Prognostic significance of lymph node yield after long-course preoperative radiotherapy in patients with rectal cancer: a systematic review.

AIM: A literature review was performed to elucidate whether long-course preoperative radiotherapy for patients with rectal cancer affects lymph node yield, and whether this influences prognosis. METHOD: Cochrane Database, PubMed/MEDLINE, Scopus, Web of Knowledge, Embase and CINAHL databases and reference lists from published journal articles published between 1 January 1990 and 30 June 2011 were searched. Studies examining lymph node yield and prognosis were selected for review. RESULTS: One thousand and twenty-nine articles were found, of which 11 met the inclusion criteria. None was a randomized controlled trial and all were cohort studies. Four studies showed that long-course preoperative radiotherapy reduced lymph node yield; however only one demonstrated a statistically significant survival benefit in patients with higher lymph node yields. Five-year survival was 48% in patients with fewer than and 69% in those with more than 11 lymph nodes identified in the operative specimen (P = 0.04). CONCLUSION: Whilst long-course preoperative radiotherapy appears to reduce lymph node yield in patients with rectal cancer, no causal relationship between lymph node yield and survival can be established in this group of patients.

Induction of STAT3-related genes in fast degenerating cone photoreceptors of cpfl1 mice.

Cone dystrophies are genetic diseases characterized by loss of cone photoreceptor function and severe impairment of daylight vision. Loss of function is accompanied by a progressive degeneration of cones limiting potential therapeutic interventions. In this study we combined microarray-based gene-expression analysis with electroretinography and immunohistochemistry to characterize the pathological processes in the cone photoreceptor function loss 1 (cpfl1) mouse model. The cpfl1-mouse is a naturally arising mouse mutant with a loss-of-function mutation in the cone-specific Pde6c gene. Cpfl1-mice displayed normal rod-specific light responses while cone-specific responses were strongly diminished. Despite the lack of a general retinal degeneration, the cone-specific functional defect resulted in a marked activation of GFAP, a hallmark of Müller-cell gliosis. Microarray-based network-analysis confirmed activation of Müller-glia-specific transcripts. Unexpectedly, we found up-regulation of the cytokine LIF and the anti-apoptotic transcription factor STAT3 in cpfl1 cone photoreceptors. We postulate that STAT3-related pathways are induced in cpfl1 cone photoreceptors to counteract degeneration.

Australasian Laparoscopic Colon Cancer Study shows that elderly patients may benefit from lower postoperative complication rates following laparoscopic versus open resection.

BACKGROUND: A retrospective analysis of age-related postoperative morbidity in the Australia and New Zealand prospective randomized controlled trial comparing laparoscopic and open resection for right- and left-sided colonic cancer is presented. METHODS: A total of 592 eligible patients were entered and studied from 1998 to 2005. RESULTS: Data from 294 patients who underwent laparoscopic and 298 who had open colonic resection were analysed; 266 patients were aged less than 70 years and 326 were 70 years or older (mean(s.d.) 70.3(11.0) years). Forty-three laparoscopic operations (14.6 per cent) were converted to an open procedure. Fewer complications were reported for intention-to-treat laparoscopic resections compared with open procedures (P = 0.002), owing primarily to a lower rate in patients aged 70 years or more (P = 0.002). Fewer patients in the laparoscopic group experienced any complication (P = 0.035), especially patients aged 70 years or above (P = 0.019). CONCLUSION: Treatment choices for colonic cancer depend principally upon disease-free survival; however, patients aged 70 years or over should have rigorous preoperative investigation to avoid conversion and should be considered for laparoscopic colonic resection. REGISTRATION NUMBER: NCT00202111 (http://www.clinicaltrials.gov).

Management and survival trends in advanced colorectal cancer.

