A phase I study of an adenoviral vector delivering a MUC1/CD40-ligand fusion protein in patients with advanced adenocarcinoma.

Cancer vaccines as immunotherapy for solid tumours are currently in development with promising results. We report a phase 1 study of Ad-sig-hMUC1/ecdCD40L (NCT02140996), an adenoviral-vector vaccine encoding the tumour-associated antigen MUC1 linked to CD40 ligand, in patients with advanced adenocarcinoma. The primary objective of this study is safety and tolerability. We also study the immunome in vaccinated patients as a secondary outcome. This trial, while not designed to determine clinical efficacy, reports an exploratory endpoint of overall response rate. The study meets its pre-specified primary endpoint demonstrating safety and tolerability in a cohort of 21 patients with advanced adenocarcinomas (breast, lung and ovary). The maximal dose of the vaccine is 1 ×1011 viral particles, with no dose limiting toxicities. All drug related adverse events are of low grades, most commonly injection site reactions in 15 (71%) patients. Using exploratory high-dimensional analyses, we find both quantitative and relational changes in the cancer immunome after vaccination. Our data highlights the utility of high-dimensional analyses in understanding and predicting effective immunotherapy, underscoring the importance of immune competency in cancer prognosis.

POMMS: Pre-operative misoprostol in myomectomy surgery: A randomised controlled pilot study.

OBJECTIVE: To assess the effect of pre-operative sublingual misoprostol on intra-operative blood loss in abdominal myomectomy as compared to placebo. STUDY DESIGN: Double-blind randomised controlled pilot study. A single tertiary Gynaecology Unit in Melbourne, Australia. Women ≥ 18 years old undergoing laparoscopic or open myomectomy. Women undergoing laparoscopic or open myomectomy for symptomatic uterine leiomyomas were randomised to pre-operative sublingual 400mcg misoprostol or placebo. Intra-operative blood loss was measured via accurate record keeping of the post-operative volume in the suction canister and weighed packs, minus any irrigation fluid used. RESULTS: Intraoperative blood loss in the misoprostol treatment group was 306 ml ± 281 ml, compared to 325 ± 352 ml in the placebo group; P = 0.83. Fibroid volume was a consistent predictor of intra-operative blood loss. For each 1 ml increase in fibroid volume there is an increase in blood loss by 0.26 ml (95 % CI: 0.07 - 0.46). CONCLUSIONS: In this study, we found that there was no significant difference in blood loss between women who received and did not receive sublingual misoprostol before abdominal myomectomy. This is an exploratory study laying the foundation for further randomised clinical trials.

Treatment of symptomatic fibroid disease using uterine fibroid embolisation: An Australian perspective.

Uterine leiomyomata (fibroids) are symptomatic in up to 35% of women and treatment can be a costly burden to the individual and society. Options for treatment range from non-hormonal, hormonal, minimally invasive, to surgery. While symptoms from smaller fibroids may respond to simple treatment, those with larger fibroids or with a large volume of disease require a more definitive option. Surgery (hysterectomy or myomectomy) are both well-established treatment modalities with good clinical outcomes. Since the 1990s, uterine fibroid embolisation has emerged as a less invasive option for women than for surgical techniques, while level 1 evidence shows that in the short to mid-term, there is a similar improvement in symptom-related quality of life outcomes to surgery, but with reduced hospital stay and reduced cost. However, in the longer term there may be a need for further treatment or retreatment in some patients compared with surgery. Since its introduction, uptake of this procedure in Australia has been low relative to surgical options. This manuscript reviews the current literature surrounding treatment, along with the trends in uptake of embolisation by Australian women, places this in context of current guidelines from major societies, and encourages gynaecologists and interventional radiologists to be aware of the advantages and limitations of embolisation.

Borrelia miyamotoi infection leads to cross-reactive antibodies to the C6 peptide in mice and men.

