Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer.

BACKGROUND: The dynamics of PD-L1 expression may limit its use as a tissue-based predictive biomarker. We sought to expand our understanding of the dynamics of PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in patients with lung cancer-related brain metastases. EXPERIMENTAL DESIGN: Paired primary lung cancers and brain metastases were identified and assessed for PD-L1 and CD3 expression by immunohistochemistry. Lesions with 5% or greater PD-L1 expression were considered positive. Agreement statistics and the χ(2) or Fisher's exact test were used for analysis. RESULTS: We analyzed 146 paired lesions from 73 cases. There was disagreement of tumor cell PD-L1 expression in 10 cases (14%, κ = 0.71), and disagreement of TIL PD-L1 expression in 19 cases (26%, κ = 0.38). Most paired lesions with discordant tumor cell expression of PD-L1 were obtained 6 or more months apart. When specimens were categorized using a proposed tumor microenvironment categorization scheme based on PD-L1 expression and TILs, there were significant changes in the classifications because many of the brain metastases lacked either PD-L1 expression, tumor lymphocyte infiltration or both even when they were present in the primary lung cancer specimens (P = 0.009). CONCLUSIONS: We identified that there are significant differences between the tumor microenvironment of paired primary lung cancers and brain metastases. When physicians decide to treat patients with lung cancer with a PD-1 or PD-L1 inhibitor, they must do so in the context of the spatial and temporal heterogeneity of the tumor microenvironment.

ASCL1 and RET expression defines a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation.

ASCL1 is an important regulatory transcription factor in pulmonary neuroendocrine (NE) cell development, but its value as a biomarker of NE differentiation in lung adenocarcinoma (AD) and as a potential prognostic biomarker remains unclear. We examined ASCL1 expression in lung cancer samples of varied histologic subtype, clinical outcome and smoking status and compared with expression of traditional NE markers. ASCL1 mRNA expression was found almost exclusively in smokers with AD, in contrast to non-smokers and other lung cancer subtypes. ASCL1 protein expression by immunohistochemical (IHC) analysis correlated best with synaptophysin compared with chromogranin and CD56/NCAM. Analysis of a compendium of 367 microarray-based gene expression profiles in stage I lung adenocarcinomas identified significantly higher expression levels of the RET oncogene in ASCL1-positive tumors (ASCL1(+)) compared with ASCL1(-) tumors (q-value <10(-9)). High levels of RET expression in ASCL1(+) but not in ASCL1(-) tumors was associated with significantly shorter overall survival (OS) in stage 1 (P=0.007) and in all AD (P=0.037). RET protein expression by IHC had an association with OS in the context of ASCL1 expression. In silico gene set analysis and in vitro experiments by ASCL1 shRNA in AD cells with high endogenous expression of ASCL1 and RET implicated ASCL1 as a potential upstream regulator of the RET oncogene. Also, silencing ASCL1 in AD cells markedly reduced cell growth and motility. These results suggest that ASCL1 and RET expression defines a clinically relevant subgroup of ∼10% of AD characterized by NE differentiation.

Three-dimensional helical computed tomography in prenatal diagnosis of fetal skeletal dysplasia.

