Possible high-grade squamous intraepithelial lesion (pHSIL) in the new cervical screening paradigm: The outcomes and the role of clinicopathological review.

BACKGROUND: A renewed National Cervical Screening Program (NCSP) was introduced in Australia in December 2017. Under the renewed NCSP, there are limited data to guide the management of discordant colposcopy and biopsy results after a liquid-based cytology (LBC) finding of 'possible high-grade squamous intraepithelial lesion' (pHSIL). AIMS: This study aims to determine the proportion of women referred with pHSIL who are found to have HSIL, identify influencing factors of women most at risk, and examine the role that cytopathology review plays in management decisions. MATERIALS AND METHODS: Two-hundred and thirty-two women presenting to a tertiary women's hospital in Australia with pHSIL since December 2017 were identified. Women with HSIL following colposcopy directed biopsy were referred for treatment. When HSIL was not identified, these patients were referred for multidisciplinary clinicopathological review. Pathological outcomes and treatment recommendations are included. MAIN OUTCOME MEASURES: The primary outcome of the study was histological confirmation of HSIL. RESULTS: Primary outcome data were available for 182 women (78.5%); 62 (34.1%) had HSIL on histology, three (1.7%) had adenocarcinoma in situ (AIS) and one (1%) had cervical squamous cell carcinoma (SCC). There was no association between age and the presence of HSIL. The presence of human papillomavirus 16 and/or 18 increased the likelihood of HSIL on histology (relative risk 1.9; 95% CI 1.27-2.80, P = 0.002). Fifty-nine (25.4%) women were referred for observation who had low-grade squamous intraepithelial lesion/no dysplasia. CONCLUSIONS: Clinicopathological review optimises management and triage of patients with pHSIL on referral cytology. Understanding outcomes in these patients informs counselling and management.

Interaction between hypotension and age on adrenal crisis diagnosis.

Objective: To determine whether adrenal crisis (AC) identification may be affected by the definition of hypotension. Context: Delays in AC diagnosis can result in adverse outcomes. AC-related cardiovascular compromise may vary according to baseline blood pressure and may be associated with delayed AC detection in some patients. Design: A retrospective study of paired systolic blood pressure (sBP) measurements in hospitalized patients with primary AI (PAI). Patients: Patients with PAI and an acute illness admitted for urgent treatment between 2000 and 2017. Measurements: A comparison between sBP on hospital arrival and on discharge. Hypotension was classified as either absolute hypotension (sBP 100mg or lower) or relative hypotension (sBP over 100 mg but at least 20 mm Hg lower than discharge sBP). Results: Of 152 admissions with paired blood pressure measurements, 46 (30.3%) included a medically diagnosed AC. Absolute hypotension was found in 38 (25.0%) records, and a further 21 (13.8%) patients were classified as having relative hypotension. Patients aged 65 years and older had the lowest (14.8%, n = 8) proportion with absolute hypotension but the highest (27.8%, n = 15) with relative hypotension. Use of either absolute or relative hypotension as the criterion for AC diagnosis increased the proportion of patients with an AC by 28.3% and the proportion of patients with an AC in the oldest age group by 130%. Conclusions: Failure to detect cardiovascular compromise is common in older AI patients, may underestimate the AC rate in this group, and delay essential treatment. Relative hypotension may play a role in AC diagnosis.

Thyroid disease: Using diagnostic tools effectively.

BACKGROUND: Symptoms of thyroid disease are common, and patients often seek initial assessment from their general practitioners. OBJECTIVE: The aim of this article is to assist with identifying the appropriate sequence of investigations for thyroid disorders, and identify investigations with low diagnostic yield in certain clinical contexts. DISCUSSION: Common thyroid disorders - such as hypothyroidism, hyperthyroidism and thyroid nodules - require different sequences of investigations to assist with formulating a diagnosis and plan. Thyroid disorders are frequent in women of childbearing age and require a specialised approach. Awareness of less common thyroid conditions allows for individualised workup in these cases.

Prehospital Management of Acute Addison Disease: Audit of Patients Attending a Referral Hospital in a Regional Area.

