Retrograde Balloon-Assisted Deep Enteroscopy in the Diagnosis of Metastatic Melanoma.

A 74-year-old male with a history of metastatic melanoma presents with persistently abnormal small bowel findings on PET-CT scan. The patient had persistent FDG uptake near the ileocolic junction on imaging, concerning for metastatic melanoma. Capsule endoscopy demonstrated ulcerated mucosa in the distal ileum. This area was biopsied and tattooed via retrograde double-balloon enteroscopy to confirm the diagnosis of metastatic melanoma and facilitate subsequent small bowel resection. The case illustrates a unique case of metastatic melanoma to the small bowel and the utility of capsule endoscopy and balloon-assisted enteroscopy to assist in diagnosis and management of metastatic disease.

Phenome-wide association study maps new diseases to the human major histocompatibility complex region.

BACKGROUND: Over 160 disease phenotypes have been mapped to the major histocompatibility complex (MHC) region on chromosome 6 by genome-wide association study (GWAS), suggesting that the MHC region as a whole may be involved in the aetiology of many phenotypes, including unstudied diseases. The phenome-wide association study (PheWAS), a powerful and complementary approach to GWAS, has demonstrated its ability to discover and rediscover genetic associations. The objective of this study is to comprehensively investigate the MHC region by PheWAS to identify new phenotypes mapped to this genetically important region. METHODS: In the current study, we systematically explored the MHC region using PheWAS to associate 2692 MHC-linked variants (minor allele frequency ≥0.01) with 6221 phenotypes in a cohort of 7481 subjects from the Marshfield Clinic Personalized Medicine Research Project. RESULTS: Findings showed that expected associations previously identified by GWAS could be identified by PheWAS (eg, psoriasis, ankylosing spondylitis, type I diabetes and coeliac disease) with some having strong cross-phenotype associations potentially driven by pleiotropic effects. Importantly, novel associations with eight diseases not previously assessed by GWAS (eg, lichen planus) were also identified and replicated in an independent population. Many of these associated diseases appear to be immune-related disorders. Further assessment of these diseases in 16 484 Marshfield Clinic twins suggests that some of these diseases, including lichen planus, may have genetic aetiologies. CONCLUSIONS: These results demonstrate that the PheWAS approach is a powerful and novel method to discover SNP-disease associations, and is ideal when characterising cross-phenotype associations, and further emphasise the importance of the MHC region in human health and disease.

Minor anomalies in stillborn and second trimester miscarried fetuses.

In 1964, the landmark paper of Marden, Smith, and McDonald established that multiple minor anomalies in newborn infants are associated with an increased risk for major malformations. There were until now no comparable studies in stillbirths. The Wisconsin Stillbirth Service Program (WiSSP) has data regarding nearly 3,000 stillbirths and second trimester losses that have been analyzed for major anomalies and cause of death. One dysmorphologist retrospectively reviewed all 2,397 with usable photographs. Minor anomalies were identified in 1,413 (59%) with 575 of these (41%) having at least one major anomaly. Probability of a major anomaly increased from 7% with no minor anomalies to 15%, 36%, 67%, and 89% with 1, 2, 3, and >33 minor anomalies, respectively. Frequency of minor anomalies was less with lower resolution photographs, but did not show significant differences with maceration or gestational age. The most frequent minor anomalies were infraorbital creases/folds, lowset/posteriorly angulated ears, nuchal edema, flat face, equinovarus foot, camptodactyly, upslanted palpebral fissures, ear antihelix abnormalities (combined), micrognathia/retrognathia, and single transverse palmar crease. Except for infraorbital creases/folds each of these minor anomalies was strongly correlated with major anomalies (P < 0.0001). Infraorbital folds were the only anomaly which increased with placental cause of death, and reanalysis with placental causes excluded showed the expected relationship to major anomalies, suggesting that infraorbital folds may be markers for oligohydramnios due to various causes including placental hypoperfusion. Minor anomalies correlate with presence of major anomalies in stillborn fetuses, regardless of gestational age and maceration, and can provide information to guide decisions regarding laboratory testing and other evaluations.

