Mapping the colorectal tumor microbiota.

The gut microbiome in patients with colorectal cancer (CRC) is different than that of healthy controls. Previous studies have profiled the CRC tumor microbiome using a single biopsy. However, since the morphology and cellular subtype vary significantly within an individual tumor, the possibility of sampling error arises for the microbiome within an individual tumor. To test this hypothesis, seven biopsies were taken from representative areas on and off the tumor in five patients with CRC. The microbiome composition was strikingly similar across all samples from an individual. The variation in microbiome alpha-diversity was significantly greater between individuals' samples then within individuals. This is the first study, to our knowledge, that shows that the microbiome of an individual tumor is spatially homogeneous. Our finding strengthens the assumption that a single biopsy is representative of the entire tumor, and that microbiota changes are not limited to a specific area of the neoplasm.

A meta-analysis of the efficacy of prophylactic alpha-blockade for the prevention of urinary retention following primary unilateral inguinal hernia repair.

BACKGROUND: Urinary retention following inguinal hernia surgery is common and is believed to be associated with adrenergic over-stimulation of the smooth muscle in the bladder neck and prostate. The efficacy of prophylactic alpha-blockade in the prevention of urinary retention following elective inguinal hernia repair in males is unknown. METHODS: A comprehensive literature search was performed adhering to PRISMA guidelines. Each study was reviewed and data were extracted. Random-effects models were used to combine data. RESULTS: Five randomized studies describing 456 patients were identified. General or spinal anaesthetic were used. Prophylactic alpha-blockade decreases the risk of urinary retention requiring catheterisation following elective unilateral inguinal hernia repair compared to control groups (OR:0.179, 95% CI:0.043-0.747, p:0.018). Rates of urinary retention between treatment and control groups are reduced by 20.6%. No serious complications relating to alpha blockade occurred. CONCLUSIONS: Prophylactic alpha-blockade reduces urinary retention following elective inguinal hernia surgery under general or spinal anaesthetic.

Enhanced recovery after elective colorectal surgery: now the standard of care.

Enhanced recovery programmes have been studied in randomised trials with evidence of quicker recovery of gut function, reduced morbidity, mortality and hospital stay and improved physiological and nutritional outcomes. They aim to reduce the physiological and psychological stress of surgery and consequently the uncontrolled stress response. The key elements, reduced pre-operative fasting, intravenous fluid restriction and early feeding after surgery, are in conflict with traditional management plans but are supported by strong clinical evidence. Given the strength of the current data enhanced recovery should now be the standard of care.

Cautionary considerations regarding N.O.T.E.S. in oncology.

Over the last number of years, the emphasis in abdominal surgery has been to reduce invasiveness and to minimise trauma to the patient. This has led to the rapid development of laparoscopic techniques initially for the surgical management of benign disease and later for the successful management of malignant disease. Laparoscopy has now been shown to provide significant benefits to the cancer patient, in particular the reduction of wound infection, herniation and pain. More recently, benefits have been demonstrated in earlier discharge from hospital and return to normal activity. Laparoscopy has therefore been accepted as at least a valid alternative to open surgery for most types of abdominal cancer. With the objective of reducing invasiveness even more, the last few years has seen a rapid expansion in the development of Natural Orifice Translumenal Endoscopic Surgery (NOTES). Currently, NOTES is still in the early stages of evolution but its potential uses in the field of cancer surgery are already being proposed. To develop NOTES to the stage that it will be safe, effective and widely available for the management of cancer patients represents a huge challenge ranging from the development of equipment and techniques to the demonstration of safety and efficacy in clinical trials as well as training and competence issues. It is still not clear whether these challenges will be surmounted so that NOTES becomes mainstream therapy. A period of 'watchful waiting' seems appropriate therefore for the uncommitted general surgeon in order that NOTES may be given time to prove compelling and convincing before its general uptake into routine practice.

Local involvement of the urinary bladder in primary colorectal cancer: outcome with en bloc resection.