OBJECTIVES: (1) To study the use and diagnostic value, as a complement to ultrasound, of helical computed tomography (helical CT) to differentiate normal fetuses from cases of skeletal dysplasia; (2) to define the most relevant indications for helical CT; and (3) to evaluate its diagnostic performance with respect to radiological criteria considered discriminatory. METHODS: This was a retrospective study from 2005 to 2008 in 67 pregnant women who underwent helical CT after 26 weeks of gestation for suspected fetal skeletal dysplasia due to fetal shortened long bones on ultrasound (≤ 10(th) percentile), either alone or associated with other bone abnormalities. The results were compared with pediatric examinations in 41 cases and with fetal autopsy findings after elective termination of pregnancy in the others. RESULTS: Helical CT had a sensitivity of 82%, specificity of 91% and positive and negative predictive values of 90% and 83%, respectively, for diagnosis of fetal skeletal dysplasia. An etiological diagnosis that had not been suspected at ultrasound was specified in 15% of cases and diagnoses suspected at ultrasound were confirmed in 24% and discounted in 43% of cases. The prevalence of skeletal dysplasia was increased in cases of micromelia < 3(rd) percentile or if there was a combination of bone signs. Helical CT showed 69% sensitivity in identifying individual predefined pathological bone signs which were confirmed on fetal autopsy findings. CONCLUSION: Helical CT is a key examination, in combination with ultrasound, in the diagnosis of fetal skeletal dysplasia from 26 weeks of gestation. It should be reserved for cases with severe micromelia below the 3(rd) percentile and for those with micromelia ≤ 10(th) percentile associated with another bone sign. A checklist of discriminatory signs is proposed.

Integrin α9ß1 promotes malignant tumor growth and metastasis by potentiating epithelial-mesenchymal transition.

The integrin α9ß1 binds a number of extracellular matrix components to mediate cell adhesion, migration and tissue invasion. Although expressed in a variety of normal human cells including endothelium, it is also expressed in cancer cells. We have previously shown that α9ß1 binds VEGF-A to facilitate angiogenesis, an important component of the tumor microenvironment. As α9ß1 induces accelerated cancer cell migration, we wished to determine what role it played in cancer growth and metastasis. In this study, we show that α9ß1 expression induces molecular changes consistent with epithelial-mesenchymal transition. In addition, we found that α9ß1 forms a tri-partite protein complex with ß-catenin and E-cadherin, which dissociates following integrin activation and subsequent src and ß-catenin phosphorylation. These findings were consistent in cells in which: α9ß1 was exogenously over-expressed, or when its expression was suppressed in cancer cells endogenously expressing α9ß1. These in vitro results are biologically significant as α9ß1-expressing cancer cells induce greater tumor growth and metastases in mice as compared to the cells without α9ß1 expression or when integrin expression is suppressed. Furthermore, integrin α9ß1 is expressed in primary human small cell lung cancer and patients having a high expression of α9ß1 demonstrated significantly worse long-term survival compared with patients with low α9ß1 expression. These findings highlight a novel mechanism of integrin α9ß1 function in human cancer.

18F-fluoro-2-deoxy-D-glucose positron emission tomography and positron emission tomography/computed tomography imaging of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is the most common primary pleural tumor and its incidence is rising. Its diagnosis, staging and response assessment are challenging for imaging. Integrated positron emission tomography (PET)/CT increases the accuracy of overall staging in patients with mesothelioma and improves the selection of patients for curative surgical resection. It is particularly useful in identifying occult distant metastases. It may be used to predict prognosis and to assess the metabolic response to therapy.

First-trimester ultrasound diagnosis of skeletal dysplasia associated with increased nuchal translucency thickness.

A series of five cases of skeletal dysplasia is reported in which the diagnosis was reached at the 11-14-week routine ultrasound examination in our referral center. All five cases had increased nuchal translucency thickness (NT) associated with bone abnormalities. We review the current literature on skeletal dysplasia in the first trimester of pregnancy associated with increased NT.

Prenatal diagnosis and normal outcome of a 46,XX/46,XY chimera: a case report.

The phenotypic spectrum of 46,XX/46,XY chimeric patients is variable. It ranges from normal male or female genitalia to different degrees of ambiguous genitalia. Chimerism results from the amalgamation of two different zygotes in a single embryo, whereas mosaicism results from a mitotic error in a single zygote. Several other mechanisms resulting in a chimera have been discussed in the literature. Here, we report on a new case of chimerism (46,XX/46,XY) diagnosed at 17 weeks' gestation on amniocentesis performed because of advanced maternal age. Ultrasound examination revealed normal female external genitalia, and a healthy baby girl was delivered at term. We used polymorphic markers spanning the X chromosome and several autosomes in order to identify the genetic mechanism involved. Mosaicism was excluded because of the presence of 3 alleles at 11 autosomal and 4 X chromosome loci. On autosomes, the origin of this third allele was maternal for two pericentromeric markers (located on 2p11.2 band and 8p11.2 band), paternal for six markers and paternal or maternal for the other three markers. On the X chromosome, the origin of the third allele was maternal for all four markers. Thus, two different paternal and maternal haploid sets were observed. These results are compatible with a tetragametic chimera.