CONTEXT: Adrenal crisis (AC) causes morbidity and mortality in patients with Addison disease [primary adrenal insufficiency (PAI)]. Patient-initiated stress dosing (oral or parenteral hydrocortisone) is recommended to avert ACs. Although these should be effective, the continued incidence of ACs remains largely unexplained. METHODS: Audit of all attendances between 2000 and 2017 of adult patients with treated PAI to one large regional referral center in New South Wales, Australia. Measurements were those taken on arrival at hospital. RESULTS: There were 252 attendances by 56 patients with treated PAI during the study period. Women comprised 60.7% (n = 34) of the patients. The mean age of attendees was 53.7 (19.6) years. Nearly half (45.2%, n = 114) of the patients had an infection. There were 61 (24.2%) ACs diagnosed by the treating clinician. Only 17.9% (n = 45) of the hospital presentations followed any form of stress dosing. IM hydrocortisone was used prior to presentation 7 (2.8%) attendances only. Among patients with a clinician-diagnosed AC, only 32.8% (n = 20) had used stress dosing before presentation. Vomiting was reported by 47.6% (n = 120) of the patients but only 33 (27.5%) of these attempted stress dosing and 5 patients with vomiting used IM hydrocortisone. The number of prior presentations was an independent predictor of use of stress doses [1.05 (1.01, 1.09)]. CONCLUSION: Dose-escalation strategies are not used universally or correctly by unwell patients with PAI; many patients do not use IM or subcutaneous hydrocortisone injections. Previous hospital treatment increases the likelihood of stress dosing, and hospital attendance offers the opportunity for reinforcement of prevention strategies.

The precursor for nerve growth factor (proNGF) is not a serum or biopsy-rinse biomarker for thyroid cancer diagnosis.

BACKGROUND: Nerves and neurotrophic growth factors are emerging promoters of cancer growth. The precursor for Nerve Growth Factor (proNGF) is overexpressed in thyroid cancer, but its potential role as a clinical biomarker has not been reported. Here we have examined the value of proNGF as a serum and biopsy-rinse biomarker for thyroid cancer diagnosis. METHODS: Patients presenting for thyroid surgery or biopsy were enrolled in separate cohorts examining serum (n = 204, including 46 cases of thyroid cancer) and biopsy-rinse specimens (n = 188, including 26 cases of thyroid cancer). ProNGF levels in clinical samples were analysed by ELISA. Univariate and multivariate statistical analyses were used to compare proNGF levels with malignancy status and clinicopathological parameters. RESULTS: ProNGF was not detected in the majority of serum samples (176/204, 86%) and the detection of proNGF was not associated with thyroid cancer diagnosis. In the few cases where proNGF was detected in the serum, thyroidectomy did not affect proNGF concentration, demonstrating that the thyroid was not the source of serum proNGF. Intriguingly, an association between hyperthyroidism and serum proNGF was observed (OR 3.3, 95% CI 1.6-8.7 p = 0.02). In biopsy-rinse, proNGF was detected in 73/188 (39%) cases, with no association between proNGF and thyroid cancer. However, a significant positive association between follicular lesions and biopsy-rinse proNGF was found (OR 3.3, 95% CI 1.2-8.7, p = 0.02). CONCLUSIONS: ProNGF levels in serum and biopsy-rinse are not increased in thyroid cancer and therefore proNGF is not a clinical biomarker for this condition.

Increased maternal abdominal subcutaneous fat thickness and body mass index are associated with increased cesarean delivery: A prospective cohort study.

INTRODUCTION: Early pregnancy body mass index (BMI) is known to predict adverse pregnancy outcomes but does not account for body fat distribution. This study aimed to determine prospectively whether maternal abdominal subcutaneous fat thickness (SCFT) measured by ultrasound at the fetal morphology scan is a better predictor than BMI of mode of delivery and other pregnancy outcomes. MATERIAL AND METHODS: This was a prospective cohort study of women delivering singleton neonates at a tertiary public hospital. Women were included if they had appropriate images at the routine fetal anomaly ultrasound scan and delivered in the facility. The primary outcome was mode of delivery categorized as cesarean section or vaginal delivery. The relation between maternal SCFT and BMI was described using the Pearson correlation coefficient. The association of maternal abdominal SCFT BMI at booking-in was compared with pregnancy outcomes using univariate linear and logistic regression. RESULTS: SCFT and BMI were obtained for 997 women. The median (interquartile range) SCFT was 15.3 mm (12.8-19.6) and median (interquartile range) BMI 24.3 kg/m2 (21.7-28.3). Maternal abdominal SCFT and BMI were highly correlated (R2  = 0.55). Both were significantly associated with cesarean delivery: SCFT per 5 mm (odds ratio [OR] 1.32, 95% confidence interval (CI) 1.18-1.48; BMI per 5 kg/m2 OR 1.29, 95% CI 1.15-1.44. CONCLUSIONS: Maternal abdominal SCFT and BMI were both significantly associated with cesarean delivery and other outcomes. More research is needed to define the strengths of maternal SCFT in predicting pregnancy outcomes.

