The efficacy of selective arterial embolization in the management of colonic bleeding.

BACKGROUND: The aim of the present study was to determine the efficacy of mesenteric embolization in the management of acute haemorrhage from the colon. METHODS: A retrospective review was performed of a consecutive series of patients who underwent selective arterial embolization between 2002 and 2010 at two Australian institutions. An analysis was performed of each patient's present and past medical history, procedural details and subsequent post-procedural recovery. RESULTS: Seventy-one patients were reviewed in the study. Sixty-one patients (86 %) had immediate cessation of bleeding following embolization. In total, 20 % had some form of morbidity due to mesenteric embolization being performed, the three most common being worsening renal function, groin haematoma and contrast allergy (11, 9 and 7 %, respectively). Only one patient developed superficial bowel ischaemia. Overall, 11 patients (18 %) had recurrent bleeding. Of these patients, five had repeat embolization. Of the patients who underwent re-embolization, three stopped bleeding. Surgery was required in 5 patients 2 of whom died postoperatively of systemic complications. CONCLUSIONS: Colonic bleeding can be treated successfully in most patients by embolization, without causing ischaemia. Eighteen per cent of patients rebleed during the first hospital admission, and 20 % patients experienced a procedure-related complication. In those patients that proceed to surgery, the morbidity, mortality and length of hospital stay increase dramatically.

Is colonoscopy still mandatory after a CT diagnosis of left-sided diverticulitis: can colorectal cancer be confidently excluded?

BACKGROUND: It is routine practice to perform colonoscopy as a follow-up after an attack of diverticulitis, with the main aim to exclude any underlying malignancy. PURPOSE: This study aimed to determine whether colonoscopy is necessary and what additional information is gained from this procedure. DESIGN: This is a study of a retrospective cohort. SETTINGS AND PATIENTS: From January 2003 to June 2009, patients in whom left-sided diverticulitis was diagnosed on CT scan were matched with colonoscopy reports within 1 year from the date of CT by the use of radiology and endoscopy databases. Patients who had colonoscopy within 1 year before the CT scan were excluded. The Western Australian Cancer Registry was cross-referenced to identify patients who subsequently received diagnoses of cancers for whom colonoscopy reports were unavailable. MAIN OUTCOME MEASURES: The main outcome measures were the number of patients in whom colorectal cancers were diagnosed and other incidental findings, eg, polyps, colitis, and stricture. RESULTS: Left-sided diverticulitis was diagnosed in 1088 patients on CT scan, whereas follow-up colonoscopy reports were available for 319 patients. Eighty-two (26%) patients had incidental findings of polyps (9 polyps >1 cm), and 9 patients (2.8%) received diagnoses of colorectal cancers on colonoscopy. After cross-referencing with the cancer registry, the overall prevalence of colorectal cancer among the cohort within 1 year of CT scan was 2.1% (23 cases). The odds of a diagnosis of colorectal cancer were 6.7 times (95% CI 2.4-18.7) in patients with an abscess reported on CT, 4 times (95% CI 1.1-14.9) in patients with local perforation, and 18 times (95% CI 5.1-63.7) in patients with fistula compared with patients with uncomplicated diverticulitis. LIMITATIONS: This study was limited by the unavailability of data for private/interstate hospitals, and the relatively small number of cancer cases reduced the statistical power of the study. CONCLUSIONS: We recommend routine colonoscopy after an attack of presumed left-sided diverticulitis in patients who have not had recent colonic luminal evaluation. The rate of occult carcinoma is substantial in this patient population, in particular, when abscess, local perforation, and fistula are observed.

A small molecule inhibitor of XIAP induces apoptosis and synergises with vinorelbine and cisplatin in NSCLC.

