First in-human trial and prospective case series of an articulated laparoscopic camera system in minimally invasive surgery in gynecology: an IDEAL stage 1 and 2a study.

Objectives: Precision Robotics' Sirius Robotic Flexible Endoscopic System is a new, fully integrated, compact three-dimensional laparoscopic camera system with a disposable single-use flexible tip that can change its viewing direction. This IDEAL Stage 1 and 2a study assessed its safety, reliability and potential efficacy particularly for single incision laparoscopic surgery and vaginal natural orifice transluminal endoscopic surgery. Design: Prospective single-institution, single-surgeon study. Setting: The study was conducted in a multispecialty hospital. Participants: Women aged 18-70 years scheduled for gynecological laparoscopic surgery were invited to participate. An information sheet and consent was available for the women and an informed consent was obtained. Thirteen participants completed this study. Interventions: The laparoscopic procedures were done in the usual manner. The only difference was the Sirius System was used in place of the conventional laparoscope. All other procedures and instruments remained the same. Main outcome measures: Primary outcome was the proportion of women who successfully completed the intended procedure using the Sirius System without conversion to another camera system, camera users and surgeon's view and experience, and iterations and modifications to the system. Secondary outcomes were the incidence of intraoperative and postoperative complications during the first 6 weeks following surgery, and duration of surgery. Results: 85% (11/13) of women had their procedure completed successfully using the Sirius System. Two women required immediate conversion to the conventional laparoscope due to technical issues. There were no intraoperative complications. Users agreed that the improved field of view was beneficial for laparoscopic surgery. Iterative improvements were made in the imaging quality, user interface and manufacturing quality. Conclusions: Sirius System has early indications for safety and efficacy for intermediate and major minimally invasive laparoscopic procedures in gynecology. Further studies are needed to confirm it can replace a conventional laparoscope in the surgical workflow. Trial registration number: NCT05048407.

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.

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.

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.

Potential use of the adenosine triphosphate cell viability assay in endometrial cancer.

OBJECTIVE: Adenosine triphosphate cell viability assay (ATP-CVA) was used previously to evaluate chemotherapy in uterine cancer cell lines. In this study, we have performed the ATP-CVA on endometrial cancer patients to study the feasibility of using ATP-CVA in endometrial cancer to determine the intrinsic chemosensitivity of the cytotoxic drugs. METHODS: Thirty-three patients with endometrial adenocarcinoma who presented for a staging operation were recruited. Endometrial cancer samples were obtained at the time of operation. In vitro ATP-CVA and chemosensitivity testing was performed using cisplatin, carboplatin, paclitaxel, etoposide, doxorubicin, 4-epidoxorubicin, and topotecan. RESULTS: Thirty-two of the 33 endometrial cancer samples were evaluable for SF50 (survival fraction at 50% of the peak plasma concentration [PPC]) using ATP-CVA. The median SF50 of carboplatin (0.33) was significantly less than the median SF50 of cisplatin (0.71), topotecan (0.93), paclitaxel (0.68), doxorubicin (1.0), etoposide (0.70), or 4-epidoxorubicin (0.88) (Wilcoxon signed rank test, P <.001). CONCLUSION: This study showed the feasibility of using the ATP-CVA in endometrial cancer to determine the intrinsic chemosensitivity of cytotoxic drugs.

Semi-quantitative fluorescent PCR analysis identifies PRKAA1 on chromosome 5 as a potential candidate cancer gene of cervical cancer.

OBJECTIVE: Comparative genomic hybridization has frequently detected amplification of chromosome 5p in cervical cancer, but candidate cancer genes within the region are rarely known. Therefore, we pursued to identify potential candidate gene related to cervical cancer development. METHODS: A series of 128 cervical tumor samples were examined by semi-quantitative fluorescent differential PCR for copy number changes on three candidate genes (PRKAA1, CTNND2 and POLS) mapped to chromosome 5p and one gene (ERBIN) mapped to chromosome 5q12.3. The impact of gene copy number was later analyzed in relation to HPV infection, tumor stage or tumor radiosensitivity. RESULTS: DNA copy numbers of PRKAA1, CTNND2 and ERBIN were significantly different from normal controls (P < 0.05). DNA copy number changes did not correlate with HPV infection, tumor stages or tumor radiosensitivity. Using RT-PCR, PRKAA1 mRNA expression in seven tumor samples with known 5p amplification was amplified from 3- to 15-fold. Over-expression of PRKAA1 was further confirmed by immunohistochemical staining on 125 paraffin-embedded cervical cancer tissues. The expression level in cervical tumor was significantly higher than that in normal epithelium (P < 0.001). CONCLUSIONS: PRKAA1 gene codes for the catalytic alpha 1 subunit of the AMP-activated protein kinase which is an important cellular metabolic stress regulator. It might assist tumor cells growth under stress. Thus, PRKAA1 may be one of the potential candidate genes for cervical carcinogenesis.

Hepatic arteriogram for gestational trophoblastic tumor: is it useful?