BACKGROUND: Colorectal cancers that adhere to the urinary bladder require en bloc partial or total cystectomy to achieve negative tumor margins. METHODS: This prospective study evaluated the outcome of combined bladder resection for carcinoma of the colon or rectum at a unit specializing in gastrointestinal cancer. RESULTS: Patients (n = 63) with colorectal tumors adherent to the bladder at operation and without distal metastases were followed. Fifty-eight patients (92%) had tumors of the sigmoid colon or upper rectum. Operative morbidity and mortality rates were 18% and 1.5%, respectively. Histological staging demonstrated bladder adherence in 46% (29/63) and invasion in 54% (34/63). Overall disease-specific survival was 54%, with a mean follow-up of 7.6 (range 5-12) years. Five-year survival for margin negative patients was 72% (26/36) and 27% (4/15) for node negative and positive tumors, respectively. The bladder was closed primarily in 48 patients and reconstructed by enterocystoplasty in five, with ten patients requiring urinary diversion. CONCLUSIONS: En bloc bladder resection for adherent or invading tumors of the colon and rectum achieves good local control, but an infiltrative extravesical margin denotes poor prognosis. The potential for cure in completely excised node negative tumors is good. Bladder reconstruction is achievable in most patients.

Local involvement of the urinary bladder in primary colorectal cancer: outcome with en-bloc resection.

BACKGROUND: Colorectal cancers that adhere to the urinary bladder require en-bloc partial or total cystectomy to achieve negative tumor margins. METHODS: This prospective study evaluated the outcome of combined bladder resection for carcinoma of the colon or rectum at a unit specializing in gastrointestinal cancer. RESULTS: Patients (n = 63) with colorectal tumors adherent to the bladder at operation and without distal metastases were followed. Fifty-eight patients (92%) had tumors of the sigmoid colon or upper rectum. Operative morbidity and mortality rates were 18% and 1.5%, respectively. Histological staging demonstrated bladder adherence in 46% (29/63) and invasion in 54% (34/63). Overall disease-specific survival was 54% with a mean follow-up of 7.6 years (range 5-12). Five-year survival for margin-negative patients was 72% (26/36) and 27% (4/15) for node-negative and -positive tumors, respectively. The bladder was closed primarily in 48 patients and reconstructed by enterocystoplasty in 5, with 10 patients requiring urinary diversion. CONCLUSIONS: En-bloc bladder resection for adherent or invading tumors of the colon and rectum achieves good local control, but an infiltrative extravesical margin denotes poor prognosis. The potential for cure in completely excised node-negative tumors is good. Bladder reconstruction is achievable in most patients.

Mucosectomy vs. stapled ileal pouch-anal anastomosis in patients with familial adenomatous polyposis: functional outcome and neoplasia control.

PURPOSE: The tradeoff of neoplasia control for better function represented by a stapled ileal pouch-anal anastomosis is still controversial in patients with familial adenomatous polyposis. We compared outcomes after mucosectomy and hand-sewn ileal pouch-anal anastomosis with those after stapled ileal pouch-anal anastomosis in 119 patients with familial adenomatous polyposis who underwent surgery since 1983. METHODS: Age, gender, length of follow-up, complications, quality of life, incontinence, urgency, nighttime and daytime seepage, pad usage, necessity of ileostomy, and incidence of adenomas developing in pouch and anal transitional zone were recorded. RESULTS: There were 42 mucosectomy and 77 stapled patients who were followed up for an average of 5.8 and 3.6 years, respectively, with endoscopic surveillance. There was one postoperative death in the stapled group that prohibited long-term follow-up. Nine of 42 mucosectomy patients developed pouch adenomas vs. 8 of 76 in the stapled group. Six of 42 patients developed adenomas in the mucosectomized anal transitional zone in the mucosectomy group. Twenty-one of 76 patients developed adenomas in the anal transitional zone in the stapled group. All were managed with local procedures or further surveillance. One of 76 patients developed cancer in the residual low rectum; this required further resection. Patients with stapled anastomosis had better outcomes in every category. Differences in incontinence, daytime and nighttime seepage, pad usage, and avoidance of ileostomy were statistically significant. All patients with mucosectomy required ileostomy vs. only 40 of 77 patients with stapled anastomosis. CONCLUSION: Familial adenomatous polyposis patients with stapled ileal pouch-anal anastomosis have better functional outcome and can avoid temporary diversion. This should be balanced against a 28 percent incidence of adenomas in the anal transitional zone.

