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In 2017–2019, the March of Dimes convened a workgroup with biomedical, clinical, and epidemiologic expertise to review knowledge of the causes of the persistent Black-White disparity in preterm birth (PTB). Multiple databases were searched to identify hypothesized causes examined in peer-reviewed literature, 33 hypothesized causes were reviewed for whether they plausibly affect PTB and either occur more/less frequently and/or have a larger/smaller effect size among Black women vs. White women. While definitive proof is lacking for most potential causes, most are biologically plausible. No single downstream or midstream factor explains the disparity or its social patterning, however, many likely play limited roles, e.g., while genetic factors likely contribute to PTB, they explain at most a small fraction of the disparity. Research links most hypothesized midstream causes, including socioeconomic factors and stress, with the disparity through their influence on the hypothesized downstream factors. Socioeconomic factors alone cannot explain the disparity's social patterning. Chronic stress could affect PTB through neuroendocrine and immune mechanisms leading to inflammation and immune dysfunction, stress could alter a woman's microbiota, immune response to infection, chronic disease risks, and behaviors, and trigger epigenetic changes influencing PTB risk. As an upstream factor, racism in multiple forms has repeatedly been linked with the plausible midstream/downstream factors, including socioeconomic disadvantage, stress, and toxic exposures. Racism is the only factor identified that directly or indirectly could explain the racial disparities in the plausible midstream/downstream causes and the observed social patterning. Historical and contemporary systemic racism can explain the racial disparities in socioeconomic opportunities that differentially expose African Americans to lifelong financial stress and associated health-harming conditions. Segregation places Black women in stressful surroundings and exposes them to environmental hazards. Race-based discriminatory treatment is a pervasive stressor for Black women of all socioeconomic levels, considering both incidents and the constant vigilance needed to prepare oneself for potential incidents. Racism is a highly plausible, major upstream contributor to the Black-White disparity in PTB through multiple pathways and biological mechanisms. While much is unknown, existing knowledge and core values (equity, justice) support addressing racism in efforts to eliminate the racial disparity in PTB.

Although preterm birth37 weeks' gestation is the leading cause of neonatal morbidity and mortality in the United States, the majority of data regarding preterm neonatal outcomes come from older studies, and many reports have been limited to only very preterm neonates. Delineation of neonatal outcomes by delivery gestational age is needed to further clarify the continuum of mortality and morbidity frequencies among preterm neonates.We sought to describe the contemporary frequencies of neonatal death, neonatal morbidities, and neonatal length of stay across the spectrum of preterm gestational ages.This was a secondary analysis of an obstetric cohort of 115,502 women and their neonates who were born in 25 hospitals nationwide, 2008 through 2011. All liveborn nonanomalous singleton preterm (23.0-36.9 weeks of gestation) neonates were included in this analysis. The frequency of neonatal death, major neonatal morbidity (intraventricular hemorrhage grade III/IV, seizures, hypoxic-ischemic encephalopathy, necrotizing enterocolitis stage II/III, bronchopulmonary dysplasia, persistent pulmonary hypertension), and minor neonatal morbidity (hypotension requiring treatment, intraventricular hemorrhage grade I/II, necrotizing enterocolitis stage I, respiratory distress syndrome, hyperbilirubinemia requiring treatment) were calculated by delivery gestational age; each neonate was classified once by the worst outcome for which criteria was met.In all, 8334 deliveries met inclusion criteria. There were 119 (1.4%) neonatal deaths. In all, 657 (7.9%) neonates had major morbidity, 3136 (37.6%) had minor morbidity, and 4422 (53.1%) survived without any of the studied morbidities. Deaths declined rapidly with each advancing week of gestation. This decline in death was accompanied by an increase in major neonatal morbidity, which peaked at 54.8% at 25 weeks of gestation. As frequencies of death and major neonatal morbidity fell, minor neonatal morbidity increased, peaking at 81.7% at 31 weeks of gestation. The frequency of all morbidities fell32 weeks. After 25 weeks, neonatal length of hospital stay decreased significantly with each additional completed week of pregnancy; among babies delivered from 26-32 weeks of gestation, each additional week in utero reduced the subsequent length of neonatal hospitalization by a minimum of 8 days. The median postmenstrual age at discharge nadired around 36 weeks' postmenstrual age for babies born at 31-35 weeks of gestation.Our data show that there is a continuum of outcomes, with each additional week of gestation conferring survival benefit while reducing the length of initial hospitalization. These contemporary data can be useful for patient counseling regarding preterm outcomes.

Cytogenetic microarray analysis (CMA) in prenatal testing detects chromosome abnormalities and new genetic syndromes that would be missed by conventional cytogenetics and has the potential to significantly enhance prenatal genetic evaluation. A large Eunice Kennedy Shriver National Institute Of Child Health and Human Development (NICHD)-sponsored multicentered trial to assess the role of CMA as a primary prenatal diagnostic tool has been completed, and results will soon be available. Integration of this technology into clinical care will require thoughtful changes in patient counseling. Here, we examine four cases, all ascertained in the NICHD prenatal microarray study, to illustrate the challenges and subtleties of genetic counseling required with prenatal CMA testing. Although the specifics of each case are distinct, the underlying genetic principles of uncertainty, variable expressivity, and lack of precise genotype-phenotype correlation are well known and already part of prenatal counseling. Counselor and practitioner education will need to include both the science of interpreting array findings as well as development of improved approaches to uncertainty. A team approach to interpretation will need to be developed, as will standardized guidelines by professional organizations and laboratories. Of equal import is additional research into patient attitudes and desires, and a better understanding of the full phenotypic spectrum of copy number variants discovered in utero.

The 22q11 Deletion Syndrome includes the overlapping phenotypes of DiGeorge/Velocardiofacial Syndromes, characterized by conotruncal heart defects, cleft palate, thymus, and parathyroid gland dysplasia. The majority (90%) of patients harbor detectable chr22q11.2 deletions, but a genetic etiology for the remainder of patients without a deletion can remain undefined despite major birth defects. We analyzed DNA from eight patients with normal 22q11 FISH studies by high-density single nucleotide polymorphism (SNP) arrays and identified potentially pathogenic copy number variants (CNVs) in four of eight patients. Two patients showed large CNVs in regions of known genomic disorders: one a deletion of distal chr22q11.2 and the other a duplication of chr5q35. A 3-Mb deletion of chr19p13.3 that includes a gene associated with conotruncal heart defects was found in a third patient. Two potentially pathogenic CNVs were found in a fourth patient: a large heterozygous deletion of chr6p24 and a smaller duplication of chr9p24. Our findings support a recent consensus statement advocating chromosomal microarray analysis as a first-line diagnostic approach for patients with multiple congenital anomalies. In patients with phenotypes suggestive of the 22q11.2 syndrome spectrum and normal FISH, microarray analysis can uncover the molecular basis of other genomic disorders whose features overlap those of 22q11.2 deletions.

