Oesophageal atresia,related malformations,and medical problems: A family study

Oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) are life-threatening malformations of generally undefined cause. Previous reports of familial cases suggest a genetic contribution. The pattern of inheritance appears non-Mendelian, i.e., multifactorial. Individuals with OA/TOF often have other malformations and medical problems. The aim of this study was to determine the association in OA/TOF cases and healthy control subjects of associated malformations, midline defects, and medical conditions. We also investigate the relationships of these conditions in the relatives of the cases and controls. The results show that infants with OA/TOF frequently have VACTERL anomalies (vertebral, 17%; anal, 12%; cardiac, 20%; renal, 16%; limb, 10%) and other midline defects (cleft lip and palate, 2%; sacral dysgenesis, 2%; urogenital anomalies, 5%). The following medical problems were also reported: oesophageal dysmotility, 21%; gastro-oesophageal reflux, 22%; chest infections, 6%; and autonomic dysfunction, 0.5%. The first-degree relatives of children with OA are much more likely to have one of the aforementioned malformations or medical conditions when compared with the control group: one or more VACTERL anomalies (P < 0.01), gastro-oesophageal reflux (P < 0.05), recurrent respiratory infections (P < 0.05), and autonomic dysfunction (P < 0.001). The more distant relatives also show an increased incidence of such problems although in this case the data must be viewed with caution. The results confirm that the associated malformations and related medical problems occur significantly more frequently in the relatives of individuals with OA/TOF. These families may prove valuable for linkage analysis in an attempt to determine the genetics of OA/TOF. Am. J. Med. Genet. 85:31–37, 1999. © 1999 Wiley-Liss, Inc.     

Parental consanguinity as a cause of increased incidence of birth defects in a study of 131, 760 consecutive birthsxs

The risk for birth defects in the offspring of first cousin parents is substantially higher than in the offspring of non-consanguineous parents. As a general decline in the frequency of consanguineous marriages was observed in this century, one wonders whether consanguinity is still a factor in the appearance of birth defects in developed countries. Based on our registry of congenital anomalies, we think that the answer to this question is “yes.” In the population studied in Northeastern France, consanguineous matings were known in 1.08% of the cases with congenital anomalies, vs. 0.28% in controls (P < 0.001). The frequency of the malformations recorded paralleled the degree of consanguinity: out of 38 malformed children, 24 were seen in first cousin matings (10.5 times more frequent than in offspring of nonconsanguineous couples), 8 in second cousin marriages, and 6 in more distantly consanguineous matings. Consanguineous mothers were more often pregnant than nonconsanguineous mothers (P < 0.01) and they had more stillbirths than nonconsanguineous mothers. These results must be taken into account when counseling consanguineous couples. © 1994 Wiley-Liss, Inc.     

Altitude as a risk factor for congenital anomalies

The birth prevalence of specific types of congenital anomalies at low and high altitudes in South America were compared after adjustment for prenatal growth, ethnicity, and socioeconomic status. The material includes all 1,668,722 consecutive births occurring in 53 hospitals participating in the Latin-American Collaborative Study of Congenital Malformations (ECLAMC), having registered at least 100 malformed/control pairs between 1967 and 1995. The lowland subsample (below 2,000 m above the sea level) included 46,729 case-control pairs, ascertained in 1,539,432 births from 49 hospitals in 38 cities. The highlands (above 2,000 m) comprised 3,498 case-control pairs from 129,301 births, occurring in four hospitals from three cities. Unconditional logistic regression was used to estimate the relative risks for the exposure at high altitudes, adjusted by ethnicity (Amerindian yes/no), type of health service (public/private), and birth weight (below/equal and greater than 2,500 g). The adjusted relative risks showed significantly (P < 0.01) higher values in the high than in the lowlands for four types of defects: cleft lip [relative risks (RR): 1.57; 95% confidence interval (CI): 1.27–1.94], microtia (RR: 3.21; 95% CI: 2.35–4.79), preauricular tag (RR: 2.09; 95% CI: 1.86–2.36), branchial arch anomaly complex (RR: 1.79; 95% CI: 1.23–2.61), constriction band complex (RR: 1.92; 95% CI: 1.11–3.31), and anal atresia (RR: 1.61; 95% CI: 1.01–2.57). Conversely, lower risks in the highlands were registered for two neural tube defects: anencephaly (RR: 0.33; 95% CI: 0.20–0.54), spina bifida (RR: 0.57; 95% CI: 0.37–0.78), as well as for hydrocephaly (RR: 0.41; 95% CI: 0.22–0.77) and pes equinovarus (RR: 0.70; 95% CI: 0.51–0.96). Even though some of these differences may be caused by undetected confounders, the coincidental finding of four types of craniofacial defects with higher, and two types of neural tube defect with lower frequencies in the highlands, suggest a real biological foundation. Am. J. Med. Genet. 86:9–14, 1999. © 1999 Wiley-Liss, Inc.     

