Vaginal vault smear cytology in detection of recurrence after hysterectomy for early cervical cancer.

OBJECTIVE: To determine the role of vaginal vault cytology as a surveillance tool for the detection of recurrence in patients with early stage cervical cancer treated with hysterectomy without adjuvant therapy. METHODS: A retrospective cohort study was conducted of all women with cervical cancer treated with a hysterectomy from January 2000 to July 2016 at the Royal Brisbane & Women's Hospital, Australia. Women included were diagnosed with the equivalent of International Federation of Gynecology and Obstetrics (FIGO) 2018 stage 1A1 to 1B3 squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma, received either simple or radical hysterectomy with or without pelvic lymph node dissection, and did not receive adjuvant therapy. Age, stage, histology, surgical procedure, and details of individual surveillance regimens including examination findings and indications and results for all vault cytology tests performed in the first 5 years following surgical management were collected. RESULTS: A total of 155 women met the inclusion criteria. Most cases were FIGO 2018 stage 1B1 (61.9%) and squamous cell carcinoma (64.5%). Included women underwent a median of 80 months of surveillance (range 25-200, IQR 64-108). In the first 5 years of surveillance, there were a total of 1001 vault cytology smears performed, with a median of 6 smears (IQR 5-9) per woman. A total of 19 smears were abnormal (1.9%). Of the cohort of 155 women, 19 (12.3%) had an abnormality detected; 1 (0.65%) had a high-grade intraepithelial abnormality and 2 (1.3%) had recurrences detected on cytology; however, a lesion was also seen and biopsied in all three women. A total of 16 of 1001 smears (1.6%) had low-grade abnormalities detected, all of which resolved with clinical observation only. All were alive and well at last review. There were in total 6 (3.9%) recurrences, 2 (33%) of which had abnormal cytology as above, and all of which had a lesion to biopsy and/or abnormal medical imaging. CONCLUSIONS: The routine use of vaginal vault cytology in surveillance following hysterectomy for early stage cervical cancer did not appear to alter the detection of recurrent malignancy.

Patient-derived xenograft models capture genomic heterogeneity in endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprises four molecular subtypes with differing etiology, prognoses, and responses to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. As pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models. METHODS: Here, we report whole exome or whole genome sequencing of 11 PDX models and their matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the copy number high/p53-mutant and mismatch-repair deficient molecular subtypes of EC. RESULTS: PDX models were successfully generated from grade 2/3 tumors, including three uterine carcinosarcomas. The models showed similar histomorphology to the primary tumors and represented all four molecular subtypes of EC, including five mismatch-repair deficient models. The different PDX lineages showed a wide range of inter-tumor and intra-tumor heterogeneity. However, for most PDX models, one arm recapitulated the molecular landscape of the primary tumor without major genomic drift. An in vivo response to talazoparib was detected in four copy number high models. Two models (carcinosarcomas) showed a response consistent with stable disease and two models (one copy number high serous EC and another carcinosarcoma) showed significant tumor growth inhibition, albeit one consistent with progressive disease; however, all lacked the HR deficiency genomic signature. CONCLUSIONS: EC PDX models represent the four molecular subtypes of disease and can capture intra-tumor heterogeneity of the original primary tumor. PDXs of the copy number high molecular subtype showed sensitivity to PARPi; however, deeper and more durable responses will likely require combination of PARPi with other agents.

A novel technique for a rare diagnosis: MRI-guided vaginal biopsy of Skene gland adenocarcinoma: Pictorial Essay.

FDG-PET and MRI imaging of the pelvis identified a suspicious lesion in a patient with a history of small cell neuroendocrine tumour of the vagina, and after a negative surgical biopsy, a multidisciplinary team meeting decided to proceed with MRGB (magnetic resonance-guided biopsy). The patient remains well and in remission two years after anterior exenteration, with final histology of the lesion determined to be Skene gland adenocarcinoma. MRGB is a novel and effective way to diagnose vaginal lesions.

Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial.

