Outpatient hysteroscopy: Suitable for all? A retrospective cohort study of safety, success and acceptability in Australia.

BACKGROUND: In Australia, gynaecologists continue to assess and investigate abnormal uterine bleeding with inpatient hysteroscopy despite evidence validating outpatient hysteroscopy services. AIM: This retrospective cohort study assessed the safety, success and acceptability of office hysteroscopy in a gynae-oncology rapid-access clinic over six years in Sydney, Australia, and included all women without an age or body mass index (BMI) cut-off using a 'see and treat' concept. METHODS: A database was created and analysed retrospectively for patients who attended office hysteroscopy service between January 2016 and March 2021 (63 months, 481 eligible). An anonymous modified PAT-32 patient satisfaction questionnaire was also offered to an initial cohort after their procedure to gauge insightful feedback about acceptability. RESULTS: A total of 92% of patients had successful outpatient hysteroscopic access; 24% of cases required hysteroscopy under general anaesthesia (GA) despite pathology in over 50% of cases; 68% of the total were able to be managed with outpatient hysteroscopy and did not require a follow-up GA hysteroscopy. This paper is also the first of its kind to our knowledge to incorporate patients >65 years, those with a BMI >35 and those with a history of cervical stenosis. This study suggests that age and BMI do not impact the success rate of the procedure. CONCLUSION: This study demonstrates that outpatient hysteroscopy is an acceptable, safe procedure that is well tolerated by patients. Considering our rapid-access hysteroscopy service allowed 68% of the patient cohort to avoid hysteroscopy under GA, we estimate conservatively ~$63 million per year in Australia could be saved by performing office hysteroscopies.

Identifying risk factors for post-operative bleeding in women undergoing loop electrosurgical excision procedure for cervical dysplasia.

BACKGROUND: Loop electrosurgical excision is a procedure utilised in the treatment of high-grade squamous intraepithelial lesion (HSIL) of the cervix. Post-operatively women may experience immediate and/or delayed per vaginal bleeding. AIMS: The objective of this prospective pilot study was to assess the feasibility of identifying and quantifying patients' subjective experiences of post-operative bleeding following a loop electrosurgical excision procedure (LEEP) for HSIL. In addition, an analysis of demographical, lifestyle and surgical factors was undertaken to assess for any statistically significant correlation with post-operative bleeding. MATERIALS AND METHODS: This study included 110 patients who underwent a LEEP for biopsy-proven or suspected HSIL between 2017 and 2020. Subjective data were collected from weekly post-operative surveys and correlated with procedural data. Primary outcome assessed was the subjective rate of bleeding experienced. Baseline demographics were age, body mass index (BMI), specimen size, human papilloma virus variant and histopathology. Other variables of interest collected were exercise intensity, and alcohol intake. RESULTS: No association of statistical significance was discovered between age, BMI, or day of menstrual cycle. There was a statistically significant association between exercise intensity or specimen size (greater than the median) and increased bleeding, primarily in the first 2 weeks. CONCLUSIONS: Women who undergo intense or prolonged exercise in the post-operative period may experience heavier bleeding particularly in the first 2 weeks post-LEEP. Heavy bleeding was also associated with a larger specimen size. There was no correlation between BMI, age or any other demographical factor.

Patient expectations and experiences with loop electrosurgical excision procedure in inpatient and outpatient settings.

BACKGROUND: Loop electrosurgical excision procedure (LEEP) for high-grade squamous intraepithelial lesion is performed in both an inpatient setting under general anaesthesia and an outpatient setting under local anaesthesia. Efficacy and safety are comparable and outpatient LEEP may save time and cost in the Australian setting. AIMS: We aim to compare patient satisfaction with inpatient LEEP compared to outpatient LEEP for Australian best practice. MATERIALS AND METHODS: This was a prospective quantitative and qualitative cohort study. An online questionnaire was sent to patients undergoing inpatient and outpatient LEEP to assess satisfaction with the procedure. Further histopathological and demographic data were also collected from the medical records. Groups were compared using Fischer's exact test and pain scores were compared using non-parametric tests. RESULTS: Ninety-three outpatients and 52 inpatients responded to the survey. No difference was found between groups with regard to rate of positive histopathological margins or number of passes required. Outpatients found the procedure to be more convenient than inpatients (P = 0.007), and experienced more pain during the procedure than the inpatient group (P < 0.001). There was no significant difference in pain scores following the procedure or post-procedure anxiety. CONCLUSIONS: Outpatient LEEP is an acceptable and well-tolerated procedure, comparable to inpatient LEEP. Regardless of the option chosen, patients are highly likely to be satisfied with their choice. Increased efforts should be made to reduce pre-procedural anxiety, which may in turn reduce expectations and experiences of pain.

