Standardized incidence ratios and risk factors for cancer in patients with systemic sclerosis: Data from the Spanish Scleroderma Registry (RESCLE)

AimPatients with systemic sclerosis (SSc) are at increased risk of cancer, a growing cause of non–SSc-related death among these patients. We analyzed the increased cancer risk among Spanish patients with SSc using standardized incidence ratios (SIRs) and identified independent cancer risk factors in this population.Material and methodsSpanish Scleroderma Registry data were analyzed to determine the demographic characteristics of patients with SSc, and logistic regression was used to identify cancer risk factors. SIRs with 95% confidence intervals (CIs) relative to the general Spanish population were calculated.ResultsOf 1930 patients with SSc, 206 had cancer, most commonly breast, lung, hematological, and colorectal cancers. Patients with SSc had increased risks of overall cancer (SIR 1.48, 95% CI 1.36–1.60; P < 0.001), and of lung (SIR 2.22, 95% CI 1.77–2.73; P < 0.001), breast (SIR 1.31, 95% CI 1.10–1.54; P = 0.003), and hematological (SIR 2.03, 95% CI 1.52–2.62; P < 0.001) cancers. Cancer was associated with older age at SSc onset (odds ratio [OR] 1.22, 95% CI 1.01–1.03; P < 0.001), the presence of primary biliary cholangitis (OR 2.35, 95% CI 1.18–4.68; P = 0.015) and forced vital capacity <70% (OR 1.8, 95% CI 1.24–2.70; P = 0.002). The presence of anticentromere antibodies lowered the risk of cancer (OR 0.66, 95% CI 0.45–0.97; P = 0.036).ConclusionsSpanish patients with SSc had an increased cancer risk compared with the general population. Some characteristics, including specific autoantibodies, may be related to this increased risk.     

Bosnian study of APOE distribution (BOSAD): a comparison with other European populations

Background: The ε2, ε3 and ε4 alleles of APOE gene have been associated with several diseases in different populations. Data on the frequency of alleles are used in both a clinical and evolutionary context. Although the data on frequency of these alleles are numerous, there are no reports for the population of Bosnia and Herzegovina.

Aim: To estimate the frequency of APOE alleles in a healthy Bosnian population and compare it to data for other European populations.

Subjects and Methods: Overall, 170 unrelated Bosnian subjects (108 female and 62 male), aged 53.0 (±5.0) years were included in this study. Genotypes were determined by real-time PCR.

Results: In our group the prevalence of heterozygotes E2/E3, E2/E4 and E3/E4 was 20.6%, 3.5% and 12.9%, respectively, while the prevalence of homozygotes E2/E2, E3/E3, E4/E4 was 0.6%, 61.2% and 1.2%, respectively, with a mean frequency of ε2, ε3 and ε4 alleles of 12.6%, 78.0% and 9.4%, respectively.

Conclusions: In studied European populations we observed a linear, gradually increasing trend in the frequency of ε4 allele from South to North (Pearson’s test 0,7656, p value?<0.00001), and the Bosnian population fits into this pattern perfectly.     

Spectrum of sequence variations in the FANCA gene: an International Fanconi Anemia Registry (IFAR) study

Fanconi anemia (FA) is an autosomal recessive disorder that is defined by cellular hypersensitivity to DNA cross-linking agents, and is characterized clinically by developmental abnormalities, progressive bone-marrow failure, and predisposition to leukemia and solid tumors. There is extensive genetic heterogeneity, with at least 11 different FA complementation groups. FA-A is the most common group, accounting for approximately 65% of all affected individuals. The mutation spectrum of the FANCA gene, located on chromosome 16q24.3, is highly heterogeneous. Here we summarize all sequence variations (mutations and polymorphisms) in FANCA described in the literature and listed in the Fanconi Anemia Mutation Database as of March 2004, and report 61 novel FANCA mutations identified in FA patients registered in the International Fanconi Anemia Registry (IFAR). Thirty-eight novel SNPs, previously unreported in the literature or in dbSNP, were also identified. We studied the segregation of common FANCA SNPs in FA families to generate haplotypes. We found that FANCA SNP data are highly useful for carrier testing, prenatal diagnosis, and preimplantation genetic diagnosis, particularly when the disease-causing mutations are unknown. Twenty-two large genomic deletions were identified by detection of apparent homozygosity for rare SNPs. In addition, a conserved SNP haplotype block spanning at least 60 kb of the FANCA gene was identified in individuals from various ethnic groups.     

Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the α-L-iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype-phenotype correlation in large MPS I cohorts have been performed. Understanding genotype-phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction.     

Spectrum of sequence variation in the FANCG gene: an International Fanconi Anemia Registry (IFAR) study

Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive syndrome associated with chromosomal instability, hypersensitivity to DNA cross-linking agents, and predisposition to malignancy. The gene for FA complementation group G (FANCG) was the third FA gene to be cloned, and was found to be identical with human XRCC9, which maps to 9p13. The cDNA is predicted to encode a polypeptide of 622 amino acids, with no sequence similarities to any other known protein or motifs that could point to a molecular function for FANCG/XRCC9. We used single strand conformational polymorphism analysis (SSCP) to screen genomic DNA from a panel of 307 racially and ethnically diverse unrelated FA patients from the International Fanconi Anemia Registry (IFAR) for variants in FANCG. Twenty-seven abnormal SSCP patterns were found; 18 of these variants appear to be pathogenic mutations while nine are likely to be nonpathogenic polymorphisms. Direct sequencing of genomic DNA from seven FA-G probands with one mutant allele not detected in the SSCP study and three additional probands assigned to the FA-G complementation group by retroviral correction with FANCG resulted in the detection of nine additional pathogenic mutations and two common SNPs. Conditions for rapid screening for these mutations by DHPLC for use in a clinical laboratory setting were established. The most common FANCG mutations in the IFAR population were: IVS8-2A>G (seven Portuguese-Brazilian probands), IVS11+1G>C (seven French-Acadian probands), 1794_1803del10 (seven European probands), and IVS3+1G>C (five Korean or Japanese probands). Our data suggest that the Portuguese-Brazilian, French-Acadian, and Korean/Japanese mutations were likely to have been present in a founding member of each of these populations.     

胃肠胰高增殖活性神经内分泌肿瘤60例临床病理学特征和预后分析

目的探讨胃肠胰高增殖活性神经内分泌肿瘤(NET G3)的临床病理学特征,并对其预后进行分析。方法收集复旦大学附属肿瘤医院2013年1月1日至2018年12月31日诊断的胃肠胰NET G3病例60例,总结分析临床病理特征和免疫组织化学结果,并进行生存相关的数据分析。同时收集2018年该院诊断的胃肠胰神经内分泌肿瘤(NEN)157例,比较各级NEN的发病比例。结果60例胃肠胰NET G3中,男性32例,女性28例,年龄13~80岁,平均年龄54岁,其中胰腺原发最多见(48%,29/60),手术清扫病例中淋巴结转移比例达9/16,远处转移达41%(18/44),其中肝脏为最常见的转移部位(36%,16/44)。2018年该院诊断的胃肠胰NEN中,NET G3所占比率最低(7%,11/157)。显微镜下NET G3具有典型的分化好/中等的神经内分泌瘤病理形态特征,核分裂象计数病例之间差异显著。免疫组织化学染色显示大部分肿瘤细胞表达神经内分泌标志物,生长抑素受体2在60%病例中表达(12/20),Ki-67阳性指数平均值在30%~40%,不同病例之间Ki-67阳性指数差异显著(18%~80%)。胃肠胰NET G3总体生存时间为43个月,无病生存时间为12个月。结论胃肠胰NET G3是最少见的一类NEN,具有独特的临床病理特征,预后较好。胃肠胰NEN的病理分类及分级能帮助临床选择合适的治疗并准确评估预后。     

pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up

Morphological assessment of the degree of differentiation has been shown in numerous studies to provide useful prognostic information in breast cancer, but until recently histological grading has not been accepted as a routine procedure, mainly because of perceived problems with reproducibility and consistency. In the Nottingham/Tenovus Primary Breast Cancer Study the most commonly used method, described by Bloom & Richardson, has been modified in order to make the criteria more objective. The revised technique involves semiquantitative evaluation of three morphological features--the percentage of tubule formation, the degree of nuclear pleomorphism and an accurate mitotic count using a defined field area. A numerical scoring system is used and the overall grade is derived from a summation of individual scores for the three variables: three grades of differentiation are used. Since 1973, over 2200 patients with primary operable breast cancer have been entered into a study of multiple prognostic factors. Histological grade, assessed in 1831 patients, shows a very strong correlation with prognosis; patients with grade I tumours have a significantly better survival than those with grade II and III tumours (P less than 0.0001). These results demonstrate that this method for histological grading provides important prognostic information and, if the grading protocol is followed consistently, reproducible results can be obtained. Histological grade forms part of the multifactorial Nottingham prognostic index, together with tumour size and lymph node stage, which is used to stratify individual patients for appropriate therapy.     