PURPOSE: Intrauterine levonorgestrel (LNG-IUD) is used to treat patients with endometrial adenocarcinoma (EAC) and endometrial hyperplasia with atypia (EHA) but limited evidence is available on its effectiveness. The study determined the extent to which LNG-IUD with or without metformin (M) or weight loss (WL) achieves a pathological complete response (pCR) in patients with EAC or EHA. PATIENTS AND METHODS: This phase II randomized controlled clinical trial enrolled patients with histologically confirmed, clinically stage 1 FIGO grade 1 EAC or EHA; a body mass index > 30 kg/m2; a depth of myometrial invasion of less than 50% on MRI; a serum CA125 ≤ 30 U/mL. All patients received LNG-IUD and were randomized to observation (OBS), M (500 mg orally twice daily), or WL (pooled analysis). The primary outcome measure was the proportion of patients developing a pCR (defined as absence of any evidence of EAC or EHA) after 6 months. RESULTS: From December 2012 to October 2019, 165 patients were enrolled and 154 completed the 6-months follow up. Women had a mean age of 53 years, and a mean BMI of 48 kg/m2. Ninety-six patients were diagnosed with EAC (58%) and 69 patients with EHA (42%). Thirty-five participants were randomized to OBS, 36 to WL and 47 to M (10 patients were withdrawn). After 6 months the rate of pCR was 61% (95% CI 42% to 77%) for OBS, 67% (95% CI 48% to 82%) for WL and 57% (95% CI 41% to 72%) for M. Across the three treatment groups, the pCR was 82% and 43% for EHA and EAC, respectively. CONCLUSION: Complete response rates at 6 months were encouraging for patients with EAC and EHA across the three groups. TRIAL REGISTRATION: U.S. National Library of Medicine, NCT01686126.

Development of a surgical competency assessment tool for sentinel lymph node dissection by minimally invasive surgery for endometrial cancer.

INTRODUCTION: Sentinel lymph node dissection is widely used in the staging of endometrial cancer. Variation in surgical techniques potentially impacts diagnostic accuracy and oncologic outcomes, and poses barriers to the comparison of outcomes across institutions or clinical trial sites. Standardization of surgical technique and surgical quality assessment tools are critical to the conduct of clinical trials. By identifying mandatory and prohibited steps of sentinel lymph node (SLN) dissection in endometrial cancer, the purpose of this study was to develop and validate a competency assessment tool for use in surgical quality assurance. METHODS: A Delphi methodology was applied, included 35 expert gynecological oncology surgeons from 16 countries. Interviews identified key steps and tasks which were rated mandatory, optional, or prohibited using questionnaires. Using the surgical steps for which consensus was achieved, a competency assessment tool was developed and subjected to assessments of validity and reliability. RESULTS: Seventy percent consensus agreement standardized the specific mandatory, optional, and prohibited steps of SLN dissection for endometrial cancer and informed the development of a competency assessment tool. Consensus agreement identified 21 mandatory and three prohibited steps to complete a SLN dissection. The competency assessment tool was used to rate surgical quality in three preselected videos, demonstrating clear separation in the rating of the skill level displayed with mean skills summary scores differing significantly between the three videos (F score=89.4; P<0.001). Internal consistency of the items was high (Cronbach α=0.88). CONCLUSION: Specific mandatory and prohibited steps of SLN dissection in endometrial cancer have been identified and validated based on consensus among a large number of international experts. A competency assessment tool is now available and can be used for surgeon selection in clinical trials and for ongoing, prospective quality assurance in routine clinical care.

Survival outcomes after delayed cytoreduction surgery following neoadjuvant chemotherapy in advanced epithelial ovarian cancer.