BACKGROUND: Evasion of apoptosis contributes to the pathogenesis of solid tumours including non-small cell lung cancer (NSCLC). Malignant cells resist apoptosis through over-expression of inhibitor of apoptosis proteins (IAPs), such as X-linked IAP (XIAP). METHODS: A phenylurea-based small molecule inhibitor of XIAP, XIAP antagonist compound (XAC) 1396-11, was investigated preclincally to determine its ability to sensitise to clinically relevant cytotoxics, potentially allowing dose reduction while maintaining therapeutic efficacy. RESULTS: XIAP protein expression was detected in six NSCLC cell lines examined. The cytotoxicity of XAC 1396-11 against cultured NSCLC cell lines in vitro was concentration- and time-dependent in both short-term and clonogenic assays. XAC 1396-11-induced apoptosis was confirmed by PARP cleavage and characteristic nuclear morphology. XAC 1396-11 synergised with vinorelbine+/-cisplatin in H460 and A549 NSCLC cells. The mechanism of synergy was enhanced apoptosis, shown by increased cleavage of caspase-3 and PARP and by the reversal of synergy by a pan-caspase inhibitor. Synergy between XAC 1396-11 and vinorelbine was augmented by optimising drug scheduling with superior effects when XAC 1396-11 was administered before vinorelbine. CONCLUSION: These preclinical data suggest that XIAP inhibition in combination with vinorelbine holds potential as a therapeutic strategy in NSCLC.

Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours.

BACKGROUND: Despite substantial improvements in childhood cancer survival, drug resistance remains problematic for several paediatric tumour types. The urgent need to access novel agents to treat drug-resistant disease should be expedited by pre-clinical evaluation of paediatric tumour models during the early stages of drug development in adult cancer patients. METHODS/RESULTS: The novel cytotoxic RH1 (2,5-diaziridinyl-3-[hydroxymethyl]-6-methyl-1,4-benzoquinone) is activated by the obligate two-electron reductase DT-diaphorase (DTD, widely expressed in adult tumour cells) to a potent DNA interstrand cross-linker. In acute viability assays against neuroblastoma, osteosarcoma, and Ewing's sarcoma cell lines RH1 IC(50) values ranged from 1-200 nM and drug potency correlated both with DTD levels and drug-induced apoptosis. However, synergy between RH1 and cisplatin or doxorubicin was only seen in low DTD expressing cell lines. In clonogenic assays RH1 IC(50) values ranged from 1.5-7.5 nM and drug potency did not correlate with DTD level. In A673 Ewing's sarcoma and 791T osteosarcoma tumour xenografts in mice RH1 induced apoptosis 24 h after a single bolus injection (0.4 mg/kg) and daily dosing for 5 days delayed tumour growth relative to control. CONCLUSION: The demonstration of RH1 efficacy against paediatric tumour cell lines, which was performed concurrently with the adult Phase 1 Trial, suggests that this agent may have clinical usefulness in childhood cancer.

The cellular adaptations to hypoxia as novel therapeutic targets in childhood cancer.

Exposure of tumour cells to reduced levels of oxygen (hypoxia) is a common finding in adult tumours. Hypoxia induces a myriad of adaptive changes within tumour cells which result in increased anaerobic glycolysis, new blood vessel formation, genetic instability and a decreased responsiveness to both radio and chemotherapy. Hypoxia correlates with disease stage and outcome in adult epithelial tumours and increasingly it is becoming apparent that hypoxia is also important in paediatric tumours. Despite its adverse effects upon tumour response to treatment hypoxia offers several avenues for new drug development. Bioreductive agents already exist, which are preferentially activated in areas of hypoxia, and thus have less toxicity for normal tissue. Additionally the adaptive cellular response to hypoxia offers several novel targets, including vascular endothelial growth factor (VEGF), carbonic anhydrase, and the central regulator of the cellular response to hypoxia, hypoxia inducible factor-1 (HIF-1). Novel agents have emerged against all of these targets and are at various stages of clinical and pre-clinical development. Hypoxia offers an exciting opportunity for new drug development that can include paediatric tumours at an early stage.

