Studies using the anti-idiotypic monoclonal antibody 105AD7 in patients with advanced and primary colorectal cancer

Introduction. The anti-idiotypic monoclonal antibody 10SAD7 mimics the tumour associated antigen 791T/ gp72, present on approximately 80% of colorectal cancer cells. A Phase I study using 10SAD7 in 13 patients with advanced colorectal cancer has shown that it is nontoxic, and conferred a survival advantage on patients who received it [Denton GWL 1994]. Aim. There were two aims of this work. The first was to assess whether. the survival advantage seen in the Phase I study was reproducible in a Phase II study. The second was to immunise patients with primary colorectal cancer, in a non-randomised adjuvant study, and explore further the immune responses generated. Materials and Methods. Patients with advanced colorectal cancer were recruited to a randomised, double-blind, placebo controlled survival study. The first patient was recruited to this Phase II study in April 1994, and the last in October 1996. Four trial centres were used- Nottingham, Hull, Leeds, and Newcastle. Eligible patients had a life expectancy of 3 months, and none had received radiotherapy or chemotherapy in the preceding 1 and 3 months, respectively. Patients attended on 3 occasions, 6 weeks apart, receiving 10µg of 10SAD7/alum i.d. followed by 100µg i.m. Venous blood was assayed for blood count and differential, liver function, urea and electrolytes, and CEA. Chest X-rays and CT scans were performed at trial entry and week 12 where possible. Dates of death were recorded following consultation with General Practitioner or referring clinician. In addition, patients with primary colorectal cancer were recruited to a non-randomised adjuvant study, whereby they received 10SAD7 before surgery. Venous blood samples were taken between immunisation and operation, and assayed for lymphocyte subsets. Samples taken from resection specimens were analysed immunohistochemically. Fresh tumours were in addition disaggregated, and separated TIL labelled with a panel of monoclonal antibodies, and analysed by flow cytometry. Control tumours were similarly labelled. All analysis was performed blind. Results. 162 patients were randomised to the Phase II study, between April 1994 and October 1996. 85 received 105AD7 and 77 placebo. The mean ages and sex-ratios of the two groups were comparable, as was the time from diagnosis of advanced disease to trial entry (172v179 days). Median survival from date on study was 124 and 184 days, in 105AD7 and placebo arms, respectively (p=O.38). Survival from date of diagnosis of advanced disease was 456 and 486 days (p=O.82). Chemotherapy and radiotherapy all prolonged survival in a multivariate analysis. Only one serious adverse event was seen in the 105AD7 arm, and this was felt unlikely to be attributable to the vaccine. Twenty-four patients were recruited to the adjuvant study. Immunohistochemical analysis of tumour sections from 16 patients showed increased infiltration of CD4 and CD8 expressing lymphocytes, relative to a well matched control group (p<O.05). Infiltration of CD4, CD8 and CD56 expressing lymphocytes combined was significantly higher, as was that of the mitochondrial antigen 7A6, expressed on cells undergoing apoptosis (p<O.005). The activation marker CD25 was also significantly increased (p<O.05). Flow cytometric analysis of disaggregated tumours from 16 trial and 22 control patients, confirmed the increased expression of CD25 on TIL in the 105AD7 group (p<O.01). Peripheral blood phenotyping failed to show any significant increase in any lymphocyte subset, following immunisation. A separate analysis was performed comparing 2 year survival and recurrence in 23 patients immunised by the previous CRC Fellow, with 97 matched controls from the Trent Audit. No significant difference was seen between the two groups. Discussion. No survival difference was seen between patients receiving l05AD7 and placebo, in the Phase II study. This suggests that any immune responses generated by l05AD7 are insufficient to have a significant effect on tumour growth, in patients with advanced disease. Work has therefore focused on immunising patients with primary colorectal cancer. Patients receiving l05AD7 prior to resection of their primary tumours, showed an increased number of activated lymphocytes, and apoptosis, at the tumour site, relative to a well-matched control group. The numbers in the survival analysis based on patients recruited by the previous CRC fellow, are insufficient to show whether any of these immunological changes confer a survival advantage. This question can only be answered in a large, prospective, placebo-controlled study in patients with primary colorectal cancer

