic polyneuritis.
The objective of this study was to explore the cytogenetic profiles of variant Ph chromosome translocations (VT) in patients with chronic myelogenous leukemia (CML) and to assess the applications of fluorescence in situ hybridization (FISH) technique for analysis of CML patients with variant translocation by using dual color-single fusion signal (DC-SF) and dual color-dual fusion signal (DC-DF) probe. 42 CML patients with VT were studied by conventional cytogenetic analysis (CCA). Among them, nine and eleven cases were analyzed by DC-SF-FISH and DC-DF-FISH, respectively. The results showed that 42 out of 643 (6.5%) CML cases received CCA were found to have VT, which were composed of 18 cases of simple VT, 23 of complex VT and one of masked VT. The VT involved all over the chromosomes but No. 4 and 6. Four patterns of them appeared recurrent because each occurred in at least two cases. VT with additional chromosomal aberrations were shown in 35.7% of patients with VT (15/42). 19 of 20 patients who received FISH detection were positive for bcr/abl fusion. DC-DF-FISH analysis revealed absence of abl/bcr fusion signal in all patients but one (8.8%) with abl/bcr positive cells. However, it was not an implication of gene loss but the translocation led to part of bcr retaining on der (9q34) and other part of bcr translocating to involve another chromosome. It was unable to observe variant signal features by DC-SF-FISH analysis. In conclusion, variant Ph translocations in CML involved almost all chromosomes in a varying frequencies and ways except chromosomes 9 and 22, and some of them showed recurrent aberrations. FISH provides accurate molecular diagnosis for CML with VT, while DC-DF-FISH facilitates the assessment of variant signals.
PURPOSE: To facilitate understanding of the long-term course and visual outcome of a severe variant of central serous chorioretinopathy. DESIGN: Consecutive observational case series. PATIENTS AND METHODS: The authors reviewed 25 patients with multifocal posterior pigment epitheliopathy and bullous retinal detachment, who had a mean follow-up time of 10.6 years (range, 6-22 years), with reference to the demographic feature, fundus changes, recurrence, and final anatomic and visual outcome. Two patients underwent optical coherence tomography. RESULTS: The patients were 21 men and 4 women, with a mean age at disease onset of 43.1 years (range, 30-63 years). Twenty-one patients were otherwise healthy, and four developed ocular disease during systemic corticosteroid therapy for metabolic or autoimmune diseases including systemic lupus erythematosus. The disease was bilateral in 21 patients (84%). Nine patients (36%) presented initially with classic central serous chorioretinopathy, followed by its severe variant 7 months to 9 years later. Active disease was characterized by multifocal exudative lesions in the posterior pole and bullous retinal detachment with shifting subretinal fluid in the inferior periphery. Optical coherence tomography of exudative lesions disclosed cloudy and fibrinous subretinal fluid. The exudative lesions were self-limited or responded to photocoagulation. During the follow-up period, 13 patients (52%) showed 1 to 5 recurrent disease, but the disease eventually became quiescent with multifocal atrophic scars in the posterior pole with or without atrophic tracts in the inferior periphery. Final best-corrected visual acuity was 2020 or better in 24 of 46 affected eyes (52%) of 25 patients and 2040 or better in 37 eyes (80.4%). CONCLUSIONS: A severe variant of central serous chorioretinopathy characterized by multifocal posterior exudations and bullous inferior retinal detachment with shifting subretinal fluid may affect otherwise healthy, middle-aged males or individuals receiving systemic corticosteroid therapy for metabolic or autoimmune diseases. Exudative chorioretinal lesions are self-limited or respond to photocoagulation. Recurrence is common, but the disease eventually becomes quiescent with favorable visual acuity unless the macula is damaged.
Gastric secretion and the state of D-somatostatin- and G-gastrin-producing cells of gastric antrum were studied in 41 patient with continuously recurrent course and complications of the disease to choose the operative treatment method for duodenal ulcer disease. Atropine-dependent (AD) gastric secretion was revealed in 90.3% of patients, and atropine-resistant (AR)-9.7%.G-cells hyperplasia was revealed in 19.5% of patients. Three clinically important variants of D- and G-cells ratio were chosen: hyperplasia it absent, G-cell hyperplasia is present with the balanced ratio to D-cells, G-cell hyperplasia is present with aggressive ratio to D-cells. Truncal vagotomy with antrumectomy was conducted in patients with the third ratio variant, various kinds of vagotomy were done in patients with the first and second variants against the AD gastric secretion.