AIMS: Significant improvements in the outcome for patients with advanced colorectal cancer (CRC) have been achieved. The median survival for advanced CRC reported in clinical trials now approaches 2 years, but there is often a question as to whether this partly represents patient selection. We aimed to explore whether the availability of new chemotherapy drugs (irinotecan and oxaliplatin) and surgical advances have affected survival in a normal clinical setting. MATERIALS AND METHODS: A review of the Queen Elizabeth and Lyell McEwin health service prospective CRC database from 1992 to 2004 was carried out to assess outcome differences between two time cohorts (1 January 1992-31 December 1997 and 1 January 1998-31 December 2004). RESULTS: For all patients (n = 744) overall survival was seen to improve over time and is maintained out to 5 years. There have been a number of trends over time (1992-1997 vs 1998-2004) that have probably contributed to this gain; increased overall chemotherapy use (33% vs 43%); use of combination chemotherapy (i.e. oxaliplatin and irinotecan regimens); increased hepatic resection rates (1.9% vs 10.8%) and increased clinical trial uptake (0.6% vs 14.5%). CONCLUSION: This current analysis confirms an improvement in survival over time for advanced CRC and this is seen in unselected patients including those over 70 years of age.

Laparoscopically assisted colectomy: a study of risk factors and predictors of open conversion.

BACKGROUND: Conversion to an open procedure during laparoscopically assisted colorectal resection may be necessary because of technical, patient, or pathologic factors. Recent literature has indicated that converted patients may have poorer outcomes than those undergoing open or completed laparoscopically assisted procedure. This study aimed to audit the authors' experience with laparoscopically assisted colectomy and to assess the clinical outcomes of patients undergoing conversion. METHODS: All laparoscopic right hemicolectomies or anterior resections performed at seven South Australian hospitals from 1997 to 2006 were reviewed. Data pertaining to patient sex, age, American Society of Anesthesiology (ASA) score, pathology, operative outcomes including operating time, conversion, reason for conversion, length of hospital stay, and intra- and postoperative complications were analyzed. RESULTS: Laparoscopic anterior resection had a higher rate of open conversion than laparoscopic right hemicolectomy (18.7% vs 10.4%; p = 0.028). In the right hemicolectomy group, none of the investigated risk factors for conversion were statistically significant, and the morbidity rates for the two groups were similar. The median hospital stay was significantly longer in the anterior resection group (p < 0.001), and the wound morbidity rate was higher in the converted group (12.8% vs 3.0%; p = 0.022). Age older than 75 years and a high ASA status were independent risk factors for conversion in anterior resection. CONCLUSIONS: Conversion of laparoscopic anterior resection to open procedure is associated with higher wound morbidity and a longer hospital stay. The authors recommend that surgeons carefully consider the selection of patients 75 years of age or older and high ASA status for laparoscopic anterior resection.

Treatment and survival from colorectal cancer: the experience of patients at South Australian teaching hospitals between 1980 and 2002.

AIMS: To evaluate trends in colorectal cancer survival and treatment at South Australian teaching hospitals and degree of adherence to treatment guidelines which recommend adjuvant chemotherapy for Dukes' C colon cancers and combined chemotherapy and radiotherapy for high-risk rectal cancers. MATERIALS AND METHODS: Trends in disease specific survival and primary treatment were analysed, and comparisons drawn between diagnostic epochs, using cancer registry data from South Australian teaching hospitals. Statistical methods included univariate and multivariable disease specific survival analyses. RESULTS: Five-year survival increased from 48% in 1980-1986 to 56% in 1995-2002. Largest gains were for stage C, where survivals were higher when chemotherapy was part of the primary treatment. By comparison, gains in 1-year survival were largest for stage D. Chemotherapy was provided for 4% of patients with colorectal cancers in 1980-1986, increasing to 32% in 1995-2002. Among stage C cases below 70 years at diagnosis, the proportion having chemotherapy increased to 83% in 1995-2002. The most common chemotherapy was fluorouracil (5FU) as a single agent in 1980-1986 and 5FU with leucovorin in 1995-2002. As expected, radiotherapy was used more frequently for rectal than colon cancers, and particularly for stage C. Among stage C rectal cases below 70 years, the proportion having radiotherapy increased from 10% in 1980-1986 to 57% in 1995-2002. Approximately 93% of colorectal cancers were treated surgically. Patients not treated surgically tended to be aged 80 years or more and to present with distant metastases. CONCLUSIONS: Trends in chemotherapy and radiotherapy accord with evidence-based recommendations. There have been reassuring gains in survivals after adjusting for stage, grade and other prognostic indicators. The data show survival gains and treatment patterns that individual hospitals can use as benchmarks when evaluating their own experience.