Epidemiology of neural tube defect subtypes in Tunisia, 1991–2011

BackgroundNeural tube defects are common major congenital anomalies that result from very early disruption in the development of the brain and spinal cord.Aim of the studyWe conducted an epidemiological study to determine the impact of some feto-maternal characteristics in the occurrence of NTD subtypes.MethodsCharacteristics and outcomes of births with NTD and pregnancy characteristics of mothers over a period of twenty years (1991–2011) were recorded in the medical chart.ResultsFrom 1991 through 2011, 769 stillborns with NTD were delivered, yielding a prevalence of 2.02/10,000. The increase in NTD prevalences over these years was statistically significant (P = 0.000). In addition, differences between prevalences of NTD subtypes over season (P = 0.003) and between genders (P < 0.001) were significant. The highest frequency was noticed in winter with 3, 7 per 10,000 births among females. The difference in fetal term between subtypes was significant (P = 0.017). The probability to have a malformed fetus with a weight less than 1500 g was three times higher in myelomeningocele than in craniorachischisis, two times higher in anencephaly and encephalocele, but two times lower than rachischisis. Mothers with one gestation were two fold higher in anencephaly than in encephalocele. Nulliparous mothers’ cases were significantly more likely to have NTD than uni- or multiparous mothers. O+ mother's blood type presented a significant risk factor and was significantly less common in myelomeningocele than in rachischisis, but three times higher than in craniorachischisis. Consanguinity was present in cases with rachischisis and was two times higher than in cases with anencephaly, and three times higher than in cases with encephalocele.In this study, the results have been interpreted with caution due to analyses not being adjusted.ConclusionOne of the main findings of the study is that there are many differences between NTD subtypes, which suggests that there may be etiologic differences between subtypes. This suggests that, although epidemiologic studies frequently do not distinguish between NTD subtypes in analyses, they should be analyzed separately when possible.     

Cardiovascular malformations: Changes in prevalence and birth status, 1972–1990

Through an ongoing hospital-based active malformation surveillance program, we identified cardiovascular malformations (CVMs) in 3.3 per 1,000 liveborn and stillborn infants, and fetuses from pregnancies terminated electively during a 15-year period. We excluded the children of mothers who had planned delivery elsewhere, but were transferred for care of anomalies that had been detected in prenatal screening. Birth status changed markedly during the study with a significant increase in elective terminations of fetuses with a CVM from 0 to 22% (P < 0.01 based on a test for trend). The proportion of liveborn infants with CVMs decreased from 90% to 73% (P < 0.01); the frequency of stillbirths did not change. During the study period, there was a significant increase in the prevalence of CVMs in all births (P < 0.01) and elective terminations (P < 0.01). The increase in liveborn prevalence was not statistically significant (P = 0.08). Stillborn prevalence was unchanged. The number of mothers having prenatal ultrasonography (P < 0.01 for trend) and amniocentesis (P < 0.01 for trend) increased steadily. There were significant increases in the proportion of mothers having any ultrasound examination (P < 0.01 for trend), the number of initial ultrasound examinations occurring in the second trimester (P < 0.01 for trend), and the proportion of mothers having amniocentesis (P < 0.01 for trend). There was a significant increasing trend in the proportion of mothers who were 35 years and older (10% in 1972–1974, 26% in 1988–1990, P < 0.01). This hospital-based active surveillance program suggests that more frequent elective terminations had a significant effect on overall birth prevalence of CVMs. This trend would not have been detected by most other surveillance systems which determine prevalence of common birth defects from birth certificates and other forms of administrative reporting, and exclude elective terminations of pregnancy. Am. J. Med. Genet. 84:102–110, 1999. © 1999 Wiley-Liss, Inc.     