Studies using the anti-idiotypic monoclonal antibody 105AD7 in patients with advanced and primary colorectal cancer

Introduction. The anti-idiotypic monoclonal antibody 10SAD7 mimics the tumour associated antigen 791T/ gp72, present on approximately 80% of colorectal cancer cells. A Phase I study using 10SAD7 in 13 patients with advanced colorectal cancer has shown that it is nontoxic, and conferred a survival advantage on patients who received it [Denton GWL 1994]. Aim. There were two aims of this work. The first was to assess whether. the survival advantage seen in the Phase I study was reproducible in a Phase II study. The second was to immunise patients with primary colorectal cancer, in a non-randomised adjuvant study, and explore further the immune responses generated. Materials and Methods. Patients with advanced colorectal cancer were recruited to a randomised, double-blind, placebo controlled survival study. The first patient was recruited to this Phase II study in April 1994, and the last in October 1996. Four trial centres were used- Nottingham, Hull, Leeds, and Newcastle. Eligible patients had a life expectancy of 3 months, and none had received radiotherapy or chemotherapy in the preceding 1 and 3 months, respectively. Patients attended on 3 occasions, 6 weeks apart, receiving 10µg of 10SAD7/alum i.d. followed by 100µg i.m. Venous blood was assayed for blood count and differential, liver function, urea and electrolytes, and CEA. Chest X-rays and CT scans were performed at trial entry and week 12 where possible. Dates of death were recorded following consultation with General Practitioner or referring clinician. In addition, patients with primary colorectal cancer were recruited to a non-randomised adjuvant study, whereby they received 10SAD7 before surgery. Venous blood samples were taken between immunisation and operation, and assayed for lymphocyte subsets. Samples taken from resection specimens were analysed immunohistochemically. Fresh tumours were in addition disaggregated, and separated TIL labelled with a panel of monoclonal antibodies, and analysed by flow cytometry. Control tumours were similarly labelled. All analysis was performed blind. Results. 162 patients were randomised to the Phase II study, between April 1994 and October 1996. 85 received 105AD7 and 77 placebo. The mean ages and sex-ratios of the two groups were comparable, as was the time from diagnosis of advanced disease to trial entry (172v179 days). Median survival from date on study was 124 and 184 days, in 105AD7 and placebo arms, respectively (p=O.38). Survival from date of diagnosis of advanced disease was 456 and 486 days (p=O.82). Chemotherapy and radiotherapy all prolonged survival in a multivariate analysis. Only one serious adverse event was seen in the 105AD7 arm, and this was felt unlikely to be attributable to the vaccine. Twenty-four patients were recruited to the adjuvant study. Immunohistochemical analysis of tumour sections from 16 patients showed increased infiltration of CD4 and CD8 expressing lymphocytes, relative to a well matched control group (p<O.05). Infiltration of CD4, CD8 and CD56 expressing lymphocytes combined was significantly higher, as was that of the mitochondrial antigen 7A6, expressed on cells undergoing apoptosis (p<O.005). The activation marker CD25 was also significantly increased (p<O.05). Flow cytometric analysis of disaggregated tumours from 16 trial and 22 control patients, confirmed the increased expression of CD25 on TIL in the 105AD7 group (p<O.01). Peripheral blood phenotyping failed to show any significant increase in any lymphocyte subset, following immunisation. A separate analysis was performed comparing 2 year survival and recurrence in 23 patients immunised by the previous CRC Fellow, with 97 matched controls from the Trent Audit. No significant difference was seen between the two groups. Discussion. No survival difference was seen between patients receiving l05AD7 and placebo, in the Phase II study. This suggests that any immune responses generated by l05AD7 are insufficient to have a significant effect on tumour growth, in patients with advanced disease. Work has therefore focused on immunising patients with primary colorectal cancer. Patients receiving l05AD7 prior to resection of their primary tumours, showed an increased number of activated lymphocytes, and apoptosis, at the tumour site, relative to a well-matched control group. The numbers in the survival analysis based on patients recruited by the previous CRC fellow, are insufficient to show whether any of these immunological changes confer a survival advantage. This question can only be answered in a large, prospective, placebo-controlled study in patients with primary colorectal cancer