OBJECTIVE: Interval cytoreduction following neoadjuvant chemotherapy is a well-recognized treatment alternative to primary debulking surgery in the treatment of advanced epithelial ovarian cancer where patient and/or disease factors prevent complete macroscopic disease resection to be achieved. More recently, the strain of the global COVID-19 pandemic on hospital resources has forced many units to alter the timing of interval surgery and extend the number of neoadjuvant chemotherapy cycles. In order to support this paradigm shift and provide more accurate counseling during these unprecedented times, we investigated the survival outcomes in advanced epithelial ovarian cancer patients with the intent of maximal cytoreduction following neoadjuvant chemotherapy with respect to timing of surgery and degree of cytoreduction. METHODS: A retrospective review of all patients aged 18 years and above with FIGO (2014) stage III/IV epithelial ovarian cancer treated with neoadjuvant chemotherapy and the intention of interval cytoreduction surgery between January 2008 and December 2017 was conducted. Overall and progression-free survival outcomes were analyzed and compared with patients who only received chemotherapy. Outcome measures were correlated with the number of neoadjuvant chemotherapy cycles and amount of residual disease following surgery. RESULTS: Six hundred and seventy-one patients (median age 67 (range 20-91) years) were included in the study with 572 patients treated with neoadjuvant chemotherapy and surgery and 99 patients with chemotherapy only. There was no difference in the proportion of patients in whom complete cytoreduction was achieved based on number of cycles of neoadjuvant chemotherapy (2-4 cycles: 67.7%, n=337/498); ≥5 cycles: 62.2%, n=46/74). Patients undergoing cytoreduction surgery after neoadjuvant chemotherapy had a median 5-year progression-free and overall survival of 24 and 38 months, respectively. No significant difference in overall survival between surgical groups was observed (interval cytoreduction: 41 months vs delayed cytoreduction: 43 months, p=0.52). Those who achieved complete cytoreduction to R0 (no macroscopic disease) had a significant median overall survival advantage compared with those with any macroscopic residual disease (R0: 49-51 months vs R<1: 22-39 months, p<0.001 vs R≥1: 23-26 months, p<0.001). CONCLUSIONS: Survival outcomes do not appear to be worse for patients treated with neoadjuvant chemotherapy if cytoreduction surgery is delayed beyond three cycles. In advanced epithelial ovarian cancer patients the imperative to achieve complete surgical cytoreduction remains gold standard, irrespective of surgical timing, for best survival benefit.

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.

Outcomes of women diagnosed and treated for low-risk gestational trophoblastic neoplasia at the Queensland Trophoblast Centre (QTC).

BACKGROUND: Gestational trophoblastic neoplasia (GTN) is classified as a highly curable group of pregnancy-related malignancies; however, approximately 15% will be persistent and require chemotherapy. Up to 25% of these women will develop resistance and 2% will develop disease relapse after initial chemotherapy. Despite the need for further chemotherapy in these women, cure rates are high. OBJECTIVE: To evaluate the outcomes of women diagnosed with low-risk GTN, assessing the type of treatment, the number of chemotherapy cycles received, development of resistance or disease relapse, survival, and to assess the feasibility of changing to a new drug regimen. METHODS: From March 2012 until February 2015, a retrospective study was conducted and 38 cases with low-risk GTN were reviewed. The number of cycles, type of treatment received, duration of treatment, development of resistance and disease relapse, and adverse side effects were analysed. RESULTS: The median duration of follow-up was 12 months. Disease-free survival was 100% and primary complete remission rates were achieved in 85.3% of patients who were treated with actinomycin D and 25% patients who were treated with methotrexate (MTX). A change in chemotherapy was required for nine patients. One patient developed disease relapse. Nausea, fatigue and constipation were the most frequent adverse events reported with actinomycin D. All women were cured of their disease. CONCLUSION: All women were successfully treated and achieved complete remission. Changing from MTX to actinomycin D as first-line chemotherapy for women with low-risk GTN was feasible and safe.

Effect of Total Laparoscopic Hysterectomy vs Total Abdominal Hysterectomy on Disease-Free Survival Among Women With Stage I Endometrial Cancer: A Randomized Clinical Trial.