OBJECTIVES: Borrelia miyamotoi is a relapsing fever Borrelia, transmitted by hard (Ixodes) ticks, which are also the main vector for Borrelia burgdorferi. A widely used test for serodiagnosis of Lyme borreliosis is an enzyme immunoassay (EIA) based on the C6 peptide of the B. burgdorferi sl VlsE protein. We set out to study C6 reactivity upon infection with B. miyamotoi in a large well-characterized set of B. miyamotoi disease (BMD) patient sera and in experimental murine infection. METHODS: We performed in silico analyses, comparing the C6-peptide to immunodominant B. miyamotoi variable large proteins (Vlps). Next, we determined C6 reactivity in sera from mice infected with B. miyamotoi and in a unique longitudinal set of 191 sera from 46 BMD patients. RESULTS: In silico analyses revealed similarity of the C6 peptide to domains within B. miyamotoi Vlps. Cross-reactivity against the C6 peptide was confirmed in 21 out of 24 mice experimentally infected with B. miyamotoi. Moreover, 35 out of 46 BMD patients had a C6 EIA Lyme index higher than 1.1 (positive). Interestingly, 27 out of 37 patients with a C6 EIA Lyme index higher than 0.9 (equivocal) were negative when tested for specific B. burgdorferi sl antibodies using a commercially available immunoblot. CONCLUSIONS: We show that infection with B. miyamotoi leads to cross-reactive antibodies to the C6 peptide. Since BMD and Lyme borreliosis are found in the same geographical locations, caution should be used when relying solely on C6 reactivity testing. We propose that a positive C6 EIA with negative immunoblot, especially in patients with fever several weeks after a tick bite, warrants further testing for B. miyamotoi.

Necroptosis of infiltrated macrophages drives Yersinia pestis dispersal within buboes.

When draining lymph nodes become infected by Yersinia pestis (Y. pestis), a massive influx of phagocytic cells occurs, resulting in distended and necrotic structures known as buboes. The bubonic stage of the Y. pestis life cycle precedes septicemia, which is facilitated by trafficking of infected mononuclear phagocytes through these buboes. However, how Y. pestis convert these immunocytes recruited by host to contain the pathogen into vehicles for bacterial dispersal and the role of immune cell death in this context are unknown. We show that the lymphatic spread requires Yersinia outer protein J (YopJ), which triggers death of infected macrophages by downregulating a suppressor of receptor-interacting protein kinase 1-mediated (RIPK1-mediated) cell death programs. The YopJ-triggered cell death was identified as necroptotic, which released intracellular bacteria, allowing them to infect new neighboring cell targets. Dying macrophages also produced chemotactic sphingosine 1-phosphate, enhancing cell-to-cell contact, further promoting infection. This necroptosis-driven expansion of infected macrophages in buboes maximized the number of bacteria-bearing macrophages reaching secondary lymph nodes, leading to sepsis. In support, necrostatins confined bacteria within macrophages and protected mice from lethal infection. These findings define necrotization of buboes as a mechanism for bacterial spread and a potential target for therapeutic intervention.

Comparison of management regimens following ultrasound diagnosis of nontubal ectopic pregnancies: a retrospective cohort study.

OBJECTIVE: To review management options for nontubal ectopic pregnancies. DESIGN: Retrospective cohort study. SETTING: Tertiary hospital in Melbourne, Australia. POPULATION: A total of 100 nontubal pregnancies: 1 abdominal, 32 caesarean scar, 14 cervical, 41 cornual-interstitial, 12 ovarian. METHODS: Cases were classified according to ectopic site. Management categories were medical, surgical, combination or expectant. Use of minimally invasive approaches (ultrasound-guided intra-sac injections or selective surgical techniques) was identified. Primary management was considered to be successful if no further unplanned interventions were required. MAIN OUTCOME MEASURES: Success of primary management and frequency of unplanned interventions. RESULTS: A high rate of success (82%) was demonstrated for all management regimens, with minimal morbidity and no deaths occurring. A high success rate was shown when the primary management regimen was systemic methotrexate or ultrasound-guided intra-sac injection (88%). The success rate for primary surgical management was 57%. High success rates were reported for both primary management with ultrasound-guided injections or in combination with systemic methotrexate (94%) and for primary management with systemic methotrexate alone (81%). Seventy-five per cent of women managed with minimally invasive surgical approaches avoided the need for more extensive surgery, but required longer follow up and additional interventions. CONCLUSION: Minimally invasive approaches were found to be safe and effective treatment for women desiring to conserve fertility. Ultrasound-guided intra-sac injection and laparoscopic ectopic removal procedures aimed at preserving reproductive organs should be included as minimally invasive primary management tools in addition to the well-recognised option of systemic methotrexate. TWEETABLE ABSTRACT: Nontubal ectopics: minimally invasive procedures a safe alternative to surgery in selected cases.