Maternal serum screening for neural tube defects and fetal aneuploidy in the second trimester has been incorporated into obstetrical practice over the past two decades. Now, as a result of several multicenter trials, first trimester screening between 11 and 14 weeks has been shown to be an effective and reliable screening test for Down syndrome and trisomy 18. This policy updates the American College of Medical Genetics policy statement entitled Second Trimester Maternal Serum Screening for Fetal Open Neural Tube Defects and Aneuploidy (2004), incorporates First trimester diagnosis and screening for fetal aneuploidy (2008) and complements the sections of American College of Medical Genetic's Standards and Guidelines for Clinical Genetics Laboratories entitled Prenatal Screening for Down syndrome (2005) and Prenatal Screening for Open Neural Tube Defects (2005).

A 37-year-old woman, gravida 1, seeks prenatal care at 8 weeks' gestation. Her family history and medical history are unremarkable. What would you advise regarding her risk of fetal chromosomal abnormalities such as Down's syndrome and her options for prenatal screening and diagnosis?

BACKGROUND: The phenotype associated with deletion of the 22q11.2 chromosomal region is highly variable, yet little is known about the source of this variability. Cardiovascular anomalies, including tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, perimembranous ventricular septal defects, and aortic arch anomalies, occur in approximately 75% of individuals with a 22q11.2 deletion. METHODS: Data from 343 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the cardiac phenotype in this disorder. Subjects with and without cardiac malformations, and subjects with and without aortic arch anomalies were compared with respect to sex and race. In addition, in the subset of subjects from whom a DNA sample was available, genotypes for variants of four genes that are involved in the folate-homocysteine metabolic pathway and that have been implicated as risk factors for other birth defects were compared. Five variants in four genes were genotyped by heteroduplex or restriction digest assays. The chi-square or Fisher's exact test was used to evaluate the association between the cardiac phenotype and each potential modifier. RESULTS: The cardiac phenotype observed in individuals with a 22q11.2 deletion was not significantly associated with either sex or race. The genetic variants that were evaluated also did not appear to be associated with the cardiovascular phenotype. CONCLUSIONS: Variation in the cardiac phenotype observed between individuals with a 22q11.2 deletion does not appear to be related to sex, race, or five sequence variants in four folate-related genes that are located outside of the 22q11.2 region. Birth Defects Research (Part A), 2009. © 2008 Wiley-Liss, Inc.

Purpose: In an effort to identify cell surface targets and single short-chain antibody (scFv) for ovarian cancer therapy, we used a phage display approach to isolate an antibody with high reactivity against ovarian cancer.Experimental Design: A phage scFv library was subjected to panning against human SK-OV-3 ovarian cancer cells. A clone with high reactivity was selected and tested in immunoperoxidase staining on a panel of normal tissues and ovarian carcinoma. Using immunoprecipitation, a differentially expressed band was analyzed by mass spectrometry. The antigen subclass was characterized with reverse transcription-PCR on cDNA library of normal tissues, and 91 ovarian cancer specimens, and correlated with clinicohistopathologic characteristics.Results: Ninety-six individual scFv clones were screened in ELISA following panning. scFv F7 revealed high reactivity with ovarian cancer cell lines and showed intense staining of 15 fresh ovarian cancer specimens and no staining of a panel of normal tissues. A 40-kDa protein was identified to be translation elongation factor 1α1 (EEF1A1; P < 0.05). The expression of EEF1A2, a highly homologous and functionally similar oncogene, was found to be restricted only to the normal tissues of the heart, brain, and skeletal muscle. Aberrant EEF1A2 mRNA expression was found in 21 of 91 (23%) of ovarian cancer specimens and significantly correlated with increased likelihood of recurrence (P = 0.021).Conclusions: scFv F7 may represent an ovarian cancer–specific antibody against translation EEF1A family of translational factors. We propose that EEF1A2 may be a useful target for therapy of human ovarian cancer.

Disclaimer: This guideline is designed primarily as an educational resource for medical geneticists and other healthcare providers to help them provide quality medical genetic services. Adherence to this guideline does not necessarily assure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient's record the rationale for any significant deviation from this guideline.

Objective We sought to describe the prevalence of serious maternal complications following early preterm birth by gestational age (GA), delivery route, and type of cesarean incision. Study Design Trained personnel abstracted data from maternal and neonatal charts for all deliveries on randomly selected days representing one third of deliveries across 25 US hospitals over 3 years (n = 115,502). All women delivering nonanomalous singletons between 23-33 weeks' gestation were included. Women were excluded for antepartum stillbirth and highly morbid conditions for which route of delivery would not likely impact morbidity including nonreassuring fetal status, cord prolapse, placenta previa, placenta accreta, placental abruption, and severe and unstable maternal conditions (cardiopulmonary collapse, acute respiratory distress syndrome, seizures). Serious maternal complications were defined as: hemorrhage (blood loss ≥1500 mL, blood transfusion, or hysterectomy for hemorrhage), infection (endometritis, wound dehiscence, or wound infection requiring antibiotics, reopening, or unexpected procedure), intensive care unit admission, or death. Delivery route was categorized as classic cesarean delivery (CCD), low transverse cesarean delivery (LTCD), low vertical cesarean delivery (LVCD), and vaginal delivery. Association of delivery route with complications was estimated using multivariable regression models yielding adjusted relative risks (aRR) controlling for maternal age, race, body mass index, hypertension, diabetes, preterm premature rupture of membranes, preterm labor, GA, and hospital of delivery. Results Of 2659 women who met criteria for inclusion in this analysis, 8.6% of women experienced serious maternal complications. Complications were associated with GA and were highest between 23-27 weeks of gestation. The frequency of complications was associated with delivery route; compared with 3.5% of vaginal delivery, 23.0% of CCD (aRR, 3.54; 95% confidence interval (CI), 2.29–5.48), 12.1% of LTCD (aRR, 2.59; 95% CI, 1.77–3.77), and 10.3% of LVCD (aRR, 2.27; 95% CI, 0.68–7.55) experienced complications. There was no significant difference in complication rates between CCD and LTCD (aRR, 1.37; 95% CI, 0.95–1.97) or between CCD and LVCD (aRR, 1.56; 95% CI, 0.48–5.07). Conclusion The risk of maternal complications after early preterm delivery is substantial, particularly in women who undergo cesarean delivery. Obstetricians need to be prepared to manage potential hemorrhage, infection, and intensive care unit admission for early preterm births requiring cesarean delivery.

