Comparison of major abdominal emergency surgery outcomes across organizational models of emergency surgical care: Analysis of the UK NELA national database.

BACKGROUND: Emergency general surgery (EGS) admissions account for a large proportion of surgical care and represent the majority of surgical patients who suffer in-hospital mortality. Health care systems continue to experience growing demand for emergency services: one way in which this is being increasingly addressed is dedicated subspecialty teams for emergency surgical admissions, most commonly termed "emergency general surgery" in the United Kingdom. This study aims to understand the impact of the emergency general surgery model of care on outcomes from emergency laparotomies. METHODS: Data was obtained from the National Emergency Laparotomy Audit database. Patients were dichotomized into EGS hospital or non-EGS hospital. Emergency general surgery hospital is defined as a hospital where >50% of in-hours emergency laparotomy operating is performed by an emergency general surgeon. The primary outcome was in-hospital mortality. Secondary outcomes were intensive therapy unit (ITU) length of stay and duration of hospital stay. A propensity score weighting approach was used to reduce confounding and selection bias. RESULTS: There were 115,509 patients from 175 hospitals included in the final analysis. The EGS hospital care group included 5,789 patients versus 109,720 patients in the non-EGS group. Following propensity score weighting, mean standardized mean difference reduced from 0.055 to <0.001. In-hospital mortality was similar (10.8% vs. 11.1%, p = 0.094), with mean length of stay (16.7 days vs. 16.1 days, p < 0.001) and ITU stay (2.8 days vs. 2.6 days, p < 0.001) persistently longer in patients treated in EGS systems. CONCLUSION: No significant association between the emergency surgery hospital model of care and in-hospital mortality in emergency laparotomy patients was seen. There is a significant association between the emergency surgery hospital model of care and an increased length of ITU stay and overall hospital stay. Further studies are required to examine the impact of changing models of EGS delivery in the United Kingdom. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.

Intra-operative ultrasound assessment of the biliary tree during robotic cholecystectomy.

Image-guided assessment of bile ducts and associated anatomy during laparoscopic cholecystectomy can be achieved with intra-operative cholangiography (IOC) or laparoscopic ultrasound (LUS). Rates of robotically assisted cholecystectomy (RC) are increasing and herein we describe the technique of intra-corporeal biliary ultrasound during RC using the Da Vinci system. For intraoperative evaluation of the biliary tree during RC, in cases of suspected choledocholithiasis, the L51K Ultrasound Probe (Hitachi, Tokyo, Japan) is used. The extrahepatic biliary tree is scanned along its length, capitalising on the benefits of the full range of motion offered by the articulated robotic instruments and integrated ultrasonic image display using TileProTM software. Additionally, this technique avoids the additional time and efforts required to undock and re-dock the robot that would otherwise be required for selective IOC or LUS. The average time taken to perform a comprehensive evaluation of the biliary tree, from the hepatic ducts to the ampulla of Vater, is 164.1 s. This assessment is supplemented by Doppler ultrasound, which is used to fully delineate anatomy of the porta hepatis, and accurate measurements of the biliary tree and any ductal stones can be taken, allowing for contemporaneous decision making and management of ductal pathologies. Biliary tract ultrasound has been shown to be equal to IOC in its ability to diagnose choledocholithiasis, but with the additional benefits of being quicker and having higher completion rates. We have described our practice of using biliary ultrasound during robotically assisted cholecystectomy, which is ergonomically superior to LUS, accurate and reproducible.

Systematic review: robot-assisted versus conventional laparoscopic multiport cholecystectomy.