Neuroblastoma in a 17-week fetus: a stimulus for investigation of tumors in a series of 2786 stillbirth and late miscarriages.

Although tumors are an occasional cause of neonatal death and have been reported in stillbirths, there are no studies specifically evaluating the frequency or types of tumors in stillborn infants. We observed metastatic neuroblastoma in a fetus miscarried at 17 weeks of gestational age. Fetal death was attributed to endocrine effects of the tumor causing fetal hypertension, arrhythmia, and/or placental dysfunction. This case, which is the earliest report of a pathologically confirmed neuroblastoma, prompted review of all tumors in the Wisconsin Stillbirth Service Program database. There were 10 lethal and two incidental tumors among the 2,786 stillbirths and second trimester miscarriages in the database for an overall incidence of 1/232, which is about 50 times the incidence of clinically recognized tumors in liveborn infants. The most frequent tumors were teratoma and hemangioma that, while benign, caused death due to high output cardiac failure, hemorrhage into the tumor, or obstruction of vital organs. Only three tumors were malignant, and except for the index case, mechanisms of death were similar to those of the benign tumors. Except for the index case, all were found in the third trimester, suggesting that congenital tumors rarely become lethal until the third trimester. However, it is also possible that tumors may be missed in younger fetuses. The possibility of detecting an unsuspected tumor is yet another reason for autopsy in stillbirths and late miscarriages.

Stillbirth: the heart of the matter.

We evaluated 2,083 cases within the Wisconsin Stillbirth Service Program (WiSSP) that had autopsy reports or ultrasound data relevant to the heart. Of these, 167/1,782 (9.4%) stillbirths after 20 weeks and 11/301 (3.7%) miscarriages <20 weeks had congenital heart disease (CHD). Cases were classified by type of heart defect and whether it related to cause of death. Among cardiac anomalies that contributed significantly to fetal death, 125/151 (83%) were associated with underlying conditions or syndromes, nearly half of which were chromosomal. The most common forms of CHD in stillborns were severe cyanotic lesions (3%), then ventricular (2.6%) and atrial (1.9%) septal defects. Compared to livebirths, this represents a shift toward more severe cardiac lesions, although all comparable categories, including non-lethal conditions such as atrial septal defect, are more common in stillbirths. Clinical cardiomyopathy was identified as cause of death in 1.2% of stillborns. Cardiomegaly, occurring in 26.7% of all cases and 76.7% of infants born to diabetic mothers, may represent undiagnosed cardiomyopathy and/or may decrease fetal tolerance of hypoxia. In contrast, 78.5% of Turner syndrome infants, all <32 weeks, had small hearts. More attention to cardiac findings can lead to increased understanding of stillbirth causes. Based on our findings, we recommend chromosome studies on all stillbirths and close attention to the heart during second trimester ultrasounds, with chromosome studies offered if CHD is found. Consideration of heart size can result in prenatal identification of infants at risk for stillbirth, particularly large hearts in fetuses of diabetic mothers in the third trimester, which may identify fetal cardiomyopathy before it becomes life-threatening.

Cutaneous corpuscular receptors of the human glans clitoris: descriptive characteristics and comparison with the glans penis.

INTRODUCTION: The female genital sensory pathways that initiate sexual arousal reflexes begin with cutaneous corpuscular receptors in the glabrous genital skin, including those of the glans clitoris. AIM: The aim of this study is to characterize the corpuscular receptors of the glans clitoris. In addition, we compared basic features with the receptors of the glans penis. MAIN OUTCOME MEASURE: Number of stained receptors. METHODS: Five cadaveric vulvectomy specimens and four cadaveric penile specimens were used. They were serially sectioned and stained with hematoxylin and eosin. Selected blocks were stained with Masson's trichrome, and immunohistochemical staining was done with neuronal markers S-100 and neurofilament. RESULTS: Using the three stains, we identified an abundance of corpuscular receptors within the glans clitoris, as compared with the surrounding prepuce. These receptors were of varied arrangements, situated in the subepithelial tissues of the glans clitoris. They were indistinguishable from the receptors of the glans penis. The number of receptors per 100× high-powered field ranged from 1 to 14, whereas the receptor density in the glans penis ranged from 1 to 3. A second type of receptor, the Pacinian corpuscle, was identified within the suspensory ligament along the trunks of the dorsal nerve but not within the glans itself. CONCLUSIONS: The glans clitoris is densely innervated with cutaneous corpuscular receptors, and these receptors are morphologically similar to the corpuscular receptors of the glans penis. The glans clitoris has greater variability in receptor density compared with the glans penis.