Pursuing the second ipsilateral gland during minimally invasive video-assisted parathyroidectomy.

BACKGROUND: In patients with primary hyperparathyroidism (PHPT) and preoperative imaging suggesting a solitary parathyroid adenoma (SPA), focused parathyroidectomy is most often curative. Even so, large studies show up to 3% of patients experience persistent or recurrent PHPT. Unilateral neck exploration (UNE) aiming to identify the SPA and the other ipsilateral parathyroid may reduce this failure rate. We hypothesized that: (i) minimally invasive video-assisted (MIVA) approach would facilitate UNE and (ii) this would be a clinically relevant strategy. METHODS: Prospective case series of a consecutive cohort of PHPT patients (with preoperative diagnosis of SPA), who underwent MIVA-UNE. A 15 mm collar incision and endoscopic magnification were utilized to both excise the SPA and seek the ipsilateral parathyroid gland. RESULTS: From 2009 to 2014, 132 patients were offered MIVA-UNE (age: 63.0 (interquartile range: 11.2); females: 94 (71.2%); symptomatic: 89 (67.4%); mean serum corrected calcium: 2.7 (standard deviation: 0.9) mmol/L; mean serum parathyroid hormone: 16.8 (standard deviation: 11.8) pmol/L). Conversion from MIVA-UNE to open UNE was required in 14 (10.6%) patients (excluded from subsequent analysis). MIVA-UNE was concluded in 118 patients. The second ipsilateral parathyroid was identified in 62 (52.5%) patients and in 13 (11.0%) it appeared enlarged and was excised. Histopathology confirmed five (4.2%) of these glands to be hyperplastic. CONCLUSION: MIVA-UNE allows identification of the second ipsilateral parathyroid in about half the patients. This approach helped to diagnose and treat unexpected multigland disease in almost 5% of patients.

The shift toward neo-adjuvant chemotherapy and interval debulking surgery for management of advanced ovarian and related cancers in a population-based setting: Impact on clinical outcomes.

OBJECTIVES: The aim of this study was to determine the proportion of patients with advanced ovarian and related cancers (EOC+RC), treated with neoadjuvant chemotherapy and interval debulking surgery (NACT - IDS), and to determine if there was any relationship with optimal cytoreduction rates and overall survival (OS) in a state-wide gynaecologic oncology service over time. METHODS: A retrospective review was undertaken using a population-based database of patients with stages 3 and 4 EOC+RC treated from 1982 till 2013 at the Queensland Centre for Gynaecological Cancer (QCGC). The proportion of patients treated with NACT - IDS compared with primary debulking surgery (PDS) was determined and compared with debulking rates and with the moving five-year OS probability. RESULTS: From 1982-2013, 2601 patients with advanced EOC+RC were managed at QCGC. No patients received NACT - IDS till 1995 when the first two patients received this treatment, rising to 55% of patients in 2013. Surgical cytoreduction rates to no macroscopic residual (R0) were achieved 32% of the time by 2006, rising to 48% in 2009, and 62% in 2013. Despite the increase in utilisation of NACT - IDS, our unit has noted a continued rise in the OS probability at five years to 45%. CONCLUSIONS: The increasing utilisation of NACT - IDS in the setting of a large centralised clinical service has been associated with increasing rates of optimal cytoreduction and survival rates have continued to rise in excess of those achieved in the trials reported to date.

Prolactin correction for adequacy of petrosal sinus cannulation may diminish diagnostic accuracy in Cushing's disease.