To examine the importance of coronary spasm for recurrences following coronary angioplasty, the incidence of spontaneous and ergonivine-provoked coronary spasm was studied, during initial and 6 months follow-up coronary angiography, in a consecutive series of 102 patients with single-vessel disease and successful coronary angioplasty. Repeat angiography demonstrated restenosis in 35 patients (34%). In patients with no demonstrable coronary spasm before and 6 months after PTCA, restenosis occurred in 23% (14/61). The recurrence rate for patients with spasms only before PTCA was similar (29%; 6/21). An increase of recurrences was observed in patients with coronary spasm before and 6 months after PTCA (69%; 9/13) and was extremely high in patients with detectable spasms only after PTCA (86%; 6/7). The importance of the severity of underlying coronary stenosis as regards the ergonovine testing result, demonstrated no relationship between the degree of underlying stenosis and the incidence of provokable coronary spasms. Thus, coronary spasms provokable only before PTCA do not increase the risk for recurrences. Spasms persisting after PTCA or seen only after the procedure are associated with a significantly higher rate of restenoses.
Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipolar (recurrent major depression) and bipolar.(1) Modification of serotonergic neurotransmission is pivotally implicated in the mechanism of action of antidepressant drugs(2) and also in the action of mood stabilizing agents, particularly lithium carbonate.(3) Accordingly, genes that code for the multiple subtypes of serotonin receptors that have been cloned and are expressed in brain,(4) are strong candidates for a role in the genetic etiology of affective illness. We examined a structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser),(5) in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and 901 normal controls. The subjects were drawn from nine European countries participating in the European Collaborative Project on Affective Disorders. There was significant variation in the frequency of the HT2CR ser23 allele among the 10 population groups included in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, chi(2) = 20.9, df 9, P = 0.01). Logistic regression analysis demonstrated that over and above this inter-population variability, there was a significant excess of HT2CR ser23 allele carriers in patients compared to normal controls that was demonstrable for both the MDD (chi(2) = 7.34, df 1, P = 0.006) and BP (chi(2) = 5.45, df 1, P = 0.02) patients. These findings support a possible role for genetically based structural variation in 5-HT2C receptors in the pathogenesis of major affective disorder.
Infection with human immunodeficiency virus (HIV) increases the risk of developing non-Hodgkin lymphoma. Plasmablastic lymphoma (PBL) is a rare variant of diffuse large cell lymphoma that often involves the oral cavity of HIV+ patients. It is characterized by immunoblastic morphology and plasma cell phenotype. Cutaneous involvement in PBL appears to be rare. We report a 44-year-old man with AIDS and Kaposi sarcoma (KS) previously treated with doxorubicin who, following treatment with highly active antiretroviral therapy, developed an erythematous infiltrated nodule on the right arm. Histology showed subcutaneous fat necrosis and clusters of atypical large plasma cells (plasmablastic cells). Immunohistochemistry revealed lambda light chain restriction. Epstein-Barr virus (EBV) mRNA was detected by in situ hybridization within the plasmablastic cells. Polymerase chain reaction amplification with specific primers for human herpesvirus 8 (HHV-8) performed on the skin biopsy specimen detected a specific band. A complete screening (bone marrow biopsy, computed tomographic scan, radiological survey) disclosed no abnormalities. The lesion resolved spontaneously after 3 months. Two years later an infiltrated plaque developed on the abdominal wall. The clinical and histopathological features of this new lesion were similar to those observed 2 years previously. No evidence of extracutaneous involvement was detected. The lesion again resolved spontaneously after 25 days. PBL may be seen in patients with transplants or receiving chemotherapy, but is usually observed in patients with advanced AIDS. The observation of recurrent self-healing EBV- and HHV-8-associated cutaneous monoclonal plasmablastic infiltrates, in a patient with AIDS and KS, expands the clinical spectrum of AIDS-associated plasmablastic lymphoproliferative disorders.
Basing his argument on a study of 58 tibial varicose recurrences, the author shows the long-term unreliability of systematic resections of the sapheno-femoral junctions of short saphenous veins not directly pathological. The reasons for this unreliability are to be found in the large number of anatomical variants, especially those concerning emptying into the popliteal vein, which is often sited several centimetres away from the interline of the knee, and the possibility of a double sapheno-femoral junction. Moreover, the existence of large, incompetent long, or less frequently short, sural veins has been found in two-thirds of the cases, contributing to the recurrence or constituting the determining factor. The author draws from this fact the conclusion that surgical indications are restricted. Surgery should be carried out on short saphenous veins which are clearly dilated and incompetent; the emptying level of the sapheno-femoral junction should be ascertained, as should duplicity or major sural incompetence, so that an operation may be carried out which is as complete as possible.