Genetic diagnoses and associated anomalies in fetuses prenatally diagnosed with esophageal atresia

Esophageal atresia (EA) is a congenital anomaly occurring in 2.3 per 10,000 live births. Due to advances in prenatal imaging, EA is more readily diagnosed, but data on the associated genetic diagnoses, other anomalies, and postnatal outcome for fetuses diagnosed prenatally with EA are scarce. We collected data from two academic medical centers (n = 61). Our data included fetuses with suspected EA on prenatal imaging that was confirmed postnatally and had at least one genetic test. In our cohort of 61 cases, 29 (49%) were born prematurely and 19% of those born alive died in the first 9 years of life. The most commonly associated birth defects were cardiac anomalies (67%) and spine anomalies (50%). A diagnosis was made in 61% of the cases; the most common diagnoses were vertebral defects, anal atresia, cardiac anomalies, tracheoesophageal fistula with esophageal atresia, radial or renal dysplasia, and limb anomalies association (43%, although 12% met only 2 of the criteria), trisomy 21 (5%), and CHARGE syndrome (5%). Our findings suggest that most fetuses with prenatally diagnosed EA have one or more additional major anomaly that warrants a more comprehensive clinical genetics evaluation. Fetuses diagnosed prenatally appear to represent a cohort with a worse outcome.     

VACTERL association,epidemiologic definition and delineation

This study departed from a preconceived definition of VACTERL, including more than one of these six anomalies in the same infant:; V (vertebral anomalies), A (anal atresia), C (congenital heart disease), TE (tracheoesophageal fistula or esophageal atresia), R (reno-urinary anomalies), and L (radial limb defect). Under this definition, 524 infants were ascertained by ECLAMC from almost 3,000,000 births examined from 1967 through 1990. Observed association rates among VACTERL components as well as between VACTERL and other defects were compared against randomly expected values obtained from 10,084 multiply malformed infants (casuistic method) from the same birth sample. Conclusions were: 1) Cardiac defects are not a part of VACTERL. 2) Single umbilical artery, ambiguous genitalia, abdominal wall defects, diaphragmatic hernia, and anomalies that are secondary to VACTERL components (intestinal and respiratory anomalies, and oligohydramnios sequence defects) are frequent enough to be considered an “extension” of VACTERL, and cardiac defects should be included in this category. 3) Neural tube defects are negatively associated with VACTERL which could not be explained by selection bias or any other operational artifact. High embryonic lethality or mutually exclusive pathogenetic mechanisms could be suitable explanations. 4) Results were not clear enough to determine whether VACTERL should be defined by at least two or three component defects. © 1996 Wiley-Liss, Inc.     

Enhancement of the Expression of Progesterone Receptor on Progesterone-Treated Lymphocytes After Immunotherapy in Unexplained Recurrent Spontaneous Abortion

PROBLEM: The immunological mechanism of an effective immunotherapy with paternal lymphocytes for unexplained recurrent spontaneous abortion (RSA) is not yet clear. Previous studies revealed that progesterone plays an important role in maintaining normal pregnancy and lower expression of progesterone receptor (PGR) on lymphocytes was found in RSA. Therefore, it was of interest to investigate whether immunotherapy for RSA would be able to enhance the expression of PGR on lymphocytes of RSA. METHOD: PGR expression on lymphocytes was analyzed with indirect immunofluorescence using flow cytometry. RESULTS: There was no change of PGR expression on PBL of RSA between pre- and post-immunotherapy (P > 0.05), while in the presence of 10.0 ug/ml progesterone for 24 h, PGR expressed on PBL on post-immunotherapy was increased significantly as compared with that of pre-immunotherapy in successful cases (P < 0.05) and decreased in abortive cases (P < 0.05). Most PGR was expressed on both CD4⁺ and CD8⁺ lymphocyte subsets. In successful cases, CD8⁺PGR⁺ subset of post-immunotherapy was found to be increased significantly (P < 0.05) in comparison with that of pre-immunotherapy. CONCLUSION: The data in the present study suggest that immunotherapy for RSA induced a higher expression of PGR on progesterone-treated lymphocytes, which may be involved in successful pregnancy.     