Pediatric adrenocortical tumors: morphological diagnostic criteria and immunohistochemical expression of matrix metalloproteinase type 2 and human leucocyte-associated antigen (HLA) class II antigens. Results from the Italian Pediatric Rare Tumor (TREP) Study project

Pediatric adrenocortical tumors are neoplasms that only rarely occur in pediatric patients. Their clinical behavior is often unpredictable, and the histologic criteria of malignancy used in adults are not always useful in children. The aim of this study was to validate the prognostic value of the pathologic criteria of Wieneke et al and to evaluate the potential prognostic expression of matrix metalloproteinase 2 and human leucocyte-associated antigen (HLA) class II antigens in a series of 20 pediatric patients affected by adrenocortical tumors, who were enrolled in the Italian Pediatric Rare Tumor (TREP) Study between 2000 and 2007. The age range was 0 to 17.5 years (mean, 7.28 years) with a male-female ratio of 1:2. The mean follow-up was 64.4 months. The histologic diagnoses were reviewed, and the cases were classified using the criteria for malignancy proposed by Wieneke et al. The immunohistochemical expression of matrix metalloproteinase 2 and HLA class II antigens was scored by semiquantitative analysis and compared with the clinicopathologic parameters and outcome. Based on the scoring system of Wieneke et al, 7 tumors were classified as malignant; 12 tumors, as benign; and only 1 tumor, with "unpredictable behavior." In all cases, the clinical behavior was consistent with the pathologic criteria of Wieneke et al. Notably, areas of regressive myxoid changes, not included among the criteria of Wieneke et al, were observed in all but 1 case of malignant tumors and only in 2 cases of benign tumors. Matrix metalloproteinase 2 was focally to diffusely expressed in all malignant and in most benign tumors. HLA class II antigens immunoreactivity was absent in all benign tumors and restricted to rare isolated cells in most malignant tumors. Our findings confirm that the pathologic scoring system of Wieneke et al is a simple and reproducible diagnostic tool to predict prognosis in pediatric adrenocortical tumors. Unlike in their adult counterpart, the expression of matrix metalloproteinase 2 or the loss of HLA class II antigens does not discriminate between benign and malignant tumors in children. Although pediatric adrenocortical tumors seem to be similar histologically to their adult counterparts, it is likely that they have distinctive molecular features.     

Atypical carcinoid tumour of the lung: a study of 33 cases with prognostic features

Atypical carcinoids of the lung (well-differentiated neuroendocrine carcinomas) are rare tumours of uncertain prognosis. We have studied 33 cases—male to female ratio 2:1, age range 22–75 years, mean 55 years, 80% smokers, 15 peripheral and 18 central, tumour size 1.2–9.5 cm. Microscopically they had a nesting/insular, trabecular or lobular pattern. Nuclear morphology was variable, round cells, large cells and spindle cells being identified with small cell areas in five tumours. Mitotic activity varied from 4 to 80 per 1.52 mm². Areas of necrosis were seen in all tumours. All 33 tumours were cytokeratin positive (AE1/AE3 and CAM 5.2), 32 were positive for neuron-specific enolase, synaptophysin and chromogranin A. Electronmicroscopy showed dense core granules in 29 available cases. Nineteen cases were stage I, nine stage II, four stage III and one stage IV. Follow-up information was available for 22 cases. Size, location, stage and large cell/small cell morphology were important prognostic indicators. Large tumour size, large cell or mixed large cell/small cell morphology, peripheral localization and advanced stage were adverse prognostic indicators. Mitotic activity and the presence of necrosis did not appear to influence stage or behaviour.     