An Australian, single-centre study of surgical management outcomes for early-stage cervical cancer.

BACKGROUND: The Laparoscopic Approach to Cervical Cancer (LACC) trial is the first phase III randomised, multicentred trial to compare oncologic outcomes associated with open radical hysterectomy vs minimally invasive surgery (MIS) for treatment of early cervical cancer. AIM: To evaluate our surgical experience in patients with early cervical cancer. METHODS AND MATERIALS: The Lifehouse Gynaecologic Oncology database was queried based upon the eligibility criteria of the LACC study and included all FIGO 2009 stage (1A1 with lymph vascular space invasion, 1A2, 1B1) cervical cancer women from 2008-2018. Patients were also included in our study if they had abdominal radical trachelectomy (ART), laparoscopic radical hysterectomy (TLRH) and robotic radical trachelectomy (RRT). RESULTS: Forty-six women were identified with four exclusions. Thirty-seven women had stage 1B1 disease, 24 had a squamous cell carcinoma, 15 had an adenocarcinoma and three had an adenosquamous carcinoma of the cervix. Of the 42 eligible patients, 32 underwent an open abdominal approach (26 total abdominal radical hysterectomy (TARH), six ART) and ten a MIS approach (nine TLRH and one RRT) with a mean follow-up of 4.8 years. All 42 women had a pelvic lymph node dissection, eight women had nodal metastases and 16 patients received adjuvant chemoradiation. Two of the nine women in the laparoscopic radical hysterectomy group had a recurrence. Both had adenocarcinoma, stage 1B1 disease. There were no recurrences in the TARH group or radical trachelectomy groups. CONCLUSION: Our data, albeit limited in number, have reflected the results of the LACC trial that MIS was associated with a lower disease-free survival than open radical hysterectomy.

The impact of primary human papillomavirus screening on negative loop excision histology following biopsy-proven high-grade cervical intra-epithelial lesions: A review from a large tertiary colposcopy unit.

BACKGROUND: The renewed National Cervical Screening Program incorporating primary human papillomavirus (HPV) screening was implemented in Australia in December 2017. In a previous study conducted in the UK, primary HPV screening was found to be associated with a 25% reduction in the incidence of negative histology following loop electrosurgery excision procedure (LEEP). AIM: To examine the change in incidence and associated risk factors for a negative LEEP with introduction of primary HPV screening. MATERIALS AND METHODS: A retrospective review of the records of all patients undergoing a LEEP excision for biopsy-proven high-grade cervical intra-epithelial lesions between 1 January 2014 and 30 June 2019 in a specialised centre. RESULTS: There were 1123 patients who underwent a LEEP included in the analysis. The incidence of a negative LEEP specimen was 7.5% (59/784) and 5.3% (18/339) in the pre- and post-HPV screening cohort. More patients in the post-HPV screening group had low-grade cytology on referral (P < 0.001), smaller cervical lesions on colposcopy (P = 0.012) and longer biopsy to treatment interval (P = 0.020). Primary HPV screening was associated with a significant reduction in the incidence of a negative LEEP specimen in a propensity matched cohort (11.2% to 5.1%, P = 0.006) and a 41% (P = 0.045) decreased relative risk of a negative LEEP on multivariate analysis. CONCLUSIONS: Primary HPV screening results in a lower incidence of negative LEEP histology, despite a longer biopsy to treatment wait time and higher proportion of low-grade cytology at triage.

Follow-up after treatment of high-grade cervical dysplasia: The utility of six-month colposcopy and cytology and routine 12-month colposcopy.