Can an eye tracker be used as a marker of surgical progress?

Can an eye tracker be used as a marker of surgical progress

Visual search behaviour during laparoscopic cadaveric procedures

Laparoscopic surgery provides a very complex example of medical image interpretation. The task entails: visually examining a display that portrays the laparoscopic procedure from a varying viewpoint; eye-hand co-ordination; complex 3D interpretation of the 2D display imagery; efficient and safe usage of appropriate surgical tools, as well as other factors. Training in laparoscopic surgery typically entails practice using surgical simulators. Another approach is to use cadavers. Viewing previously recorded laparoscopic operations is also a viable additional approach and to examine this a study was undertaken to determine what differences exist between where surgeons look during actual operations and where they look when simply viewing the same pre-recorded operations. It was hypothesised that there would be differences related to the different experimental conditions; however the relative nature of such differences was unknown. The visual search behaviour of two experienced surgeons was recorded as they performed three types of laparoscopic operations on a cadaver. The operations were also digitally recorded. Subsequently they viewed the recording of their operations, again whilst their eye movements were monitored. Differences were found in various eye movement parameters when the two surgeons performed the operations and where they looked when they simply watched the recordings of the operations. It is argued that this reflects the different perceptual motor skills pertinent to the different situations. The relevance of this for surgical training is explored

Laparoscopic surgical skills training: an investigation of the potential of using surgeons' visual search behaviour as a performance indicator

Laparoscopic surgery is a difficult perceptual-motor task and effective and efficient training in the technique is important. Viewing previously recorded laparoscopic operations is a possible available training technique for surgeons to increase their knowledge of such minimal access surgery (MAS). It is not well known whether this is a useful technique, how effective it is or what effect it has on the surgeon watching the recorded video. As part of an on-going series of studies into laparoscopic surgery, an experiment was conducted to examine whether surgical skill level has an effect on the visual search behaviour of individuals of different surgical experience when they examine such imagery. Medically naive observers, medical students, junior surgeons and experienced surgeons viewed a laparoscopic recording of a recent operation. Initial examination of the recorded eye movement data indicated commonalities between all observers, largely irrespective of surgical experience. This, it is argued, is due to visual search in this situation largely being driven by the dynamic nature of the images. The data were then examined in terms of surgical steps and also in terms of interventions when differences were found related to surgical experience. Consequently, it is argued that monitoring the eye movements of trainee surgeons whilst they watch pre-recorded operations is a potential useful adjunct to existing training regimes

Development of a telehealth monitoring service after colorectal surgery: a feasibility study

AIM: To evaluate the feasibility of a text-messaging system to remotely monitor and support patients after discharge following elective colorectal surgery, within an enhanced recovery protocol. METHODS: Florence (FLO) is a National Health Service telehealth solution utilised for monitoring chronic health conditions, such as hypertension, using text-messaging. New algorithms were designed to monitor the well-being, basic physiological observations and any patient-reported symptoms, and provide support messages to patients undergoing colorectal surgery within an enhanced recovery after surgery protocol for 30 d after discharge. All interactions with FLO and physiological readings were recorded and patients were invited to provide feedback. RESULTS: Over a four-week period, 16 out of 17 patients used the FLO telehealth service at home. These patients did not receive telephone follow-up at three days, as per our standard protocol, unless they reported being unwell or did not make use of the technology. Three patients were readmitted within 30 d, and two of these were identified as being unwell by FLO prior to readmission. No adverse events attributable to the use of the technology were encountered. CONCLUSION:The utilisation of telehealth in the early follow-up of patients who have undergone major colorectal surgery after discharge is feasible. The use of this technology may assist in the early recognition and management of complications after discharge

Effect of public reporting of surgeons' outcomes on patient selection, "gaming," and mortality in colorectal cancer surgery in England: population based cohort study.