The pars intermedia: an anatomic basis for a coordinated vascular response to female genital arousal.

INTRODUCTION: The pars intermedia is an area of the vulva that has been inconsistently described in the literature. AIM: We conducted anatomic studies to better describe the tissues and vascular structures of the pars intermedia and proposed a functional rationale of the pars intermedia in the female sexual response. METHODS: Nine cadaveric vulvectomy specimens were used. Each was serially sectioned and stained with hematoxylin and eosin and Masson's trichrome. MAIN OUTCOME MEASURES: Histologic ultrastructural description of the pars intermedia. RESULTS: The pars intermedia contains veins traveling longitudinally in the angle of the clitoris, supported by collagen-rich stromal tissues. These veins drain the different vascular compartments of the vulva, including the clitoris, the bulbs, and labia minora; also, the interconnecting veins link the different vascular compartments. The pars intermedia is not composed of erectile tissue, distinguishing it from the erectile tissues of the corpora cavernosa of the clitoris as well as the corpus spongiosum of the clitoral (vestibular) bulbs. CONCLUSIONS: The venous communications of the pars intermedia, linking the erectile tissues with the other vascular compartments of the vulva, appear to provide the anatomic basis for a coordinated vascular response during female sexual arousal.

Wisconsin Stillbirth Service Program: analysis of large for gestational age cases.

Since its inception in 1983, the Wisconsin Stillbirth Service Program (WiSSP) has reviewed over 2,600 referrals. Among 2,451 with fetal weight and gestational age recorded, 186 (7.6%) were large for gestational age (LGA), which is more than expected. We reviewed these cases to identify factors causing or contributing to fetal death as well as increased fetal size. LGA losses tended to occur later in pregnancy than non-LGA losses. The most common cause of death in LGA fetuses was fetal (43.5%), followed by placental (22.6%), and maternal (11.2%), which contrasts with previous studies involving the same database, but unselected for fetal weight, in which 21.5%, 40.0%, and 12.7% had fetal, placental, and maternal causes, respectively. The most common fetal cause was hydrops (60 cases/32.4%), which was most frequently idiopathic (16/26.6%), followed by cardiac (11/18.3%), Turner syndrome (8/13.3%), and twin-twin transfusions (6/10.0%). Placental causes, most commonly abruption and infarct, were more frequent in diabetic mothers, accounting for 33% versus only 18% in the entire LGA group. In the LGA group overall, 21% of mothers were diabetic, and most stillbirths in diabetic mothers occurred after 28 weeks. Despite large placentas (>95th centile) in 71.8% of the LGA cohort compared to 11% previously reported in the entire database, the most extreme LGA cases had a high fetoplacental ratio. We recommend pathologic evaluation of placentas from all stillbirths, close follow-up of pregnancies complicated by diabetes, and continued research into causes and pathophysiology of hydrops.

Wisconsin stillbirth services program: a multifocal approach to stillbirth analysis.