BACKGROUND: Australian Cervical Screening Program guidelines no longer recommend colposcopy and cytology at six months following treatment of cervical intraepithelial neoplasia (CIN2/3) and a co-test of cure can be performed at 12 months without colposcopy. AIMS: To determine the usefulness of six-month colposcopy and cytology and routine colposcopy with co-testing at 12 months in detecting persistent or recurrent disease in patients treated for CIN2/3. MATERIALS AND METHODS: We conducted a review of all patients with histologically proven CIN2/3 who underwent a cervical excisional procedure between March 2012 and March 2017 in one specialised centre. RESULTS: We examined 1215 cases and 750 remained after exclusions for analysis. At six months (722 cases, 96.2%) seven of 42 (16.7%) patients with high-grade cytology had a high-grade colposcopy and 24 of 42 (57.1%) had a normal colposcopy. Persistent CIN2/3 was diagnosed in 12 cases (1.7%) and only 1/3 had a high-grade colposcopy. Cytology was more useful than colposcopy in detecting persistent disease. At 12 months (638 cases, 85%) routine colposcopy at the time of co-testing had a high false positive rate with all high-grade changes negative on biopsy and co-test. Recurrent CIN2/3 was diagnosed in five cases, and four had normal colposcopy at co-testing. CONCLUSIONS: There may be a delay in detection of persistent/recurrent CIN2/3 in a small number of cases without six-month colposcopy and cytology; however, it is not likely to negatively impact overall clinical outcome. Co-testing at 12 months following treatment of CIN2/3 without colposcopy is safe and routine colposcopy at collection of the co-test can be omitted.

Patterns of surgical care for women with ovarian cancer in New South Wales.

BACKGROUND: Little is known about the delivery of surgical services and outcomes for women with ovarian cancer across New South Wales (NSW). AIM: The study objective was to provide a descriptive analysis of the proportion of women who had surgery for ovarian cancer in NSW in specialist gynaecological oncology hospitals and compare outcomes for women attending specialist and non-specialist services in NSW. MATERIALS AND METHODS: This study is a retrospective analysis of women with primary ovarian, fallopian tube or peritoneal cancer from 2009 to 2012. Data were analysed from the NSW Cancer Registry, NSW Admitted Patient Data Collection and Register of Births Deaths and Marriages. Treating hospitals were characterised as public specialist, public non-specialist and private. Morbidity and mortality outcomes are reported. RESULTS: The study included 1106 women. Fifty-seven hospitals performed surgery: seven public specialist, 27 private and 23 public non-specialist hospitals. The highest proportion of surgery was performed in public specialist hospitals (61%). There was considerable variation in the utilisation of public specialist hospitals between local health districts. There was no significant difference in outcomes related to the type of hospital where surgery was performed. CONCLUSIONS: Although the majority of women are having surgery in a specialist gynaecological oncology public hospital across NSW, many are not. Women living in regional and remote NSW were less likely to have their surgery in a specialist hospital. This is the first step in understanding where women in NSW are currently receiving their surgical care, as well as the outcomes related to this.

Intraoperative Frozen Section of Ovarian Tumors: A 6-Year Review of Performance and Potential Pitfalls in an Australian Tertiary Referral Center.

OBJECTIVES: Intraoperative frozen section (IFS) offers a rapid test to guide the extent of surgery, which is essential for optimal treatment of ovarian cancer. This study evaluated the diagnostic performance and influence of IFS in the surgical management of ovarian tumors. METHODS: A retrospective review was conducted of IFS of adnexal lesions from 2008 to 2013, with diagnoses classified as benign, borderline, or malignant. The diagnostic performance of IFS was calculated, with a focus on primary epithelial tumors. In discordant cases, it was determined whether the results of the IFS influenced the nature of the primary surgery. RESULTS: There were 277 consecutive cases over the study period. The overall sensitivity for diagnosing malignant disease was 75.9% and the specificity was 100%. With a benign IFS result, there was a 6.25% (9/144) chance that the final diagnosis would be malignant, and a 7.6% (11/144) chance that the final diagnosis would be borderline, resulting in the potential for understaging. The predictive values for benign, borderline, and malignant IFS results were 86.1%, 66.6%, and 100%, respectively. For a borderline IFS result, there was a 33.3% chance that the final diagnosis would be malignant disease, and this was higher in older patients (53.3%). There were no instances of overdiagnosis in this series. Of 37 cases underdiagnosed, 19 received incomplete primary staging surgery guided by the IFS, and most of these were mucinous tumors. CONCLUSIONS: Intraoperative frozen section is most valuable for its high specificity in diagnosing malignancy. It should be interpreted with caution in borderline tumors, particularly in older patients and in mucinous tumors. Overdiagnosis did not occur in this series; however, in younger patients, the limitations of IFS must be considered before surgery that would result in loss of fertility.