OBJECTIVE: Petrosal venous prolactin concentrations have been promoted to improve the diagnostic accuracy of inferior petrosal sinus sampling (IPSS), beyond that achieved with ACTH measurement alone, in diagnosing a pituitary ACTH source and determining corticotrophinoma side (L/R). Our objective was to assess the effect of using prolactin to confirm adequacy of petrosal cannulation in a cohort of patients with ACTH-dependent Cushing's syndrome. DESIGN: Retrospective cohort study. PATIENTS: Thirteen patients with clinical and biochemical Cushing's syndrome who underwent IPSS. MEASUREMENTS: Serum prolactin and ACTH in peripheral and inferior petrosal sinus blood before and after corticotrophin-releasing hormone (CRH) injection. RESULTS: Thirteen consecutive patients were diagnosed with Cushing's disease using uncorrected ACTH ratios. The side of PRL excess was the same as the side of ACTH excess in all cases. Use of various published prolactin-related equations suggested that the ACTH non-dominant side was not cannulated in four, six or seven patients depending on the equation used. The equations generally decreased the central-to-peripheral gradient on the uncorrected ACTH dominant side, increased the central-to-peripheral gradient on the contralateral side and diminished or even reversed the ACTH intersinus gradient. CONCLUSIONS: Consistent co-lateralisation of prolactin and ACTH in IPSS strongly suggests that prolactin cannot act as an independent guide to the diagnosis and lateralisation of Cushing's disease. All patients with Cushing's disease had a prolactin intersinus gradient towards the tumourous side of the pituitary, for likely biological reasons. PRL-corrected ACTH concentrations may threaten the sensitivity and specificity of IPSS in diagnosing Cushing's disease and conceal lateralisation.

Targeting the TSH receptor in thyroid cancer.

Recent advances in the arena of theranostics have necessitated a re-examining of previously established fields. The existing paradigm of therapeutic thyroid-stimulating hormone receptor (TSHR) targeting in the post-surgical management of differentiated thyroid cancer using levothyroxine and recombinant human thyroid-stimulating hormone (TSH) is well understood. However, in an era of personalized medicine, and with an increasing awareness of the risk profile of longstanding pharmacological hyperthyroidism, it is imperative clinicians understand the molecular basis and magnitude of benefit for individual patients. Furthermore, TSHR has been recently re-conceived as a selective target for residual metastatic thyroid cancer, with pilot data demonstrating effective targeting of nanoparticles to thyroid cancers using this receptor as a target. This review examines the evidence for TSHR signaling as an oncogenic pathway and assesses the evidence for ongoing TSHR expression in thyroid cancer metastases. Priorities for further research are highlighted.

Clinicopathological study of ovarian carcinoid tumours.

OBJECTIVE: To describe the clinical features, treatment, clinical course and survival rates of women diagnosed with ovarian carcinoid tumours. METHODS: A retrospective chart review was performed of all patients diagnosed with primary ovarian carcinoid tumours who were managed by the Queensland Centre for Gynaecological Cancer from 1982 to 2015. RESULTS: Eighteen patients were identified with ovarian carcinoid tumours over the 32 years of the study period. Of the 18 patients, 14 were diagnosed with stage 1 disease, two were diagnosed with stage 3 disease and two were diagnosed with stage 4 disease. Carcinoid syndrome was present in two patients. All patients underwent surgical management. Follow-up strategies varied for early stage disease, but no patient with early stage disease received any adjuvant treatment and no patient developed recurrent disease. Patients with advanced stage disease were treated with cytoreductive surgery and chemotherapy. The five year survival was 100% for stage 1 disease, and 25% for stages 3 and 4 disease. CONCLUSIONS: The vast majority of carcinoid tumours are diagnosed as an incidental finding. Prognosis for early stage disease is excellent, whether conservative or more extensive surgery with staging was performed, and intensive follow up did not influence survival. Optimal treatment for advanced disease remains unknown and requires further study.

Charting a course through the CEAs: diagnosis and management of medullary thyroid cancer.