Importance: Standard treatment for endometrial cancer involves removal of the uterus, tubes, ovaries, and lymph nodes. Few randomized trials have compared disease-free survival outcomes for surgical approaches. Objective: To investigate whether total laparoscopic hysterectomy (TLH) is equivalent to total abdominal hysterectomy (TAH) in women with treatment-naive endometrial cancer. Design, Setting, and Participants: The Laparoscopic Approach to Cancer of the Endometrium (LACE) trial was a multinational, randomized equivalence trial conducted between October 7, 2005, and June 30, 2010, in which 27 surgeons from 20 tertiary gynecological cancer centers in Australia, New Zealand, and Hong Kong randomized 760 women with stage I endometrioid endometrial cancer to either TLH or TAH. Follow-up ended on March 3, 2016. Interventions: Patients were randomly assigned to undergo TAH (n = 353) or TLH (n = 407). Main Outcomes and Measures: The primary outcome was disease-free survival, which was measured as the interval between surgery and the date of first recurrence, including disease progression or the development of a new primary cancer or death assessed at 4.5 years after randomization. The prespecified equivalence margin was 7% or less. Secondary outcomes included recurrence of endometrial cancer and overall survival. Results: Patients were followed up for a median of 4.5 years. Of 760 patients who were randomized (mean age, 63 years), 679 (89%) completed the trial. At 4.5 years of follow-up, disease-free survival was 81.3% in the TAH group and 81.6% in the TLH group. The disease-free survival rate difference was 0.3% (favoring TLH; 95% CI, -5.5% to 6.1%; P = .007), meeting criteria for equivalence. There was no statistically significant between-group difference in recurrence of endometrial cancer (28/353 in TAH group [7.9%] vs 33/407 in TLH group [8.1%]; risk difference, 0.2% [95% CI, -3.7% to 4.0%]; P = .93) or in overall survival (24/353 in TAH group [6.8%] vs 30/407 in TLH group [7.4%]; risk difference, 0.6% [95% CI, -3.0% to 4.2%]; P = .76). Conclusions and Relevance: Among women with stage I endometrial cancer, the use of total abdominal hysterectomy compared with total laparoscopic hysterectomy resulted in equivalent disease-free survival at 4.5 years and no difference in overall survival. These findings support the use of laparoscopic hysterectomy for women with stage I endometrial cancer. Trial Registration: clinicaltrials.gov Identifier: NCT00096408; Australian New Zealand Clinical Trials Registry: CTRN12606000261516.

Quality of life after early enteral feeding versus standard care for proven or suspected advanced epithelial ovarian cancer: Results from a randomised trial.

BACKGROUND: Malnutrition is common in patients with advanced epithelial ovarian cancer (EOC), and is associated with impaired quality of life (QoL), longer hospital stay and higher risk of treatment-related adverse events. This phase III multi-centre randomised clinical trial tested early enteral feeding versus standard care on postoperative QoL. METHODS: From 2009 to 2013, 109 patients requiring surgery for suspected advanced EOC, moderately to severely malnourished were enrolled at five sites across Queensland and randomised to intervention (n=53) or control (n=56) groups. Intervention involved intraoperative nasojejunal tube placement and enteral feeding until adequate oral intake could be maintained. Despite being randomised to intervention, 20 patients did not receive feeds (13 did not receive the feeding tube; 7 had it removed early). Control involved postoperative diet as tolerated. QoL was measured at baseline, 6weeks postoperatively and 30days after the third cycle of chemotherapy. The primary outcome measure was the difference in QoL between the intervention and the control group. Secondary endpoints included treatment-related adverse event occurrence, length of stay, postoperative services use, and nutritional status. RESULTS: Baseline characteristics were comparable between treatment groups. No significant difference in QoL was found between the groups at any time point. There was a trend towards better nutritional status in patients who received the intervention but the differences did not reach statistical significance except for the intention-to-treat analysis at 7days postoperatively (11.8 intervention vs. 13.8 control, p 0.04). CONCLUSION: Early enteral feeding did not significantly improve patients' QoL compared to standard of care but may improve nutritional status.

Improved surgical safety after laparoscopic compared to open surgery for apparent early stage endometrial cancer: results from a randomised controlled trial.

AIM: To compare Total Laparoscopic Hysterectomy (TLH) and Total Abdominal Hysterectomy (TAH) with regard to surgical safety. METHODS: Between October 2005 and June 2010, 760 patients with apparent early stage endometrial cancer were enroled in a multicentre, randomised clinical trial (LACE) comparing outcomes following TLH or TAH. The main study end points for this analysis were surgical adverse events (AE), hospital length of stay, conversion from laparoscopy to laparotomy, including 753 patients who completed at least 6 weeks of follow-up. Postoperative AEs were graded according to Common Toxicity Criteria (V3), and those immediately life-threatening, requiring inpatient hospitalisation or prolonged hospitalisation, or resulting in persistent or significant disability/incapacity were regarded as serious AEs. RESULTS: The incidence of intra-operative AEs was comparable in either group. The incidence of post-operative AE CTC grade 3+ (18.6% in TAH, 12.9% in TLH, p 0.03) and serious AE (14.3% in TAH, 8.2% in TLH, p 0.007) was significantly higher in the TAH group compared to the TLH group. Mean operating time was 132 and 107 min, and median length of hospital stay was 2 and 5 days in the TLH and TAH group, respectively (p<0.0001). The decline of haemoglobin from baseline to day 1 postoperatively was 2g/L less in the TLH group (p 0.006). CONCLUSIONS: Compared to TAH, TLH is associated with a significantly decreased risk of major surgical AEs. A laparoscopic surgical approach to early stage endometrial cancer is safe.