HE4, CA125, the Risk of Malignancy Algorithm and the Risk of Malignancy Index and complex pelvic masses - a prospective comparison in the pre-operative evaluation of pelvic masses in an Australian population.

BACKGROUND: Human epididymis protein 4 (HE4) has been proposed as a novel biomarker for the diagnosis of epithelial ovarian cancer. Using HE4 and CA125, the risk of malignancy algorithm (ROMA) has been shown to be effective in the stratification of epithelial ovarian cancer risk. AIMS: To determine the effectiveness of HE4 and ROMA in the diagnosis of malignancy of women presenting with a complex pelvic mass in an Australian population and to compare it with CA125 and the risk of malignancy index (RMI). MATERIALS AND METHODS: Prospective recruitment of women was conducted between October 2012 and March 2014 (n = 50). CA125 and HE4 serum concentrations were collected and stored for subsequent analysis. Sensitivities, specificities, positive predictive values (PPV) and negative predictive values (NPV) were calculated for HE4, CA125, ROMA and the RMI. Receiver operating characteristic (ROC) area under the curves (AUC) were also calculated for comparison. RESULTS: There was a higher HE4 level in women with ovarian cancer compared with women with benign pathology (P = 0.008), and this observation was seen in benign versus stage 1 ovarian cancer women (P = 0.025). HE4 had a better specificity than CA125 for the diagnosis of ovarian cancer in all women (P = 0.022), and this effect was also observed in premenopausal women (P = 0.012). Furthermore, the ROC-AUC for HE4 was superior than CA125 in all women (P = 0.0451). The ROMA algorithm was not inferior to the RMI calculation in this population. CONCLUSIONS: In an Australian population, HE4 and ROMA are useful in the diagnosis of epithelial ovarian cancer.

Evaluation of compact pulsed lasers for two-photon microscopy using a simple method for measuring two-photon excitation efficiency.

Significance: Two-photon (2p) microscopy has historically relied on titanium sapphire pulsed lasers that are expensive and have a large footprint. Recently, several manufacturers have developed less expensive compact pulsed lasers optimized for 2p excitation of green fluorophores. However, quantitative evaluation of their quality is lacking. Aim: We describe a simple approach to systematically evaluate 2p excitation efficiency, an empiric measure of the quality of a pulsed laser and its ability to elicit 2p induced fluorescence. Approach: By measuring pulse width, repetition rate, and fluorescence output, we calculated a measure of 2p excitation efficiency η, which we compared for four commercially available compact pulsed lasers in the 920 to 930 nm wavelength range. Results: 2p excitation efficiency varied substantially among tested lasers. The Coherent Axon exhibited the best 2p excitation efficiency (1.09±0.03), exceeding that of a titanium sapphire reference laser (defined to have efficiency = 1). However, its measured fluorescence was modest due to its long pulse width. Of the compact lasers, the Toptica Femtofiber Ultra exhibited the best combination of measured fluorescence (0.75±0.01) and 2p excitation efficiency (0.86±0.01). Conclusions: We describe a simple method that both laser developers and end users can use to benchmark the 2p excitation efficiency of lasers used for 2p microscopy.

Radiology-pathology correlation of endometrial carcinoma assessment on magnetic resonance imaging.

Endometrial carcinoma is the most common gynaecological cancer in developed countries. Most cases are low-volume/low-grade tumour at presentation; however, high-grade subtypes may present with locally advanced disease with higher propensity for spread outside of the pelvis. MRI has a role in local staging of the tumour and helping the clinicians in treatment decision making. This pictorial essay gives examples of endometrial carcinoma at different stages with histological correlation. It also explores the potential limitations and pitfalls of imaging in this context.

Glomangiomyoma of the clitoris: A case report and literature review.