Laparoscopic cholecystectomy has become the standard of care for the treatment of symptomatic gallstone disease. In the context of the increasing uptake of robotic surgery, robotic cholecystectomy has seen a substantial growth over the past decades. Despite this, a formal assessment of the evidence for this practice remains elusive and a randomised controlled trial is yet to be performed. This paper reviews the evidence to date for robotic multiport cholecystectomy compared to conventional multiport cholecystectomy. This systematic review was performed conducted using the Medline, Embase and Cochrane databases; in line with the PRISMA guideline. All articles that compared robotic and conventional laparoscopic cholecystectomy were included. The studies were assessed with regards to operative outcomes, postoperative recovery and complications. Fourteen studies were included, describing a total of 3002 patients. There was no difference in operative blood loss, complication rates, incidence of bile duct injury or length of hospital stay between the robotic and laparoscopic groups. The operative time for robotic cholecystectomy was longer, whereas the risk of conversion to open surgery was lower. There was marked variation in definitions of measured outcomes, and most studies lacked data on training and quality assessment, leading to substantial heterogeneity of the data. Available evidence on multiport robotic cholecystectomy compared to conventional laparoscopic cholecystectomy is scarce and the quality of the available studies is generally poor. Results suggest longer operating time for robotic cholecystectomy, although many studies included the learning curve period. Postoperative recovery and complications were similar in both groups.

Proctored adoption of robotic hiatus hernia surgery: outcomes and learning curves in a high-volume UK centre.

BACKGROUND: The adoption of new surgical technologies is inevitably accompanied by a learning curve. With the increasing adoption of robotic techniques in benign foregut surgery, it is imperative to define optimal learning pathways, to ensure a clinically safe introduction of such a technique. The aim of this study was to assess the learning curve for robotic hiatal hernia repair with a pre-defined adoption process and proctoring. METHODS: The learning curve was assessed in four surgeons in a high-volume tertiary referral centre, performing over a 100 hiatal hernia repairs annually. The robotic adoption process included simulation-based training and a multi-day wet lab-based course, followed by robotic operations proctored by robotic upper GI experts. CUSUM analysis was performed to assess changes in operating time in sequential cases. RESULTS: Each surgeon (A, B, C and D) performed between 22 and 32 cases, including a total of 109 patients. Overall, 40 cases were identified as 'complex' (36.7%), including 16 revisional cases (16/109, 14.7%). With CUSUM analysis inflection points for operating time were seen after 7 (surgeon B) to 15 cases (surgeon B). CONCLUSION: The learning curve for robotic laparoscopic fundoplication may be as little as 7-15 cases in the setting of a clearly organized learning pathway with proctoring. By integrating these organized learning pathways learning curves may be shortened, ensuring patient safety, preventing detrimental outcomes due to longer learning curves, and accelerating adoption and integration of novel surgical techniques.

Learning curve for adoption of robot-assisted minimally invasive esophagectomy: a systematic review of oncological, clinical, and efficiency outcomes.

BACKGROUND: Robot-assisted minimally invasive esophagectomy (RAMIE) is gaining increasing popularity as an operative approach. Learning curves to achieve surgical competency in robotic-assisted techniques have shown significant variation in learning curve lengths and outcomes. This study aimed to summarize the current literature on learning curves for RAMIE. METHODS: A systematic review was conducted in line with PRISMA guidelines. Electronic databases PubMed, MEDLINE, and Cochrane Library were searched, and articles reporting on learning curves in RAMIE were identified and scrutinized. Studies were eligible if they reported changes in operative outcomes over time, or learning curves, for surgeons newly adopting RAMIE. RESULTS: Fifteen studies reporting on 1767 patients were included. Nine studies reported on surgeons with prior experience of robot-assisted surgery prior to adopting RAMIE, with only four studies outlining a specified RAMIE adoption pathway. Learning curves were most commonly analyzed using cumulative sum control chart (CUSUM) and were typically reported for lymph node yields and operative times, with significant variation in learning curve lengths (18-73 cases and 20-80 cases, respectively). Most studies reported adoption without significant impact on clinical outcomes such as anastomotic leak; significant learning curves were more likely in studies, which did not report a formal learning or adoption pathway. CONCLUSION: Reported RAMIE adoption phases are variable, with some authors suggesting significant impact to patients. With robust training through formal programmes or proctorship, however, others report RAMIE adoption without impact on clinical outcomes. A formalized adoption curriculum appears critical to prevent adverse effects on operative efficiency and patient care.

Outcomes After Independent Trainee Versus Consultant-led Emergency Laparotomy: Inverse Propensity Score Population Dataset Analysis.