Incidence and natural history of dysplasia of the anal transitional zone after ileal pouch-anal anastomosis: results of a five-year to ten-year follow-up.

PURPOSE: Preservation of the anal transitional zone during ileal pouch-anal anastomosis is still controversial because of the risk of dysplasia and the theoretical risk of associated cancer. Without long-term follow-up data, the natural history and optimal treatment of anal transitional zone dysplasia are unknown. The aim of this study was to determine the long-term risk of dysplasia in the anal transitional zone and to evaluate the outcome of a conservative management policy for anal transitional zone dysplasia. METHODS: Two hundred ten patients undergoing anal transitional zone-sparing ileal pouch-anal anastomosis for ulcerative or indeterminate colitis between 1987 and 1992 and who were studied with serial anal transitional zone biopsies for at least five years postoperatively were included. Median follow up was 77 (range, 60-124) months. RESULTS: Anal transitional zone dysplasia developed in seven patients 4 to 51 (median, 11) months postoperatively. There was no association with gender, age, preoperative disease duration or extent of colitis, but the risk of anal transitional zone dysplasia was significantly increased in patients with prior cancer or dysplasia in the colon or rectum. Dysplasia was high grade in one and low grade in six. Two patients each with low-grade dysplasia detected on three separate occasions underwent mucosectomy 29 and 38 months after detection of low-grade dysplasia, but no cancer was found. The five other patients with dysplasia on one or two occasions were treated expectantly and were apparently dysplasia-free for a median of 72 (range, 48-100) months. CONCLUSIONS: Anal transitional zone dysplasia after ileal pouch-anal anastomosis is infrequent, is most common in the first two to three years postoperatively and may apparently disappear on repeated biopsy. Anal transitional zone preservation did not lead to the development of cancer in the anal transitional zone after five to ten years of follow-up. Long-term surveillance is recommended to monitor dysplasia. If repeat biopsy confirms persistent dysplasia, anal transitional zone excision with neoileal pouch-anal anastomosis is recommended.

Long-term functional outcome and quality of life after stapled restorative proctocolectomy.

OBJECTIVE: To evaluate prospectively long-term quality of life and functional outcome after restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis, and to evaluate and validate a novel quality-of-life indicator in this group of patients. SUMMARY BACKGROUND DATA: Restorative proctocolectomy with ileal pouch-anal anastomosis is now the preferred option when total proctocolectomy is required for ulcerative colitis or familial adenomatous polyposis, but long-term data on functional outcome and quality of life after the procedure are lacking. METHODS: Patients (n = 977) who underwent RPC with stapled anastomosis for colitis or polyposis coli and who were followed for > or =12 months were included. Quality of life, fecal incontinence, and satisfaction with surgery were prospectively evaluated by structured interview or questionnaire for 1 to 12 years after surgery (median 5.0). Quality of life was scored using the Cleveland Global Quality of Life (CGQL) instrument (Fazio Score). This is a novel score developed over the past 15 years by the senior author. Quality of life was also evaluated in a subgroup of patients with the Short Form 36 (SF-36). The CGQL was validated by determining its reliability, responsiveness, and validity as well as its correlation with the SF-36 score. RESULTS: Postoperative quality of life as measured by SF-36 was excellent and compared well with published norms for the general U.S. population. The CGQL was found to be reliable, responsive, and valid, and there was a high correlation with the SF-36 scores. Using the CGQL, quality of life was shown to increase after the first 2 years after surgery, and there was no deterioration thereafter. The prevalence of perfect continence increased from 75.5% before surgery to 82.4% after surgery, and although this deteriorated somewhat >2 years after surgery, it was no worse than preoperative values. Ninety-eight percent of patients would recommend the surgery to others. CONCLUSIONS: Long-term quality of life after ileal pouch surgery is excellent and the level of continence is satisfactory. This surgery is an excellent long-term option in patients requiring total proctocolectomy. The CGQL is a simple, valid, and reliable measure of quality of life after pelvic pouch surgery and may well be applicable in many other clinical conditions.