Objectives. The identification of proteins that are selectively expressed in cancer and with potential to elicit an immune response is the first step towards antigen-specific immunotherapy. The Wilms tumor gene product (WT1) is inherently immunogenic and is now thought to be oncogenic. The aim of this study was to determine the expression of WT1 in epithelial ovarian cancer (EOC) and correlate with clinico-pathologic characteristics. Methods. WT1 expression was examined using immunohistochemistry applied on a tissue microarray of normal tissues and a panel of 100 EOC tissues. The distribution of WT1 expression and clinico-pathologic variables were analyzed. Survival probabilities were estimated by Kaplan–Meier method, and statistical significance was determined by the log-rank test. Results. WT1 expression was observed in 78/100 of specimens. The predominant expression pattern was homogenous, occurring in 66/100 (66%) of WT1-positive specimens, while 12/100 (12%) demonstrated heterogeneous staining. In normal tissues, WT1 expression was noted in kidneys, splenic capsule, Sertoli cells of the testis, and granulosa cells of the ovary. The median follow-up of the patient population was 30 months. Patients with WT1-positive tumors tended to have a higher grade ( P = 0.006) and stage ( P = 0.002) of tumor. However, there were no significant differences in the distribution of patients with WT1-positive tumors in relation to disease-free and overall survival. Conclusions. Our data demonstrate that WT1 is expressed at high frequency in patients with EOC. Since WT1 demonstrates tissue-restricted expression and is inherently immunogenic, it could represent an attractive target for antigen-specific immunotherapy in EOC.

A significant proportion of newly diagnosed melanomas are thin lesions (or = 1.00 mm). Because tumor thickness correlates with the risk for nodal metastases, sentinel lymph node (SLN) biopsy in this subset is controversial. Incorporating other prognostic factors (Clark level and ulceration), we evaluated the 6th edition American Joint Committee on Cancer (AJCC) clinical stage as a simple and widely applicable guideline for offering SLN biopsy for thin melanoma.This study was a review of a prospective melanoma SLN database from 1993 to 2003 with emphasis on SLN positivity rates based on the 6th edition AJCC primary tumor thickness intervals and clinical stage.Three hundred five patients underwent SLN biopsy, with an overall positivity rate of 17.7%. By the 6th edition AJCC, lesionsor = 1.00 mm had an SLN positivity rate of 6.6%. By 6th edition clinical stage, SLN positivity rates were 4.9% for stage IA and 10.4% for stage IB. By using stage IA as the criterion for not offering SLN biopsy, this procedure would have been avoided in 46% (39 of 85) ofor = 1.00-mm melanoma patients with a negative SLN.Sixth edition AJCC clinical stage IB as a selection criterion for performing SLN biopsy in thin melanoma identifies most patients with a positive SLN while also avoiding a negative SLN biopsy in many patients. Until additional widely accepted and validated selection criteria are available, SLN biopsy for clinical stage IB, but not stage IA, thin melanomas is a reasonable approach.

The following are the recommendations of the American College of Medical Genetics (ACMG) Professional Practice and Guidelines Committee, convened to assist health care professionals in making decisions regarding genetic diagnosis and testing. The purpose of this document is to provide a brief overview of fragile X syndrome (FXS), and to make recommendations that can serve as general guidelines to aid clinicians in making referrals for diagnostic and carrier testing for this condition. Fragile X syndrome is the most common cause of inherited mental retardation and is caused by a mutation in the X-linked FMR1 gene. DNA studies are used for testing individuals with symptoms of FXS and individuals at risk for carrying the mutation. Genotypes are determined by examining the size of the trinucleotide repeat segment and the methylation status of the FMR1 gene. These guidelines supersede the 1994 ACMG statement of the same name.

Objectives. Cancer-testis (CT) antigens are expressed in tumors but not normal tissues except the testis and could be targets for vaccine therapy in epithelial ovarian cancer (EOC). A-kinase anchoring protein 3 (AKAP-3) is a novel member of the CT antigen family. The aim of this study was to examine the expression of AKAP-3 in EOC and correlate with clinico-pathologic characteristics. Methods. One step RT-PCR was performed with RNA from normal and ovarian cancer cell lines and 74 epithelial ovarian tumor tissues. AKAP-3-specific PCR product was amplified. The distribution of AKAP-3 expression and clinico-pathologic variables was analyzed. Survival distributions were estimated, and multivariate analyses were performed. Results. AKAP-3 mRNA expression was demonstrated in 43/74 (58%) of the ovarian cancer specimens. AKAP-3 was expressed in normal testis, but not in other normal tissues. AKAP-3 expression significantly correlated with increased likelihood of residual tumor ( P = 0.005), but no increase in the likelihood of recurrence or persistent disease ( P = 0.06). Patients with AKAP-3 mRNA expression were found to have a significantly poorer overall survival (median 50 months) compared with patients without AKAP-3 expression (median not reached) ( P = 0.007). Multivariate analysis of AKAP-3 expression, residual disease, and response to frontline chemotherapy found response to be the strongest predictor of overall survival ( P = 0.012). Conclusions. Our data demonstrate that AKAP-3 is expressed at high frequency in patients with EOC. Since AKAP-3 demonstrates tumor-restricted expression and appears to be associated with worse overall survival, it could represent an attractive target for antigen-specific immunotherapy in EOC.

The objective of this study is to review the experience with pelvic exenterations for gynecological malignancies at our cancer institute. Charts of 48 women who underwent a pelvic exenteration between January 1980 and December 1999 were reviewed, and several outcomes were analyzed. Majority of patients had received prior radiation therapy. The median survival was 35 months, and the disease-free survival was 32 months. Mortality from the procedure was 4.2%. Early and late postoperative complication rates were 27% and 75%, respectively. Recurrence rate was 60%. Eight patients received intraoperative radiation. Median survival in this group was 11.3 vs 35 months (P = 0.003). Univariate analysis failed to show an association between type of pelvic exenteration, type of fecal and urinary diversion, outcome, need for reoperation, and recurrence.Contemporary pelvic exenterations are associated with a low mortality and a potential for long-term survival in a subset of patients who historically have been given a poor prognosis. In patients with recurrent gynecological cancer confined centrally to the pelvis, pelvic exenteration still remains the choice of therapy as response to chemotherapy to a centrally recurrent tumor in radiated area continues to be poor. Intraoperative radiation in select few patients needs to be further studied.