OBJECTIVE: We utilized a population dataset to compare outcomes for patients where surgery was independently performed by trainees to cases led by a consultant. SUMMARY OF BACKGROUND DATA: Emergency laparotomy is a common, high-risk, procedure. Although trainee involvement to improve future surgeons' experience and ability in the management of such cases is crucial, some studies have suggested this is to the detriment of patient outcomes. In the UK, appropriately skilled trainees may be entrusted to perform emergency laparotomy without supervision of a consultant (attending). METHODS: Patients who underwent emergency laparotomy between 2013 and 2018 were identified from the National Emergency Laparotomy Audit of England and Wales. To reduce selection and confounding bias, the inverse probability of treatment weighting approach was used, allowing robust comparison of trainee-led and consultant-led laparotomy cases accounting for eighteen variables, including details of patient, treatment, pathology, and preoperative mortality risk. Groups were compared for mortality and length of stay. RESULTS: A total of 111,583 patients were included in the study. The operating surgeon was a consultant in 103,462 cases (92.7%) and atrainee in 8121 cases (7.3%). Mortality at discharge was 11.6%. Trainees were less likely to operate on high-risk and colorectal cases. After weighting, mortality (12.2% vs 11.6%, P = 0.338) was equivalent between trainee- and consultant-led cases. Median length of stay was 11 (interquartile range 7, 19) versus 11 (7, 20) days ( P = 0.004), respectively. Trainee-led operations reported fewer cases of blood loss >500mL (9.1% vs 11.1%, P < 0.001). CONCLUSIONS: Major laparotomy maybe safely entrusted to appropriately skilled trainees without impacting patient outcomes.

Specialist-led urgent cholecystectomy for acute gallstone disease.

BACKGROUND: Despite overwhelming evidence of the clinical and financial benefit of urgent cholecystectomy, there is variable enthusiasm and uptake across the UK. In 2014, following the First National Emergency Laparotomy Audit Organisational Report, we implemented a specialist-led urgent surgery service, whereby all patients with gallstone-related pathologies were admitted under the direct care of specialist upper gastrointestinal surgeons. We have analysed 5 years of data to investigate the results of this service model. METHODS: Computerised operating theatre records were interrogated to identify all patients within a 5-year period undergoing cholecystectomy. Patient demographics, admission details, length of stay, duration of surgery, and complications were analysed. RESULTS: Between 01/01/2016 and 31/12/2020, a total of 4870 cholecystectomies were performed; 1793 (36.8%) were urgent cases and 3077 (63.2%) were elective cases. All cases were started laparoscopically; 25 (0.5%) were converted to open surgery-14 of 1793 (0.78%) urgent cases and 11 of 3077 (0.36%) elective cases. Urgent cholecystectomy took 20 min longer than elective surgery (median 74 versus 52 min). No relevant difference in conversion rate was observed when urgent cholecystectomy was performed within 2 days, between 2 and 4 days, or greater than 4 days from admission (P = 0.197). Median total hospital stay was 4 days. CONCLUSION: Urgent laparoscopic cholecystectomy is safe and feasible in most patients with acute gall bladder disease. Surgery under the direct care of upper gastrointestinal specialist surgeons is associated with a low conversion rate, low complication rate, and short hospital stay. Timing of surgery has no effect on conversion rate or complication rate.

P-POSSUM and the NELA Score Overpredict Mortality for Laparoscopic Emergency Bowel Surgery: An Analysis of the NELA Database.

