A molecular staging model for accurately dating the endometrial biopsy.

Natural variability in menstrual cycle length, coupled with rapid changes in endometrial gene expression, makes it difficult to accurately define and compare different stages of the endometrial cycle. Here we develop and validate a method for precisely determining endometrial cycle stage based on global gene expression. Our 'molecular staging model' reveals significant and remarkably synchronised daily changes in expression for over 3400 endometrial genes throughout the cycle, with the most dramatic changes occurring during the secretory phase. Our study significantly extends existing data on the endometrial transcriptome, and for the first time enables identification of differentially expressed endometrial genes with increasing age and different ethnicities. It also allows reinterpretation of all endometrial RNA-seq and array data that has been published to date. Our molecular staging model will significantly advance understanding of endometrial-related disorders that affect nearly all women at some stage of their lives, such as heavy menstrual bleeding, endometriosis, adenomyosis, and recurrent implantation failure.

Prions are secreted in milk from clinically normal scrapie-exposed sheep.

The potential spread of prion infectivity in secreta is a crucial concern for prion disease transmission. Here, serial protein misfolding cyclic amplification (sPMCA) allowed the detection of prions in milk from clinically affected animals as well as scrapie-exposed sheep at least 20 months before clinical onset of disease, irrespective of the immunohistochemical detection of protease-resistant PrP(Sc) within lymphoreticular and central nervous system tissues. These data indicate the secretion of prions within milk during the early stages of disease progression and a role for milk in prion transmission. Furthermore, the application of sPMCA to milk samples offers a noninvasive methodology to detect scrapie during preclinical/subclinical disease.

p57(KIP2) immunohistochemical staining of gestational trophoblastic tumours does not identify the type of the causative pregnancy.

AIM: To determine whether immunohistochemical staining for p57(KIP2), the product of the maternally expressed gene CDKN1C, can be used to differentiate between gestational trophoblastic tumours arising from a complete hydatidiform mole and those originating from non-molar pregnancies. METHODS: The immunohistochemical expression of p57(KIP2) was investigated in 23 cases of choriocarcinoma and 17 placental site trophoblastic tumours. Fourteen of the tumours examined were shown by DNA analysis to have arisen from complete hydatidiform moles and 26 from non-molar pregnancies. RESULTS: Five of 11 (45%) post-complete hydatidiform mole choriocarcinomas and two of three (67%) post-complete hydatidiform mole placental site trophoblastic tumours were found to be p57(KIP2)+ and showed similar immunostaining characteristics to tumours that developed from non-molar pregnancies. Although there was a statistically significant reduction in the proportion of cases showing positive p57(KIP2) staining in post-complete hydatidiform mole tumours compared with those originating in non-molar pregnancies [proportion difference 0.35 [95% confidence interval (CI) 0.05, 0.61], P = 0.02], immunostaining did not provide diagnostically useful information to differentiate between these tumours in clinical practice. There was no significant difference between the extent of staining in choriocarcinoma versus placental site trophoblastic tumours [proportion difference 0.17 (95% CI - 12, 42), P = 0.19]. The majority of both types of gestational trophoblastic tumour were positive for the presence of the p57(KIP2) protein irrespective of their genetic origin. CONCLUSION: Immunostaining for p57(KIP2) fails to discriminate between gestational trophoblastic tumours that have arisen from complete hydatidiform moles and those that have originated from other types of pregnancy.

Triploid/diploid mosaicism (69XXY/46XX) presenting as severe early onset preeclampsia with a live birth: placental and cytogenetic features.

Triploid/diploid mosaicism was diagnosed following karyotyping of an infant with musculo-skeletal abnormalities delivered because of severe preeclampsia. An area of the placenta appeared unusual with histology suggestive of trophoblastic abnormality. The importance of detailed histopathological examination and ploidy and flow cytometry studies where diagnostic uncertainty exists are highlighted.

Pseudo-partial moles: placental stem vessel hydrops and the association with Beckwith-Wiedemann syndrome and complete moles.

AIMS: To describe the clinical and histological features of a series of cases of placentas originally diagnosed as partial moles in which the final diagnosis was that of placental stem villous hydrops, mesenchymal dysplasia or Beckwith-Wiedemann syndrome. METHODS AND RESULTS: We searched a computerized database containing cases of suspected or proven trophoblastic disease examined at the Trophoblastic Disease Unit at Charing Cross Hospital, London, to identify cases in which stem vessel hydrops was present without other histological features of partial mole. For each case, histological sections were examined and the histological features present recorded. There were 15 cases identified. Placental weight was above the 95th centile of the normal for gestation in all cases in which this information was documented. In an additional five cases the placenta was described as 'large'. All cases had marked stem vessel hydropic change with cyst formation and in the majority of cases some terminal villous hydrops was also present. In 13 of the 15 cases there was marked aneurysmal dilatation of stem villous vessels. Nine had focal chorioangiomatoid change and in four of these extramedullary haematopoiesis was focally present in these areas. No excessive trophoblast proliferation was noted in any case and no trophoblastic inclusions typical of partial mole were identified. CONCLUSIONS: This study has identified cases of stem villous hydrops, mesenchymal dysplasia or Beckwith-Wiedemann spectrum in pregnancies initially diagnosed as partial hydatidiform mole in the second half of pregnancy and has highlighted the need for detailed pathological examination and clinicopathological correlation in all such cases.

Radial ray defects, renal ectopia, duodenal atresia and hydrocephalus: the extended spectrum for Fanconi anaemia.

