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Angioleiomyoma is a classic painful cutaneous tumor of the limbs of middle aged adults. They are usually a straight-forward histologic diagnosis, being well-circumscribed or encapsulated lesions with both smooth muscle and vascular components.We report the case of an angioleiomyoma on the toe of an 8-year-old girl which displayed an unusual plexiform growth pattern. It was treated successfully with surgical excision, with no recurrence at one month.Angioleiomyoma is uncommon in children, particularly at acral sites. We describe the first such lesion to display a plexiform growth pattern.

Background Stillbirth rates have shown little improvement for two decades in Australia. Perinatal mortality audit is key to prevention, but the literature suggests that implementation is suboptimal. Aim To determine the proportion of perinatal deaths which are associated with contributing factors relating to care in Queensland, Australia. Materials and methods Retrospective audit of perinatal deaths ≥ 34 weeks gestation by the Health Department in Queensland was undertaken. Cases and demographic information were obtained from the Queensland Perinatal Data Collection. A multidisciplinary panel used the Perinatal Society of Australia and New Zealand (PSANZ) perinatal mortality audit guidelines to classify the cause of death and to identify contributing factors. Contributing factors were classified as 'insignificant', 'possible', or 'significant'. Results From 1 January to 31 December 2018, 65 deaths (56 stillbirths and nine neonatal deaths) were eligible and audited. Most deaths were classified as unexplained (51.8% of stillbirths). Contributing factors were identified in 46 (71%) deaths: six insignificant (all stillbirths), 20 possibly related to outcome (17 stillbirths), and 20 significantly (16 stillbirths). Areas for practice improvements mainly related to the care for women with risk factors for stillbirth, especially antenatal care. The PSANZ guidelines were applied and enabled a systematic approach. Conclusions A high proportion of late gestation perinatal deaths are associated with contributing factors relating to care. Improving antenatal care for women with risk factors for stillbirth is a priority. Perinatal mortality audit is a valuable step in stillbirth prevention and the PSANZ guidelines allow a systematic approach to aid implementation and reporting.

Australia has implemented a high-coverage HPV vaccination program but has not, to date, established the distribution of HPV types that occur in cervical cancers in Australia. This information is important for determining the potential for cervical cancer prevention with both current and broader spectrum HPV vaccines. We analysed 847 cervical cancers diagnosed 2005 to 2015 in tertiary centres in the three most populous Australian states with resolution of specimens containing multiple HPV types using laser-capture microdissection. Archived FFPE tissue was reviewed by specialist pathologists, sandwich sectioned, and initially whole-tissue sections genotyped for HPV. Samples were first genotyped using SPF10-LiPA25 (version 1). Negative samples were screened with DNA ELISA kit HPV SPF10, followed by genotyping with SPF+ LiPA if ELISA positive. If still negative, samples were tested on a qPCR assay targeting the E6 region of HPV16, 18, 45 and 33. Of the 847 cancers (65.1% squamous, 28.7% adenocarcinoma, 4.3% adenosquamous, 2.0% other), 92.9% had HPV detected. Of the HPV-positive cancers, 607 of 787 (77.1%) contained HPV16 or 18, 125 of 787 (15.9%) contained HPV31/33/45/52 or 58, and 55 (7.0%) another HPV type. There was a strong correlation between HPV type and age, with younger women most likely to have HPV16/18 detected and least likely HPV negative. Our findings indicate that cervical cancers diagnosed in Australia more frequently contain HPV16/18 than in international series. This could be due to cervical screening in Australia increasing the proportion of adenocarcinomas, in which types 18 and 16 more strongly predominate, due to prevention of squamous cancers.