BACKGROUND: Risk stratification has become a key part of the care processes for patients having emergency bowel surgery. This study aimed to determine if operative approach influences risk-model performance, and risk-adjusted mortality rates in the United Kingdom. METHODS: A prospectively planned analysis was conducted using National Emergency Laparotomy Audit (NELA) data from December 2013 to November 2018. The risk-models investigated were P-POSSUM and the NELA Score, with model performance assessed in terms of discrimination and calibration. Risk-adjusted mortality was assessed using Standardised Mortality Ratios (SMR). Analysis was performed for the total cohort, and cases performed open, laparoscopically and converted to open. Sub-analysis was performed for cases with ≤ 20% predicted mortality. RESULTS: Data were available for 116 396 patients with P-POSSUM predicted mortality, and 46 935 patients with the NELA score. Both models displayed excellent discrimination with little variation between operative approaches (c-statistic: P-POSSUM 0.801-0.836; NELA Score 0.811-0.862). The NELA score was well calibrated across all deciles of risk, but P-POSSUM over-predicted risk beyond 20% mortality. Calibration plots for operative approach demonstrated that both models increasingly over-predicted mortality for laparoscopy, relative to open and converted to open surgery. SMRs calculated using both models consistently demonstrated that risk-adjusted mortality with laparoscopy was a third lower than open surgery. CONCLUSION: Risk-adjusted mortality for emergency bowel surgery is lower for laparoscopy than open surgery, with P-POSSUM and NELA score both over-predicting mortality for laparoscopy. Operative approach should be considered in the development of future risk-models that rely on operative data.

Feasibility of laparoscopy and factors associated with conversion to open in minimally invasive emergency major abdominal surgery: population database analysis.

BACKGROUND: There is limited evidence regarding the overall feasibility and success rates of the laparoscopic approach in major emergency surgery, despite its potential to improve outcomes. This study aims to investigate the association between patient, procedural, and surgical factors and likelihood of successful laparoscopic completion in emergency major surgery and derive a predictive model to aid clinical decision-making. METHOD: All patients recorded in the NELA emergency laparotomy database 1 December 2013-31 November 2018 who underwent laparoscopically attempted surgery were included. A retrospective cohort multivariable regression analysis was conducted for the outcome of conversion to open surgery. A predictive model was developed and internally validated. RESULTS: Of 118,355 patients, 17,040 (7.7%) underwent attempted laparoscopic surgery, of which 7.915 (46.4%) were converted to open surgery. Procedure type was the strongest predictor of conversion (compared to washout as reference, small bowel resection OR 25.93 (95% CI 20.42-32.94), right colectomy OR 6.92 (5.5-8.71)). Diagnostic [free pus, blood, or blood OR 3.67 (3.29-4.1)] and surgeon [subspecialist surgeon OR 0.56 (0.52-0.61)] factors were also significant, whereas age, gender, and pre-operative mortality risk were not. A derived predictive model had high internal validity, C-index 0.758 (95% CI 0.748-0.768), and is available for free-use online. CONCLUSION: Surgical, patient, and diagnostic variables can be used to predict likelihood of laparoscopic success with a high degree of accuracy. This information can be used to inform peri-operative decision-making and patient selection.

Reduction in late diagnosis of colorectal cancer following introduction of a specialist colorectal surgery service.

INTRODUCTION: An audit of patients presenting with colorectal cancer to our district general hospital during a 2-year period from November 1994 found that 12.1% of cases were diagnosed later than 6 months after initial presentation to a physician. This audit was repeated for a 2-year period from December 2001, to determine whether the introduction of a specialist coloproctology surgery service had led to a reduction in late diagnosis of colorectal cancer. PATIENTS AND METHODS: Case notes were reviewed of all patients presenting with colorectal cancer between December 2001 and November 2003. Late diagnosis was defined as diagnosis of colorectal cancer more than 6 months after their first attendance to either their general practitioner or district general hospital. The results were compared with those of the previous study. RESULTS: Of a total of 218 patients presenting with colorectal cancer during the study period, 14 (6.4%; 10 men and 4 women) satisfied the criteria for late diagnosis, with the longest delay being 12.5 months. Reasons for late diagnosis were false-negative reporting of barium studies (n = 3), inaccurate tumour biopsy (n = 2), concurrent pathology causing anaemia (n = 4), inappropriate delay in definitive investigation (n = 3), and refusal of investigation by patients (n = 2). CONCLUSIONS: There has been a reduction of nearly 50% (12.1% to 6.4%) in the proportion of patients with a late diagnosis of colorectal cancer compared with our previous audit. It is suggested that an important factor in this improvement in diagnosis has been the introduction of a specialist coloproctology surgery service.