Open vs. closed lateral internal sphincterotomy for idiopathic fissure-in-ano: a prospective, randomized, controlled trial.

PURPOSE: Internal sphincterotomy remains the "gold standard" for treatment of anal fissure but is associated with a risk of imperfect continence. Recent studies have suggested that surgical technique (open vs. closed) may influence incontinence rates after sphincterotomy. This study was designed to assess the short-term and long-term incidence of incontinence after open and closed internal sphincterotomy. METHODS: Seventy-nine patients were randomly assigned to open or closed internal sphincterotomy, performed in standardized fashion by trainee staff. Standardized questionnaires assessing continence (modified Wexner score) were administered preoperatively and at 1, 6, and 52 weeks. Postoperative stay, pain scores, complications, and fissure healing were prospectively assessed by an independent observer. RESULTS: Three patients were lost to follow-up, leaving 36 closed (16 males; mean age, 45.1 years) and 40 open (21 males; mean age, 47.9 years) internal sphincterotomy patients for assessment. All operations were performed as day case procedures with no readmissions. At six weeks postoperative, 96 percent of fissures had healed. There were no significant differences in pain scores between closed and open internal sphincterotomy at Day 1 or Day 3 postoperative. New incontinence of any grade was seen in 6.8 percent of patients at 52-week follow-up. Three patients (4.1 percent, 1 closed, 2 open) suffered major incontinence at 52 weeks. There were no significant differences in continence at 1, 6, or 52 weeks, although more open patients experienced minor imperfections at 1 week. CONCLUSIONS: Incontinence after internal sphincterotomy is not insignificant. The technique (closed vs. open) does not seem to influence incontinence rates.

Parastomal hernia repair.

OBJECTIVE: The aim of this study was to audit the results of parastomal hernia repair. METHODS: A retrospective review was made of all patients having parastomal hernia repair at 2 teaching hospitals over a 12-year period. RESULTS: Forty-three patients had 51 parastomal hernia repairs. Three types of hernia repair were used: 14 (28%) local suture, 19 (37%) local mesh repair and 18 (35%) stoma relocation. Three patients died and significant complications occurred in 65% of repairs. Parastomal hernia recurred in 18 (38%) of repairs. This was greatest with a sutured repair (59%) and least in patients having stoma relocation (24%). Repair with mesh was associated with a 39% recurrence rate. No significant statistical difference was found for the results of these repairs. CONCLUSION: Parastomal hernia repair is associated with high rates of morbidity, mortality and recurrence. Repair should not be undertaken without a good indication.

Sentinel node biopsy for squamous-cell carcinoma of the anus and anal margin.

PURPOSE: The majority of anal tumors are squamous-cell carcinomas. These may be tumors of the anal canal or margin. They are best treated by combination of chemotherapy and radiotherapy. T1 and T2 tumors in this regime do not receive radiotherapy to the inguinal regions despite approximately 5 to 10 percent incidence of inguinal lymph node involvement. If the nodal status of the inguinal region could be accurately assessed, then a more tailored radiotherapy regime may be given. This article describes a novel method of assessment of the status of the inguinal lymph nodes in patients. METHODS: Patients with anal squamous-cell carcinoma had four injections of 0.2 ml of antimony sulfide (30 MBq) around the tumor. Under a gamma camera, a distant high-intensity signal was located, and this point was marked on the overlying skin using an indelible ink pen. In the operating theater, patent blue dye was injected all around the tumor. The localized lymph node was removed and sent for histopathology. RESULTS: This procedure was performed on 12 patients. The sentinel node was localized to the inguinal region and removed in eight of these patients. In two patients, metastatic squamous-cell carcinoma was identified histologically in the sentinel node. CONCLUSION: We advocate that this as a safe technique for detecting metastatic disease in the inguinal nodes in patients with anal squamous-cell carcinoma.