Predicting pulmonary hypoplasia using the sonographic fetal lung volume to body weight ratio--how precise and accurate is it?

OBJECTIVES: To determine the precision and accuracy of ultrasound in estimating the fetal lung to body weight ratio (FLB ratio) using two-dimensional (2D) and three-dimensional (3D) ultrasound by comparison with postmortem measurements, and to evaluate its potential to diagnose pulmonary hypoplasia. METHODS: Lung volumes were estimated by 3D ultrasound (rotational technique) and fetal weights were measured by 2D ultrasound (Hadlock equation) in 35 fetuses immediately before termination of pregnancy at 15-38 weeks. Sonographic estimates of FLB ratio were compared with postmortem values. Based on the pathological definition of pulmonary hypoplasia, the accuracy of sonographic estimation of the FLB ratio was analyzed. RESULTS: The mean gestational age at termination of pregnancy was 26.7 (range, 15-38) weeks. The mean FLB ratios were 0.018 (SD, 0.006) on ultrasound and 0.019 (SD, 0.007) at autopsy (P = 0.730). Bias and precision of sonographic FLB ratio were - 0.001 and 0.003 (absolute limits, - 0.007 to + 0.006), respectively. Pulmonary hypoplasia was diagnosed in 12 (34.3%) cases at autopsy. The sonographic FLB ratio was significantly lower in fetuses with pulmonary hypoplasia at autopsy (median, 0.011; range, 0.004-0.014) than it was in those without pulmonary hypoplasia (median, 0.022; range, 0.013-0.045, P < 0.001). The sensitivity and specificity of the sonographic FLB ratio for diagnosing pulmonary hypoplasia were 91.7% (11/12) and 91.3% (21/23), respectively, the positive and negative predictive values were 84.6% (11/13) and 95.5% (21/22), and the accuracy was 91.4% (32/35). CONCLUSION: FLB ratio can be estimated precisely on ultrasound examination, albeit with wide limits of agreement. The sonographically estimated FLB ratio may be useful in the prediction and diagnosis of pulmonary hypoplasia.

Phenotypic spectrum of CHARGE syndrome in fetuses with CHD7 truncating mutations correlates with expression during human development.

BACKGROUND: The acronym CHARGE refers to a non-random cluster of malformations including coloboma, heart malformation, choanal atresia, retardation of growth and/or development, genital anomalies, and ear anomalies. This set of multiple congenital anomalies is frequent, despite rare patients with normal intelligence, and prognosis remains poor. Recently, CHD7 gene mutations have been identified in CHARGE patients; however, the function of CHD7 during development remains unknown. METHODS: We studied a series of 10 antenatal cases in whom the diagnosis of CHARGE syndrome was suspected, considering that a careful pathological description would shed light on the CHD7 function during development. CHD7 sequence analysis and in situ hybridisation were employed. RESULTS: The diagnosis of CHARGE syndrome was confirmed in all 10 fetuses by the identification of a CHD7 heterozygous truncating mutation. Interestingly, arhinencephaly and semi-circular canal agenesis were two constant features which are not included in formal diagnostic criteria so far. In situ hybridisation analysis of the CHD7 gene during early human development emphasised the role of CHD7 in the development of the central nervous system, internal ear, and neural crest of pharyngeal arches, and more generally showed a good correlation between specific CHD7 expression pattern and the developmental anomalies observed in CHARGE syndrome. CONCLUSIONS: These results allowed us to further refine the phenotypic spectrum of developmental anomalies resulting from CHD7 dysfunction.