The cost of trauma operating theatre inefficiency.

The National Health Service (NHS) is currently facing a financial crisis with a projected deficit of £2billion by the end of financial year 2015/16. As operating rooms (OR) are one of the costliest components in secondary care, improving theatre efficiency should be at the forefront of efforts to improve health service efficiency. The objectives of this study were to characterize the causes of trauma OR delays and to estimate the cost of this inefficiency. A 1-month prospective single-centre study in St. Mary's Hospital. Turnaround time (TT) was used as the surrogate parameter to measure theatre efficiency. Factors including patient age, ASA score and presence of surgical and anaesthetic consultant were evaluated to identify positive or negative associations with theatre delays. Inefficiency cost was calculated by multiplying the time wasted with staff capacity costs and opportunity costs, found to be £24.77/minute. The commonest causes for increased TT were delays in sending for patients (50%) and problems with patient transport to the OR (31%). 461 min of delay was observed in 12 days, equivalent to loss of £951.58/theatre/day. Non-statistically significant trends were seen between length of delays and advancing patient age, ASA score and absence of either a senior clinician or an anaesthetic consultant. Interestingly, the trend was not as strong for absence of an anaesthetic consultant. This study found delays in operating TT to represent a sizable cost, with potential efficiency savings based on TT of £347,327/theatre/year. Further study of a larger sample is warranted to better evaluate the identified trends.

Complex atypical hyperplasia of the endometrium: differences in outcome following conservative management of pre- and postmenopausal women.

OBJECTIVE: To compare the safety and regression rates of conservative treatments for complex atypical hyperplasia (CAH) between pre- and postmenopausal women. METHODS: Historical cohort study of pre- and postmenopausal women with CAH managed conservatively at one center (Royal Women's Hospital, Melbourne, Australia) between September 1999 to June 2012. RESULTS: Of the 153 women with CAH, 92 (60%) underwent hysterectomy and the remaining 61 were managed conservatively with oral or intrauterine progestogen: 42 were premenopausal and 19 were postmenopausal. Within 12 months, 32 (76%) premenopausal women demonstrated regression of CAH and none developed endometrial cancer. In contrast, only 4 (21%) postmenopausal women showed disease regression and 4 (21%) progressed to endometrial cancer. Over a median of 24 months, 3 premenopausal women relapsed with CAH and 2 developed endometrial cancer. Four premenopausal women had successful pregnancies. CONCLUSION: Conservative treatment with progestogen in premenopausal women with CAH leads to high regression rates within the first 12 months. In contrast, postmenopausal women have high rates of ongoing disease and cancer progression and conservative therapy should be avoided.

A generation of laparoscopic nephrectomy: stage-specific surgical and oncologic outcomes for laparoscopic nephrectomy in a single center.

PURPOSE: To determine the stage-specific operative, postoperative and oncologic outcomes, for patients undergoing a laparoscopic radical nephrectomy (LRN) for renal cell carcinoma (RCC) in a single center and assess changes over a generation of practice. PATIENTS AND METHODS: From December 1992 to July 2011, data were collected prospectively for 854 consecutive simple laparoscopic necphrectomies (LNs) and LRNs, 397 of which were LRNs for RCC. The first LRN was performed in December 1997. Stage-specific surgical and oncologic outcomes were assessed across the study period. Patients were then grouped into three equal consecutive cohorts. Case mix and surgical outcomes were compared to assess changes with departmental experience. RESULTS: There were 206, 71, 118, and 2 patients across stages pT1, pT2, pT3, and pT4, respectively. Median operative time was significantly shorter for pT1 tumors (125, 150 and 150 min for pT1-3, P<0.021), while median estimated blood loss (EBL) was greater for pT3 tumors (50, 50, 100 mL, for pT1-3, P<0.001). Median follow-up time was 31, 30, and 18 months, respectively, across pT1-pT3. There was a significant difference in 5-year overall survival (82.4%, 68.4%, 58.9%), cancer-specific survival (99.5%, 83.6%, 66.5%) and progression free survival (86.5%, 66.3%, 47.5%) across these stage-specific subgroups. Over the three cohorts, there was an increase in LRN performed for locally advanced disease and cytoreduction. With greater surgical experience, there was improvement in median operative time and median EBL in localized disease over the three periods, but no significant changes for locally advanced disease. CONCLUSION: This is the largest reported series of LRN in the United Kingdom. Departmental experience has resulted in improved surgical outcomes for localized RCC, with expansion of practice in more complex advanced disease. Laparoscopic nephrectomy is both operatively and oncologically safe in T1 and T2 disease, and although technically more demanding, it is also safe in selected T3 disease.