Muscle activity of the core during bilateral,unilateral, seated and standing resistance exercise

Little is known about the effect of performing common resistance exercises standing compared to seated and unilaterally compared to bilaterally on muscle activation of the core. Thus, the purpose of this study was to compare the electromyographic activity (EMG) of the superficial core muscles (i.e. rectus abdominis, external oblique and erector spinae) between seated, standing, bilateral and unilateral dumbbell shoulder presses. 15 healthy males performed five repetitions at 80% of one-repetition maximum of the exercises in randomized order. Results were analyzed with a two-way analysis of variance and a Bonferroni post hoc test. The position × exercise interaction was significantly different for rectus abdominis (P = 0.016), but not for external oblique (P = 0.100) and erector spinae (P = 0.151). The following EMG results were observed: For rectus abdominis: ~49% lower in seated bilateral versus unilateral (P < 0.001), similar in standing bilateral versus unilateral (P = 0.408), ~81% lower in bilateral seated versus standing (P < 0.001), ~59% lower in unilateral seated versus standing (P < 0.001); For external oblique: ~81% lower in seated bilateral versus unilateral (P < 0.001), ~68% lower in standing bilateral than unilateral (P < 0.001), ~58% lower in bilateral seated versus standing (P < 0.001), ~28% lower in unilateral seated versus standing (P = 0.002); For erector spinae: similar in seated bilateral versus unilateral (P = 0.737), ~18% lower in standing bilateral versus unilateral (P = 0.001), similar in seated versus standing bilateral (P = 0.480) and unilateral (P = 0.690). In conclusion, to enhance neuromuscular activation of the superficial core muscles, standing exercises should be used instead of seated exercises, and unilateral exercises should be used instead of bilateral exercises.     

Correlation of cytomorphology, immunophenotyping, and interphase fluorescence in situ hybridization in 381 patients with monoclonal gammopathy of undetermined significance and 301 patients with plasma cell myeloma

To further clarify the transformation from monoclonal gammopathy of undetermined significance (MGUS) to plasma cell myeloma (PCM), we compared interphase fluorescence in situ hybridization (FISH) patterns in 381 MGUS and 301 PCM patients. According to the World Health Organization and the International Myeloma Working Group, a threshold of 10% of bone marrow plasma cells separated MGUS from PCM. After magnetic activated cell sorting for CD138⁺ cells, FISH succeeded in 272 of 301 (90.4%) PCM, but in only 302 of 381 (79.3%) MGUS cases (P < 0.001). Cytogenetic alterations were more frequent in PCM (237 of 272; 87.1%) than MGUS (169 of 302; 56.0%; P = 0.0002). PCM showed a median of two cytogenetic alterations (range, 0–9) and MGUS one (range, 0–6). Considering only cases with a yield of plasma cells allowing five or more FISH probes, del(13)(q14) was found in 99 of 251 (39.3%) PCM but in only 59 of 267 (22.1%) MGUS (P = 0.0001), del(17p) in 15 PCM (6.0%) and in 6 MGUS (2.2%) patients (P = 0.029). A t(4;14)/IGH-FGFR3 was detected in 28 PCM (11.1%) and 5 MGUS (1.9%; P < 0.001). The t(11;14)/IGH-CCND1 and the t(14;16)/IGH-MAF showed no significant differences. Cytomorphology detected higher numbers of plasma cells than multiparameter flow cytometry (median ratio 4.25). This study underlines the genetic heterogeneity of MGUS similar to PCM. Genetic analysis might contribute to more diversified monitoring strategies for MGUS patients.     

Genetic factors in esophageal atresia,tracheo-esophageal fistula and the VACTERL association: Roles for FOXF1 and the 16q24.1 FOX transcription factor gene cluster,and review of the literature

Esophageal atresia with/without tracheo-esophageal fistula is a relatively common malformation, occurring in around 1 in 3500 births. In around half of cases, additional malformations are present, forming either a syndrome of known genetic aetiology, or a recognised association, of which the VACTERL association (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal and Limb malformations) is the most recognised. Recently, microdeletions of the FOX gene cluster at 16q24.1, comprising four genes, FOXF1, MTHFSD, FOXC2 and FOXL1, were reported to cause a phenotype resembling VACTERL association, with vertebral anomalies, gastro-intestinal atresias (esophageal, duodenal and anal), congenital heart malformations, and urinary tract malformations, as well as a rare lethal developmental anomaly of the lung, alveolar capillary dysplasia. This article reviews these new data alongside other genetic causes of syndromic esophageal atresia, and also highlights information from relevant mouse models, particularly those for genes in the Sonic Hedgehog pathway.     