The effect of imatinib mesylate (Glivec) on human tumor-derived cells.

Imatinib mesylate is a specific inhibitor of the Bcr-Abl protein tyrosine kinase that competes with ATP for its specific binding site in the kinase domain. It has activity against platelet-derived growth factor receptor alpha and beta (PDGFR-alpha and -beta), and c-kit, the receptor for stem cell factor. We have used a standardized ATP-tumor chemosensitivity assay and immunohistochemistry to determine the cytotoxicity of imatinib mesylate in tumor-derived cells from cutaneous and uveal melanoma, and ovarian carcinoma. Imatinib mesylate was tested at concentrations ranging from 2.0 to 0.0625 micromol/l alone and in combination with a cytotoxic drug (cisplatin, doxorubicin, paclitaxel or treosulfan). Imatinib mesylate showed low inhibition (IndexSUM>300) across the range of concentrations tested in this study, with few tumors exhibiting increasing inhibition with increased drug concentration. The median IC90 values for cutaneous and uveal melanoma and ovarian carcinoma were 13.2 micromol/l (4.0-294.3 micromol/l), 12.0 micromol/l (2.0-285.4 micromol/l) and 7.71 micromol/l (6.51-11.02 micromol/l), respectively. Imatinib mesylate potentiated the effect of different cytotoxics in 9% (5/54) of cases and had a negative effect in 13% (7/54) of cases, with no effect in the remainder. No correlation of effect was noted with c-kit, platelet-derived growth factor receptor-alpha or platelet-derived growth factor receptor-beta expression, assessed by immunohistochemistry. The signaling pathways mediated by activation of c-kit or platelet-derived growth factor receptor may act as antiapoptotic survival signals in some cancers and inhibition of these pathways may potentiate the activity of some cytotoxic drugs by inhibiting the survival signal. Growth inhibition, however, may reduce the efficacy of cytotoxic drugs, which tend to target proliferating cells preferentially, and clinical effects are therefore difficult to predict.

Cancer cell adaptation to chemotherapy.

BACKGROUND: Tumor resistance to chemotherapy may be present at the beginning of treatment, develop during treatment, or become apparent on re-treatment of the patient. The mechanisms involved are usually inferred from experiments with cell lines, as studies in tumor-derived cells are difficult. Studies of human tumors show that cells adapt to chemotherapy, but it has been largely assumed that clonal selection leads to the resistance of recurrent tumors. METHODS: Cells derived from 47 tumors of breast, ovarian, esophageal, and colorectal origin and 16 paired esophageal biopsies were exposed to anticancer agents (cisplatin; 5-fluorouracil; epirubicin; doxorubicin; paclitaxel; irinotecan and topotecan) in short-term cell culture (6 days). Real-time quantitative PCR was used to measure up- or down-regulation of 16 different resistance/target genes, and when tissue was available, immunohistochemistry was used to assess the protein levels. RESULTS: In 8/16 paired esophageal biopsies, there was an increase in the expression of multi-drug resistance gene 1 (MDR1) following epirubicin + cisplatin + 5-fluorouracil (ECF) chemotherapy and this was accompanied by increased expression of the MDR-1 encoded protein, P-gp. Following exposure to doxorubicin in vitro, 13/14 breast carcinomas and 9/12 ovarian carcinomas showed >2-fold down-regulation of topoisomerase IIalpha (TOPOIIalpha). Exposure to topotecan in vitro, resulted in >4-fold down-regulation of TOPOIIalpha in 6/7 colorectal tumors and 8/10 ovarian tumors. CONCLUSION: This study suggests that up-regulation of resistance genes or down-regulation in target genes may occur rapidly in human solid tumors, within days of the start of treatment, and that similar changes are present in pre- and post-chemotherapy biopsy material. The molecular processes used by each tumor appear to be linked to the drug used, but there is also heterogeneity between individual tumors, even those with the same histological type, in the pattern and magnitude of response to the same drugs. Adaptation to chemotherapy may explain why prediction of resistance mechanisms is difficult on the basis of tumor type alone or individual markers, and suggests that more complex predictive methods are required to improve the response rates to chemotherapy.