Background Atorvastatin and metformin are known energy restricting mimetic agents that act synergistically to produce molecular and metabolic changes in advanced prostate cancer (PCa). This trial seeks to determine whether these drugs favourably alter selected parameters in men with clinically-localized, aggressive PCa. Methods/design This prospective phase II randomized, controlled window trial is recruiting men with clinically significant PCa, confirmed by biopsy following multiparametric MRI and intending to undergo radical prostatectomy. Ethical approval was granted by the Royal Brisbane and Women's Hospital Human and The University of Queensland Medical Research Ethics Committees. Participants are being randomized into four groups: metformin with placebo; atorvastatin with placebo; metformin with atorvastatin; or placebo alone. Capsules are consumed for 8 weeks, a duration selected as the most appropriate period in which histological and biochemical changes may be observed while allowing prompt treatment with curative intent of clinically significant PCa. At recruitment and prior to RP, participants provide blood, urine and seminal fluid. A subset of participants will undergo 7Tesla magnetic resonance spectroscopy to compare metabolites in-vivo with those in seminal fluid and biopsied tissue. The primary end point is biochemical evolution, defined using biomarkers (serum prostate specific antigen; PCA3 and citrate in seminal fluid and prostatic tissue). Standard pathological assessment will be undertaken. Discussion This study is designed to assess the potential synergistic action of metformin and atorvastatin on PCa tumour biology. The results may determine simple methods of tumour modulation to reduce disease progression.

BACKGROUND AND METHODS. Here, we report on the evaluation of the diagnostic performance of ejaculate-derived PCA3, Hepsin, and miRNAs to complement serum PSA to detect prostate cancer. cDNA was prepared from 152 candidate specimens following RNA isolation and amplification for PSA, PCA3 and Hepsin qPCR, with 66 having adequate RNA for all three assays. Small RNA sequencing and examination of PCa-associated miRNAs miR-200b, miR-200c, miR-375 and miR-125b was performed on 20 specimens. We compared findings from prostate biopsies using D’Amico and PRIAS classifications and in relation to whole gland histopathology following radical prostatectomy. Multivariate logistic regression modeling and clinical risk (incorporating standard clinicopathological variables) were performed for all ejaculate-based markers. RESULTS. While Hepsin alone was not of predictive value, the Hepsin:PCA3 ratio together with serum PSA, expressed as a univariate composite score based on multivariate logistic regression, was shown to be a better predictor than PSA alone of prostate cancer status (AUC 0.724 vs. 0.676) and risk, using D’Amico (AUC 0.701 vs. 0.680) and PRIAS (AUC 0.679 vs. 0.659) risk stratification criteria as classified using prostate biopsies. It was also possible to analyse a subgroup of patients for miRNA expression with miR-200c (AUC 0.788) and miR-375 (AUC 0.758) showing best single marker performance, while a combination of serum PSA, miR-200c, and miR-125b further improved prediction for prostate cancer status when compared to PSA alone determined by biopsy (AUC 0.869 vs. 0.672; P

Background Abnormal retinoic acid (RA) signalling is considered a major cause of congenital diaphragmatic hernia (CDH). Pulmonary hypoplasia and pulmonary hypertension are the major causes of morbidity and mortality in infants born with CDH. Experimental studies in animals have found that RA signalling is involved in lung and liver development, but animal models of CDH do not directly correlate with CDH in human fetuses. This study investigated if RA status is also linked to lung and liver growth in human fetuses with CDH. Study design and patients Hepatic stellate cells (HSC) in autopsy human fetal liver tissue were identified using cRBP-1 immunohistochemistry and the numbers of HSC manually counted. In mammals, RA is principally stored in HSC complexed to cRBP-1 and therefore cRBP-1+ HSC numbers were used as an indicator of fetal RA status. The number of HSCs was correlated with liver and lung weights, calculated relative to either normal biometric values or fetal body weight. Results The number of cRBP-1+ HSCs correlated with lung weight contralateral to the side of the diaphragmatic hernia (r = 0.82, p = 0.025) and combined lung weight (r = 0.78, p = 0.039) but not with ipsilateral lung weight (r = 0.43, p = 0.33), in fetuses with right and left CDH and a case of giant omphalocoele. Liver growth was influenced by contact with diaphragm but not significantly correlated with cRBP-1 expression (r = 0.52, p = 0.056). Conclusion Fetal RA stores, reflected in the number of cRBP-1+ HSCs, influence lung growth as well as diaphragm development in human fetuses with CDH. Contact with diaphragm influenced liver growth.