We present two families with a striking concordance of multiple anomalies. These include duodenal and other bowel atresia, radial ray defects especially absent or vestigial thumb, renal ectopia and hydrocephalus. The presence of diagnostically raised sensitivity to mitomycin C in the first family has confirmed Fanconi anaemia. This has further increased the spectrum of abnormalities in Fanconi anaemia and highlights the importance of mitomycin C analysis if elements of this spectrum are encountered.

Trisomy 22 and intersex.

Complete trisomy 22, with or without mosaicism, has been reported as a distinct syndrome. In this report an infant is described who was externally male but with female rudimentary internal organs and whose karyotype was 47,XX+22.

Membranoproliferative glomerulonephritis type II associated with central serous retinopathy.

Membranoproliferative glomerulonephritis type II is specifically associated with the presence of dense deposits in the basement membrane of Bruch's membrane, which result in lesions similar to basal laminar drusen, exudative drusen, and retinal pigment epithelial detachments. In advanced stages of this dense-deposit retinopathy, choroidal neovascularization may occur. We observed a 36-year-old patient with membranoproliferative glomerulonephritis type II who developed central serous retinopathy in the presence of specific dense-deposit-associated fundus lesions. The diffuse drusenlike dense deposits (at the level of Bruch's membrane) and associated retinal pigment epithelial detachments appear to contribute to the pathogenesis of central serous retinopathy. Thus changes in Bruch's membrane may be involved in the development of central serous retinopathy.

Association between extent of colonic mucosal sialomucin change and subsequent local recurrence after curative excision of primary colorectal cancer.

Two interrelated studies were carried out to determine whether extent of sialomucin change adjacent to a primary colorectal carcinoma predicted local tumour invasiveness and risk of local recurrence. In the first, depth of tumour penetration was correlated with the length of the sialomucin band adjacent to 72 primary colorectal cancers. There was a significant (P less than 0.05) increase in sialomucin band length adjacent to tumours invading adjacent structures compared with those which had not (Mann-Whitney U test), although there was no overall correlation between depth of penetration, Duke's classification or degree of differentiation (Kruskal-Wallis test). A sialomucin band of greater than 3 cm was associated with a 70 per cent probability of adjacent structure (T4) invasion. These observations were then tested prospectively in a second study involving 256 patients to determine whether the presence of a greater than 3 cm sialomucin band could predict local recurrence. Presence of a greater than 3 cm sialomucin band was a significant (x2 = 7.12, d.f. = 1, P less than 0.001) and independent predictor of local but not distant recurrence. In addition both the interval to local recurrence and survival were significantly shorter if a greater than 3 cm sialomucin band was present. However the accuracy of greater than 3 cm sialomucin band as a predictive test for local recurrence was only 70 per cent. The extent of sialomucin adjacent to a primary colorectal cancer does provide a crude assessment of tumour invasiveness and risk of local recurrence.

Kinetic changes in experimental colonic urinary diversion.

An experimental model of colonic urinary diversion was performed on male Wistar rats to see if faeces, urine or a faeces and urine mixture produces tumours. Cell kinetic techniques, including the crypt cell production rate, and cellular DNA measurement were used to examine the effect of urine and of faeces on the colonic mucosa. Urinary diversion into the colon significantly increased colonic crypt activity. Tumours were found at the anastomosis when urine and faeces were mixed at 4 months, and at 6 months with urine alone.

Influence of sialomucin at the resection margin on local tumour recurrence and survival of patients with colorectal cancer: a multivariate analysis.

In a multicentre prospective trial 358 patients undergoing curative surgery for colorectal cancer were followed for a median 18.0 months (+/- 7.2 months). The presence or absence of sialomucin in either resection margin was studied using the high iron diamine-alcian blue stain. There was evidence of excess sialomucin at one or other resection margin in 106 patients (29.6 per cent). Apart from sigmoid carcinomas occurring more often in the sialomucin positive group, there were no significant differences in any histological or clinical parameters between groups. Survival analysis for the events 'death', 'local recurrence', and 'all recurrence' was undertaken using the Cox regression model. The best prognostic variables selected in a stepwise fashion for death and all recurrence were 'Dukes' classification', 'sialomucin present' and 'histological differentiation'. The best prognostic variables selected for local recurrence were 'sialomucin present', 'Dukes' classification' and 'histological differentiation'. Sialomucin in a resection margin is an important independent prognostic variable for the development of local tumour recurrence and of subsequent survival for patients with colorectal carcinoma.

Mucosal field change in colorectal cancer.

One hundred surgically excised colorectal carcinomas were examined histochemically using the high-iron diamine-alcian blue stain. Transitional mucosa surrounding the tumor was identified in 90 cases. The extent varied from 0 to 17 cm (mean 3.1 cm). In addition, the appearance of multiple patch lesions of increased sialomucin production was confirmed at sites far removed from the tumor in 35 cases. A predominant sialomucin pattern was seen in the proximal resection margin in 14 cases (17.9 percent), occurring as an isolated patch in 6 (43 percent). Sialomucin was also seen in the distal resection margin in 15 cases (15.9 percent), occurring as a direct extension of transitional mucosa surrounding the tumor in 12 (80 percent). These findings suggest that sialomucin production is a primary phenomenon that occurs as part of a field change in the human colon that develops cancer, and that these changes may occur in a resection margin and, by inference, remain at an anastomosis after resection.

Mucin changes adjacent to carcinoma following ureterosigmoidostomy.

A patient with epispadias had a ureterosigmoidostomy. This was converted to an ileal conduit 3.5 years later. 24 years after this, he developed an adenocarcinoma at the site of the ureteric stump. Abnormal mucin staining was found in the resected colon. This stain is not predictive of malignant change, and therefore regular colonoscopy is required for these patients.