Rapid up-regulation of cyclooxygenase-2 by 5-fluorouracil in human solid tumors.

Inhibition of cyclooxygenase (COX)-2 has been associated with reduced growth of malignant cells. Current therapy of gastrointestinal carcinomas involves the use of 5-fluorouracil (5-FU)-based chemotherapy and we have therefore studied the effect of this agent on the expression of COX-2. COX-2 expression was measured by quantitative RT-PCR in biopsies from a series of 14 esophageal carcinomas, six of which had paired samples taken before and after chemotherapy, and in tumor-derived cells exposed to 5-FU in vitro from a series of 44 tumors, including breast, ovarian, esophageal and colonic carcinomas. COX-2 expression was increased by exposure to 5-FU or 5-FU combination chemotherapy in all the tumor types studied, whether measured in biopsies taken before and after 5-FU-based chemotherapy (4-fold increase, p<0.015) or in primary cells exposed to drugs in vitro (24-fold increase, p<0.001). A modest increase of COX-2 mRNA was also seen after in vitro treatment of cells with cisplatin. In contrast, doxorubicin and paclitaxel caused no up-regulation in vitro, while irinotecan caused inhibition of COX-2 (2.7-fold decrease, p<0.01). These data provide a molecular rationale for clinical trials of combination chemotherapy with COX-2 inhibitors.

Ex vivo characterization of XR11576 (MLN576) against ovarian cancer and other solid tumors.

XR11576 (MLN576) is a novel monophenazine with a mechanism of action that includes interaction with both topoisomerase (Topo) I and II. The aim of this study was to evaluate its cytotoxicity against fresh tumor cells taken from patients with a variety of solid tumors. Cells were obtained from 89 patients and exposed for 6 days to XR11576 alone, or in combination with doxorubicin, cisplatin, treosulfan, paclitaxel or vinorelbine. Cell survival was measured using the ATP-Tumor Chemosensitivity Assay (ATP-TCA). Immunohistochemical staining of Topo I, Topo IIalpha and MDR1 was performed on paraffin-embedded blocks in those tumors for which tissue was available (n = 49). Overall, the median IC90 and IC50 values of XR11576 in tumor-derived cells were 242 and 110 nM, respectively. In all samples XR11576 was more potent than the other cytotoxics tested. Breast and gynecological malignancies were most sensitive to XR11576, while the potency of this compound was slightly attenuated in gastrointestinal tumors, in which the median IC90 and IC50 values were 308 and 212 nM, respectively. Cases of synergism were identified when combining XR11576 with vinorelbine (nine of 30 samples) and doxorubicin (12 of 38 samples), while the addition of paclitaxel resulted in an antagonistic effect (CI50>1.2) in 38 of 42 tumors. A very modest correlation by linear regression analysis was found between the intensity of MDR1 staining and the IC50 of XR11576 (r = 0.311, p = 0.0312), but not with the IC90 (r = 0.247, NS). These data support the rapid introduction of XR11576 to clinical trials and suggest that it may be effective against a broad spectrum of tumor types.

Ex vivo reversal of chemoresistance by tariquidar (XR9576).