Risk factors to predict the incidence of surgical adverse events following open or laparoscopic surgery for apparent early stage endometrial cancer: results from a randomised controlled trial.

AIMS: To identify risk factors for major adverse events (AEs) and to develop a nomogram to predict the probability of such AEs in patients who have surgery for apparent early stage endometrial cancer. METHODS: We used data from 753 patients who were randomised to either total laparoscopic hysterectomy or total abdominal hysterectomy in the LACE trial. Serious adverse events that prolonged hospital stay or postoperative adverse events (using common terminology criteria 3+, CTCAE V3) were considered major AEs. We analysed pre-surgical characteristics that were associated with the risk of developing major AEs by multivariate logistic regression. We identified a parsimonious model by backward stepwise logistic regression. The six most significant or clinically important variables were included in the nomogram to predict the risk of major AEs within 6weeks of surgery and the nomogram was internally validated. RESULTS: Overall, 132 (17.5%) patients had at least one major AE. An open surgical approach (laparotomy), higher Charlson's medical co-morbidities score, moderately differentiated tumours on curettings, higher baseline Eastern Cooperative Oncology Group (ECOG) score, higher body mass index and low haemoglobin levels were associated with AE and were used in the nomogram. The bootstrap corrected concordance index of the nomogram was 0.63 and it showed good calibration. CONCLUSIONS: Six pre-surgical factors independently predicted the risk of major AEs. This research might form the basis to develop risk reduction strategies to minimise the risk of AEs among patients undergoing surgery for apparent early stage endometrial cancer.

Nomograms to predict isolated loco-regional or distant recurrence among women with uterine cancer.

OBJECTIVE: While there is ample literature on prognostic factors for uterine cancer, currently there are nomeans to estimate an individual's risk for recurrence or to differentiate the risk of loco-regional recurrence from distant recurrence. We addressed this gap by developing nomograms to individualize the risk of recurrence. METHODS: A total of 2097 consecutive patients who underwent primary surgery between 1997 and 2007 were included. Sixteen covariates were evaluated for their prognostic significance and modeled using multivariable competing risks regression to predict three-year outcomes as part of a nomogram. Each covariate in the nomogram is assigned a value, and a sum of these values form the overall risk score from which three-year incidence probabilities can be predicted for each individual. Predictive accuracy was assessed with concordance index and then corrected for optimism. RESULTS: The median follow-up time (inter-quartile range, IQR) was 50.0 (28.3-77.5) months and 221 patients developed a recurrence (127 patients with isolated loco-regional recurrence, 94 patients with distant recurrence). The nomograms included the following covariates: age at diagnosis, FIGO stage (2009), grade, lymphovascular invasion, histological type, depth of myometrial invasion, and peritoneal cytology. Concordance indices for isolated loco-regional and distant recurrences were 0.73 and 0.86, respectively. CONCLUSIONS: Our nomograms quantify an individual patient's risk of isolated loco-regional and distant recurrence, using factors that are routinely collected. They may assist clinicians to assess an individual's prognosis, individualize treatment and also assist in the risk stratification in prospective randomized clinical trials evaluating the effectiveness of treatments for uterine cancer.

Validation of the FIGO 2009 staging system for carcinoma of the vulva.