Colorectal cancer in patients with chronic renal failure: the effect of dialysis or renal transplantation.

OBJECTIVE: This study reports the characteristics and surgical outcome of colorectal cancer in patients with chronic renal failure treated either by renal transplantation or dialysis. METHODS: Two thousand four hundred and seventeen patients with CRF (1387 transplant and 1030 dialysis) were treated at The Queen Elizabeth Hospital, South Australia, between January 1967 and September 2000. RESULTS: Fourteen have developed colorectal cancer and had their clinical records reviewed. Nine patients were renal transplant recipients and 5 patients were treated with dialysis. Eight patients had surgery. Chemotherapy was given palliatively to 3 patients. One patient died in hospital postoperatively. Seven patients with a renal transplant had notes available. Six presented with late stage disease and all were dead within 9 months of presentation from their disease. In the dialysis patients, tumour stage at presentation was not so advanced and although all the patients have died, the cause of death was secondary to the colorectal cancer in only 2 patients. CONCLUSIONS: This study highlights the poor outcome of patients who have had renal transplant and develop colorectal cancer. Immunosuppression and late diagnosis are implicated in this poor outcome.

The Ca2+-binding proteins S100A8 and S100A9 are encoded by novel injury-regulated genes.

To gain insight into the molecular mechanisms underlying cutaneous wound repair, we performed a large scale screen to identify novel injury-regulated genes. Here we show a strong up-regulation of the RNA and protein levels of the two Ca(2+)-binding proteins S100A8 and S100A9 in the hyperthickened epidermis of acute murine and human wounds and of human ulcers. Furthermore, both genes were expressed by inflammatory cells in the wound. The increased expression of S100A8 and S100A9 in wound keratinocytes is most likely related to the activated state of the keratinocytes and not secondary to the inflammation of the skin, since we also found up-regulation of S100A8 and S100A9 in the epidermis of activin-overexpressing mice, which develop a hyperproliferative and abnormally differentiated epidermis in the absence of inflammation. Furthermore, S100A8 and S100A9 expression was found to be associated with partially differentiated keratinocytes in vitro. Using confocal microscopy, both proteins were shown to be at least partially associated with the keratin cytoskeleton. In addition, cultured keratinocytes efficiently secreted the S100A8/A9 dimer. These results together with previously published data suggest that S100A8 and S100A9 are novel players in wound repair, where they might be involved in the reorganization of the keratin cytoskeleton in the wounded epidermis, in the chemoattraction of inflammatory cells, and/or in the defense against microorganisms.

Delayed pudendal nerve conduction and endosonographic appearance of the anal sphincter complex.

PURPOSE: The aim of this study was to test the hypothesis that a delay in pudendal nerve conduction as measured by pudendal nerve terminal motor latency should be associated with atrophy of the external anal sphincter as measured using endoanal ultrasound. METHODS: Sixty-two adult females (median age, 58.9 (range, 22-88) years) presenting for evaluation of fecal incontinence with no evidence of an external anal sphincter tear on ultrasound were recruited. Ultrasound was performed with a 7.5-MHz radial rotating axial endoprobe in the left lateral position. Four measurements were made in the transverse plane--the external anal sphincter thickness in the midanal canal at the 6 o'clock and 9 o'clock positions, the internal sphincter at the 9 o'clock position, and the external anal sphincter in the low canal at the 9 o'clock position. Pudendal nerve terminal motor latency was measured using a transrectal nerve stimulation technique with measurement of the evoked muscle response. RESULTS: Although there was a trend toward thinner external sphincter muscles in those with bilateral prolonged pudendal nerve terminal motor latency, independent sample t-tests and Pearson correlation coefficients showed no statistically significant relationship (right pudendal nerve terminal motor latency: P = 0.083, 0.184, 0.128, 0.910; r = 0.228, 0.175, -0.201, -0.015; left pudendal nerve terminal motor latency: P = 0.946, 0.276, 0.510, 0.123; r = -0.009, -0.143, -0.087, -0.201). CONCLUSIONS: No statistically significant relationship between ultrasound-measured anal sphincter muscle thickness and pudendal nerve terminal motor latency was identified. Although a trend was suggested that could be further evaluated by a study with a larger sample size and a control group with asymptomatic patients, the small differences in muscle thickness involved and the difficulties in measurement suggest that the establishment of clinically useful ultrasound criteria for the detection of the neuropathic anal sphincter complex is unlikely.