The incidence of anastomotic leaks in patients undergoing colorectal surgery.

BACKGROUND: There is evolving interest in auditing and credentialling the performance of surgeons. The incidence of anastomotic leakage has been proposed as a measure of performance following colorectal surgery. The aim of this study was to evaluate the incidence and risk factors associated with anastomotic leakage in patients undergoing resections of the colon and rectum. METHODS: A prospective database was developed for all patients undergoing colorectal surgery. Anastomotic leakage was defined prior to the commencement of the study. A logistic regression analysis was performed to determine independent predictors of leakage. The variables analysed included age, sex, American Society of Anesthesiology (ASA) score, anatomical location, pathology, emergency surgery, type of anastomosis, a covering stoma and radiotherapy. Significance was defined as the probability of a type 1 error of < 5%. The results are presented as odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: There were 1598 patients who underwent 1639 anastomoses. Their mean age was 63 years, 34% of patients were ASA 3 or 4, and 16% of the operations were emergencies. Anastomotic leaks occurred in 2.4% (40/1639) of anastomoses. The leak rate for intraperitoneal anastomoses was 1.5% (19/1283) vs 6.6% for extraperitoneal anastomoses (21/316). Half of these leaks (20/40) were managed with re-operation or percutaneous drainage procedures. Ultra-low anterior resections were associated with the highest leak rate (8%, 18/225). A logistic regression analysis identified a covering stoma (P = 0.0001, OR 5.078, 95% CI 2.527-10.23) and diverticular disease (P = 0.037, OR 2.304, 95% CI 1.053-5.042) as independent predictors of a leak. CONCLUSIONS: Within this surgical unit, the incidence of leaks from intraabdominal anastomoses was relatively low. However, leaks in patients undergoing extraperitoneal anastomoses continue to be a major cause of morbidity and mortality.

Randomized clinical trial of bowel preparation with a single phosphate enema or polyethylene glycol before elective colorectal surgery.

BACKGROUND: A recent meta-analysis has questioned the value of bowel preparation in patients undergoing colorectal resection. The aim of this clinical trial was to evaluate whether a single phosphate enema was as effective as oral polyethylene glycol (PEG) solution in preventing anastomotic leakage. METHODS: Patients were randomized to receive either a single phosphate enema or 3 litres of oral PEG solution before surgery. Patients were followed for a minimum of 6 weeks to detect anastomotic leakage. RESULTS: There were 147 patients in each group and the groups were evenly matched for putative risk factors at baseline. Patients in the enema group had more anastomotic leaks requiring reoperation than those in the PEG group (4.1 versus 0 per cent, P = 0.013; relative risk 2.04 (95 per cent confidence interval (c.i.) 1.82 to 2.30)). The mortality rate was higher in the PEG group (2.7 versus 0.7 per cent, P = 0.176; odds ratio 1.62 (95 per cent c.i. 0.45 to 36.98)). CONCLUSION: Bowel preparation with a phosphate enema was associated with an increased risk of anastomotic leakage requiring reoperation compared with oral PEG. These results do not support the routine use of a phosphate enema in patients undergoing elective colorectal surgery.

Sperm banking in adolescent cancer patients.

BACKGROUND: Semen cryopreservation is a widely available method of maintaining fertility in male cancer patients. However this facility is not always used. AIMS: To identify the barriers to successful sperm banking in a group of adolescent and young adult patients. METHODS: Questionnaires were administered to 55 patients aged 13-21 years who had received potentially gonadotoxic therapy between 1997 and 2001 and had been offered sperm banking. RESULTS: Forty five questionnaires were completed; 67% of respondents were able to bank sperm. Those who had been unsuccessful were younger and described higher levels of anxiety at diagnosis and greater difficulty in talking about fertility. They also described less understanding of sperm banking at the time of diagnosis. CONCLUSION: Most adolescent cancer patients who have been offered fertility preservation are able to bank sperm. Younger patients may be helped by the provision of high quality information and more open discussion of the technique.