Accuracy of fetal lung volume assessed by three-dimensional sonography.

OBJECTIVE: To determine the accuracy and precision of prenatal three-dimensional (3D) ultrasound in estimating fetal lung volume using the rotational multiplanar technique (VOCAL) by comparing it to postmortem volume measurements. METHODS: Fetal lung volume was measured during 3D ultrasound examination using a rotational multiplanar technique in eight cases of congenital diaphragmatic hernia (CDH) (six left and two right-sided) and in 25 controls without pulmonary malformation, immediately before termination. Prenatal 3D sonographic estimates of fetal lung volume were compared with postmortem measurement of fetal lung volume achieved by water displacement. RESULTS: The intraclass correlation coefficient of fetal lung volume estimated by 3D ultrasound and measured at postmortem examination was 0.95 in CDH cases and 0.99 in controls. Based on Bland-Altman analysis, the bias, precision and limits of agreement were, respectively, 0.35 cm(3), 1.46 cm(3) and between -2.51 and + 3.21 cm(3) in cases with CDH and 0.08 cm(3), 2.80 cm(3) and between -5.41 and + 5.57 cm(3) in controls. The mean relative error of 3D ultrasound fetal lung volume measurement was -7.19% (from -42.70% to + 18.11%) in CDH cases and -0.72% (from -30.25% to + 19.22%) in controls, while the mean absolute error of 3D ultrasound fetal lung volume measurement was 1.40 (range, 0.71-2.52) cm(3) and 2.12 (range, 0.05-4.98) cm(3), respectively. Accuracy of 3D ultrasound for measuring fetal lung volumes was 84.86 (range, 57.30-99.48)% in cases with CDH and 91.38 (range, 69.75-99.45)% in controls. The mean intraobserver variability for lung volume estimated by 3D ultrasound was 0.28 cm(3) in controls and 0.17 cm(3) in CDH cases. CONCLUSION: Prenatal 3D ultrasound can estimate accurately fetal lung volume using the rotational multiplanar technique for volume measurements (VOCAL), even in fetuses with very small lungs, such as cases with isolated CDH.

A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study.

BACKGROUND: The aim of the present study was to evaluate the clinical activity of imatinib mesylate in patients with recurrent and refractory c-kit-expressing small-cell lung cancer. PATIENTS AND METHODS: Patients with c-kit-expressing SCLC (> or =1+ by immunohistochemistry) were enrolled in two groups. Arm A included patients with disease progression <3 months and arm B included patients with disease progression > or =3 months after previous treatment. Imatinib was administered at a dose of 400 mg b.i.d. continuously, with a cycle length of 28 days. A single stage Simon design with a planned interim analysis was used to evaluate the 16-week progression free rate in each arm. RESULTS: A total of 29 evaluable patients were entered into the study (seven in arm A, median age 68; 22 in arm B, median age 64.5). Median number of treatment cycles was one in both arms. Grade 3+ non-hematologic adverse events were seen in 15 (52%) patients, with nausea, vomiting, dyspnea, fatigue, anorexia and dehydration each occurring in at least 10% of patients. Median survival was 3.9 and 5.3 months and median time to progression was 1 and 1.1 months for arms A and B, respectively. Enrollment to arm A was temporarily suspended prior to reaching interim analysis due to striking early disease progression (29%), early deaths (29%) and patient refusal (42%). No objective responses and no confirmed stable disease > or =6 weeks were seen in either arm. Accrual was permanently terminated to both arms as only one patient was progression-free at 16 weeks. CONCLUSION: Imatinib failed to demonstrate any clinical activity in spite of patient selection for c-kit-expressing SCLC. Our results strengthen the collective evidence that prediction of efficacy of novel therapeutic agents based on target expression, rather than pathway activation (for example, through activating mutations), may not be a valid paradigm for drug development.

