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Impact of surgeon organization and specialization in rectal cancer outcome.

PURPOSE: The present study was designed to assess the differences in the outcome of patients with rectal cancer treated by a group of surgeons before and after being organized as a Coloproctology Unit at the same University Department of Surgery. METHODS: Comparison of two periods of rectal cancer surgery: I (1986-91) and II (1992-95). Period I: 94 patients were operated on by 14 general surgeons. Period II: 108 patients were operated on by only 4 surgeons of the same group organized as a Colorectal Surgery Unit after visiting referral centres abroad, adopting techniques such as total mesorectal excision (TME) for middle and low rectal cancer and washout of rectal stump. Mean follow-up during periods I and II was 69.1 and 42.0 months, respectively. A prospective data base analysis was used. Survival and local recurrence rates were calculated by the actuarial method. For comparison between groups the log rank method was used. RESULTS: The two groups were comparable with respect to mean age, gender, TNM and rectal tumour location. A significant increase in radical resectability and a decrease of the Abdominoperineal resection (APR)/Low anterior resection (LAR) ratio were observed in the second period. The overall pelvic recurrence rate was 25% in the first period and 11 in the second (P < 0.01). Significant differences were also found when the patients with LAR were compared between both periods, 30% vs 9% (P < 0.01) and specially when the 10 cm anal verge distance was considered to divide the LAR groups. No differences were found regarding the APR procedures in both periods. There was improved cancer-specific survival for the LAR group in the second period (P=0.03). CONCLUSION: Specialization and centralization influence the quality of rectal cancer surgery, mainly local recurrence rates and survival after low anterior resection.

Journal Article↗

Mesorectal excision for rectal cancer: functional outcome after low anterior resection and colorectal anastomosis without a reservoir.

OBJECTIVE: The anal sphincters, neorectal capacity and motility may be affected by injury to the autonomic nerves during rectal resection. Anorectal function also depends on the method used for restoration of intestinal continuity, and colonic reservoir reconstruction has been recommended in ultralow anastomosis. This study was undertaken to evaluate the results after nerve preserving mesorectal excision and colorectal anastomosis without a reservoir. PATIENTS AND METHODS: Thirty-five consecutive patients who underwent low anterior resection with primary healing of the anastomosis, were included. Anal manometry with stationary pull through technique, rectal volumetry and symptom scoring (written questionnaires with visual analogue scales) were performed prior to and 12 months after surgery. Anal sphincter function was evaluated in all patients, but five patients with a colonic reservoir were excluded from the other evaluations. Thirty patients entered the main study; 14 patients having a total mesorectal excision (TME) and a low anastomosis (LA) (4-6 cm) and 16 patients a partial mesorectal excision (PME) and a high anastomosis (HA) (7-11 cm from the anal verge). RESULTS: Anal resting and squeeze pressure and rectal sensibility (threshold volume) were unchanged after the operation. The rectal volume eliciting urge to defecate was reduced from median 95 ml to 70 ml (P < 0.01), and the maximum tolerable rectal volume was reduced from 200 to 135 ml (P < 0.01) after the operation. The maximum tolerable volume was significantly lower in patients with LA than in patients with HA (P < 0.01). Overall functional results were good. The patients reported problems with complete bowel emptying (median VAS-score reduction from 90 to 60, P < 0.01), and minor incontinence problems (median VAS-score reduction from 100 to 90, P= 0.03). The reduction of VAS-scores was more pronounced in LA than HA patients (without reaching statistical significance). CONCLUSIONS: Anal sphincter function was preserved after mesorectal excision. Neorectal capacity was reduced, most pronounced in patients with LA. The overall functional results were satisfactory and slightly better in patients with HA than in those with LA.

Journal Article↗

Surgery for locally recurrent rectal cancer.

After the diagnosis of a locally recurrent rectal cancer, imaging is the first step to estimate the extent and location of the local tumour growth and the presence or absence of distant metastases. The aim of the treatment is a R0 resection (microscopically tumour free circumferential margin) by multimodality treatment consisting of pre-operative radiation, extended resection and intra-operative radiotherapy by either electron beam irradiation or with high dose rate brachytherapy. Filling the pelvic cavity with vital tissue such as an omentoplasty should considered carefully. With this treatment the overall three-year survival rate of a group of 33 patients was 60% with a local control rate of 73%. The combination of chemotherapy as a radiosensitizer resulted in an increase of R0 resections by 20%. Introduction of TME surgery and pre-operative radiotherapy has created a new situation with limited possibilities due to dose-accumulation toxicity of the radiotherapy and extensive scarring of the tissues making estimation of the extent of the tumour growth more difficult. The prevention of local recurrence by proper selection of primary cases, the training of experienced surgeons and the optimal use of pre-operative radiotherapy is the way forward to improve results.

Combined Modality Therapy↗

Long-term results of radical surgery for rectal cancer: multivariate analysis of prognostic factors influencing survival and local recurrence.