Summary Background The absence of trial data comparing robot-assisted laparoscopic prostatectomy and open radical retropubic prostatectomy is a crucial knowledge gap in uro-oncology. We aimed to compare these two approaches in terms of functional and oncological outcomes and report the early postoperative outcomes at 12 weeks. Method In this randomised controlled phase 3 study, men who had newly diagnosed clinically localised prostate cancer and who had chosen surgery as their treatment approach, were able to read and speak English, had no previous history of head injury, dementia, or psychiatric illness or no other concurrent cancer, had an estimated life expectancy of 10 years or more, and were aged between 35 years and 70 years were eligible and recruited from the Royal Brisbane and Women's Hospital (Brisbane, QLD). Participants were randomly assigned (1:1) to receive either robot-assisted laparoscopic prostatectomy or radical retropubic prostatectomy. Randomisation was computer generated and occurred in blocks of ten. This was an open trial; however, study investigators involved in data analysis were masked to each patient's condition. Further, a masked central pathologist reviewed the biopsy and radical prostatectomy specimens. Primary outcomes were urinary function (urinary domain of EPIC) and sexual function (sexual domain of EPIC and IIEF) at 6 weeks, 12 weeks, and 24 months and oncological outcome (positive surgical margin status and biochemical and imaging evidence of progression at 24 months). The trial was powered to assess health-related and domain-specific quality of life outcomes over 24 months. We report here the early outcomes at 6 weeks and 12 weeks. The per-protocol populations were included in the primary and safety analyses. This trial was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), number ACTRN12611000661976. Findings Between Aug 23, 2010, and Nov 25, 2014, 326 men were enrolled, of whom 163 were randomly assigned to radical retropubic prostatectomy and 163 to robot-assisted laparoscopic prostatectomy. 18 withdrew (12 assigned to radical retropubic prostatectomy and six assigned to robot-assisted laparoscopic prostatectomy); thus, 151 in the radical retropubic prostatectomy group proceeded to surgery and 157 in the robot-assisted laparoscopic prostatectomy group. 121 assigned to radical retropubic prostatectomy completed the 12 week questionnaire versus 131 assigned to robot-assisted laparoscopic prostatectomy. Urinary function scores did not differ significantly between the radical retropubic prostatectomy group and robot-assisted laparoscopic prostatectomy group at 6 weeks post-surgery (74·50 vs 71·10; p=0·09) or 12 weeks post-surgery (83·80 vs 82·50; p=0·48). Sexual function scores did not differ significantly between the radical retropubic prostatectomy group and robot-assisted laparoscopic prostatectomy group at 6 weeks post-surgery (30·70 vs 32·70; p=0·45) or 12 weeks post-surgery (35·00 vs 38·90; p=0·18). Equivalence testing on the difference between the proportion of positive surgical margins between the two groups (15 [10%] in the radical retropubic prostatectomy group vs 23 [15%] in the robot-assisted laparoscopic prostatectomy group) showed that equality between the two techniques could not be established based on a 90% CI with a Δ of 10%. However, a superiority test showed that the two proportions were not significantly different (p=0·21). 14 patients (9%) in the radical retropubic prostatectomy group versus six (4%) in the robot-assisted laparoscopic prostatectomy group had postoperative complications (p=0·052). 12 (8%) men receiving radical retropubic prostatectomy and three (2%) men receiving robot-assisted laparoscopic prostatectomy experienced intraoperative adverse events. Interpretation These two techniques yield similar functional outcomes at 12 weeks. Longer term follow-up is needed. In the interim, we encourage patients to choose an experienced surgeon they trust and with whom they have rapport, rather than a specific surgical approach. Funding Cancer Council Queensland.

The association of peripheral bronchial atresia and congenital pulmonary airway malformation (CPAM) has recently been recognised, but the pathology of the lesions evolving together has not been described. We present autopsy findings in a 20 week fetus showing areas of peripheral bronchial destruction and airway malformation consistent with developing CPAM in the right lung supporting a causal relationship between these lesions. This fetus also had congenital heart defect, bilateral renal agenesis and syndactyly. We identified another fetus from our autopsy files, with bilateral renal agenesis, similar right sided pulmonary malformation and cardiac defects. Similar bilateral renal agenesis and defects of the heart and lungs are found in wt1−-/–mice and we have investigated the expression of WT1 in these fetuses. We hypothesise that the cardiac, liver, renal and possibly lung lesions in these two cases may arise due to mesenchymal defects consequent to WT1 misexpression and discuss evidence for this from the scientific literature. We used immunoperoxidase stains to analyse WT1 expression in autopsy hepatic tissue in both fetuses. We also investigated the expression of α-smooth muscle actin (α-SMA), a marker of activated hepatic stellate cells/myofibroblasts, and desmin in hepatic mesenchyme and compare these findings with control fetuses, without congenital malformations. We found reduced WT1 expression in hepatic mesothelium in both fetuses with malformations. There was also increased expression of α-SMA in liver perisinusoidal cells, as seen in the wt1−-/–mouse model. We therefore propose that abnormality of WT1 signalling may be an underlying factor, as WT1 is expressed in coelomic lining cells from which mesenchyme is derived in many organs.