Overgrowth of skin in growth hormone transgenic mice depends on the presence of male gonads.

Growth hormone has been shown to possess stimulatory effects on various connective tissues. We observed that skin growth in male rat phosphoenolpyruvate carboxykinase-bovine growth hormone transgenic mice (serum growth hormone levels: 740-1940 ng per ml) is progressive with age, resulting in an "oversized coat" phenotype with a marked increase in absolute and relative skin weight and surface area, and in thickness of the dermis. Histologic changes include severe dermal fibrosis and replacement of subdermal adipose tissue by fibrous tissue. Apart from an increase in skin surface area, these changes were not noted in female transgenic mice, arguing for a specific interaction of growth hormone with male sex hormones. To clarify this point, 6 wk old male transgenic mice and control mice were castrated and compared with their noncastrated counterparts in parameters of skin growth at an age of 8 mo. The skin weight of castrated transgenic mice was smaller (p < 0.01) than that of intact transgenic mice both absolutely and relative to body weight. The relative skin weight of castrated transgenic mice was in the same range as in intact and castrated control mice. Absolute and relative skin area of castrated transgenic mice was greater (p < 0. 001 and p < 0.05) than in controls but lower than in intact transgenic mice (p < 0.001 and p < 0.05). When compared with control mice, intact transgenic mice displayed an increase (p < 0.01) in the thickness of dermis. In castrated transgenic mice the thickness of the dermis was in the same range as in control mice. Our findings demonstrate a specific interaction of growth hormone with male sex hormones resulting in a marked stimulation of skin growth.

Chimeric pigs following blastocyst injection of transgenic porcine primordial germ cells.

Porcine primordial germ cell (PGC) derived cell lines of WAPhGH-transgenic pigs have been established that were able to contribute to chimeras. PGCs were isolated from day 25 to 28 genital ridges of more than 30 individual transgenic fetuses in order to have an easy to follow marker gene. To support undifferentiated growth, cell lines were derived and stable maintained on STO no. 8 feeder cells, a murine embryonic fibroblast cell line expressing recombinant, membrane-bound porcine stem cell factor (SCF). Fifteen lines proliferated in an undifferentiated state up to passage 13; two lines were maintained for more than 23 passages. Cell staining experiments for differentiation markers in several cell lines, indicated the presence of pluripotent cells in prolonged cultures. Further characterization using karyotyping revealed a normal, euploid set of chromosomes in cells of passages 15 and higher. Pluripotency of freshly isolated, short-term (up to 24 hr before injection) and long-term cultured, frozen/thawed cells was tested by injection into day 6 recipient blastocysts to give rise to chimeric piglets. The injected embryos (n = 209) were endoscopically transferred into the uterine horns of 11 recipient gilts. Tissue analysis from 49 fetuses and eighteen liveborn piglets for PGC contribution in chimeras was carried out using PCR analysis for the presence of the marker transgene. Thirty-two fetuses showed detectable chimerism in up to five out of 12 tissues analyzed. Skin samples from eight piglets were positive for the transgene, four of them displayed coat colour chimerism.

The effect of vaginal delivery on anal function.