The expression of P-glycoprotein (P-gp) has been demonstrated to confer resistance to several anticancer drugs, including anthracyclines, taxanes and vinca alkaloids. Tariquidar is a novel inhibitor of P-gp that has been shown to reverse resistance to cytotoxic drugs in tumor cell lines and mouse xenografts. We have used an ATP-based chemosensitivity assay (ATP-TCA) to compare the activity of cytotoxic drugs in combination with tariquidar against a variety of solid tumors (n = 37). The expression of P-gp was determined in a subset of solid tumor samples by immunohistochemistry (n = 16). Resistance was seen in 20 of 37 (54%) tumors tested with doxorubicin, in 27 of 34 (79%) samples tested with paclitaxel and 17 of 31 (55%) with vinorelbine. Tariquidar alone showed no activity over a wide range of concentrations up to 2 microM (n = 14). The median IC90s for doxorubicin, paclitaxel and vinorelbine, alone were 2.57, 27.4 and 15.5 microM. These decreased to 1.67 (p<0.0005), 20.6 (p<0.05) and 9.5 microM (p<0.001), respectively, in combination with tariquidar. Tariquidar also significantly decreased resistance in 14 of 20 (70%), six of 27 (22%) and six of 17 (35%) samples tested with doxorubicin, paclitaxel and vinorelbine, respectively. Immunohistochemical staining for P-gp was positive in nine of 16 (56%) samples and in all of these cases addition of tariquidar improved the activity of the cytotoxic. The results show that tariquidar is able to decrease resistance in a number of solid tumors resistant to cytotoxic drugs known to be P-gp substrates. These data support the introduction of tariquidar in combination with chemotherapy to clinical trials of patients expressing P-gp.

The ex vivo characterization of XR5944 (MLN944) against a panel of human clinical tumor samples.

XR5944 (MLN944) is a novel DNA targeting agent with potent antitumor activity, both in vitro and in vivo, against several murine and human tumor models. We have used an ATP-tumor chemosensitivity assay to assess the ex vivo sensitivity of a variety of solid tumors (n = 90) and a CCRF-CEM leukemia cell line selected with XR5944. Differences in gene expression between the parental CCRF-CEM and the resistant subline were investigated by quantitative reverse transcription-PCR. Immunohistochemistry for topoisomerases I and IIalpha and multidrug resistance (MDR1) protein was done on those tumors for which tissue was available (n = 32). The CCRF-CEM XR5944 line showed increased mRNA levels of MDR1, major vault protein, and MDR-associated protein 1 compared with the parental line, whereas the expression of topoisomerases I, IIalpha, and IIbeta was essentially unchanged, suggesting that XR5944 is susceptible to MDR mechanisms. The median IC90 and IC50 values for XR5944 in tumor-derived cells were 68 and 26 nmol/L, respectively, 6-fold greater than in resistant cell lines. XR5944 was 40- to 300-fold more potent than the other cytotoxics tested, such as doxorubicin, topotecan, and paclitaxel. Breast and gynecologic malignancies were most sensitive to XR5944, whereas gastrointestinal tumors showed greater resistance. A positive correlation (r = 0.68; P < 0.0001) was found between the IC50 values of XR5944 and P-glycoprotein/MDR1 staining but not with either topoisomerase I or IIalpha immunohistochemistry index. These data support the rapid introduction of XR5944 to clinical trials and suggest that it may be effective against a broad spectrum of tumor types, especially ovarian and breast cancer.

Heterogeneity of chemosensitivity of esophageal and gastric carcinoma.

Esophageal and gastric cancer have a poor prognosis, and chemotherapy is rarely of long-term benefit. This may be related in part to heterogeneity of chemosensitivity and to constitutive resistance to individual cytotoxic drugs. This study aimed to demonstrate the degree of heterogeneity of chemosensitivity between tumors. We have examined the heterogeneity of chemosensitivity in esophageal and gastric cancer specimens (n=85) using an ex vivo ATP-based chemosensitivity assay (ATP-TCA). A variety of chemotherapeutic agents were tested. Sixty-four specimens were endoscopic biopsy samples; the remainder were from resection specimens. Cells were obtained from 62 specimens (73%). Eight assays were infected due to contamination/infection of the biopsy material, giving an evaluability rate of 87%. Analysis of the data showed considerable heterogeneity of chemosensitivity. The most active single agents identified by the assay were mitomycin C (56% sensitivity) and 5-fluorouracil (5-FU; 42% sensitivity). Exposure of tumor cells to combinations of drugs showed ECF (epirubicin, cisplatin, 5-FU) and mitomycin C+5-FU to be moderately active regimens. Other experimental drug combinations showed greater activity. There is a marked heterogeneity of chemosensitivity in esophageal and gastric cancers. The degree of heterogeneity observed suggests that the ATP-TCA could be used to individualize chemotherapy by selecting agents for particular patients. This approach provides the rationale for a trial of ATP-TCA-directed therapy to determine whether individualization of chemotherapy might improve patient response and survival.

Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma.

BACKGROUND: We wished to evaluate the clinical response following ATP-Tumor Chemosensitivity Assay (ATP-TCA) directed salvage chemotherapy in a series of UK patients with advanced ovarian cancer. The results are compared with that of a similar assay used in a different country in terms of evaluability and clinical endpoints. METHODS: From November 1998 to November 2001, 46 patients with pre-treated, advanced ovarian cancer were given a total of 56 courses of chemotherapy based on in-vitro ATP-TCA responses obtained from fresh tumor samples or ascites. Forty-four patients were evaluable for results. Of these, 18 patients had clinically platinum resistant disease (relapse < 6 months after first course of chemotherapy). There was evidence of cisplatin resistance in 31 patients from their first ATP-TCA. Response to treatment was assessed by radiology, clinical assessment and tumor marker level (CA 125). RESULTS: The overall response rate was 59% (33/56) per course of chemotherapy, including 12 complete responses, 21 partial responses, 6 with stable disease, and 15 with progressive disease. Two patients were not evaluable for response having received just one cycle of chemotherapy: if these were excluded the response rate is 61%. Fifteen patients are still alive. Median progression free survival (PFS) was 6.6 months per course of chemotherapy; median overall survival (OAS) for each patient following the start of TCA-directed therapy was 10.4 months (95% confidence interval 7.9-12.8 months). CONCLUSION: The results show similar response rates to previous studies using ATP-TCA directed therapy in recurrent ovarian cancer. The assay shows high evaluability and this study adds weight to the reproducibility of results from different centres.

Heterogeneity of chemosensitivity of colorectal adenocarcinoma determined by a modified ex vivo ATP-tumor chemosensitivity assay (ATP-TCA).

Advanced colorectal cancer (CRC) has a poor prognosis with a 5-year survival of only 5% despite treatment with chemotherapeutic agents. Response rate and overall survival varies little between the commonly used single agents, although combinations achieve better outcomes. It is well established that considerable heterogeneity exists between cancers of the same tissue type, but it has been difficult to establish this for CRC. We therefore investigated the heterogeneity of chemosensitivity in CRC using a modified version of the ex vivo ATP-tumor chemosensitivity assay (ATP-TCA) capable of handling infected tumor tissue. Fifty-three specimens of primary solid or malignant effusions of CRC were tested, of which 46 (87%) were evaluable. There were considerable differences in sensitivities between individuals. The most active single cytotoxic agents in the assay were identified as 5-fluorouracil, irinotecan and mitomycin C (MMC). Cells were exposed to combinations of drugs added simultaneously at the same concentrations tested as single agents. All drug combinations achieved greater growth inhibition than drugs used alone. MMC+gemcitabine was found to be the most effective combination in 83% of specimens. The ATP-TCA has previously been shown to be a good predictor of response to chemotherapy in other tissue types. The degree of heterogeneity demonstrated from these results suggests that the ATP-TCA could be used to identify patients who might benefit from specific chemotherapeutic agents alone or in combination.

'War surgery at sea': maritime trauma experience in the Gulf War 2003.

During the second Gulf War in 2003, the Primary Casualty Receiving facility onboard R.F.A. Argus treated thirty six patients with injuries sustained in the conflict, including thirty Iraqi enemy prisoners of war and displaced persons. Their injuries and operative management are reported. Eighteen casualties sustained fragmentation injuries, six casualties sustained gunshot wounds and seven casualties suffered a combination of both. In addition to penetrating missile injuries five casualties from road traffic accidents were treated. All wounds were managed following the established principles of war surgery. The extremities were involved in twenty eight patients (78%) including nine open, multifragmented long bone fractures which were managed with external skeletal fixators. Two laparotomies and one thoracotomy were performed. The average duration of surgery was one hundred and thirty two minutes with the longest procedure lasting for six hours and ten minutes. This was the first time that the Primary Casualty Receiving Facility had been used to surgically manage war casualties and it fulfilled this role to good effect.