Ureaplasma species are the bacteria most frequently isolated from human amniotic fluid in asymptomatic pregnancies and placental infections. Ureaplasma parvum serovars 3 and 6 are the most prevalent serovars isolated from men and women. We hypothesized that the effects on the fetus and chorioamnion of chronic ureaplasma infection in amniotic fluid are dependent on the serovar, dose, and variation of the ureaplasma multiple-banded antigen (MBA) and mba gene. We injected high- or low-dose U. parvum serovar 3, serovar 6, or vehicle intra-amniotically into pregnant ewes at 55 days of gestation (term = 150 days) and examined the chorioamnion, amniotic fluid, and fetal lung tissue of animals delivered by cesarean section at 125 days of gestation. Variation of the multiple banded antigen/mba generated by serovar 3 and serovar 6 ureaplasmas in vivo were compared by PCR assay and Western blot. Ureaplasma inoculums demonstrated only one (serovar 3) or two (serovar 6) MBA variants in vitro, but numerous antigenic variants were generated in vivo: serovar 6 passage 1 amniotic fluid cultures contained more MBA size variants than serovar 3 (P = 0.005), and ureaplasma titers were inversely related to the number of variants (P = 0.025). The severity of chorioamnionitis varied between animals. Low numbers of mba size variants (five or fewer) within amniotic fluid were associated with severe inflammation, whereas the chorioamnion from animals with nine or more mba variants showed little or no inflammation. These differences in chorioamnion inflammation may explain why not all women with in utero Ureaplasma spp. experience adverse pregnancy outcomes.

We report a 12-month-old infant who presented with a 4-month history of isosexual precocious puberty secondary to an estrogenizing Sertoli-Leydig cell tumor of the ovary. Total serum immunoreactive inhibin and subunits A and B were markedly elevated before surgical resection and subsequently decreased 7 wk later into the normal prepubertal range. Twenty weeks following surgical removal, the patient presented again with central precocious puberty; inhibin B levels were raised on this occasion, a luteinizing releasing hormone stimulation test confirmed central precocious puberty. This is the youngest reported occurrence of this rare sex cord stromal neoplasm. The prognosis of this extremely rare tumor presenting at this early juvenile stage is uncertain. This report illustrates the usefulness of serum inhibin as a tumor marker during therapeutic suppression with leuprorelin acetate for central precocious puberty. Analysis of genomic and tumor DNA revealed a normal nucleotide sequence for the LH receptor and the Gαs gene. To understand the molecular pathogenesis of this tumor we analyzed mRNA levels for the inhibin A and B subunits, FSH receptor, LH receptor aromatase, steroidogenic factor-1 and the ER β genes. Molecular characterization reveals the presence of genes specific for granulosa and Leydig cells; the relative expression of these genes, in addition to its histologic characteristics, suggests that this tumor may result from a dysdifferentiation of a primordial follicle.

Myostatin is a highly conserved secretory protein that negatively regulates muscle development by affecting both proliferation and differentiation of muscle cells. In human placentae the expression of myostatin is negatively correlated with gestational age, and in placental explants, myostatin acts to facilitate glucose uptake. Myostatin expression is known to be higher in the placentae of pregnancies complicated by preeclampsia. Proper placental development is crucial for a healthy and successful pregnancy. Alterations to the function of the placental cells after treatment with myostatin have not previously been published.This study investigated the localization of myostatin in extravillous trophoblast (EVT) of human placentae. Furthermore, the effect of myostatin treatment on the proliferative and migrative capabilities of these placental cells was investigated.Myostatin is localized in EVT, as identified by the immunohistochemistry of third-trimester placentae and immunocytochemistry of first-trimester EVT isolations positively staining for myostatin and human leukocyte antigen-G. Treatment of an EVT cell line (HTR-8/SVneo) and primary isolated EVT with varied concentrations of myostatin resulted in a significant increase in the proliferation (HTR-8/SVneo; P.0001) and migration (HTR-8/SVneo and primary isolated EVT; P.05), with proliferation being dose dependent and migration being dose independent.Myostatin localization was positively identified in EVT. Myostatin positively affected proliferation (HTR-8/SVneo) and migration of EVT (HTR-8/SVneo and primary isolated EVT). For the first time, the effect of myostatin treatment on placental cells is described. The results provide a base from which further in vitro investigations on myostatin's ability to modulate placental cell function can be made.