Medullary thyroid cancer (MTC) is an uncommon thyroid cancer that requires a high index of suspicion to facilitate diagnosis of early-stage disease amenable to surgical cure. The challenges of diagnosis, as well as management in the setting of persistent disease, are explored in the context of a case presenting with the incidental finding of elevated carcinoembryonic antigen (CEA) and an (18) F-fluorodeoxyglucose positron emission tomography ((18) F-FDG-PET)-positive thyroid incidentaloma detected following treatment of colorectal cancer. Strategies to individualize prognosis, and emerging PET-based imaging modalities, particularly the potential role of (18) F-DOPA-PET in staging, are reviewed.

Is minimally invasive parathyroid surgery an option for patients with gestational primary hyperparathyroidism?

BACKGROUND: Gestational primary hyperparathyroidism is associated with serious maternal and neonatal complications, which require prompt surgical treatment. Minimally invasive parathyroidectomy reduces pain, improves cosmesis and may achieve cure rates comparable to traditional open bilateral neck exploration. We report the clinical course of a woman with newly diagnosed gestational primary hyperparathyroidism and discuss the decision making behind the choice of video-assisted minimally invasive parathyroidectomy, amongst the other minimally invasive parathyroidectomy techniques available. CASE PRESENTATION: A 38-years-old pregnant woman at 9 weeks of gestation, with severe hyperemesis and hypercalcaemia secondary to gestational primary hyperparathyroidism (ionised calcium 1.28 mmol/l) was referred for surgery. Ultrasound examination of her neck identified 2 suspicious parathyroid enlargements. In view of pregnancy, a radioisotope Sestamibi parathyroid scan was not performed. Bilateral four-gland exploration was therefore deemed necessary to guarantee cure. This was performed with video-assisted minimally invasive parathyroidectomy, which relies on a single 15 mm central incision with external retraction and endoscopic magnification, allowing bilateral neck exploration. CONCLUSION: Video-assisted minimally invasive parathyroidectomy allows bilateral four-gland exploration, and is an optimal technique to treat gestational primary hyperparathyroidism. This procedure removes the need for radiation exposure, reduces pain, improves cosmesis and may achieve cure rates comparable to traditional open bilateral neck exploration.

Androgen deficiency in the aging man.

BACKGROUND: Androgen deficiency in the aging man is an area of considerable debate because a gradual decline in testosterone may simply be part of the normal aging process. However, there is an alternative view that androgen deficiency in the aging man may constitute a valid and underdiagnosed disorder. OBJECTIVE: To discuss the aetiology, clinical features, diagnosis and management of androgen deficiency in the aging man. DISCUSSION: Late onset hypogonadism has clinical features that overlap with both normal aging and some pathological conditions. It can only be diagnosed on the basis of both suggestive clinical features and clear biochemical evidence of testosterone deficiency. In this group of patients medication may play a role.

Human uterine wall tension trajectories and the onset of parturition.

Uterine wall tension is thought to be an important determinant of the onset of labor in pregnant women. We characterize human uterine wall tension using ultrasound from the second trimester of pregnancy until parturition and compare preterm, term and twin pregnancies. A total of 320 pregnant women were followed from first antenatal visit to delivery during the period 2000-2004 at the John Hunter Hospital, NSW, Australia. The uterine wall thickness, length, anterior-posterior diameter and transverse diameter were determined by serial ultrasounds. Subjects were divided into three groups: women with singleton pregnancies and spontaneous labor onset, either preterm or term and women with twin pregnancies. Intrauterine pressure results from the literature were combined with our data to form trajectories for uterine wall thickness, volume and tension for each woman using the prolate ellipsoid method and the groups were compared at 20, 25 and 30 weeks gestation. Uterine wall tension followed an exponential curve, with results increasing throughout pregnancy with the site of maximum tension on the anterior wall. For those delivering preterm, uterine wall thickness was increased P < 0.05 compared with term. For twin pregnancies intrauterine volume was increased compared to singletons (P < 0.001), but wall thickness was not. There was no evidence for increased tension in those delivering preterm or those with twin gestations. These data are not consistent with a role for high uterine wall tension as a causal factor in preterm spontaneous labor in singleton or twin gestations. It seems likely that hormonal differences in multiple gestations are responsible for increased rates of preterm birth in this group rather than increased tension.

Premature arthritis is a distinct type II collagen phenotype.