Glomus tumor is an uncommon, benign, soft-tissue lesion in which the cells recapitulate the structure of the normal modified smooth muscle cells of the glomus body. Glomus tumors usually occur in tissues that normally contain glomus bodies; only rarely can they develop in sites where glomus bodies are normally sparse or absent. There are three subtypes of glomus tumor, with glomangiomyoma being the rarest. No more than 10 cases of glomus tumor in female genitalia have previously been reported, involving the vulva, vaginal area, periurethral area and clitoris. A clitoral glomangiomyoma is extremely rare. This is a case report of a glomangiomyoma in the clitoral area. Published reports of glomus tumor in the female external genitalia are reviewed.

Periodic and non-periodic frequency selection in an erbium doped fiber laser by silica microdisk optical cavity filters.

Integrated silica microdisk resonators can be used to create a variety of very high performance spectral filters. These filters can control the spectral emission of an erbium doped fiber laser. By modifying the number and sizes of the microdisks constituting these filters it is possible to produce single wavelength, periodic multi-frequency and non-periodic multi-wavelength fiber lasers. Channel spacing as low as 0.28 nm and non-periodic four wavelength lasers were demonstrated.

Assessing links between energy consumption, freight transport, and economic growth: evidence from dynamic simultaneous equation models.

We investigate this study to examine the relationship between economic growth, freight transport, and energy consumption for 63 developing countries over the period of 1990-2016. In order to make the panel data analysis more homogeneous, we apply the income level of countries to divide the global panel into three sub-panels, namely, lower-middle income countries (LMIC), upper-middle income countries (UMIC), and high-income countries (HIC). Using the generalized method of moments (GMM), the results prove evidence of bidirectional causal relationship between economic growth and freight transport for all selected panels and between economic growth and energy consumption for the high- and upper-middle income panels. For the lower-middle income panel, the causality is unidirectional running from energy consumption to economic growth. Also, the results indicate that the relationship between freight transport and energy use is bidirectional for the high-income countries and unidirectional from freight transport to energy consumption for the upper-middle and lower-middle income countries. Empirical evidence demonstrates the importance of energy for economic activity and rejects the neo-classical assumption that energy is neutral for growth. An important policy recommendation is that there is need of advancements in vehicle technology which can reduce energy intensity from transport sector and improve the energy efficiency in transport activity which in turn allows a greater positive role of transport in global economic activity.

In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer.

UNLABELLED: Fenofibrate, an agonist of PPAR-alpha, in doses above 25 microM, inhibits proliferation and induces apoptosis in Ishikawa endometrial cancer cells. We show that these effects are potentiated by retinoic acid, an agonist of the retinoid-X-receptor. DNA content analysis shows that G1/S phase progression through the cell cycle is inhibited. Independent Component Analysis of gene microarray experiments demonstrated downregulation of Cyclin D1 (CCND1) and associated changes in cell cycle gene expression. Expression of PPAR-alpha mRNA was reduced by >75% using RNA-interference but this resulted in only minor changes in biological effects. A nude mouse model of endometrial carcinoma was used to investigate the effect of fenofibrate in vivo but failed to show consistent inhibition of tumour growth. CONCLUSION: The combination of fenofibrate and retinoic acid is a potent inhibitor of Ishikawa endometrial cancer cell growth in vitro.

Independent component analysis of microarray data in the study of endometrial cancer.

Gene microarray technology is highly effective in screening for differential gene expression and has hence become a popular tool in the molecular investigation of cancer. When applied to tumours, molecular characteristics may be correlated with clinical features such as response to chemotherapy. Exploitation of the huge amount of data generated by microarrays is difficult, however, and constitutes a major challenge in the advancement of this methodology. Independent component analysis (ICA), a modern statistical method, allows us to better understand data in such complex and noisy measurement environments. The technique has the potential to significantly increase the quality of the resulting data and improve the biological validity of subsequent analysis. We performed microarray experiments on 31 postmenopausal endometrial biopsies, comprising 11 benign and 20 malignant samples. We compared ICA to the established methods of principal component analysis (PCA), Cyber-T, and SAM. We show that ICA generated patterns that clearly characterized the malignant samples studied, in contrast to PCA. Moreover, ICA improved the biological validity of the genes identified as differentially expressed in endometrial carcinoma, compared to those found by Cyber-T and SAM. In particular, several genes involved in lipid metabolism that are differentially expressed in endometrial carcinoma were only found using this method. This report highlights the potential of ICA in the analysis of microarray data.