EDITORIAL COMMENT: We accepted this case for publication because it seems to link graft versus host disease with intrauterine transfusions. Since the association of transfusion with graft versus host disease is exceedingly rare it would seem to the editorial subcommittee that it is reasonable to support the recommendation of the authors that irradiated blood should be used for intrauterine transfusions but as far as we can see the case for doing so for transfusions after birth is yet to be sustained. It seems important to study the fetal maturity at the time of intrauterine transfusions that are known to have been associated with graft versus host disease, the occurrence of which is presumably related to immune tolerance of the fetus to the transfused blood products. Our paediatrician reviewer informed us that at the Royal Women's Hospital, Melbourne, blood for fetal transfusions has always been irradiated since the early 1980s when intravascular transfusions were commenced. However, at this institution they do not irradiate blood for transfusions to infants after birth either for exchange transfusions, when the dose of lymphocytes transfused must be enormous, or for simple transfusions, with a reduced dose of lymphocytes. Reply to Editorial Comment: The comments by the paediatrician reviewer are noted. However the decision not to irradiate blood for transfusions to a neonate, be it for an exchange transfusion or a top up transfusion is contrary to current accepted practice. Indeed, the “dose of lymphocytes must be enormous”. Because of this, the British Blood Transfusion Task Force (A) and the American Association of Blood Banks (B) state that the indications for irradiation of blood are ABSOLUTE for the following: (i) Intrauterine and all subsequent transfusions and neonatal exchange transfusions. (ii) Premature/very low birth-weight infants (

Ureaplasma species are the microorganisms most frequently associated with adverse pregnancy outcomes. The multiple banded antigen (MBA), a surface-exposed lipoprotein, is a key virulence factor of ureaplasmas. The MBA demonstrates size variation, which we have shown previously to be correlated with the severity of chorioamnion inflammation. We aimed to investigate U. parvum serovar 3 pathogenesis in vivo, using a sheep model, by investigating: MBA variation after long term (chronic) and short term (acute) durations of in utero ureaplasma infections, and the severity of chorioamnionitis and inflammation in other fetal tissues. Inocula of 2 × 10(7) colony-forming-units (CFU) of U. parvum serovar 3 (Up) or media controls (C) were injected intra-amniotically into pregnant ewes at one of three time points: day 55 (69d Up, n = 8; C69, n = 4); day 117 (7d Up, n = 8; C7, n = 2); and day 121 (3d Up, n = 8; C3, n = 2) of gestation (term = 145-150d). At day 124, preterm fetuses were delivered surgically. Samples of chorioamnion, fetal lung, and umbilical cord were: (i) snap frozen for subsequent ureaplasma culture, and (ii) fixed, embedded, sectioned and stained by haematoxylin and eosin stain for histological analysis. Selected fetal lung clinical ureaplasma isolates were cloned and filtered to obtain cultures from a single CFU. Passage 1 and clone 2 ureaplasma cultures were tested by western blot to demonstrate MBA variation. In acute durations of ureaplasma infection no MBA variants (3d Up) or very few MBA variants (7d Up) were present when compared to the original inoculum. However, numerous MBA size variants were generated in vivo (alike within contiguous tissues, amniotic fluid and fetal lung, but different variants were present within chorioamnion), during chronic, 69d exposure to ureaplasma infection. For the first time we have shown that the degree of ureaplasma MBA variation in vivo increased with the duration of gestation.