Contribution of three-dimensional volume contrast imaging to the sonographic assessment of the fetal uterus.

OBJECTIVE: To investigate the contribution of volume contrast imaging (VCI) in assessing the fetal uterus in normally developed female fetuses. METHODS: The pelvis of 38 normal female fetuses was examined at 20-22 and 32-34 weeks' gestation using both conventional two-dimensional (2D) ultrasound and VCI on the same transverse or oblique longitudinal view of the fetal pelvis. Two experienced sonographers evaluated the ability of both techniques to image the fetal uterus. Results were compared by kappa index to evaluate the interobserver variability. RESULTS: A clear picture of the fetal uterus was obtained in 50% and 82-87% of the cases at 20-22 weeks' gestation and in 80-85% and 95-100% of the cases at 32-34 weeks' gestation using conventional 2D ultrasound and VCI, respectively. There was moderate to good agreement of uterus visualization between the two observers, with kappa values ranging from 0.43 to 0.65. The lower level of agreement was obtained for conventional 2D ultrasound during the second trimester. CONCLUSIONS: Our results suggest that VCI may be successfully applied to prenatal ultrasonography of the fetal pelvis anatomy. By enhancing the contrast between the intrapelvic organs, VCI provides a clearer picture of the fetal uterus.

Prenatal diagnosis of pulmonary sequestration using three-dimensional power Doppler ultrasound.

OBJECTIVE: To investigate the contribution of three-dimensional power Doppler ultrasound to the prenatal diagnosis of pulmonary sequestration. METHODS: Prenatal three-dimensional power Doppler ultrasound was used to screen for an abnormal pulmonary blood supply in eight fetuses with hyperechogenic lung lesions and to image the pulmonary blood supply in 50 normal controls. A comparison was made with postnatal findings. RESULTS: Postnatally the eight pulmonary lesions were found to be an isolated pulmonary sequestration (n = 3), a microcystic congenital adenomatoid malformation (n = 4), and a mixed (macrocystic and microcystic) congenital adenomatoid malformation (n = 1). Prenatal three-dimensional power Doppler ultrasound demonstrated an abnormal blood supply in all cases of pulmonary sequestration and in none of the other cases. Among the three cases that turned out to be pulmonary sequestrations, conventional two-dimensional ultrasound failed to identify the feeding vessel in one case and identified it at a later stage of gestation than did three-dimensional power Doppler in the other two. CONCLUSION: Prenatal three-dimensional power Doppler ultrasound may be useful in identifying the feeding vessel and thus establishing the diagnosis of pulmonary sequestration in the presence of a hyperechogenic pulmonary lesion, allowing its differentiation from congenital cystic adenomatoid malformation.

Duration of smoking abstinence as a predictor for non-small-cell lung cancer survival in women.

BACKGROUND: Previous studies have attempted to investigate the impact of smoking cessation on lung cancer survival but have been limited by small numbers of former smokers and incomplete data. METHODS: Over a six-year period, 5229 patients with non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) were enrolled in a prospective cohort of whom 2052 were former smokers. Patient's characteristics were obtained from medical records and a baseline interview. Vital status was determined through multiple sources. Cox proportional hazards models were used to estimate the effect of smoking abstinence on post-diagnosis mortality. RESULTS: For all patients with NSCLC, the median survival among never, former, and current smokers was 1.4 years, 1.3 years, and 1.1 years, respectively (P < 0.01). Female NSCLC patients had a significantly lower risk of mortality with a longer duration of smoking abstinence (RR per 10 years of smoking abstinence = 0.85; 95% CI: 0.75, 0.97). No effect of smoking abstinence on mortality was observed for women with SCLC or for men with either histologic group. CONCLUSIONS: The identification of smoking history as a prognostic factor in lung cancer survival supports previous research suggesting a direct biologic effect of smoking on survival. However, this effect may vary by sex and type of lung cancer.