Peripheral blood cells from weight-losing cancer patients control the hepatic acute phase response by a primarily interleukin-6 dependent mechanism.

Cancer cachexia is associated with an elevated hepatic acute phase protein response, poor outcome and elevated cytokine production from peripheral blood mononuclear cells (PBMC). This study investigates the mechanism by which PBMC can induce a hepatic acute phase response. Supernatants from the peripheral blood cells of cancer patients induced significantly higher C-reactive protein (CRP) from hepatocytes (198+/-21 ng ml-1) than did supernatants from healthy controls (64+/-20, p<0.005). CRP production in vitro correlated with IL-6 production by PBMC from patients with pancreatic cancer (r=0.76, p<0.0001). This C-reactive protein production was reduced by 84% using neutralising antibody to IL-6 (p<0.001). There was a significant negative correlation between PBMC-induced hepatocyte C-reactive protein production and survival (r=-0.45, p<0.01). PBMC from cancer patients induce the hepatic acute phase response via a primarily IL-6-dependent mechanism.

Effect of interleukin-4 on pro-inflammatory cytokine production and the acute phase response in healthy individuals and in patients with cancer or multiple organ failure.

1. This study investigates whether previously documented effects of interleukin-4 in down-regulating pro-inflammatory cytokine production by peripheral blood mononuclear cells (PBMCs) from healthy individuals would be reproducible in PBMCs isolated from patients with multiple organ failure (acute disease model) and gastrointestinal cancer (chronic disease model). The effects of interleukin-4 on the ability of PBMC supernatants to elicit an acute phase protein response from isolated human hepatocytes were also studied. 2. Incubation of PBMCs with interleukin-4 significantly reduced both spontaneous and lipopolysaccharide-induced production of tumour necrosis factor and lipopolysaccharide-induced interleukin-6 production, demonstrating that the PBMCs from patients with acute and chronic disease are not refractory to the effects of interleukin-4. The effects of interleukin-4 on the ability of PBMCs from the groups studied to elicit an acute phase response were complex and varied both between patient groups and individual acute phase proteins. Overall, interleukin-4 reduced the potential of PBMCs to stimulate production of the positive acute phase proteins C-reactive protein, alpha1-antichymotrypsin and alpha1-acid glycoprotein.3. This work emphasizes the pleiotropic nature of cytokines and the complex regulatory mechanisms which exist. The study illustrates the difficulties in devising in vivo intervention strategies using cytokines such as interleukin-4.

The effect of hysterectomy on ano-rectal physiology.

Hysterectomy is associated with severe constipation in a subgroup of patients, and an adverse effect on colonic motility has been described in the literature. The onset of irritable bowel syndrome and urinary bladder dysfunction has also been reported after hysterectomy. In this prospective study, we investigated the effect of simple hysterectomy on ano-rectal physiology and bowel function. Thirty consecutive patients were assessed before and 16 weeks after operation. An abdominal hysterectomy was performed in 16 patients, and a vaginal procedure was performed in 14. The parameters measured included the mean resting, and maximal forced voluntary contraction anal pressures, the recto-anal inhibitory reflex, and rectal sensation to distension. In 8 patients, the terminal motor latency of the pudendal nerve was assessed bilaterally. Pre-operatively, 8 patients were constipated. This improved following hysterectomy in 4, worsened in 2, and was unchanged in 2. Symptomatology did not correlate with changes in manometry. Although, the mean resting pressure was reduced after hysterectomy (57 mmHg-53 mmHg, P = 0.0541), the maximal forced voluntary contraction pressure was significantly decreased (115 mmHg-105 mmHg, P = 0.029). This effect was more pronounced in those with five or more previous vaginal deliveries (P = 0.0244, n = 9). There was no significant change in the number of patients with an intact ano-rectal inhibitory reflex after hysterectomy. There was no change in rectal sensation to distension, and the right and left pudendal nerve terminal motor latencies were unaltered at follow-up. Our results demonstrate that hysterectomy causes a decrease in the maximal forced voluntary contraction and pressure, and this appears to be due to a large decrease in a small group of patients with previous multiple vaginal deliveries.