After completing this article, readers should be able to: 1. Discuss the benefits and limitations of carrier screening. 2. Describe the recommendations for screening for hemoglobinopathies. 3. List the genetic disorders for which carrier screening is available for individuals of Ashkenazi Jewish ancestry. 4. Describe the recommendations for cystic fibrosis carrier screening. Carrier screening for hemoglobinopathies, Tay-Sachs and Canavan diseases, and more recently, cystic fibrosis has been incorporated into routine obstetric care. These genetic disorders are autosomal recessive, and when both members of a couple are carriers, there is a 25% risk of having an affected child in each pregnancy. Although many states routinely screen newborns for sickle cell disease and cystic fibrosis, recognition that a couple is at increased risk for having a child with one of these disorders permits a wider array of options, including antenatal diagnosis and termination of an affected fetus. In some cases, identification of an affected fetus allows a couple, their obstetrician, neonatologist, pediatrician, and pediatric specialists to prepare for the birth of an affected fetus. Screening completed prior to conception provides couples with additional reproductive options to consider, including donor gametes, preimplantation genetic diagnosis, and adoption if they choose to reduce their risk of having an affected child. As a result of the Human Genome Project and advances in technology, DNA-based tests can be used for carrier screening and prenatal diagnosis for many inherited conditions. In addition to screening for sickle cell disease, thalassemia, and Tay-Sachs disease, carrier screening now is available for cystic fibrosis, Canavan disease, and other disorders that are more common in individuals of Ashkenazi Jewish ancestry. Carrier screening recommendations for these genetic conditions is based on a person’s ethnicity. However, the importance of family history cannot be underestimated. The family history is used to determine whether an individual or couple is at increased …

Activation of the epidermal growth factor receptor (EGFR) has a role in oncogenesis and may correlate with prognosis. The aim of this study was to examine EGFR expression in esophageal adenocarcinoma and correlate EGFR status with pathologic and clinical prognostic features. An exploratory retrospective review of 38 patients with surgically resected esophageal adenocarcinoma was performed. All patients underwent an esophagogastrectomy with regional lymphadenectomy; 24 patients underwent primary resection and 14 patients had surgery after preoperative chemoradiation therapy. Immunohistochemical analysis was performed on paraffin-embedded tissue samples using an EGFR monoclonal antibody. Low- and moderate-grade tumors were positive for EGFR expression in 2 of 15 patients; poorly differentiated tumors were positive for EGFR expression in 13 of 23 patients (p = 0.02). The median survival was 35 months (confidence interval [CI]: 29–40) for EGFR negative patients (n = 23) and 16 months (CI: 10–22) for EGFR positive patients (n = 13) (p = 0.10). Disease recurred in 3 of 21 EGFR negative patients and 6 of 13 EGFR positive patients (p = 0.06). Poorly differentiated adenocarcinomas of the esophagus demonstrated higher EGFR expression compared to low-grade tumors based upon immunohistochemical analysis. A trend toward improved disease-free and overall survival was seen in EGFR negative patients.

Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel

The causes of abnormal pubertal development are numerous. Recent molecular investigation has increased our understanding of the genetic basis of pubertal disorders. Investigators have identified some of the genes that are critical for normal puberty and have begun to elucidate the genes and pathogenesis of genetic disorders associated with abnormal pubertal development. Identification of specific chromosomal abnormalities and gene mutations allows for diagnostic testing and enables the clinician to provide accurate counseling of the recurrence risk for relatives. In the future, knowledge of the genetic basis of these disorders will facilitate the development of novel therapies and approaches to the fertility assessment and treatment of individuals with pubertal disorders. Although great strides have been made in identifying these genes, questions remain. Why do some genetic mutations affect puberty differentially in males and females? What is the long-term impact in terms of future fertility, and what is the risk to the offspring of such patients? Further research is needed to address these issues and to identify additional genetic loci involved in pubertal development.

Deletions of chromosome 22q11.2 are found in the vast majority of patients with DiGeorge/velocardiofacial syndrome (DGS/VCFS). This most frequent microdeletion syndrome is estimated to occur in 1 in 4,000 live births. The majority of deletions are de novo, with 10% or less inherited from an affected parent. Here, we report two separate families with recurrence of a 22q11.2 deletion in first cousins. In each family, unaffected siblings (brother and sister) had an affected child. Fluorescence in situ hybridization (FISH) studies of the parents of each affected child were normal and hence, relatives were not considered at an increased risk for recurrence in another pregnancy. We used highly polymorphic microsatellite repeat markers from within 22q11.2 to determine the parental origin of each cousin's deletion and to assess whether parental germline mosaicism for the 22q11.2 deletion might be a factor in these cases. This analysis confirmed that in each case, the deletion occurred on a chromosome 22 derived from unrelated parents, consistent with independent de novo deletion events. Thus, we concluded that germline mosaicism as the underlying mechanism for affected cousins in these families was unlikely. Our findings underscore the high frequency with which the 22q11.2 deletion occurs in the general population and demonstrate the important role that PCR-based parental origin determination can have in recurrence risk counselling. Furthermore, relatives of affected individuals may benefit from genetic counselling and consider prenatal testing for the 22q11.2 deletion in future pregnancies, despite a low recurrence risk.

BACKGROUND Stereotactic core needle biopsy (SCNB) may change the size of the tumor defined pathologically at excision. This may alter tumor stage and affect recommendations for adjuvant systemic therapy. This study evaluated the effect of SCNB on assessment of pathologic tumor size and staging for invasive breast carcinomas presenting as mammographic masses. METHODS The authors reviewed the mammographic and pathologic size of 138 mammographically detected invasive carcinomas manifested as a measurable mass lesion on mammography and as a 20 mm or smaller lesion on pathologic evaluation. Group A included 61 patients with SCNB before surgical excision and the Group B (the control group) included 77 patients who had surgical excision without SCNB. The size of the mammographic central mass was compared with the pathologic tumor size. The difference between the mammographic and pathologic size was determined and the findings in Group A and B were compared by the Mann–Whitney U test. RESULTS The mean mammographic size was 12.2 and 11.83 mm and the mean pathologic size was 9.85 and 9.87 mm for Groups A and B, respectively. The mean difference between mammographic and pathologic size in Groups A and B was 2.3 mm and 1.96 mm, respectively (P = not significant). CONCLUSIONS For soft tissue masses, the difference between mammographic size and pathologic size of invasive carcinoma at excision does not appear to be affected by the use of SCNB. Except in the circumstance of complete removal of the cancer by SCNB, the pathologic size and stage of the excised tumor after SCNB is not altered significantly by SCNB. Cancer 2003;97:2137–41. © 2003 American Cancer Society. DOI 10.1002/cncr.11336