Upper limb deficiencies and associated malformations: A population-based study

As part of an ongoing analysis of limb deficiencies occurring among 1,213,913 consecutive livebirths in British Columbia during the years 1952–1984, all cases with deficiencies of the upper limbs were analysed with a view to identifying associated patterns of anomalies. This analysis resulted in seven subgroups. For each subgroup, incidence figures for cases with and without additional anomalies were calculated separately. The proportion of cases with additional anomalies varied markedly by subgroup. For example, 89% of cases with longitudinal defects of the radius had additional malformations, while only 28% of cases with transverse defects of the radius had other organ anomalies (χ² = 40.55; P < 0.001, one degree of freedom). A preponderance of males was found among the cases with associated defects, particularly in the group with longitudinal defects of the radius (28 males, 14 females; χ² = 14.10; P < 0.001). Clustering of specific patterns of associated malformations is described within subgroups. © 1992 Wiley-Liss, Inc.     

Clinical Study of 44 Cases of Staphylococcus aureus Meningitis

In order to describe the clinical features and outcome of Staphylococcus aureus meningitis, the charts of 44 cases seen at one teaching hospital during a 20-year period were retrospectively reviewed. Staphylococcus aureus was the fifth most common cause of bacterial meningitis (10.2% of cases). There were 28 (63%) cases of postoperative meningitis and 16 (37%) of spontaneous meningitis. Patients with postoperative meningitis were younger than patients with spontaneous meningitis (mean age, 40.3 vs. 59.3 years; P=0.04) and had a lower frequency of community-acquired infection (32.1% vs. 93.8%; P<0.01), severe underlying diseases (28% vs. 87%; P<0.01) and associated staphylococcal infection (35% vs. 75%; P=0.01). The clinical presentation was similar in both groups, but patients with postoperative meningitis had a lower frequency of altered mental status (39% vs. 75%; P=0.02), meningeal signs (28% vs. 62%; P=0.02), petechial rash (0% vs. 18%; P=0.04), bacteremia (7% vs. 75%; P<0.01), and septic shock (0% vs. 44%; P<0.01). Most patients were treated with cloxacillin or vancomycin, with or without rifampicin, for a mean period of 22.5 days (range, 1–100 days). Overall mortality was 27%, and the mortality rate was higher for cases of spontaneous than postoperative meningitis (50% vs. 14%; P=0.01). Mortality correlated significantly with advanced age, spontaneous meningitis, altered mental status, and the presence of severe underlying diseases, bacteremia, and septic shock. Electronic Publication     

Serial examination of 20,248 newborn fetuses and infants: Correlations between drug exposure and major malformations

Maternal medication during the first trimester of pregnancy has been discussed as a risk factor for development of birth defects. The correlation between maternal drug use and major malformations was investigated in a population-based case-control study in Mainz. Over a period of 5 years (1990–1994), 20,248 livebirths, stillbirths, and abortions underwent physical and sonographic examination, and anamnestic data were collected. A total of 1,472 births with congenital anomalies (cases) and 9,682 births without major and minor malformations (controls) were analyzed. We distinguished between 30 different drug categories, which were divided into medication taken continuously (before and during pregnancy; CM) and acute medication (drugs given within the first 3 months of gravidity; AM). Statistically highly-significant results [CM: Odds Ratios (OR) 1.2, Confidence Intervals (CI) 1.1–1.4, P = 0.008; AM: OR 1.2, CI 1.1–1.3, P = 0.008] were established for maternal drug use in correlation to birth defects. For the majority of combinations between drugs and specific malformations no teratogenic risks were found. However, statistically significant associations were recorded for antiallergics and heart anomalies (CM, AM) as well as musculoskeletal anomalies (AM); for bronchodilators and heart anomalies (CM, AM); for antiepileptics and anomalies of the internal urogenital system (CM), as well as cleft palate/cleft lips (AM); for thyroid hormones and anomalies of the nervous system (CM, AM), as well as anomalies of the external urogenital system (CM, AM); for insulin and anomalies of the musculoskeletal system (CM); for digitalis and anomalies of the musculoskeletal system (AM). © 1996 Wiley-Liss, Inc.     