Glutamine-supplemented total parenteral nutrition reduces blood mononuclear cell interleukin-8 release in severe acute pancreatitis.

Glutamine, a conditionally essential amino acid, is important for immune function. It is now being formulated for incorporation into total parenteral nutrition (TPN). The aims of this study were to examine the effect of glutamine administration on lymphocyte proliferation and proinflammatory cytokine release in patients with severe acute pancreatitis. Fourteen patients were randomized (in a double-blind fashion) to receive either conventional or isocaloric, isonitrogenous glutamine-supplemented (0.22 g glutamine x kg(-1) x d(-1) as glycyl-glutamine) TPN for 7 d. DNA synthesis (index of lymphocyte proliferation) and the 24-h release of tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 from peripheral blood mononuclear cells were measured in vitro on days 0, 4, and 7. Thirteen patients completed the study protocol (6 glutamine TPN, 7 conventional TPN). Glutamine supplementation increased median DNA synthesis by 3099 cpm over the study period against 219 cpm in the conventional group (increase not significantly different between the two groups) . Glutamine supplementation did not significantly influence TNF or IL-6 release, but, in contrast, median IL-8 release was reduced by day 7 in the glutamine group while it was increased in the conventional group (-17.7 ng/mL (median change over study period) versus +43.3 ng/mL, respectively; P=0.045). Small patient numbers and substantial interindividual variation limit the conclusions, but there is a trend for the glutamine group to have improved lymphocyte proliferation, and in the case of IL-8, reduced proinflammatory cytokine release.

The role of surgery and laser ablation in oesophageal carcinoma.

Between January 1990 and December 1994 oesophagectomy was carried out in 42 patients and comparison made with 38 who had palliative laser therapy. Apart from six patients referred after being unresectable at surgical exploration there were no agreed selection criteria, although the laser patients were in general older (mean 64 V 73 year) with a higher proportion of cardiorespiratory co-morbidity (14 per cent V 18 per cent). Lateral margins were involved in 14 per cent of known palliative resections with 50 per cent having positive nodes. The mean operating time was three hours and two chest drains inserted electively were removed after 3.6 days with mean drainage of 817 ml. The mean ICU stay was 5.4 days and 3 had radiological leaks; all but one settled conservatively. The 90 day mortality was 11.9 per cent for surgery and 34 per cent for laser patients. Twenty-three patients (61 per cent) required further courses of laser-therapy for benign anastomotic stenosis. Including the initial treatment of both groups 6.0 procedures per patient year were required in the laser groups compared with 1.1 for surgery. The 1, 2 and 3 year survival was 60 per cent, 31 per cent, 39 per cent for surgery compared with 24 per cent, 8 per cent, 3 per cent for laser--12 surgical patients are still alive and well at mean of 29 months (range 16-68). Surgery where possible with acceptable morbidity and mortality offers good palliation and long-term survival is possible; selection criteria for palliation only need to be defined.

Is circulating endotoxin the trigger for the systemic inflammatory response syndrome seen after injury?