Sexual health in women following pelvic surgery for rectal cancer.

BACKGROUND: Sexual dysfunction is a recognized complication in men undergoing pelvic surgery for rectal cancer. There is, however, little information on the influence of such surgery on sexual health in women. The aim of this study was to evaluate sexual health in women undergoing pelvic surgery for rectal cancer. METHODS: The study group included women who underwent pelvic surgery for rectal cancer at the Colorectal Surgical Unit, Fremantle Hospital between 1996 and 2002. The patients were contacted by telephone and invited to complete an anonymized questionnaire on sexual health. A control group comprised women who had undergone surgery for colonic cancer during the same interval. RESULTS: Fifty women in the study group were contacted, of whom 22 completed questionnaires. Sixty-two women in the control group were contacted and 19 completed questionnaires. Women in the study group were significantly younger than those in the control group. Compared with those in the control group, women who had undergone pelvic surgery were significantly more likely to feel less attractive, feel that the vagina was either too short or less elastic during intercourse, experience superficial pain during intercourse, and complain of faecal soiling during intercourse. Women in the study group were concerned that these limitations would persist for the rest of their lives. There were no differences between the two groups in relationship to sexual arousal or libido. CONCLUSION: Pelvic surgery for rectal cancer has a significant influence on sexual health in women.

Transanal endoscopic microsurgery: a viable operative alternative in selected patients with rectal lesions.

BACKGROUND: Local excision of rectal lesions is being increasingly undertaken, especially in those unfit for major surgery. The traditional transanal approach is often cumbersome and limited to low and mid rectal lesions. Transanal endoscopic microsurgery (TEMS) is being used to excise both benign and malignant rectal lesions, including those in the upper rectum. METHODS: Prospective analysis of all patients undergoing a TEMS excision between January 1997 and December 2000 in a specialized colorectal unit. RESULTS: Forty patients underwent a TEMS resection, with a mean age of 72 years (SD, 10 years). The mean distance of the lesions from the anal verge was 9.8 cm (SD, 3.1 cm). In 24 patients, the lesion was located >or=10 cm from the anal verge, making them unsuitable for traditional transanal resection. The mean operative time was 91 minutes (SD, 34 minutes), and the mean postoperative stay was 3 days (SD, 1.5 days). No mortality was associated with the procedure, and there was minimal morbidity in 15%. There has been no recurrence in the 18 patients who had a malignant lesion excised. CONCLUSIONS: The TEMS operating system provides the surgeon with a suitable alternative for the resection of benign and malignant rectal neoplasms in selected patients. It has the advantage of providing visual clarity of the operative field, allowing more precise dissection and a minimally invasive approach to mid and upper rectal lesions. There has been no mortality and minimal morbidity. We advocate its inclusion as part of a colorectal surgeon's operative armamentarium for these selected cases.

Mortality, morbidity and functional outcome after ileorectal anastomosis.

BACKGROUND: Total colectomy with an ileorectal anastomosis (IRA) is a commonly performed operation. Postoperative mortality and morbidity are reported to be low and functional outcome is generally rated as good to excellent. The aim of this study was to review postoperative mortality, morbidity and functional results in an effort to identify risk factors predictive of a poor outcome. METHODS: Some 215 patients (118 women and 97 men) with a median age of 33 (interquartile range (i.q.r.) 25-47) years underwent an IRA between November 1990 and December 1999. Median follow-up was 2 years 9 months (i.q.r. 1-5 years). The clinical notes of these patients were reviewed retrospectively to analyse the postoperative course, bowel function and long-term clinical outcome. RESULTS: The indications for surgery included familial adenomatous polyposis (52.1 per cent), Crohn's disease (14.4 per cent), functional bowel disorder (14.4 per cent), ulcerative colitis (8.4 per cent) and colonic carcinoma (4.7 per cent). The overall 30-day mortality and morbidity rates were 0.9 and 26.0 per cent respectively. This included anastomotic leak (6.5 per cent), small bowel obstruction (14.4 per cent), fistula (2.8 per cent) and anastomotic stricture (1.4 per cent). The incidence of fistula and anastomotic stricture was significantly higher in Crohn's disease (P < 0.001 and P = 0.005 respectively). Only 16 of 31 patients with Crohn's disease had a functioning IRA at long-term follow-up. Median stool frequency was 3 (i.q.r. 3-5) per day one year following surgery and did not change with longer follow-up. CONCLUSION: Mortality and morbidity rates following IRA are low. Postoperative fistula and anastomotic stricture are more common in patients with Crohn's disease, approximately half of whom will eventually need a permanent ileostomy. Long-term bowel function for all groups is satisfactory.