The commonest cause of faecal incontinence is considered to be childbirth. In this review we consider the available data on the prevalence of faecal incontinence in the community and the incidence of incontinence after childbirth. The results and implications of studies on childbirth using anal manometry, neurophysiological tests and anal ultrasound are discussed. The development of symptoms are more likely with a third degree tear and forceps delivery. Reduced resting and squeeze pressures are seen early after vaginal delivery with recovery noted with time. Reduced pressures have been seen in symptomatic and asymptomatic women and there is no correlation of the pressures with the presence or absence of a sphincter defect or evidence of pudendal neuropathy. Anal manometry can not be used as an indication of muscle or nerve injury. Both sphincter defects and evidence of pudendal neuropathy are common after vaginal delivery but these are not necessarily associated with symptoms. It is suggested that such occult sphincter injuries may go on to be symptomatic in later life. The number of these injuries, however, is far greater than the documented prevalence of incontinence in the community, and hence many must remain asymptomatic. Their true clinical significance remains uncertain.

Total colectomy for Crohn's disease.

BACKGROUND: Total colectomy for Crohn's disease of the colon may be restorative with ileorectal anastomosis or with an ileostomy and rectal stump. The present paper retrospectively audits the results of total colectomy and in particular assesses the number of patients who had a permanent ileostomy and whether this was related to disease in the rectum at the time of the original operation. METHODS: A retrospective case note review was undertaken of patients operated upon between 1968 and 1994. RESULTS: Thirty-eight patients were identified (mean age 35 years; range 17-65 years). One patient died perioperatively from an anastomotic leak. Median follow-up for the remaining patients was 7 years (range 1-29 years). Ileorectal anastomosis was performed in 17 patients and total colectomy and ileostomy in 20 patients. Indications for surgery were failure of medical treatment (61%); toxic colitis (18%); abscess (8%); perforation (5%); large bowel obstruction (5%); and colovesical fistula (3%). Subsequent proctectomy (14 patients, 38%) was more likely with subtotal colectomy and ileostomy (nine patients, 45%) than ileorectal anastomosis (five patients, 29%). This was not statistically significant (P = 0.33). Additionally, seven patients had diversion of the rectum making 21 with an ileostomy (57%). Rectal involvement at the time of the original procedure significantly increased the likelihood of permanent ileostomy (P = 0.001). The presence of anal disease did not increase the prospect of ileostomy. One patient died with advanced adeno carcinoma in a defunctioned rectum. CONCLUSIONS: A permanent ileostomy after total colectomy for Crohn's disease is common and significantly more likely with rectal involvement.

Intestinal sleeve anastomosis: a comparative study with end-to-end anastomosis.

This study examines the utility of a sleeve anastomosis with comparison to conventional end to end anastomosis. Thirty New Zealand white rabbits were randomized to sleeve (n = 15) or end-to-end (n = 15) small bowel anastomosis. Five rabbits of each group were sacrificed at 3 days, 7 days, and 6 weeks. Anastomoses were assessed for integrity, bursting strength, and stenosis and examined histologically. Ten control specimens of small bowel were tested for bursting pressure. Three rabbits died postoperatively (1 sleeve and 2 end-to-end). A fourth rabbit (sleeve) was sacrificed early at 3 weeks and had a total stenosis at the anastomosis. The remaining 26 rabbits were reoperated at the prescribed times. There was no evidence of infection or dehiscence in any of these rabbits. Both end-to-end and sleeve anastomoses were equivalent for bursting pressure at all times and, at 7 days and 6 weeks, were similar to controls. The stenotic index revealed no evidence of proximal dilation suggestive of obstruction in the 26 rabbits. For sleeve anastomoses the length of the projected bowel into the lumen persisted at the 6-week stage. Histologically there was good evidence of healing in both the sleeve and end-to-end anstomoses and the serosal surface of the sleeved bowel had epithelialized. Sleeve anastomosis has been demonstrated to heal well and to be as strong as conventional end-to-end anastomosis. Further studies are warranted to determine its role in intestinal anastomosis and potential as a valve.