Objective: Approximately 50% of patients with ovarian cancer who have normal CA 125 levels at the completion of therapy have persistent disease. In an effort to improve the ability to detect small volume disease, we have evaluated the usefulness of N -acetylglucosamine:β1,4-galactosyltransferase as a potential biomarker for the detection of subclinical disease after the completion of primary therapy for ovarian cancer. Study Design: The sera of 33 patients with stage IIIC epithelial ovarian cancer in complete clinical remission after chemotherapy (CA 125 N -acetylglucosamine:β1,4-galactosyltransferase activity. The values were determined from sera that had been obtained before primary cytoreductive operation and before second-look surgery after the completion of platinum-based chemotherapy. Determinations of the levels of CA 125 were performed with the Bayer Immuno ITM CA-125 II assay. N -acetylglucosamine:β1,4-galactosyltransferase activity was determined by measuring the transfer of galactose from uridine diphosphate– carbon 14–labeled galactose to the terminal N -acetylglucosamine residue of a very well-defined synthetic acceptor, N -acetylglucosamine:β1,6GalNAcα-o-benzyl, which is a portion of the core structure of mucin glycoproteins. The cutoff value of N -acetylglucosamine:β1,4-galactosyltransferase was determined to be 22,000 counts/min, based on the analysis of 25 healthy control subjects. Correlation between serum CA 125 and N -acetylglucosamine:β1,4-galactosyltransferase levels was determined with the use of the Pearson correlation coefficient. The ability of galactosyltransferase to identify small volume disease correctly was also evaluated. Results: There was a significant correlation between serum CA 125 and N -acetylglucosamine:β1,4-galactosyltransferase levels before the operation ( r = 0.57; P =.03) but not before second-look surgery ( r = 0.10; P =.57). Thirteen patients (39.4%) had residual disease at second-look surgery. Elevated N -acetylglucosamine:β-1,4galactosyltransferase activity >22,000 cpm correctly identified 10 of these patients (76.9%). The sensitivity, specificity, and positive and negative predictive values of N -acetylglucosamine:β1,4-galactosyltransferase activity (>22,000 counts/min) for the prediction of residual disease at second-look surgery were 77%, 45%, 48%, and 77%, respectively. Conclusion: Our comparative study of serum CA 125 and N -acetylglucosamine:β1,4-galactosyltransferase levels showed a significant correlation between the two tumor markers before the beginning of ovarian cancer therapy. This correlation disappeared before second-look surgery because 60% of patients with normal serum CA 125 and N -acetylglucosamine:β1,4-galactosyltransferase levels. CA 125 antigen appears to be inferior to N -acetylglucosamine:β1,4-galactosyltransferase in the detection of small-volume residual disease. N -acetylglucosamine:β1,4-galactosyltransferase may be useful as a biomarker in the monitoring of patients with ovarian cancer when the serum CA 125 level is normal. These findings require confirmation in larger studies. (Am J Obstet Gynecol 2002;187:575-80.)

This study was performed to determine whether the sisters of women with polycystic ovary syndrome (PCOS) have evidence for insulin resistance. Three hundred and thirty-six women with PCOS, 307 sisters of these probands, and 47 control women were studied. The sisters were grouped by phenotypes: PCOS [hyperandrogenemia (HA) with chronic oligoor amenorrhea, n 39], HA with regular menses (n 36), unaffected (UA; n 122), and unknown (n 110). The analyses were adjusted for age and body mass index. PCOS and HA sisters of women with PCOS had similar and significantly elevated fasting insulin levels (P 0.001) as well as similar and significantly decreased fasting glucose/insulin ratios (P < 0.001) suggestive of insulin resistance compared with UA sisters and control women. Markers of insulin resistance were associated with hyperandrogenemia and not with menstrual irregularity. PCOS sisters also had decreased levels of SHBG (P 0.02) suggestive of higher ambient insulin levels. PCOS sisters had increased levels of proinsulin (P 0.04) compared with control women, which suggested pancreatic -cell dysfunction in this group of sisters. The magnitude of obesity also differed significantly among the groups of sisters. The PCOS sisters were significantly more obese than all the other groups, and the HA sisters were more obese than the UA sisters. We conclude that markers of insulin resistance are associated with hyperandrogenemia rather than menstrual irregularity in the sisters of women with PCOS. Menstrual irregularity may be related to the magnitude of insulin sensitivity or insulin secretion or to other factors associated with obesity. (J Clin Endocrinol Metab 87: 2128 –2133, 2002)

Background: Previous studies have shown that early postoperative oral feeding is feasible. Traditionally patients were fed when flatus or defecation documented the return of bowel function. This study was undertaken to determine factors that may preclude early feeding. Methods: One hundred four successive patients underwent colorectal surgery from October 1999 to January 2001. Eighty-nine patients started an oral diet either on postoperative day 1 or 2. Their clinical outcomes were recorded prospectively. Fifteen of the 104 patients were excluded for small-bowel resection 5 patients, perioperative complications 5 patients, prior radiation 3 patients, and small-bowel obstruction 2 patients. A failure in postoperative feeding consisted of nausea, vomiting, or readmission. Results: The mean age of our cohort was 65 years range, 28–87 years. There were 45 male and 44 female patients. The mean postoperative hospital stay was 6 days range, 3–13 days. The median American Society of Anesthesiology score was II range, I–IV. The types of resection performed were right colectomy 27 patients, low anterior resection 26 patients, sigmoid resection 11 patients, abdominoperineal resection 8 patients, formation or closure of colostomy 7 patients, posterior pelvic exenteration 4 patients, total colectomy 3 patients, left colectomy 2 patients, and transverse colectomy 1 patient. Sixty-five patients 73% tolerated early oral feeding. Of the 24 patients that did not, 16 had nausea or emesis, and 8 required readmission for postoperative complications small-bowel obstruction [4 patients], wound dehiscence [1 patient], abdominal pain [1 patient], and anastomotic leak [2 patients]. Univariate analysis revealed that the use of volume expanders contributed to intolerance of early feeding. On multivariate analysis, blood loss during the operation was the only factor contributing to failure of early postoperative oral feeding. Conclusions: Early oral feeding is safe and feasible for postcolectomy patients with a history of colorectal neoplasms.

Objective. Although thoracotomy for removal of pulmonary metastasis is well documented in a wide variety of solid tumors, data are sparse regarding management of patients with gynecologic malignancies metastatic to the lung. Methods. We retrospectively reviewed the Roswell Park Cancer Institute experience between 1982 and 1999. Of 82 eligible patients with gynecologic tumors metastatic and confined to the lung, 25 underwent pulmonary resection. Results. There were 60 uterine and 22 cervix cancer patients with pulmonary metastases. Among patients with uterine cancer primaries undergoing pulmonary resection (n 5 19) median survival was 26 months. Uterine cancer patients who underwent surgical resection for leiomyosarcomas (n 5 11) had a median survival of 25 months compared to 46 months in patients with adenocarcinoma (n 5 6, P 5 0.02). Median survival in cervix cancer patients undergoing resection for pulmonary metastases (n 5 6) was 36 months. Conclusions. Pulmonary resection may provide a survival advantage for selected patients with uterine and cervical malignancies with metastases isolated to the lung. © 2001 Academic Press

Purpose: The chromosome 22q11.2 deletion has been identified in the majority of patients with DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome and in some patients with the autosomal dominant Opitz G/BBB syndrome and Cayler cardiofacial syndrome. In addition, 22q11.2 deletion studies are becoming part of a standardized diagnostic workup for some isolated defects such as conotruncal cardiac anomalies and velopharyngeal incompetence. However, there is little information available on the clinical findings of unselected patients. For example, those individuals identified during prenatal diagnosis, as part of a generalized screening protocol, or following the diagnosis in a relative. This information will be invaluable in defining the variability of the disorder and in observing long-term outcome in the absence of targeted remediations. This study allows one to examine the first unselected cohort of patients and serves to highlight the importance of deletion testing in parents of affected probands. Methods: Thirty individuals with a 22q11.2 deletion were identified following the diagnosis in a relative. Nineteen were adults ascertained only following the diagnosis in their child, 10 were children identified following the diagnosis in their sibling, and one was a child diagnosed prenatally following the diagnosis in her parent. Results: Sixty percent of patients had no visceral anomalies. In fact, only 6 of the 19 adults (32%) and 6 of the 11 children (55%) had major findings which would have brought them to medical attention. Deletion sizing demonstrated the same large 3–4MB deletion in most families despite wide inter and intrafamilial variability and there was no difference in clinical findings based on the parent of origin. Thus, no genotype-phenotype correlations could be made. Conclusion: We report the first unselected cohort of patients with the 22q11.2 deletion identified through an affected relative. Analysis of this series of 30 patients, many with very mild manifestations of the deletion, allows one to examine the outcome in individuals who lacked specific remediations for this disorder. It emphasizes the importance of broadening the index of suspicion in order to provide appropriate recurrence risk counseling, cognitive remediation, and medical management. Further, it underscores the lack of familial concordance and the current lack of genotype-phenotype correlations in this disorder, and it raises the possibility that the deletion is more common than previously reported.