Stillbirth accounts for about 26,000 deaths annually in the US. In most previous studies, discrete causes are identified in less than half of all stillbirths. In order to identify causes and non-causal but potentially contributing abnormalities, we analyzed 416 of the most recent (2004-2010) Wisconsin Stillbirth Service Program (WiSSP) cases from a multifocal approach. In 70% of cases a cause sufficient to independently explain the demise was identified including 40% placental, 21.5% fetal, and 12.7% maternal. Results for stillbirths and second trimester miscarriages did not differ significantly. In 95% of cases at least one cause or non-causal abnormality was recognizable, and in two-thirds of cases, more than one cause or non-causal abnormality was identified. In cases with maternal cause, the placenta was virtually always abnormal. Both placentas (59%) and fetuses (38%) were frequently smaller than expected for gestational age. Previous miscarriage and/or stillbirth were risk factors for second and third trimester losses, with 35% of previous pregnancies ending in fetal demise. Recommendations include complete evaluation of all second and third trimester losses with special attention to placental pathology and thorough investigation for multiple causes or abnormalities whether or not a primary cause is initially recognized. Improved understanding of the causes of late miscarriage and stillbirth may contribute to recognition and management of pregnancies at risk and eventually to prevention of stillbirth.

Surgical anatomy of the dorsal nerve of the clitoris.

AIMS: The purpose of this study was to describe the distal pathway of the dorsal nerve of the clitoris (DNC) from gross anatomical and histological studies of cadaver specimens. METHODS: We performed dissections on 14 intact adult cadaver vulva specimens using 2× loupe magnification and microscopy. The DNC was identified by gross dissection and confirmed histologically by staining with hematoxylin and eosin (H&E), Masson's trichrome (MT), and S100 antibody. The DNC pathway and its branches were followed from the pubic rami to the glans clitoris. RESULTS: The DNC travels inferior to the inferior pubic ramus along the superior/posterior edge of the clitoral crus. At the angle of the clitoral body, inferior to the pubic symphysis, the DNC enters the deep component of the suspensory ligament, which attaches to the clitoral body and to the pubic symphysis. The dorsal nerves, at the angle of the clitoral body, travel along the dorsal aspect of the clitoral body at the 11 and 1 o'clock positions. At the base of the clitoral body, the DNC is suspended superiorly away from the tunica. Distally along the clitoral body, the DNC descends and runs along the tunica and enters the glans. Within the glans, the terminal fibers are widely dispersed, and numerous receptors populate the supporting tissue of the glans beneath the epithelium. CONCLUSIONS: The detailed description of the distal course of the nerve presented here has not been previously described in adult humans and is pertinent for surgical procedures involving the clitoris.

Structure and innervation of the labia minora: more than minor skin folds.

OBJECTIVE: : The objective of this study was to examine the histologic features of the labia minora, within the context of the female sexual response. METHODS: : Eight cadaver vulvectomy specimens were used for this study. All specimens were embedded in paraffin and were serially sectioned. Selected sections were stained with hematoxylin and eosin, elastic Masson trichrome, and S-100 antibody stains. RESULTS: : The labia minora are thinly keratinized structures. The primary supporting tissue is collagen, with many vascular and neural elements structures throughout its core and elastin interspersed throughout. CONCLUSIONS: : The labia minora are specialized, highly vascular folds of tissue with an abundance of neural elements. These features corroborate previous functional and observational data that the labia minora engorge with arousal and have a role in the female sexual response.

Sexually responsive vascular tissue of the vulva.

OBJECTIVE: To better understand the genital changes that occur during the female sexual response, using a gross anatomical and histological study of the vascular tissue of the vulva, supplemented with magnetic resonance imaging (MRI). MATERIALS AND METHODS: Seven cadaveric vulvectomy specimens were used; they were serially sectioned in coronal, sagittal, and axial planes, and stained with haematoxylin and eosin. Selected blocks were stained with elastic Masson's trichrome. Axial MR images were taken of two healthy women with intact sexual functioning using a gadolinium-based blood-pool contrast agent. A 1.5 T system was used for all MRI studies, with images taken at baseline and during sexual arousal while viewing an erotic videotape. RESULTS: There are five vascular compartments of the female external genitalia, found in the clitoris, clitoral bulbs, labia minora, urethra, and vestibule/vagina. Of these five compartments, two distinct types of vascular tissue were identified, i.e. erectile and non-erectile/specialized genital. The erectile tissue compartments had the greatest change in blood volume during sexual arousal, as assessed by MRI. CONCLUSIONS: The vulva contains a substantial amount of vascular tissue. These specialized tissues show a variable, but unified response to sexual arousal.