The operative safety and oncological outcomes of laparoscopic nephrectomy for T3 renal cell cancer.

UNLABELLED: What's known on the subject? and What does the study add? Laparoscopic radical nephrectomy is a well established treatment for localized RCC, where nephron-sparing approaches are not appropriate. As surgeon and departmental experience grow more extensive tumours will be tackled laparoscopically. However, little is known about the operative safety and oncological outcomes of the laparoscopic approach for locally advanced RCC. The present study describes the largest reported cohort of patients receiving laparoscopic radical nephrectomy for locally advanced RCC. In the context of suitably experienced personnel in an established centre, we have established that this approach is safe from operative, postoperative and oncological standpoints, with comparable data to existing open series. OBJECTIVE: To determine the operative, postoperative and oncological outcomes of laparoscopic radical nephrectomy (LRN) for locally advanced renal cell cancer (RCC), which, as surgeon and departmental experience increases, is being performed more often. PATIENTS AND METHODS: In total, 94 consecutive patients receiving LRN for pathologically confirmed T3 or T4 RCC at a tertiary referral centre between March 2002 and May 2010 were analyzed. Preoperative, operative, tumour and postoperative characteristics were evaluated together with recurrence and outcome data. Survival was estimated using the Kaplan-Meier method. Cox's proportional hazards model was used for multivariate analysis. RESULTS: In total, 77 patients had LRN with curative intent and 17 patients had LRN with cytoreductive intent. There were six LRNs (6.4%) that were converted to open procedures. Overall, there were two (2.1%) Clavien grade IIIa complications, one (1.1%) grade IVa complication and one (1.1%) postoperative death. Overall median follow-up was 17.4 months. In total, 22 (28.6%) patients receiving curative LRN developed a recurrence after a median of 13.9 months; 12 (54.5%) patients developed distant metastases, five (22.7%) patients had local recurrences and three (13.6%) patients had transcoelomic spread. Median predicted progression free survival was 48.4 months in patients undergoing LRN with curative intent. Median predicted overall survival was 65.6 months after curative LRN and 15.7 months after cytoreductive LRN. Multivariate analysis did not reveal any variables influencing recurrence or survival. CONCLUSIONS: In the context of suitably experienced personnel in an established centre, LRN for locally advanced RCC is safe from an operative and oncological standpoint. Patients clinically staged as T3 RCC must still be selected carefully for LRN in a multidisciplinary setting.

FBXO11, a regulator of the TGFß pathway, is associated with severe otitis media in Western Australian children.

Otitis media (OM) is a common childhood disease characterised by middle ear inflammation following infection. Susceptibility to recurrent acute OM (rAOM) and chronic OM with effusion (COME) is highly heritable. Two murine mutants, Junbo and Jeff, spontaneously develop severe OM with similar phenotypes to human disease. Fine-mapping of these mutants identified two genes (Evi1 and Fbxo11) that interact with the transforming growth factor ß (TGFß) signalling pathway. We investigated these genes, as well as four Sma- and Mad-related (SMAD) genes of the TGFß pathway, as candidate rAOM/COME susceptibility genes in two predominantly Caucasian populations. Single-nucleotide polymorphisms (SNPs) within FBXO11 (family-based association testing Z-Score=2.61; P(best)=0.009) were associated with severe OM in family-based analysis of 434 families (561 affected individuals) from the Western Australian Family Study of OM. The FBXO11 association was replicated by directed analysis of Illumina 660W-Quad Beadchip data available for 253 cases and 866 controls (OR=1.55 (95% CI 1.28-1.89); P(best)=6.9 × 10(-6)) available within the Western Australian Pregnancy Cohort (Raine) Study. Combined primary and replication results show P(combined)=2.98 × 10(-6). Neither cohort showed an association with EVI1 variants. Family-based associations at SMAD2 (P=0.038) and SMAD4 (P=0.048) were not replicated. Together, these data provide strong evidence for FBXO11 as a susceptibility gene for severe OM.