Study design considerations in clinical outcome research of lung cancer using microarray analysis.

BACKGROUND: Prognosis following a diagnosis of primary lung cancer is very poor and varies significantly even after adjusting for known predictors. Inherent and acquired gene alterations could cause failure in lung cancer treatment and patient survival. To search for potential molecular markers with significant and independent predictive value in lung cancer survival, we applied oligo-nucleotide microarray analysis, along with patients' phenotypic profile, in a case-control study. The focus of this report is on the methodology used in the identification of potential genes as prognostic factors. METHODS: Selected from 304 patients at Mayo Clinic, 18 stage I squamous cell lung cancer patients who died within 2 years (high-aggressive) or lived beyond 5 years (low-aggressive) were included in this study. Both a one-to-one matched design (paired) and a two-group design (grouped) were utilized. Matching variables were age, gender, tumor size and grade, smoking status, and treatment. Two-GeneChip-array sets from Affymetrix (HG-U133) were used. We applied multiple analytic approaches including Dchip (Harvard University), SAM (Stanford University), ArrayTools (US National Cancer Institute), and MAS5 (Affymetrix); and integrated multiple results to generate the final candidate genes for further investigation. We evaluated the consistency across the methods and the effects of matched versus grouped design on the results. RESULTS: Using the same pre-processed data under the same criteria for type I error and fold-change in expression intensity, results are 94-100% concordant in the list of significant genes by Dchip and by ArrayTools, and 53% concordant between the paired and the grouped analysis. If using differently pre-processed data, the concordance rate is under 6% even by the same analytic tool. Combining results from all analyses, we found 23 potentially important genes that may distinguish the high- versus low-aggressive squamous cell tumors of the lung. CONCLUSION: Given the generally low consistency of results across analytic algorithms and study design, poor agreement is expected from different investigators reporting candidate genes for the same endpoint. A well-designed study with a carefully planned analytic strategy is critical. We are in the process of validating the 23 preliminary candidate genes found from this study among independent yet comparable cases.

Pericardial teratoma complicated by hydrops: successful fetal therapy by thoracoamniotic shunting.

Pericardial teratoma is a potentially curable lesion that may become life threatening when it induces mediastinal compression and fetal hydrops. So far, cases with fetal hydrops have been managed by elective delivery or pericardial needle decompression. We report a case in which pericardial teratoma resulted in fetal hydrops. Following transpleural needling of the fetal pericardium at 29 weeks and 6 days, pericardial effusion decreased but hydrops persisted, while major unilateral pleural effusion appeared. A thoracoamniotic shunt was placed at 30 weeks and 5 days. Hydrops resolved, although incompletely. The baby was delivered at 32 weeks and was operated upon on day 3. This observation suggests that fetal hydrops associated with pericardial teratoma may improve following thoracoamniotic shunting. Fetal therapy may limit the risks of respiratory distress arising from the combined effect of airways compression and lung immaturity.

Sonographic prenatal diagnosis of central nervous system abnormalities.