BACKGROUND: The previous (1988) International Federation of Gynecology and Obstetrics (FIGO) vulval cancer staging system failed in 3 important areas: (1) stage 1 and 2 disease showed similar survival; (2) stage 3 represented a most heterogeneous group of patients with a wide survival range; and (3) the number and morphology of positive nodes were not taken into account. OBJECTIVE: To compare the 1988 FIGO vulval carcinoma staging system with that of 2009 with regard to stage migration and prognostication. METHODS: Information on all patients treated for vulval cancer at the Queensland Centre for Gynecological Cancers, Australia, between 1988 to the present was obtained. Data included patients' characteristics as well as details on histopathology, treatments, and follow-up. We recorded the original 1988 FIGO stage, reviewed all patients' histopathology information, and restaged all patients to the 2009 FIGO staging system. Data were analyzed using the Kaplan-Meier method to compare relapse-free survival and overall survival. RESULTS: Data from 394 patients with primary vulval carcinoma were eligible for analysis. Patients with stage IA disease remained unchanged. Tumors formerly classified as stage II are now classified as stage IB. Therefore, FIGO 2009 stage II has become rare, with only 6 of 394 patients allocated to stage II. Stage III has been broken down into 3 substages, thus creating distinct differences in relapse-free survival and overall survival. Prognosis of patients with stage IIIC disease is remarkably poor. CONCLUSION: The FIGO 2009 staging system for vulval carcinoma successfully addresses some concerns of the 1988 system. Especially, it identifies high-risk patients within the heterogeneous group of lymph node-positive patients.

Quality of life after total laparoscopic hysterectomy versus total abdominal hysterectomy for stage I endometrial cancer (LACE): a randomised trial.

BACKGROUND: This two-stage randomised controlled trial, comparing total laparoscopic hysterectomy (TLH) with total abdominal hysterectomy (TAH) for stage I endometrial cancer (LACE), began in 2005. The primary objective of stage 1 was to assess whether TLH results in equivalent or improved quality of life (QoL) up to 6 months after surgery compared with TAH. The primary objective of stage 2 was to test the hypothesis that disease-free survival at 4.5 years is equivalent for TLH and TAH. Here, we present the results of stage 1. METHODS: Between Oct 7, 2005, and April 16, 2008, 361 participants were enrolled in the QoL substudy at 19 centres across Australia, New Zealand, and Hong Kong; 332 completed the QoL analysis. Randomisation was done centrally and independently from other study procedures via a computer-generated, web-based system (providing concealment of the next assigned treatment), using stratified permuted blocks of three and six patients. Patients with histologically confirmed stage I endometrioid adenocarcinoma and Eastern Cooperative Oncology Group performance status less than 2 were randomly assigned to TLH (n=190) or TAH (n=142), stratified by histological grade and study centre. Patients and study personnel were not masked to treatment assignment. QoL was measured at baseline, 1 and 4 weeks (early), and 3 and 6 months (late) after surgery, using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire. The primary endpoint was the difference between groups in QoL change from baseline at early and late timepoints (a 5% difference was considered clinically significant). Analysis was done according to the intention-to-treat principle. Patients for both stages of the trial have now been recruited and are being followed up for disease-specific outcomes. The LACE trial is registered with ClinicalTrials.gov, number NCT00096408. FINDINGS: Eight of 332 patients (2.4%) had treatment conversion-seven from TLH to TAH and one from TAH to TLH (patient preference). In the early phase of recovery, patients who had TLH reported significantly greater improvement in QoL from baseline compared with those who had TAH, in all subscales apart from emotional and social wellbeing. Improvements in QoL up to 6 months after surgery continued to favour TLH, except in the emotional and social wellbeing measures of FACT and the visual analogue scale of the EuroQoL five dimensions (EuroQoL-VAS). Operating time was significantly longer in the TLH group (138 min [SD 43]) than in the TAH group (109 min [34]; p=0.001). Although the proportion of intraoperative adverse events was similar between groups (TAH eight of 142 [5.6%] vs TLH 14 of 190 [7.4%]; p=0.53); postoperatively, twice as many patients in the TAH group experienced adverse events of grade 3 or higher (33 of 142 [23.2%] vs 22 of 190 [11.6%] in the TLH group; p=0.004). Postoperative serious adverse events occurred more in the TAH group (27 of 142 [19.0%]) than in the TLH group (16 of 190 [7.9%]; p=0.002). INTERPRETATION: QoL improvements from baseline during early and later phases of recovery, and the adverse event profile, favour TLH compared with TAH for treatment of stage I endometrial cancer. FUNDING: Cancer Council Queensland, Cancer Council New South Wales, Cancer Council Victoria, Cancer Council Western Australia; NHMRC project grant 456110; Cancer Australia project grant 631523; The Women and Infants Research Foundation, Western Australia; Royal Brisbane and Women's Hospital Foundation; Wesley Research Institute; Gallipoli Research Foundation; Gynetech; TYCO Healthcare, Australia; Johnson and Johnson Medical, Australia; Hunter New England Centre for Gynaecological Cancer; Genesis Oncology Trust; and Smart Health Research Grant QLD Health.