Damage-induced Bax N-terminal change, translocation to mitochondria and formation of Bax dimers/complexes occur regardless of cell fate.

Sequential steps in the activation of the pro-apoptotic protein Bax are described for cells with different sensitivity to cytotoxins. SH-EP1 and SH-SY5Y human neuroblastoma cells, derived from a single precursor cell line, differed in their sensitivity to taxol but showed the same sensitivity to cisplatin. Both drugs, in both cell lines, induced exposure of a constitutively occluded N-terminal epitope of Bax. This was reversible and occurred before the translocation of cytosolic Bax to mitochondria. The N-terminal change in Bax, its subsequent movement to mitochondria and its dimerization/complex formation were insufficient for commitment to death, occurring in the same proportion of cells that either maintained (SH-SY5Y) or lost (SH-EP1) clonogenic survival after taxol treatment. Suppression of taxol-induced apoptosis occurred upstream of cytochrome c release from mitochondria in SH-SY5Y cells. The data suggest that a further drug damage-induced event occurs after Bax dimerization/complex formation but prior to cytochrome c release. This event was absent in the taxol-resistant cells.

Apoptosis and cancer chemotherapy.

The explosion of interest in apoptosis amongst cancer biologists has been underpinned by the hope that a mechanistic understanding of cell death will inform our understanding of tumour drug resistance. A framework for drug-induced apoptosis can now be described in which a balance exists between intrinsic and extrinsic survival signals and drug-induced death signals. Pro- and anti-apoptotic signals impact upon pro-apoptotic members of the Bcl-2 family of proteins, which ultimately control the cellular fate. This framework suggests multiple points at which therapeutic interventions could be made to overcome drug resistance and, in addition, generates novel molecular targets for the induction of apoptosis in cancer cells.

Modulating sensitivity to drug-induced apoptosis: the future for chemotherapy?

Drug resistance is a fundamental problem in the treatment of most common human cancers. Our understanding of the cellular mechanisms underlying death and survival has allowed the development of rational approaches to overcoming drug resistance. The mitogen activated protein kinase family of protein serine/threonine kinases has been implicated in this complex web of signalling, with some members acting to enhance death and other members to prevent it. A recent publication by MacKeigan et al is the first to demonstrate an enhancement of drug-induced cell death by simultaneous blockade of MEK-mediated survival signalling, and offers the potential for targeted adjuvant therapy as a means of overcoming drug resistance.

The impact of new technology on surgery for colorectal cancer.