INTRODUCTION: Over the past 20 years, the spectrum of neonatal neurological malformations has changed due to the diffusion of ultrasound, performed either routinely or as required by maternal alpha-fetoprotein screening or history. DISCUSSION: We review and illustrate the potential of ultrasound for the prenatal diagnosis of abnormalities in size or shape of the skull (macrocephaly, microcephaly, craniostenosis), neural tube defects, ventriculomegaly, hydrocephalus, posterior fossa defects (abnormalities in the size of the cisterna magna, cerebellar abnormalities), midline abnormalities (holoprosencephaly, abnormalities of the corpus callosum), ischemic lesions and hemorrhage, tumours, and focalized hyperechogenic images. The limits of fetal ultrasound screening and of the various diagnostic strategies implemented when a fetal brain abnormality is suspected are discussed. Overall, gross lethal abnormalities such as anencephaly or major hydrocephaly are accessible to prenatal sonographic screening, and nearly always result in termination of the pregnancy. However, hydrocephaly may progress late in gestation and remain undiscovered unless a third trimester ultrasound is performed. A majority of cases with myelomeningocele are diagnosed prenatally, resulting either in termination of the pregnancy or in neonatal management. A growing number of more subtle abnormalities, including midline or posterior fossa abnormalities can be spotted by fetal ultrasound, but their postnatal outcome cannot always be predicted accurately, despite the use of fetal magnetic resonance imaging. In such cases, a trans-disciplinary approach involving perinatologists, pediatric radiologists, neuropathologists, neurosurgeons or neurologists familiar with neonates is crucial to counseling the parents. Some brain abnormalities are still extremely difficult or even impossible to diagnose in utero despite advances in sonographic imaging. This is due to the fact that severe neurological impairment may result from conditions that do not affect substantially affect the morphology of the brain, and that major structural abnormalities may develop late in gestation, and thus remain undetected at second trimester ultrasound. CONCLUSION: Ultrasound screening identifies a growing number of central nervous system abnormalities, resulting in substantial changes in the neonatal presentation of neurological congenital abnormalities.

Congenital erythropoietic porphyria (Günther's disease): two cases with very early prenatal manifestation and cystic hygroma.

Congenital erythropoietic porphyria (CEP) or Günther's disease is the rarest form of the porphyrias. The disease is usually diagnosed at birth or during early infancy, but rarely in utero. We describe here the first two cases of very early prenatal expression of CEP with cystic hygroma diagnosed at 14 weeks in the first fetus and at 19 weeks in the second. Both fetuses presented with severe nonimmune hydrops fetalis as early as 19 and 22 weeks, associated with intrauterine growth retardation, hyperechogenic kidneys and bones. Amniotic fluid was dark brown and uro- and coproporphyrin I was dramatically increased. Molecular screening of the CEP gene detected heterozygous C73R mutation in both fetuses, the other parental mutation being as yet unknown.

Prenatal diagnosis of bilateral isolated fetal hyperechogenic kidneys. Is it possible to predict long term outcome?

OBJECTIVE: To study perinatal and long term outcome following prenatal diagnosis of hyperechogenic kidneys. DESIGN: Prospective observational cohort study. SETTING: The Maternité Port-Royal Hôpital Cochin and at the Departments of Obstetrics and Paediatric Nephrology, Necker Enfants Malades in Paris, France. POPULATION: Forty-three fetuses with isolated bilateral hyperechogenic kidneys. METHODS: All patients referred with isolated bilateral hyperechogenic fetal kidneys were followed up prospectively up to 34-132 months. The following prenatal items were analysed: fetal kidney size, amniotic fluid volume, gestational age at diagnosis, family history and renal ultrasound in parents. Postmortem examination was carried out in cases with perinatal death. Postnatal follow up of survivors included postnatal ultrasound, blood pressure, serum creatinine, proteinuria, need for restricted diet, weight and height and renal biopsy when available. MAIN OUTCOME MEASURES: Aetiology of hyperechogenicity, perinatal mortality and renal function in survivors. RESULTS: The aetiology could be established by family history, postmortem or postnatal data, but not by prenatal ultrasound. There were 20 autosomal recessive, 8 autosomal dominant polycystic kidney diseases, 9 other renal disorders and 6 symptom-free survivors without aetiological diagnosis. There were 19 terminations of pregnancy, 5 neonatal deaths and 19 survivors, of whom 14 had normal renal function three had mild and two had end stage renal failure. None of those with severe oligohydramnios and fetal kidneys > 4 SD survived (n = 14, 10 terminations and 4 neonatal deaths), whereas of the 17 with normal amniotic fluid volume and kidneys < 4 SD, 14 survived, of whom 9 were symptom-free. CONCLUSION: Aetiology could not be established prenatally in the absence of familial data. Kidney size and amniotic fluid volume were the best prenatal predictors of outcome.