Endothelial cells preparing to die by apoptosis initiate a program of transcriptome and glycome regulation.

The protein-based changes that underlie the cell biology of apoptosis have been extensively studied. In contrast, mRNA- and polysaccharide-based changes have received relatively little attention. We have combined transcriptome and glycome analyses to show that apoptotic endothelial cell cultures undergo programmed changes to RNA transcript abundance and cell surface polysaccharide profiles. Although a few of the transcriptome changes were protective, most appeared to prepare cells for apoptosis by decreasing the reception and transduction of pro-survival signals, increasing pro-death signals, increasing abundance of apoptotic machinery, inhibiting cellular proliferation, recruiting phagocytes to regions of cell death, and promoting phagocytosis. Additional transcriptomal changes appeared to alter the synthesis and modification of cell surface glycosaminoglycans. The resultant reduced abundance of sulphated cell surface glycosaminoglycans may further promote cell death by inhibiting the presentation of extracellular matrix-tethered survival factors to their receptors on dying cells. We propose that the transcriptome and glycome regulation presented here synergize with previously described protein-based changes to guide the apoptotic program.

Transcriptome analysis of endometrial cancer identifies peroxisome proliferator-activated receptors as potential therapeutic targets.

Endometrial cancer is the most common gynecologic malignancy, frequently arising in association with obesity and diabetes mellitus. To identify gene pathways contributing to endometrial cancer development, we studied the transcriptome of 20 endometrial cancers and 11 benign endometrial tissues using cDNA microarrays. Among the transcript changes identified in endometrial cancer were up-regulation of the nuclear hormone receptors peroxisome proliferator-activated receptors (PPAR) alpha and gamma, whereas retinoid X receptor beta was down-regulated. To clarify the contribution of PPARalpha to endometrial carcinogenesis, we did experiments on cultured endometrial carcinoma cells expressing this transcript. Treatment with fenofibrate, an activating ligand for PPARalpha, significantly reduced proliferation and increased cell death, suggesting that altered expression of nuclear hormone receptors involved with fatty acid metabolism leads to deregulated cellular proliferation and apoptosis. These results support further investigation of members of the PPAR/retinoid X receptor pathway as novel therapeutic targets in endometrial cancer.

Clinical utility of image-guided peritoneal and omental biopsy.

Image-guided core biopsy of the omentum and peritoneum was described a decade ago and has since been validated in a number of large studies as a safe and effective means of providing a tissue diagnosis in patients with undiagnosed peritoneal disease. Some studies have addressed its ability for determining whether peritoneal infiltration and/or omental masses in patients with prior malignancy represent recurrent disease or a new disease process. Others have focused on the specific issue of women suspected to have advanced peritoneal carcinomatosis from ovarian or primary peritoneal cancer where the primary management of the patient is directed by the tissue diagnosis. The initial management of many of these women, especially those with advanced disease or substantial comorbidity, is with primary chemotherapy. With current clinical trials for ovarian cancer directed to specific morphological subtypes of the disease, image-guided core biopsy offers a rapid and well tolerated nonsurgical means of providing this information. In this Review, we discuss the technique and its clinical applications, and critically examine the currently available alternative options.

Generation and use of a tailored gene array to investigate vascular biology.

Vasculogenesis, angiogenesis and vascular remodelling are complex processes where the fate of several cell types is determined by different signalling networks. Many of these networks ultimately function by changing the abundance of RNA transcripts within the cells which constitute blood vessel walls. Researchers can now map these transcript abundance changes using gene array technology. In this review, we describe the design, production and use of a gene array specifically tailored to investigate vascular biology. We describe the advantages of tailored gene arrays, and give detailed protocols based on our experience to allow the reader to use such gene arrays to generate meaningful data. We list the issues to consider when choosing and verifying the genes and splice variants included in an array, and describe our use of Arabidopsis sp. RNA spikes for quality control. We present data that illustrates the absolute necessity for both technical and biological replicates to be incorporated in the design of gene array experiments using primary cells such as HUVECS. Finally, we describe methods for the normalisation and interpretation of the data that gene arrays produce. The approach to gene array technology described here is easily within reach of the budget and expertise of most academic research groups.