OBJECTIVE: Patients with severe traumatic or burn injury and a mouse model of burn injury were studied early after injury to determine the relation of plasma endotoxin (lipopolysaccharide [LPS]) to the production of proinflammatory cytokines and subsequent resistance to infection. SUMMARY BACKGROUND DATA: Elevated levels of plasma LPS have been reported in patients after serious injury. It has been suggested that circulating LPS may be a trigger for increased proinflammatory cytokine production and may play a role in the septic syndromes seen in a substantial portion of such patients. Yet, despite multiple reports of leakage of LPS from the gut and bacterial translocation after injury in animal models, there is little direct evidence linking circulating LPS with production of inflammatory mediators. METHODS: The authors studied serial samples of peripheral blood from 10 patients with 25% to 50% surface area burns and 8 trauma patients (injury Severity Score, 25-57). Patients were compared with 18 healthy volunteers. The study was focused on the first 10 days after injury before the onset of sepsis or the systemic inflammatory response syndrome. Plasma samples were assayed for LPS, and adherent cells from the blood were studied for basal and LPS-stimulated production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6). The correlation of increased plasma LPS with TNF-alpha production was studied as was the association of increased plasma LPS and increased TNF-alpha production with subsequent septic complications. We also studied a mouse model of 25% burn injury. Burn mice were compared with sham burn control subjects. Plasma samples were assayed at serial intervals for LPS, and adherent cells from the spleens were studied for basal- and LPS-stimulated production of TNF-alpha, IL-1 beta, and IL-6. Expression of the messenger RNAs for IL-1 beta and TNF-alpha also was measured. The relation of increased TNF-alpha production with mortality from a septic challenge, cecal ligation and puncture (CLP), was determined. Finally, the effect of administration of LPS to normal mice on subsequent mortality after CLP and on TNF-alpha production was studied. RESULTS: Elevated plasma LPS (> 1 pg/mL) was seen in 11 of the 18 patients within 10 days of injury and in no normal control subjects. In this period, patients as compared with control subjects showed increased stimulated production of TNF-alpha, IL-1 beta, and IL-6. Increased TNF-alpha production was not correlated with elevated plasma LPS in the same patients. Neither increased plasma LPS nor increased TNF-alpha production early after injury was correlated with subsequent development of systemic inflammatory response syndrome or sepsis in the patients. Burn mice, as compared with sham burn control subjects, showed elevated plasma LPS levels chiefly in the first 3 days after injury. Increased stimulated production of proinflammatory cytokines by adherent splenocytes from the burn mice also was seen at multiple intervals after injury and did not correlate with mortality from CLP. Increased production of TNF-alpha and IL-1 beta was associated with increased expression of messenger RNAs for these cytokines. Finally, two doses of 1 ng LPS administered 24 hours apart to normal mice had no effect on mortality from CLP performed 7 days later nor on the production of TNF-alpha at the time of CLP. CONCLUSIONS: These findings call into question the idea that circulating LPS is the trigger for increased proinflammatory cytokine production, systemic inflammatory response syndrome, and septic complications in injured patients.

Effect of glutamine on immune function in the surgical patient.

The beneficial effects of glutamine on immune function in vitro have been well described. Severely ill surgical patients undergo glutamine depletion and this has been implicated as a cause of immune dysfunction in vivo. With the introduction of the stable dipeptides of glutamine into total parenteral nutrition (TPN) regimens, the clinical effects of glutamine on the immune system have taken on an increased relevance and importance. In a randomized clinical trial, we have shown that glutamine-supplemented TPN increased the T cell mitogenic response in patients undergoing colorectal resection. This was not associated with an altered production of the pro-inflammatory cytokines interleukin-6 (IL-6) or tumor necrosis factor (TNF). In a subsequent clinical trial comparing glutamine-supplemented TPN with control TPN in patients with severe acute pancreatitis there was a similar modest enhancement of the T cell response in the glutamine-supplemented group. Although Il-6 and TNF production were again unchanged, there was a significant reduction in IL-8 production in the glutamine-supplemented group. Glutamine may exert its immunological effects by a direct action on the cells of the immune system. Possible indirect mechanisms by which glutamine may influence the immune system include the maintenance of gut barrier function, or the preservation of action of the antioxidant glutathione.

Laparoscopic-assisted rectopexy using a novel hand-access port.

Many surgeons who were ready converts to laparoscopic cholecystectomy did not translate the technique to more advanced procedures. There are several reasons: increased operating times, a steeper learning curve, concern for oncological efficacy, and the loss of manual tactile ability. As shown with this report on laparoscopic assisted rectopexy, many of these difficulties can be overcome using the IntromitTM while still maintaining the benefits of minimally invasive surgery.