Nephrogenic systemic fibrosis: is gadolinium the missing piece to the puzzle?

New medical disorders arise infrequently, but nephrogenic systemic fibrosis (NSF) is one such entity. It exclusively affects patients with renal failure, resulting in debilitating progressive fibrosis of the skin and systemic organs. Although much work has been done elucidating the histopathologic changes, a trigger has not been detected. Recently, case reports have implicated gadolinium (Gd) contrast agents as a potential etiology, prompting a health advisory from the US Food and Drug Administration (FDA) in June 2006. We discuss the literature regarding the effects of Gd on tissue and its potential relationship to the known histopathologic characteristics of NSF.

Hormonal therapies and gynaecological cancers.

Hormonal therapy has an established place in the management of women with gynaecological malignancies, including first-line therapy for recurrent receptor-positive endometrial cancer and low-grade stromal sarcoma. There is no place for adjuvant hormonal treatment of these cancers after primary surgery. Primary treatment with either oral or intra-uterine progestagens to preserve fertility in younger women with endometrial carcinoma is effective in about 70% of cases. Response rates to tamoxifen in advanced/recurrent ovarian cancers approximates 10%. To the authors' knowledge, no studies that reasonably compare different progestagens, different routes of therapy, different doses and different hormonal preparations have been published.

Nephrogenic systemic fibrosis: risk factors and incidence estimation.

PURPOSE: To retrospectively review data in 13 patients with biopsy-confirmed nephrogenic systemic fibrosis (NSF), assess the associated risk factors, and report the incidence of NSF at the authors' institution. MATERIALS AND METHODS: This HIPAA-compliant study had institutional review board approval; informed consent was waived. Statistical analysis was performed for all available clinical and laboratory data in patients with biopsy-confirmed NSF. The data from the patients with NSF were compared with data from a control population of patients with renal insufficiency but who did not develop NSF. RESULTS: There were eight male and five female patients, aged 17-69 years, with a diagnosis of NSF. Within 6 months of diagnosis, all 13 patients had been exposed to gadodiamide and one had been exposed to gadobenate dimeglumine in addition to gadodiamide. At the time of contrast material-enhanced magnetic resonance (MR) imaging, all 13 patients had renal insufficiency (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m(2)) and were hospitalized for a proinflammatory event (major surgery, infection, or vascular event). The group with NSF had significantly decreased eGFR (P = .01), more proinflammatory events (P < .001), and more contrast-enhanced MR examinations per patient (P = .002) than did the control group. CONCLUSION: A combination of factors, including altered kidney function, inflammatory burden, and exposure to gadolinium-based contrast agents may all play a role in development of NSF. Alternative imaging should be considered in patients with these factors. If use of a gadolinium-based agent is clinically indicated, the referring physician and patient should be informed of the potential risk of developing NSF.

Total laparoscopic hysterectomy: the Brisbane learning curve.

BACKGROUND: Total laparoscopic hysterectomy (TLH) is becoming more commonly used for gynaecological malignancies. AIMS: To describe our experience with TLH since its introduction to our tertiary referral centre for gynaecological cancer in 2003. METHODS: Retrospective analysis of the first 120 consecutive cases of TLH performed at our gynaecological cancer centre. Patients were divided into the first, second and third group of 40 patients. Operating time, estimated blood loss, hospital stay, conversion to laparotomy and intra- and postoperative morbidity were evaluated. RESULTS: The three groups were similar with regard to baseline characteristics. For the entire group the mean hospital stay was 2.4 +/- 1.4 days and eight of 120 patients (6.6%) required conversion to laparotomy. Operating time, estimated blood loss and intraoperative morbidity were similar among the three groups. Postoperative morbidity was highest (25%) in the middle one-third of the patients (P = 0.022). The percentage of pelvic lymph node dissections increased from 2.5% in the first one-third of patients to 27.5% in the final one-third of patients (P = 0.003). CONCLUSIONS: TLH can be established safely in a tertiary gynaecological cancer referral centre.