Estimation and filtering of physiological tremor for real-time compensation in surgical robotics applications.

BACKGROUND: Physiological tremor is the main cause of imprecision in microsurgical procedures/robotics applications. Existing methods, such as weighted-frequency Fourier linear combiner (WFLC), rely on estimating the tremor under the assumption that it has a single dominant frequency. This paper focuses on developing a new algorithm for accurate tremor filtering in real time. METHODS: A study conducted on several novice subjects and microsurgeons showed the tremor to contain several dominant frequencies in a band, rather than a single dominant frequency. Based on the tremor characteristics, a new algorithm band-limited multiple Fourier linear combiner (BMFLC) has been developed to estimate a band of signals with multiple dominant frequencies. A separation procedure to separate the intended motion/drift from the tremor portion is also discussed. RESULTS: A simulation study was first conducted to validate the theoretical development on recorded tremor data. The experimental set-up was designed to study the real-time performance of the proposed algorithm. Tremor sensing using accelerometers is also discussed, with the proposed algorithm. Our experiments showed that the developed BMFLC algorithm had an average tremor compensation of 64% compared to 43% for the WFLC algorithm in real-time for one degree of freedom (1-DOF) cancellation of tremor. CONCLUSIONS: The BMFLC algorithm can be applied for the three axes separately and 3-DOF cancellation of tremor can be achieved. Further research is required to deal with complex gestures involved during microsurgery.

Surgical treatment of endometriosis: a prospective randomized double-blinded trial comparing excision and ablation.

OBJECTIVE: To compare reduction of pain following laparoscopy after ablation or excision of endometriosis. DESIGN: A prospective, randomized, double-blind study. SETTING: Endometriosis and pelvic pain clinic at a university teaching hospital. PATIENT(S): Women of reproductive age presenting with pelvic pain and visually proved endometriosis. INTERVENTION(S): Subjects completed a questionnaire rating their various pains using visual analogue scales (VASs). After visual identification subjects were assigned randomly to treatment with ablation or excision by supervised training gynecologists as primary surgeon. Follow-up questionnaires at 3, 6, 9, and 12 months documented pain levels. MAIN OUTCOME MEASURE(S): Change in overall pain VAS score at 12 months after operation. RESULT(S): There was no significant difference in reduction in overall pain VAS scores at 12 months when comparing ablation and excision. CONCLUSION(S): This study has not been able to demonstrate a significant difference in pain reduction between ablation and excisional treatments. Nonsignificant trends suggest that a larger study may find a difference in outcomes looking at dyspareunia or dyschezia.

A boundary element model for investigating the effects of eye tumor on the temperature distribution inside the human eye.

A three-dimensional boundary element model of the human eye is developed to investigate the thermal effects of eye tumor on the ocular temperature distribution. The human eye is modeled as comprising several regions which have different thermal properties. The tumor is one of these regions. The thermal effects of the tumor are simulated by taking it to have a very high metabolic heat generation and blood perfusion rate. Inside the tumor, the steady state temperature is governed by the Pennes bioheat equation. Elsewhere, in normal tissues of the eye, the temperature satisfies the Laplace's equation. To compute the temperature on the corneal surface, the surface boundary of each region is divided into triangular elements.

Bandlimited multiple Fourier linear combiner for real-time tremor compensation.

Surgical accuracy of the hand-held instruments depends on the active compensation of disturbance and tremor. Physiological tremor is one of the main causes for imprecision in micro-surgery procedures. One of the popular tremor compensation methods is based on weighted-frequency Fourier linear combiner (WFLC) algorithm, that can adapt to the changes in frequency as well as amplitude of the tremor signal. WLFC estimates the dominant frequency and the amplitude. For the case of tremor with frequency variation or comprising of two or three frequencies close in spectral domain, the WFLC performance is degraded. In this paper, we present a bandlimited multiple Fourier linear combiner that can track the modulated signals with multiple frequency components. We also discuss the tremor sensing with accelerometers. Using the proposed algorithm the drift caused by the accelerometers is also eliminated. The proposed filter is tested in real-time for 1-DOF cancellation of tremor.