In an earlier study of 37 candidate genes for polycystic ovary syndrome (PCOS), the strongest evidence for genetic linkage was found with the region of the follistatin gene. We have now carried out studies to detect variation in the follistatin gene and assess its relevance to PCOS. By sequencing the gene in 85 members of 19 families of PCOS patients, we found sequence variants at 17 sites. Of these, 16 sites have variants that are too rare to make a major contribution to susceptibility; the only common variant is a single base pair change in the last exon at a site that is not translated. In our sample of 249 families, the evidence for linkage between PCOS and this variant is weak. We also examined the expression of the follistatin gene; messenger RNA levels in cultured fibroblasts from PCOS and control women did not differ appreciably. We conclude that contributions to the etiology of PCOS from the follistatin gene, if any, are likely to be small.

Objectives: To delineate feeding dysfunction in a population of children with a 22q11.2 deletion and report the associated findings noted during the modified barium swallow (MBS). Study design: Seventy-five children with a chromosome 22q11.2 deletion and history of persistent feeding difficulty received a feeding evaluation, including an MBS for those children for whom there was concern about airway penetration. Results: A consistent pattern of feeding difficulty, independent of palatal or cardiac involvement, emerged from the evaluations. This group typically has trouble coordinating the suck/swallow/breath pattern, resulting in slow nipple feedings interrupted by gagging or regurgitation. Recurrent vomiting and constipation are common. With advancement to chewable table foods, gagging or refusal develops, related to an immature oral transport pattern. The MBS studies demonstrate pharyngeal hypercontractility, cricopharyngeal prominence, and/or diverticula. Conclusions: Because of the consistency of dysphagic symptoms and MBS findings, we propose that dysmotility, especially through the pharyngoesophageal segment, is central to the dysphagia affecting this group. Dysphagia related to dysmotility may be underdiagnosed in this population or erroneously attributed to cardiac disease. Therefore attention to feeding status and investigation with MBS and gastrointestinal studies as warranted are recommended for all patients with a 22q11.2 deletion and feeding problems. (J Pediatr 2000;137:158-64)

The 22q11.2 microdeletion syndrome is a genetic disorder that is being recognized with increasing frequency. Confirmation of the diagnosis can be made using fluorescence in situ hybridization. Many medical and developmental problems are present in children with this syndrome. Communication disorders are among the most common features of this syndrome and include articulation, language, resonance, and voice problems. The purpose of this paper is to provide a description of the communicative and developmental features in a sample of children with the 22q11.2 microdeletion syndrome seen for evaluation. Because communication and feeding disorders may be presenting features of this syndrome, speech and language pathologists must be familiar with this syndrome and its various characteristics. Awareness of these features and a multidisciplinary approach are necessary for the identification and treatment of the complex communicative and medical problems present in this population.

The 22q11.2 deletion syndrome, which includes DiGeorge and velocardiofacial syndromes (DGS/VCFS), is the most common microdeletion syndrome. The majority of deleted patients share a common 3 Mb hemizygous deletion of 22q11.2. The remaining patients include those who have smaller deletions that are nested within the 3 Mb typically deleted region (TDR) and a few with rare deletions that have no overlap with the TDR. The identification of chromosome 22-specific duplicated sequences or low copy repeats (LCRs) near the end-points of the 3 Mb TDR has led to the hypothesis that they mediate deletions of 22q11.2. The entire 3 Mb TDR has been sequenced, permitting detailed investigation of the LCRs and their involvement in the 22q11.2 deletions. Sequence analysis has identified four LCRs within the 3 Mb TDR. Although the LCRs differ in content and organization of shared modules, those modules that are common between them share 97-98% sequence identity with one another. By fluorescence in situ hybridization (FISH) analysis, the end-points of four variant 22q11.2 deletions appear to localize to the LCRs. Pulsed-field gel electrophoresis and Southern hybridization have been used to identify rearranged junction fragments from three variant deletions. Analysis of junction fragments by PCR and sequencing of the PCR products implicate the LCRs directly in the formation of 22q11.2 deletions. The evolutionary origin of the duplications on chromosome 22 has been assessed by FISH analysis of non-human primates. Multiple signals in Old World monkeys suggest that the duplication events may have occurred at least 20-25 million years ago.

Background: Studies have shown that the survival of patients with gastric adenocarcinoma is related to the number of regional lymph nodes with metastases. The probability of identifying node-positive cancers increases with the number of lymph nodes resected and examined. It has been recommended that at least 15 lymph nodes be removed and examined for adequate staging. Prospective randomized studies have shown the lymph node yield is much greater with the D2 resection than the D1. This study evaluated the relative contribution of both the number of resected lymph nodes and the extent of gastric resection (D1/D2) on the outcome of patients with proximal gastric cancer. Methods: The medical records of 114 patients with adenocarcinoma of the proximal stomach, who underwent a curative gastric resection, were reviewed. Patients were stratified into four groups, i.e., two groups, D1/D1.5 and D2/D2.5, based on the extent of resection, and two groups based on the number of lymph nodes removed, fewer than 15 lymph nodes and 15 or more lymph nodes. Survival was determined by the method of Kaplan-Meier and differences compared by the log-rank test. Multivariate analysis was performed by using the Cox model. Results: The number of resected lymph nodes had no effect on the survival of the group as a whole. A significant improvement in survival was noted for patients with a D2 or greater resection. The median survival of patients with 15 or more lymph nodes resected improved from 25 months to 42 months when treated with an extended resection, (D2 or D2.5). Resection of 15 or more lymph nodes alone, or combined with an extended resection, resulted in a statistically significant improvement in survival for patients in American Joint Committee on Cancer Staging (AJCC) stage II. Conclusions: Both resection of 15 or more lymph nodes and extended lymphadenectomy contributed to the survival advantage observed in patients with AJCC stage II gastric cancer. The D2 gastric resection prolonged the median survival time and improved the 5-year survival rate for patients with 15 or more resected lymph nodes.