Cytopathological features of warty (condylomatous) carcinoma of the penis: A case report and distinction from other verruciform penile tumors

Warty (condylomatous) carcinoma (WC) is a rare specific variant of invasive squamous cell carcinoma that shows hybrid features of condyloma with invasive cell carcinoma. As compared with conventional squamous cell carcinoma, WC tends to run a less aggressive clinical course. A case is presented here in which squash smears of a penile foreskin tumor in a 65‐year‐old male revealed small cohesive clusters and sheets of tumor cells in papillary configurations. The neoplastic cells were polygonal to elongated and contained oval nuclei, coarse chromatin pattern, and distinct nucleoli. Nuclear pleomorphism and loss of nuclear polarity were observed. Characteristically, there were also many koilocytes demonstrating mild to moderate nuclear atypia and perinuclear cytoplasmic halos. A cytologic diagnosis of a verruciform penile tumor was suggested. Histologic examination of the tumor showed a hyper‐parakeratotic arborizing papillomatous growth with thin fibrovascular cores and the tips were variably rounded or tapered. Obvious koilocytic cytopathic change, nuclear pleomorphism, and focal stromal invasion were observed. Immunohistochemically, the tumor cells showed diffuse and strong membranous staining for cytokeratin (AE1/AE3) while the MIB‐1 and p53 immunoreactive cells were confined to the basal areas of the papillae. No lymphovascular invasion was detected in D2‐40 or elastic Van‐Gieson stains. On the basis of the overall features, we confirmed a final diagnosis of penile WC. We demonstrated here for the first time the cytopathological features of penile WC with emphasis on differential diagnostic considerations. Diagn. Cytopathol. 2010;38:841–845. © 2010 Wiley‐Liss, Inc.     

Haemangiopericytomas: the prognostic value of immunohistochemical staining with a monoclonal antibody to proliferating cell nuclear antigen (PCNA)

Forty-two cases of haemangiopericytoma were studied retrospectively using immunohistochemical staining with PC10, a monoclonal antibody to PCNA. The percentage of tumour cells with positive staining for PCNA was found to correlate well with histological grading. Clinical follow-up data were available in 25 adults and showed no known deaths in 11 cases with a low proportion (less than 14%) of positive cells. Out of 14 cases with a high number (greater than or equal to 14%) of positive cells, seven patients are known to have died, two had metastases, and in a further two there have been multiple recurrences of tumour. DNA flow cytometry was performed on 26 cases but this showed no correlation with PC10 staining or clinical outcome. Staining with PC10 may be of particular value in the identification of patients at greatest risk of rapid tumour metastasis and early death.     

Severe spondylocostal dysostosis associated with other congenital anomalies: A clinical/epidemiologic analysis and description of ten cases from the Spanish registry

We describe 10 cases born to nondiabetic mothers who presented with severe spondylocostal dysostosis (SCD) associated with other anomalies, identified among 20,526 malformed liveborn infants from the Spanish Collaborative Study of Congenital Malformations (ECEMC). We analyze the associated malformations in the 10 cases with severe SCD, as well as in all cases with less severe SCD among children with MCA patterns of unknown cause. Cases with SCD were preferentially associated with caudal dysgenesis, diaphragmatic hernia, and central nervous system anomalies. © 1994 Wiley-Liss, Inc.     

Association between SARS-CoV-2 infection during pregnancy and postpartum depressive and anxiety symptoms: finding from the International Registry of Coronavirus Exposure in Pregnancy (IRCEP) study

Archives of Women's Mental Health - While there has been concern over the perinatal mental health implications of the COVID-19 outbreak, evidence on the risk of postpartum depression and...     

Hb Q(India) and its interaction with beta-thalassaemia: a study of 64 cases from India

Haemoglobin Q (Hb Q), a relatively uncommon alpha-chain structural Hb variant, has been reported either in the heterozygous state or interacting with beta-thalassaemia. Individuals inheriting Hb Q generally are asymptomatic and are diagnosed by chance during population screening or as a part of a family study. This paper represents the first large study from India of 64 cases of Hb Q, documenting the haematological and molecular findings on 36 cases of Hb Q trait, 22 of Hb Q beta-thalassaemia trait and three of Hb Q beta-thalassaemia major, as well as a family of Hb Q homozygous cases. Hb Q is detected by Hb electrophoresis and chromatography. Hb Q levels in homozygous cases ranged from 32% to 35%, while in Hb Q heterozygotes the level was 20%. When there was an interaction of beta-thalassaemia heterozygotes the level was 14%, and in interacting beta-thalassaemia homozygotes the levels ranged from 7% to 9%. beta-thalassaemia mutations were characterised in cases showing elevated Hb A2 levels, which were markedly reduced in the majority of cases in which beta-thalassaemia was absent. Hb Q is rare and not a single homozygous case has been reported. However, Hb Q disease showed wide variation in clinical and haematological presentation in the same family.