Mutations in the gene encoding type II collagen (COL2A1) give rise to a spectrum of phenotypes predominantly affecting cartilage and bone. These chondrodysplasias are typically characterized by disproportionately short stature, eye abnormalities, cleft palate, and hearing loss. It is less recognized that mutations in COL2A1 can also present as degenerative joint disease in the absence of any other phenotypic clues. We report 2 Australian families presenting with an isolated arthritis phenotype, segregating as a dominant trait affecting both large and small joints, prior to age 30 years. Sequencing of COL2A1 in the propositi revealed 2 sequence changes resulting in glycine substitutions in the triple-helical domain of type II collagen. We review the increasing evidence implicating COL2A1 mutations in individuals presenting with isolated degenerative joint disease, aiming to alert physicians who assess these patients to this possibility. The importance of finding a COL2A1 mutation in such patients lies in the subsequent ability to accurately assess recurrence risks, offer early (including prenatal) diagnosis, and provide information regarding the natural history of the condition. Most importantly, it enables at-risk individuals to be identified for implementation of preventative strategies (i.e., weight loss, joint-friendly exercise programs) and early ameliorative management of their condition.

Patterns of plasma corticotropin-releasing hormone, progesterone, estradiol, and estriol change and the onset of human labor.

CONTEXT: Clinical prediction of preterm delivery is largely ineffective, and the mechanism mediating progesterone (P) withdrawal and estrogen activation at the onset of human labor is unclear. OBJECTIVES: Our objectives were to determine associations of rates of change of circulating maternal CRH in midpregnancy with preterm delivery, CRH with estriol (E3) concentrations in late pregnancy, and predelivery changes in the ratios of E3, estradiol (E2), and P. DESIGN AND SETTING: A cohort of 500 pregnant women was followed from first antenatal visits to delivery during the period 2000-2004 at John Hunter Hospital, New South Wales, Australia, a tertiary care obstetric hospital. PATIENTS: Unselected subjects were recruited (including women with multiple gestations) and serial blood samples obtained. MAIN OUTCOME MEASURES: CRH daily percentage change in term and preterm singletons at 26 wk, ratios E3/E2, P/E3, and P/E2 and the association between E3 and CRH concentrations in the last month of pregnancy (with spontaneous labor onset) were assessed. RESULTS: CRH percentage daily change was significantly higher in preterm than term singletons at 26 wk (medians 3.09 and 2.73; P = 0.003). In late pregnancy, CRH and E3 concentrations were significantly positively associated (P = 0.003). E3/E2 increased, P/E3 decreased, and P/E2 was unchanged in the month before delivery (medians: E3/E2, 7.04 and 10.59, P < 0.001; P/E3, 1.55 and 0.98, P < 0.001; P/E2, 11.78 and 10.79, P = 0.07). CONCLUSIONS: The very rapid rise of CRH in late pregnancy is associated with an E3 surge and critically altered P/E3 and E3/E2 ratios that create an estrogenic environment at the onset of labor. Our evidence provides a rationale for the use of CRH in predicting preterm birth and informs approaches to delaying labor using P supplementation.

Hormone trajectories leading to human birth.

The mechanisms regulating human parturition and labor remain unknown. This ignorance is expensive as preterm birth is responsible for 70% of neonatal mortality and 50% of cerebral palsy. Methods for the prediction of preterm birth and treatments for women in preterm labor have poor efficacy reflecting our limited knowledge of the mechanisms involved. Recent research has supported the view that parturition is a cascade of events that commences early in pregnancy and involves the mother, fetus, placenta, membranes, cervix and myometrium. Although a number of the key hormones and proteins involved have been identified, the relationships between these factors in time and tissues remain unclear. Placental production of Corticotropin-releasing hormone (CRH) is proposed as an early event regulating the cascade of events. Central to the onset of parturition will be a mechanism for progesterone withdrawal and estrogen activation in human. Two forms of progesterone receptor with opposing actions exist in the human myometrium. Progesterone receptor A (PR-A) is a dominant negative repressor of progesterone receptor B (PR-B). Preliminary studies strongly support the hypothesis that the onset of human parturition is initiated by rising concentrations of PR-A in the myometrium.