Background and Objectives: Soft-tissue sarcomas (STS) represent a diverse histologic group of malignancies at risk for local and distant failure. We studied the impact of late (5 or more years) vs. early recurrence (less than 5 years) on subsequent outcome. Methods: Four hundred sixty-eight patients with STS treated between 1962 and 1992 were evaluated for late (n = 39; 8%) or early (n = 253; 54%) recurrence. Clinical and pathologic factors were reviewed. Survival data were analyzed by the Kaplan-Meier method and the log-rank test. Results: Of the 39 patients with a late recurrence (median follow-up 156 months), 18 patients had local recurrence, 7 patients developed distant recurrence, and 14 patients had local and distant recurrence. Thirty patients with late local and/or distant recurrence underwent complete or wide excision (n = 16), amputation (n = 4), or local resection (n = 10). The overall 5-year survival rate following late recurrence was 61%. The 5-year overall survival rate was statistically better for patients with a late local recurrence alone than for patients with distant failure, 94% vs. 36%, respectively (P = 0.003). Neither the site of the primary STS, age, primary margin status, nor histology had any effect on subsequent local or distant failure and subsequent survival. Conclusions: These data suggest that an aggressive approach is appropriate in patients who present with late recurrence (more than 5 years) following treatment of the primary STS. Impressive survival rates can be achieved in the treatment of local recurrences.

Chromosome 22q11.2 deletion syndrome is a common syndrome typically consisting of variable cardiac defects, hypoparathyroidism, developmental delay, and immunodeficiency. The hemizygous deletion has variable effects on the immune system even within the same kindred, and the extent of the immunodeficiency is difficult to predict. Some patients have shown improvement over time; however, this is the first prospective longitudinal study of the dynamic nature of the immunodeficiency. Nineteen patients were studied prospectively between 1994 and 1997. The results of the newborn immunologic studies in the chromosome 22q11.2 deletion group were significantly different from those of a group of newborns with cardiac disease due to other causes. Peripheral blood T-cell numbers were decreased in the chromosome 22q11.2 deletion group, although T-cell function was largely preserved. The group as a whole demonstrated few changes in the first year of life, but a subset of patients with markedly diminished T-cell numbers did demonstrate improvement. Therefore, improvement in peripheral blood T-cell counts is variable in chromosome 22q11.2 deletion syndrome. The patients with the lowest T-cell counts improved the most in the first year of life.

Serum from an infertile male with high-titer anti-sperm antibodies was used to identify a novel human sperm antigen by screening of a testis expression library. The clone, initially designated Repro-SA-1 (HUGO-approved symbol SPAG6), was found to encode a sequence highly enriched in testis. The deduced amino acid sequence of the full-length cDNA revealed striking homology to the product of the Chlamydomonas reinhardtii PF16 locus, which encodes a protein localized to the central pair of the flagellar axoneme. The human gene encodes 1.8- and 2.8-kb mRNAs highly expressed in testis but not in prostate, ovary, spleen, thymus, small intestine, colon, peripheral blood leukocytes, heart, brain, placenta, liver, muscle, kidney, and pancreas. The gene was mapped to chromosome 10p11.2-p12. Antibodies raised against SPAG6 sequences localized the protein to the tails of permeabilized human sperm. Both the Chlamydomonas protein and SPAG6 contain eight contiguous armadillo repeats, which place them in a family of proteins known to mediate protein-protein interactions. The cloning of the human homologue of the Chlamydomonas PF16 locus provides a new avenue to explore the role of the axoneme central pair in human sperm function.

A retrospective review of our institute's tumor registry from January 1972 to January 1996 revealed 24 patients with a diagnosis of primary soft tissue sarcoma of the hand, from a total of 570 extremity soft tissue sarcomas (4%). The most frequent histologic type was malignant fibrous histiocytoma, which occurred in 9 (38%) of the 24 patients. The second most common histologic type was epithelioid sarcoma, which occurred in 6 (25%) patients. There was a statistically significant difference in the rate of local recurrence based on the type of treatment in which amputation was superior to the other forms of treatment. There was no statistically significant difference in the rate of distant failures between treatment groups. The estimated cumulative 5- and 10-year overall survival rates for all patients were 59% and 53%, respectively. Stage II patients had estimated cumulative 5- and 10-year survival rates of 68% and 59%, respectively. Stage III patients had a cumulative 5-year survival rate of 20%. Factors that were statistically significant in predicting survival were the size of the primary tumor, with tumors smaller than 5 cm having a better prognosis, and stage of the tumor at presentation, with stage I and II tumors having the highest survival rate. In selected patients with a primary hand sarcoma, aggressive limb-sparing surgery with adjuvant therapy offered equivalent survival compared with amputation.

A microscopic deletion of chromosome 22q11.2 has been identified in most patients with the DiGeorge, velocardiofacial syndrome, conotruncal anomaly face syndrome, and in some patients with isolated conotruncal cardiac anomalies. This study presents the neurodevelopmental outcome, including cognitive development, language development, speech, neuromuscular development, and behavioral characteristics of 40 preschool children (ages 13 to 63 months) who have been diagnosed with the 22q11.2 deletion. The impact of cardiac disease, cardiac surgery, and the palatal anomalies on this population was also studied. In the preschool years, children with a 22q11.2 deletion are most commonly found to be developmentally delayed, have mild hypotonia, and language and speech delays. The more significantly delayed children are at high risk to be subsequently diagnosed with mild or moderate mental retardation. The global delays and the variations in intelligence found are directly associated with the 22q11.2 deletion and are not explained by physical anomalies such as palatal defects or cardiac defects, or therapeutic interventions such as cardiac surgery. Our findings demonstrate that there is a pattern of significant speech disorders within this population. All of the children had late onset of verbal speech. Behavioral outcomes included both inhibition and attention disorders. Early intervention services are strongly recommended beginning in infancy to address the delays in gross motor skills, speech and language, and global developmental delays.

BACKGROUND AND OBJECTIVES Modern series of adult extremity soft tissue sarcomas utilize combinations of modalities in all patients. Remaining questions: 1) is it necessary to strive for wide margins in the multimodality era; 2) to use adjuvant therapy in every high-grade sarcoma? 3) Does previous partial or marginal resection seriously interfere with the definitive resection? METHODS In a retrospective review of 194 extremity soft tissue sarcomas (1977-1994), limb preservation was possible in 181/194 (93%) of cases. Patients with narrow margins received adjuvant radiation. Some patients were referred after partial (n = 39) or "complete" (n = 63) excision. RESULTS Local recurrence was observed in 181/141 (13%) of patients treated with wide or compartmental resection, and in 10 of 42 (24%) of those treated with conservative resection plus radiation (P = 0.14). The 5-year survival rate for grade III, >/=5-cm sarcomas was not significantly different (P = 0.82) with adjuvant (46%) or without (48%) adjuvant systemic chemotherapy. Five-year survival varied (P = 0.0001) according to grade. Patients referred with partial, or "complete" (63%, 38/63, had residual tumor at reoperation) excision had a local recurrence rate of 8% and 6%, and 5-year survival rates of 75% and 84%, respectively. CONCLUSIONS 1) It is important to strive for wide margins even when adjuvant radiation is intended. 2) When a wide margin is possible, adjuvant radiation may not be necessary. 3) Adjuvant systemic chemotherapy may be considered for high-grade tumors, preferably within a prospective protocol. 4) A partial or "complete" excision of the tumor before referral to a tertiary center does not appear to compromise the limb preservation, local control, or survival rates of these patients.