Endometrial cancers with the Cancer Genome Atlas (TCGA) molecular profile of TP53-mutated, POLE-wild-type, and microsatellite-stable generally exhibit a high burden of copy number (CN) alterations and carry an increased risk for adverse outcomes, meriting maximal adjuvant therapy. In contrast, the prognosis associated with a TP53 mutation that coexists with a POLE mutation or microsatellite instability aligns with that of ultramutated or hypermutated cancers, respectively. In this study, we characterized a rare molecular subclass of endometrial cancers defined by TP53 mutation but low burden of CN alterations, wild-type p53 immunoexpression (immunohistochemistry [IHC]), and low TP53 variant allele frequency (median 13% and maximum 47%). Among 723 consecutive endometrial cancers prospectively classified using next-generation sequencing, 16 (2.2%) were CN-low/TP53-mutated/p53 wild-type IHC. Two additional cases were identified in a separate retrospective cohort of 32 recurrent low-grade early-stage endometrial cancers, bringing the total to 18 cases. They affected postmenopausal patients, exhibited low-grade endometrioid histotype, and were mostly confined to the uterus without lymphovascular space invasion. The recurrence rate was 6.25% (1/16) in the prospective cohort, and none died, placing their prognosis closer to that of CN-low than CN-high cancers. We conclude that next-generation sequencing-based TCGA classification of TP53-mutated, POLE-wild-type, microsatellite-stable endometrial cancers with TP53 variant allele frequency < 50% requires further evaluation using CN analysis and/or p53 IHC to detect this rare molecular category. IHC-based TCGA classification, such as the ProMisE protocol, will not be able to detect these cases because the p53 IHC pattern is wild-type and there are no distinguishing morphological features; this may be of relevance for analyzing ProMisE protocol-based clinical trials and outcomes studies. Long-term outcome studies are needed to refine risk stratification and treatment decisions for this unique molecular class of endometrial cancers that further contributes to the evolving understanding that the clinical significance of TP53 mutation in endometrial cancer is complex and depends on coexisting molecular alterations.
Measurements of the estrogen receptor (ER) and the estrogen-induced progesterone receptor (PgR) are used by most clinicians as indicators of both overall prognosis and likelihood of response to endocrine therapy. Patients with ER+/PgR+ tumors have the highest likelihood of response; conversely, patients with ER-/PgR-tumors have the lowest likelihood of response. Unfortunately, most patients treated successfully with endocrine therapy eventually develop endocrine-resistant disease recurrence. In an effort to study potential mechanisms of endocrine resistance, we have studied discordant ER-/PgR+ tumors, in which the normally estrogen-regulated PgR gene is induced in the apparent absence of ER. Our laboratory has previously cloned, from ER-/PgR+ tumors, a variant ER mRNA precisely missing the sequence corresponding to ER exon 5, and has demonstrated that the truncated protein product translated from this variant RNA is capable of constitutively inducing the expression of an estrogen-responsive reporter gene in a yeast expression vector system (Fuqua et al. Cancer Res 51:105-109, 1991). In the present report we describe further experiments to characterize the activity and biological consequences of expression of this variant ER in human breast cancer cells. We have stably transfected MCF-7 human breast cancer cells with a mammalian expression vector for the exon 5 deletion variant ER. These transfected cells produce a truncated ER protein of the expected 40 kDa size. Cells expressing the exon 5 ER deletion variant constitutively express PgR, and manifest increased anchorage-independent colony formation in the absence of estrogen.(ABSTRACT TRUNCATED AT 250 WORDS)
Typical features of congenital dyserythropoietic anaemia (CDA) were found in a 13-year-old girl admitted for chronic recurrent multifocal osteomyelitis. The findings on light microscopy were in agreement with those described in CDA type II, whereas on electron microscopy, the ultrastructure findings were compatible with both types I and II. The acidified serum lysis test (Ham test) performed with eight normal sera was negative. The patient's red blood cells showed an increased agglutinability with anti-i antibodies. Morphological changes were also shown in the mature neutrophilic granulocyte suggesting that the primary disorder exists already in the multipotent stem cell.
We present a patient with severe Cushing's syndrome secondary to an invasive pituitary tumour. Cortisol secretion fluctuated between severe hypercortisolaemia associated with features of Cushing's syndrome to recurrent symptomatic hypocortisolaemia. Normal ACTH precursors to ACTH ratio during the various stages of cortisol secretion indicated that periodic decreased prohormone processing did not contribute to the unique presentation in the patient. Thus, the the extreme fluctuations of plasma cortisol levels are most probably due to unexplained erratic changes of ACTH secretion.
In selected patients suffering from variant angina, an implantable cardioverter-defibrillator (ICD) and coronary stenting can be helpful to prevent sudden death and treat coronary artery spasm. We report a case of a 47-year-old woman suffering from variant angina, who experienced an episode of ventricular fibrillation promptly cardioverted. After coronary angiography documentation of a mild atherosclerosis, an ICD was implanted and oral nitrates and calcium antagonists were prescribed. The recurrence of chest pain and palpitations prompted us to perform a second coronary angiography that documented a focal coronary artery spasm successfully treated with stent implantation. No other episodes of angina or ventricular arrhythmia were documented during the following 6 months of follow-up.