OBJECTIVE: To determine the effect of surgeon specific outcome reporting in colorectal cancer surgery on risk averse clinical practice, "gaming" of clinical data, and 90 day postoperative mortality. DESIGN: National cohort study. SETTING: English National Health Service hospital trusts. POPULATION: 111 431 patients diagnosed as having colorectal cancer from 1 April 2011 to 31 March 2015 included in the National Bowel Cancer Audit. INTERVENTION: Public reporting of surgeon specific 90 day mortality in elective colorectal cancer surgery in England introduced in June 2013. MAIN OUTCOME MEASURES: Proportion of patients with colorectal cancer who had an elective major resection, predicted 90 day mortality based on characteristics of patients and tumours, and observed 90 day mortality adjusted for differences in characteristics of patients and tumours, comparing patients who had surgery between April 2011 and June 2013 and between July 2013 and March 2015. RESULTS: The proportion of patients with colorectal cancer undergoing major resection did not change after the introduction of surgeon specific public outcome reporting (39 792/62 854 (63.3%) before versus 30 706/48 577 (63.2%) after; P=0.8). The proportion of these major resections categorised as elective or scheduled also did not change (33 638/39 792 (84.5%) before versus 25 905/30 706 (84.4%) after; P=0.5). The predicted 90 day mortality remained the same (2.7% v 2.7%; P=0.3), but the observed 90 day mortality fell (952/33 638 (2.8%) v 552/25 905 (2.1%)). Change point analysis showed that this reduction was over and above the existing downward trend in mortality before the introduction of public outcome reporting (P=0.03). CONCLUSIONS: This study did not find evidence that the introduction of public reporting of surgeon specific 90 day postoperative mortality in elective colorectal cancer surgery has led to risk averse clinical practice behaviour or "gaming" of data. However, its introduction coincided with a significant reduction in 90 day mortality

Recommendations for analysis of repeated-measures designs:testing and correcting for sphericity and use of manova and mixed model analysis

Purpose: A common experimental design in ophthalmic research is the repeated-measures design in which at least one variable is a within-subject factor. This design is vulnerable to lack of ‘sphericity’ which assumes that the variances of the differences among all possible pairs of within-subject means are equal. Traditionally, this design has been analysed using a repeated-measures analysis of variance (RM-anova) but increasingly more complex methods such as multivariate anova (manova) and mixed model analysis (MMA) are being used. This article surveys current practice in the analysis of designs incorporating different factors in research articles published in three optometric journals, namely Ophthalmic and Physiological Optics (OPO), Optometry and Vision Science (OVS), and Clinical and Experimental Optometry (CXO), and provides advice to authors regarding the analysis of repeated-measures designs. Recent findings: Of the total sample of articles, 66% used a repeated-measures design. Of those articles using a repeated-measures design, 59% and 8% analysed the data using RM-anova or manova respectively and 33% used MMA. The use of MMA relative to RM-anova has increased significantly since 2009/10. A further search using terms to select those papers testing and correcting for sphericity (‘Mauchly's test’, ‘Greenhouse-Geisser’, ‘Huynh and Feld’) identified 66 articles, 62% of which were published from 2012 to the present. Summary: If the design is balanced without missing data then manova should be used rather than RM-anova as it gives better protection against lack of sphericity. If the design is unbalanced or with missing data then MMA is the method of choice. However, MMA is a more complex analysis and can be difficult to set up and run, and care should be taken first, to define appropriate models to be tested and second, to ensure that sample sizes are adequate