Descriptive epidemiology of isolated anal anomalies: A survey of 4.6 million births in Europe

The prevalence of anal anomalies among 4,618,840 births recorded in 33 EUROCAT registries between 1980 and 1994 was 4.05 per 10,000 births. Of the 1,846 recorded cases, 672 (36.4%) were isolated anal anomalies while 1,174 (63.6%) occurred together with other anomalies. Only isolated anal anomalies were analyzed in this study: 75.5% were atresias, 10.1% of which were above and 89.9% were below the level of the levator ani muscle. Fistula occurred in 53% of supralevator and 37% of infralevator atresia. Other anal anomalies were ectopic anus (3.4%), congenital anal fistula (14.7%), and persistent cloaca (0.9%). There was a predominance of males in anal atresia without fistula (male to female (M:F) ratio was 6.7 for supralevator and 2.3 for infralevator atresia), but no significant sex difference in atresias with fistula. There was a predominance of females in ectopic anus and congenital anal fistula (M:F = 0.11 and 0.36 respectively). High frequencies of fetal deaths were recorded in supralevator atresia without fistula (8.3%) and in persistent cloaca (11.1%). Mean gestational length and mean birth weights were reduced for persistent cloaca but were within normal limits for other isolated anal anomalies. Odds ratios (ORs) for mothers above 35 years were increased for supralevator atresia without fistula, supralevator atresia with fistula, and congenital anal fistula. ORs for mothers below 30 years were slightly increased for supralevator atresia without fistula and decreased for persistent cloaca. There were marked differences in prevalence and distribution of anal anomalies among the EUROCAT registries. The results indicated that there are epidemiological differences among the various types of anal anomalies which might reflect different embryological origins. © 2001 Wiley‐Liss, Inc.     

Subclassification of “atypia of undetermined significance” in thyroid fine‐needle aspirates

To identify the subtypes of atypia of undetermined significance (AUS) that confers a different magnitude for the risk of malignancy (RM), thyroid fine‐needle aspiration (FNA) cases carrying a diagnosis of “atypical follicular cells” or “follicular lesion” with surgical pathology followup were included in this study. The direct smears of the aspirates were rereviewed and subclassified into four subgroups based on cytomorphology: AUS cannot exclude follicular neoplasm (AUS‐FN), AUS cannot exclude Hürthle cell neoplasm (AUS‐HCN), AUS cannot exclude papillary carcinoma (AUS‐PTC) and AUS, not otherwise specified (AUS‐NOS). Based on the followup histopathologic findings, RM not including papillary microcarcinoma (PMC), RM including PMC and the risk of neoplasm (RN) were calculated for each of the four AUS subgroups. A total of 138 AUS cases were subclassified into AUS‐NOS (48), AUS‐PTC (41), AUS‐FN (32), and AUS‐HCN (17). RM not including PMC was 32% for AUS‐PTC (P < 0.001), 25% for AUS‐FN, 8% for AUS‐NOS, 0% for AUS‐HCN, and 18% for all AUS cases. RM including PMC was 54% for AUS‐PTC (P < 0.001), 34% for AUS‐FN, 19% for AUS‐NOS, 18% for AUS‐HCN, and 33% for all AUS cases. RN was 63% for AUS‐PTC (P = 0.05), 81% for AUS‐FN (P < 0.01), AUS‐HCN 53%, AUS‐NOS 44% and 59% for all cases. In our study, subclassification enabled us to further divide AUS cases into high‐ and low‐risk groups. The high‐risk group includes AUS‐PTC with a significantly higher risk of malignancy and AUS‐FN with a significantly higher risks of neoplasm. AUS‐HCN and AUS‐NOS subgroups demonstrate a lower risk of malignancy of <10%. Diagn. Cytopathol. 2014;42:23–29. © 2013 Wiley Periodicals, Inc.     