A 14-year-old boy with end-stage renal failure secondary to reflux nephropathy received a renal transplant and was immunosuppressed with prednisone, azathioprine, and Minnesota antilymphoblast globulin, followed by cyclosporine A. A renal biopsy was performed 43 days post-transplantation because of fever and an elevated serum creatinine. The biopsy showed a mild interstitial lymphocytic infiltrate and immunosuppression was not changed. A second renal biopsy was performed 66 days after transplantation because of a persistent elevation of the serum creatinine following a cytomegalovirus (CMV) infection. CMV inclusions were seen by light microscopy (LM) in glomerular and peritubular capillary endothelial cells and tubular epithelial cells but no viral inclusions were present on the grids examined by electron microscopy (EM). However, the inclusions seen by LM were confirmed as CMV by immunohistochemistry, using polyclonal and monoclonal antibodies to CMV, and by in situ hybridization, using a biotinylated CMV DNA probe, emphasizing the usefulness of these techniques when studies by EM are not contributory.

Background Prostate cancer (PCa) diagnosis requires improvement with the aid of more accurate biomarkers. Postejaculate urethral washings (PEUW) could be a physiological equivalent to urine obtained following rectal prostatic massage, the current basis for the prostate cancer antigen 3 (PCA3) test. The aim of this study was to investigate if PEUW contained prostate-based material, evidenced by the presence of prostate specific antigen (PSA), and to evaluate the diagnostic performance of PEUW-based biomarkers. Methods Male patients referred for elevated serum PSA or abnormal digital rectal examination provided ejaculate and PEUW samples. PSA, PCA3, and β2-microglobulin (β2M) were quantified in ejaculate and PEUW and compared with absolute and clinically significant (according to D’Amico criteria) PCa presence, as determined by biopsies. Diagnostic performance was determined and compared with serum PSA using receiver operating characteristic analysis. Results From 83 patients who provided PEUW samples, paired analysis with ejaculate samples was possible for 38 patients, while analysis in an unpaired, extended cohort was possible for 62 patients. PSA and PCA3 were detected in PEUW, normalized to β2M, and PCA3:PSA was calculated. In predicting absolute PCa status, PCA3:β2M in ejaculate [area under the curve (AUC) 0.717] and PEUW (AUC 0.569) were insignificantly better than PCA3:PSA (AUC 0.668 and 0.431, respectively) and comparable with serum PSA (AUC 0.617) with similar trends observed for the extended cohort. When considering clinically significant PCa presence, serum PSA in the comparison (AUC 0.640) and extended cohorts (AUC 0.665) was comparable with PCA3: β2M (AUC 0.667) and PCA3:PSA (AUC 0.605) in ejaculate, with lower estimates for PEUW in the comparison (PCA3: β2M AUC 0.496; PCA3:PSA AUC 0.342) and extended (PCA3: β2M AUC 0.497; PCA3:PSA AUC 0.469) cohorts. The statistical analysis was limited by sample size. Conclusion PEUW contains prostatic material, but has limited diagnostic accuracy when considering cell-derived DNA analysis. PCA3-based markers in ejaculate are comparable to serum PSA and digital rectal examination–urine markers. Royal Brisbane and Women's Hospital Foundation (Ref: 2014002678), the Prostate Cancer Foundation of Australia and Cancer Council Queensland

Congenital mesoblastic nephroma (CMN) is a rare infantile renal tumor with a generally excellent prognosis. We describe 17 tumors that fit into the pathologic spectrum of CMN proposed by Beckwith, which ranges from benign renal tumors, through atypical “gray zone” lesions of more aggressive potential, to “crossover” tumors akin to clear cell sarcoma of kidney. Nine patients with histologically typical CMN were significantly younger and had smaller tumors than did eight patients with atypical CMN. Clinical features did not differ in the two groups of patients. A distinctive “ring sign” on renal sonography was commonly seen in patients with typical intrarenal CMN. All 17 patients were alive with no evidence of disease at a mean follow-up of 10 years. Nephrectomy was adequate therapy for younger infants and for those with typical CMN. Nephrectomy was probably also adequate therapy for infants 3 months of age or younger with atypical CMN, even if the tumor extended to the surgical resection margins and into the perinephric connective tissues. Adjuvant chemotherapy or radiation or both should be reserved for patients older than 3 months who have grossly unresected tumors and for those patients whose fumors have an unequivocally malignant histologic appearance or evidence of aggressive biologic behavior.