Advances in technology continue at a rapid pace and affect all aspects of life, including surgery. We have reviewed some of these advances and the impact they are having on the investigation and management of colorectal cancer. Modern endoscopes, with magnifying, variable stiffness and localisation capabilities are making the primary investigation of colonic cancer easier and more acceptable for patients. Imaging investigations looking at primary, metastatic and recurrent disease are shifting to digital data sets, which can be stored, reviewed remotely, potentially fused with other modalities and reconstructed as 3 dimensional (3D) images for the purposes of advanced diagnostic interpretation and computer assisted surgery. They include virtual colonoscopy, trans-rectal ultrasound, magnetic resonance imaging, positron emission tomography and radioimmunoscintigraphy. Once a colorectal carcinoma is diagnosed, the treatment options available are expanding. Colonic stents are being used to relieve large bowel obstruction, either as a palliative measure or to improve the patient's overall condition before definitive surgery. Transanal endoscopic microsurgery and minimally invasive techniques are being used with similar outcomes and a lower mortality, morbidity and hospital stay than open trans-abdominal surgery. Transanal endoscopic microsurgery allows precise excision of both benign and early malignant lesions in the mid and upper rectum. Survival of patients with inoperable hepatic metastases following radiofrequency ablation is encouraging. Robotics and telemedicine are taking surgery well into the 21(st) century. Artificial neural networks are being developed to enable us to predict the outcome for individual patients. New technology has a major impact on the way we practice surgery for colorectal cancer.

Apoptosis and cancer chemotherapy.

Apoptosis is a fundamental mechanism of cell death that can be engaged by a range of cellular insults. One of the major modes of action of chemotherapeutic drugs may be via the activation of apoptosis. Understanding how the cell death program is engaged following an insult, and hence why it fails to be engaged in certain settings, offers a novel approach to overcoming the clinical problem of drug resistance. The tumour suppressor gene p53 and its downstream effector genes p21, mdm-2, and gadd45 seem to be important in the cellular response to genotoxic drug induced damage. Considerable evidence has accrued about the effect of mutations of this pathway on drug sensitivity and this is discussed. The expanding Bcl-2 family of proteins also play an important role in the cell death program. Evidence suggests that these proteins may function as integrators of damage signals, and may be the final decision point as to whether a cell lives or dies. These proteins may thus represent a logical target for new approaches to overcoming drug resistance.

Leptomeningeal melanoma in childhood.

BACKGROUND: Malignant melanoma (MM) is one of the least common types of childhood cancer, accounting for less than 1% of all pediatric malignancies. Neurocutaneous melanosis (NCM) is a rare phakomatosis consisting of congenital abnormal pigmentation of the skin and meninges. The meningeal lesions are particularly prone to malignant change. METHODS: The authors describe 5 patients with NCM and 1 with primary leptomeningeal melanoma (LMM) seen at 2 treatment centers in the north of England over a 13-year period (1984-1997). RESULTS: The clinical features, progress, radiological findings, and treatment of these patients are discussed. All six died within eight months of their diagnosis, illustrating the difficulties faced in treating patients with these conditions. The authors reviewed the published literature on NCM, concentrating on the various therapeutic strategies that have been tried. Very little consistency in approach was found. Malignant skin lesions in NCM may be less responsive than primary malignant melanoma, but the small number of patients with primary LMM or brain metastases of MM make comparisons with NCM difficult. The authors' own series illustrates well the piecemeal nature of therapy for patients with these rare conditions. CONCLUSIONS: The rate of incidence of MM melanoma in the U.K. is increasing, and it will represent an increasing proportion of the pediatric oncologist's workload. A consistent approach to the therapy of patients with metastatic MM and NCM is needed if we are to have any hope of offering more than palliative therapy to these children in the future.

X linked lymphoproliferative disease in a United Kingdom family.

X linked lymphoproliferative disease (XLP; Duncan's disease) is a rare disorder affecting boys and characterised by a defective immune response to Epstein-Barr virus caused by a mutation in a gene located at chromosome Xq25. Three siblings with XLP in a single UK family are reported and the variation in phenotypic expression of the disease in these siblings described. One of the siblings with life threatening fulminant infectious mononucleosis was successfully treated by chemotherapy, followed by bone marrow transplantation using an unaffected brother as the donor. A healthy baby boy recently born into the family was identified as carrying the defective maternal X chromosome using molecular genetic linkage analysis. This family illustrates the extent of present understanding of this often fatal condition.