BACKGROUND Because of its role in cell motility and growth regulation, gelsolin, an actin-binding protein, has been considered a tumor suppressor and a potential prognostic marker in some neoplasias, such as breast and bladder cancer. Little is known about its immunoexpression in prostatic adenocarcinoma (PCA). METHODS Formalin-fixed, paraffin-embedded tissues of 72 prostatectomy specimens with adenocarcinoma and 8 nonneoplastic prostates from autopsies were stained with a gelsolin monoclonal antibody using the Avidin-biotin-peroxidase complex (ABC) method after microwave antigen retrieval. Immunoreactivity was evaluated in PCA, prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), and nonproliferative glandular tissue and stroma. The results were statistically analyzed. RESULTS Consistent gelsolin immunoreactivity was seen in prostatic stromal cells, smooth muscle, endothelia, and nerves. Variable gelsolin expression was seen in 20–100% (average (A) = 65.5%) of glandular cells in nonproliferative tissue (N = 75); 0–50% (A = 9.7%) in BPH (N = 59); 0–80% (A = 8.9%) in PIN (N = 61); and 0–90% (A = 9.3%) in PCA (N = 71). The level of gelsolin expression in nonproliferative prostatic tissue was similar between prostates with PCA (A = 63.4%) and nonneoplastic prostates (A = 67.5%). The level of gelsolin expression did not correlate with age, tumor size, Gleason score, or stage. CONCLUSIONS Gelsolin is decreased in PCA, PIN, and BPH in comparison to nonproliferative tissue. The role of this downregulation in the development of PCA is not clear. The similar reduction seen in PIN and BPH suggests that this event takes place indiscriminately in hyperplasia and early tumorigenesis in the prostate, which might limit its prognostic significance in PCA. Prostate 40:14–19, 1999. © 1999 Wiley-Liss, Inc.

This study evaluates prognostic factors that may influence survival in patients who present with carcinomatosis from colorectal cancer. Patients may present with carcinomatosis as the pattern of metastases at the initial diagnosis of colorectal cancer. Little is known about the natural history of carcinomatosis and the prognostic factors affecting outcome. All patients treated at Roswell Park Cancer Institute from 1988 to 1994 who presented with carcinomatosis at the initial diagnosis of colorectal cancer were identified. A retrospective review of the medical records for patient and tumor demographics was performed. Estimated survival distributions were calculated by the method of Kaplan and Meier. Tests of significance with respect to survival distribution were based on the log-rank test. Cox proportional hazards model was used for the multivariate analysis. There were 31 males and 38 females. The median age was 61 years (range, 26-80). The primary cancers were in the sigmoid with 24 patients (35%), cecum with 14 patients (20%), and transverse colon with 11 patients (16%). The remainder were distributed throughout the colon and rectum. The most common presentation was large bowel obstruction in 29 patients (42%). T3 and T4 cancers were present in 39 (57%) and 13 patients (19%), respectively. Lymph nodes were positive in 39 patients (57%), and mucin-producing tumors were also present in 39 patients (57%). Twelve patients (17%) had one site of disease, 17 patients (25%) had two sites of disease, and 37 (54%) patients had three or more sites of disease. Ascites was present in 29 patients (42%). Residual disease was present at the completion of surgery in 45 patients, absent in 13 patients, and status unknown in 11. The presence of residual disease (p = 0.0001), presence of ascites (p = 0.02), stage greater than T3 (p = 0.02), and increasing number of carcinomatosis sites (p = 0.006) were found to have a negative impact on survival on univariate analysis. On multivariate analysis, only the presence of residual disease at the completion of surgery was found to be an independent predictor of survival (p = 0.04). Overall median survival was 14 months with a 26% estimated 2-year survival. The presence of gross residual disease at the completion of surgery was shown to be the only independent factor negatively affecting survival. This has potential implications for the operative management of patients presenting with colorectal carcinomatosis.

Maternal serum screening for neural tube defects and fetal aneuploidy in the second trimester has been incorporated into obstetrical practice over the past two decades. Now, as a result of several multicenter trials, first trimester screening between 11 and 14 weeks has been shown to be an effective and reliable screening test for Down syndrome and trisomy 18. Benefits of first trimester screening include earlier identification of the pregnancy at risk for fetal aneuploidy and anatomic defects, in particular, cardiac anomalies, and the option of earlier diagnosis by chorionic villus sampling, if available. This policy updates the American College of Medical Genetics policy statement entitled Second Trimester Maternal Serum Screening for Fetal Open Neural Tube Defects and Aneuploidy (2004) and complements the sections of American College of Medical Genetic's Standards and Guidelines for Clinical Genetics Laboratories entitled "Prenatal screening for Down syndrome that includes first trimester biochemistry and/or ultrasound measurements."

Our preliminary family studies have suggested that some female first-degree relatives of women with polycystic ovary syndrome (PCOS) have hyperandrogenemia per se . It was our hypothesis that this may be a genetic trait and thus could represent a phenotype suitable for linkage analysis. To investigate this hypothesis, we examined 115 sisters of 80 probands with PCOS from unrelated families. PCOS was diagnosed by the combination of elevated serum androgen levels and ≤6 menses per year with the exclusion of secondary causes. The sisters were compared with 70 healthy age- and weight-comparable control women with regular menses, no clinical evidence of hyperandrogenemia, and normal glucose tolerance. Twenty-two percent of the sisters fulfilled diagnostic criteria for PCOS. In addition, 24% of the sisters had hyperandrogenemia and regular menstrual cycles. Circulating testosterone (T) and nonsex hormone-binding globulin-bound testosterone (uT) levels in both of these groups of sisters were significantly increased compared with unaffected sisters and control women ( P < 0.0001 for both T and uT). Probands, sisters with PCOS, and hyperandrogenemic sisters had elevated serum luteinizing hormone levels compared with control women. We conclude that there is familial aggregation of hyperandrogenemia (with or without oligomenorrhea) in PCOS kindreds. In affected sisters, only one-half have oligomenorrhea and hyperandrogenemia characteristic of PCOS, whereas the remaining one-half have hyperandrogenemia per se . This familial aggregation of hyperandrogenemia in PCOS kindreds suggests that it is a genetic trait. We propose that hyperandrogenemia be used to assign affected status in linkage studies designed to identify PCOS genes.