Clinicopathological significance of ‘atypical ductal proliferation’ in core needle biopsy of the breast

Atypical ductal proliferation or ADP has been used in histopathological diagnosis of core needle biopsy (CNB) but its details have not been well studied. Therefore, we examined the clinicopathological characteristics of the initial CNB cases diagnosed as ‘ADP ’ who subsequently turned out to be malignant, and compared the findings to those that did not. Among 101 cases initially diagnosed as ADP in CNB, the second biopsy revealed no carcinoma (38), ductal carcinoma in situ (DCIS) (45) and invasive carcinoma (18). Significant differences were detected between those which turned out to be carcinoma and those that did not, in the status of myoepithelial cells identified by p63 immunohistochemistry (P = 0.026) and ultrasound (US) categories (P < 0.001). We further compared the histopathological characteristics of those initially diagnosed as ADP and subsequently as DCIS or invasive ductal carcinoma (IDC) with those initially diagnosed as such. DCIS or IDC cases initially diagnosed as ADP had significantly lower Ki67 labeling index (P < 0.01, P < 0.01) and histological grade using Van nuys prognostic index (P < 0.01) or Nottingham histological grades (P < 0.01) respectively than those initially as DCIS or IDC. An assessment of myoepithelial components with US findings might contribute to determine the subsequent clinical algorithm of the patients diagnosed as ADP at initial CNB.     

Elevations of serum cancer biomarkers correlate with severity of COVID-19

In this retrospective study, we evaluated the levels of a series of serum biomarkers in coronavirus disease 2019 (COVID-19) patients (mild: 131; severe: 98; critical: 23). We found that there were significant increases in levels of human epididymis protein 4 (HE4) (73.6 ± 38.3 vs 46.5 ± 14.7 pmol/L; P < .001), cytokeratin-19 fragment (CYFRA21-1) (2.2 ± 0.9 vs 1.9 ± 0.8 μg/L; P < .001), carcinoembryonic antigen (CEA) (3.4 ± 2.2 vs 2.1 ± 1.2 μg/L; P < .001), carbohydrate antigens (CA) 125 (18.1 ± 13.5 vs 10.5 ± 4.6 μg/L; P < .001), and 153 (14.4 ± 8.9 vs 10.1 ± 4.4 μg/L; P < .001) in COVID-19 mild cases as compared to normal control subjects; their levels showed continuous and significant increases in severe and critical cases (HE4, CYFRA21-1, and CA125: P < .001; CEA and CA153: P < .01). Squamous cell carcinoma antigen (SCC) and CA199 increased significantly only in critical cases of COVID-19 as compared with mild and severe cases and normal controls (P < .01). There were positive associations between levels of C-reactive protein and levels of HE4 (R = .631; P < .001), CYFRA21-1 (R = .431; P < .001), CEA (R = .316; P < .001), SCC (R = .351; P < .001), CA153 (R = .359; P < .001) and CA125 (R = .223; P = .031). We concluded that elevations of serum cancer biomarkers positively correlated with the pathological progressions of COVID-19, demonstrating diffuse and acute pathophysiological injuries in COVID-19.     

Descriptive epidemiology of isolated anal anomalies: a survey of 4.6 million births in Europe.

The prevalence of anal anomalies among 4,618,840 births recorded in 33 EUROCAT registries between 1980 and 1994 was 4.05 per 10,000 births. Of the 1,846 recorded cases, 672 (36.4%) were isolated anal anomalies while 1,174 (63.6%) occurred together with other anomalies. Only isolated anal anomalies were analyzed in this study: 75.5% were atresias, 10.1% of which were above and 89.9% were below the level of the levator ani muscle. Fistula occurred in 53% of supralevator and 37% of infralevator atresia. Other anal anomalies were ectopic anus (3.4%), congenital anal fistula (14.7%), and persistent cloaca (0.9%). There was a predominance of males in anal atresia without fistula (male to female (M:F) ratio was 6.7 for supralevator and 2.3 for infralevator atresia), but no significant sex difference in atresias with fistula. There was a predominance of females in ectopic anus and congenital anal fistula (M:F = 0.11 and 0.36 respectively). High frequencies of fetal deaths were recorded in supralevator atresia without fistula (8.3%) and in persistent cloaca (11.1%). Mean gestational length and mean birth weights were reduced for persistent cloaca but were within normal limits for other isolated anal anomalies. Odds ratios (ORs) for mothers above 35 years were increased for supralevator atresia without fistula, supralevator atresia with fistula, and congenital anal fistula. ORs for mothers below 30 years were slightly increased for supralevator atresia without fistula and decreased for persistent cloaca. There were marked differences in prevalence and distribution of anal anomalies among the EUROCAT registries. The results indicated that there are epidemiological differences among the various types of anal anomalies which might reflect different embryological origins.