The presence of liver metastasis will be staged as IV in the FIGO 1992 Gestational Trophoblastic Tumor (GTT) staging. This study was to determine the role of hepatic arteriogram (HAG) in the management of GTT. It is a retrospective analysis of 309 patients treated from 1981 to 2001. Patients were restaged according to the FIGO 1992 classification with or without taking into account the HAG result. Outcome measures including mortality, drug resistance and recurrence of disease, as well as treatment with and without the HAG result were compared. Eighty-one (26.2 percent) patients had HAG and 11 (3.6 percent) also had ultrasound (USG) features of liver metastasis. Interval between diagnosis and treatment were significantly different between USG and HAG positive groups (Mann-Whitney U test, P < 0.05). Seventeen (5.5 percent) of the 309 patients died of the disease and 7 (41.2 percent) of them had liver metastasis. Three (27.3 percent) of the 11 patients who had USG features of liver metastasis died of the disease; mortality is significantly higher than those without USG features of metastasis (Chi-square test, P < 0.05). Patients classified as medium to high risk with or without taking HAG as a feature of liver metastasis were associated with higher mortality and recurrent rate (Chi-square test, P < 0.05). On the other hand, the chance of drug resistance was higher in the medium to high risk group after reclassifying all HAG positive patients as negative for liver metastasis (Chi-square test, P < 0.05). HAG evidence of liver metastasis did not correlate with patient mortality. HAG was not an appropriate investigation in the management of GTT.

Genetic abnormalities and HPV status in cervical and vulvar squamous cell carcinomas.

Cervical and vulvar cancers are diseases of the female lower genital tract, and high-risk human papillomavirus (HPV) infection is the most important risk factor for the development of both cancers. However, it is clear that additional genetic events are necessary for tumor progression, particularly in HPV-negative cases. We detected the presence of high-risk HPV16 and HPV18 genomes by gene-specific polymerase chain reaction and searched for common genetic imbalances by comparative genomic hybridization (CGH) in 28 cervical and 8 vulvar tumor samples and 7 cancer cell lines. The presence of the HPV genome was detected in 25/28 (89%) cervical tumors and 6/8 (75%) vulvar tumors. CGH of cervical and vulvar tumor samples revealed a consistent pattern of genetic changes in both cancers. Frequent gains were found in 1q, 3q, 5p, and 8q, and less consistent losses were detected in 2q, 3p, 4p, and 11p. Notably, a high-level amplification of 3q was found in 9/28 (32%) cervical tumors and 1/8 (12.5%) vulvar tumors, indicating a pivotal role of gain of 3q in cervical and vulvar carcinogenesis. Furthermore, gains of 5p identified in 9/28 (32%) cervical tumors and 3/8 (37.5%) vulvar tumors were seldom described, particularly in vulvar tumors. Our findings suggest that cervical and vulvar carcinomas bear similar chromosomal alteration hot spots that largely coincide with common genomic lesions during tumor progression, besides the initiation by infection and integration of oncogenic HPV.

p73 expression is associated with the cellular radiosensitivity in cervical cancer after radiotherapy.

Apoptosis is one of the causes of cell death in cervical cancer following radiotherapy. By studying the gene expression profile with cDNA apoptotic array, the p73 gene was found overexpressed in radiosensitive cervical cancers when compared with radioresistant ones. To investigate the role of the p73 gene in relation to clinical assessment of radiosensitivity in cervical cancer based on the findings of residual tumor cells in cervical biopsies after completion of radiotherapy, we studied the protein expression of p73 in 59 cervical cancers after radiotherapy and 68 normal cervices using immunohistochemistry. The expression of p73 was found to be significantly increased in cancer samples and, more importantly, in those samples sensitive to radiotherapy (P < 0.001). The overexpression of p73 actually predicted a better prognosis in cervical cancer patients (P < 0.001). To investigate the possible involvement of p73 downstream genes, the protein expressions of p21 and Bax were studied. The expression of p21, but not Bax, was found to be positively correlated with the expression of p73 (P = 0.001). Furthermore, the epigenetic regulation of p73 expression via DNA methylation was also investigated in 103 cervical cancers and 124 normals. Hypermethylation of p73 gene was observed in 38.8% of cervical cancers, and it was significantly associated with reduced or absent p73 expression (P < 0.001). Reactivation of p73 expression in two cervical cancer cell lines by demethylation treatment supported the role of methylation in the regulation of p73 expression. Our findings suggested that p73 expression was related to the radiosensitivity of cervical cancer cells and may play an important role in the regulation of cellular radiosensitivity.

Comparison of human papillomavirus DNA levels in gynecological cancers: implication for cancer development.

We have previously demonstrated the presence of human papillomavirus (HPV) DNA in several gynecological cancers using conventional PCR. In the present study, to further understand the role of HPV in malignant transformation of these cancers, the infection rates and viral loads of HPV 16 and 18 in gynecological cancers were analyzed using real-time quantitative PCR (qPCR). HPV 16 DNA was detected in 61.0% (58/95), 15.2% (7/46) and 32.1% (18/56) of cases of cervical, endometrial and ovarian cancers, respectively. On the other hand, HPV 18 DNA was detected in 23.2% (22/95) of cervical cancers, 1.8% (1/56) of ovarian cancers, and in no cases of endometrial cancer. Thus, HPV 16 is much more prevalent than HPV 18 in malignancies of the female genital tract. We also found that both HPV 16 and 18 were significantly (p < 0.05) less frequently present in endometrial and ovarian cancers than in cervical cancer. The median copy numbers of HPV 16 DNA in endometrial and ovarian cancers were 3,500 and 7,590 copies/microg DNA, respectively. These amounts were also significantly (p < 0.05) lower than HPV 16 DNA in cervical cancer (492,800 copies/microg DNA). Thus, HPV 16 could be detected in all three types of gynecological cancer, whilst HPV 18 is extremely rare in endometrial and ovarian cancers. The lower HPV 16 infection rates and lower copy numbers when compared with cervical cancer tend to suggest that HPV plays a less essential role in the development of endometrial cancer and ovarian cancer.