AIMS: To evaluate consistent radical surgery performed over a 13-year period for rectal cancer in terms of local tumour control and long-term survival. METHODS: Radical surgical procedure principally using total mesorectal excision (TME) for middle and lower rectal tumours, high ligation of the inferior mesenteric artery and sphincter-saving resections (SSR) whenever possible, has been performed prospectively since January 1984. RESULTS: Tumour resection was possible in 98.8% (636/644), potentially curative resections (UICC/AJCC R0 resection) in 85.7% (552/644) and sphincter preservation in 71.7% (462/644). Five- and 10-year observed survival rates, surgical mortality not excluded, for all patients were 49.2% and 37.4%. Tumour-adjusted 5- and 10-year survival rates were 60.5% and 55.3%. For curatively operated patients (UICC/AJCC R0) 5- and 10-year observed survival rates were 56.3% and 42.6% and tumour-adjusted survival rates were 68.6% and 62.7%. The 5- and 10-year local recurrence rates for R0 resected patients were 12.0% and 12.6%. Post-operative hospital mortality was 3.1%. CONCLUSIONS: Multivariate analysis using Cox's model identified increasing pT category and pN category, old age and low tumour location as detrimental factors having independent influence on survival. For local tumour failure only pT and pN category as well as adjuvant radiation therapy were identified in the Cox model as having an independent detrimental influence.

Adult↗

[Options for quality improvement in the treatment of rectum carcinoma].

By means of a prospective multi centre study, 13 419 cases of surgically treated patients with rectum carcinomas were registered between 1.1.2000 and 31.12.2003 and assessed in regard to possible problems concerning indications and operative procedures. Beside a high rate of non-local resective procedures in T1-low risk carcinomas, unnecessary extirpations in cases of tumour localisation over 8 cm from the anal verge were found. Tumours of the lower two-thirds of the rectum were treated by incomplete TME in 20 % of the patients. In addition, there seems to be too low a rate of neo-adjuvant therapy procedures. Protective stomata were frequently foregone after low anterior resection. Endoscopic interventional methods were still used reluctantly in inoperable situations.

Germany↗

Total mesorectal excision is not necessary for cancers of the upper rectum.

BACKGROUND: The technical aspects of surgery of the upper rectum (10 to 15 cm from the anal verge) and sigmoid colon are similar, but a change in technique is required for surgery of the lower rectum (< 10 cm). The aim of this study was to compare the outcomes of the treatment of upper rectal cancer (UR), in which total mesorectal excision (TME) was not performed, with outcomes of sigmoid colon cancers (S) and lower rectal cancers (LR). METHODS: Between 1980 and 1990, 891 patients were treated with curative intent for sigmoid (n = 225) and rectal cancer (UR = 229; LR = 437). The Kaplan-Meier and Cox proportional hazards analyses were used to compare outcomes. RESULTS: The risk of local recurrence alone, local and distant recurrence, death as a result of cancer, or any recurrence or death as a result of cancer was 3.5, 2.7, 2.1, and 1.9 times higher for patients with LR than for patients with UR, but the risk was not increased for UR relative to S. CONCLUSIONS: The outcome of treatment for UR is the same as for S and differs favorably from that for LR. UR should be treated by the same technique as S.

Adenocarcinoma↗

A prospective evaluation of anorectal function after total mesorectal excision in patients with a rectal carcinoma.

BACKGROUND: Rectum resection with total mesorectal excision (TME) and neorectal anastomosis often compromises anorectal function. Insight into the underlying mechanisms is lacking. Therefore, a prospective study was designed to investigate the relationship between clinical and functional outcomes preoperatively and postoperatively. METHODS: Eleven patients with rectal cancer were examined before and 4 and 12 months after surgery and compared with 11 healthy volunteers (HVs). Anorectal (neorectal) function was examined by clinical outcome questionnaire, anal manometry, rectal compliance, and sensation. Six HVs also underwent barostat measurements in the sigmoid colon. RESULTS: Clinical parameters of soiling and passive incontinence (loss of stool without sensation) increased significantly until 12 months postoperatively, whereas urgency and tenesmus increased temporarily, returning to preoperative values at 12 months. In anorectal measurements, anal sphincter function was grossly preserved; however, rectal-anal inhibitory reflex (RAIR) was decreased at 4 months but recovered after 1 year. Neorectal compliance was similar to that of HV sigmoid, increasing slightly after 12 months but still significantly lower than that of normal rectum. Neorectal sensation to pressure distention was similar to that of normal rectum, however accompanied by smaller volumes. Neorectal distention induced contractions of large amplitude at 4 months, returning to normal after 12 months. CONCLUSIONS: Our results suggest that the transient increase in urgency and tenesmus after surgery results from a temporary increase in neorectal "irritability" accompanied by some adaptation of compliance in time. In contrast, episodes of incontinence and soiling are increased after 1 year most likely because of reduced neorectal capacity and RAIR recovery in the presence of a low basal anal sphincter pressure.

Compliance↗

Survival of rectal cancer patients in Belgium 1997-98 and the potential benefit of a national project.

BACKGROUND: PROCARE, a Belgian multidisciplinary project on rectal cancer (RC), will be launched in 2006. Guidelines have been developed, but remain to be implemented. AIM: A population-based study on RC treatment and outcome in Belgium and comparison with recent international benchmarks in order to better define targets that should be reached. PATIENTS AND METHODS: Anonymous data of 3079 patients with rectal cancer registered in the National Cancer Registry in 1997 and 1998 were analysed. Observed (OS) and relative survival (RS) were compared with figures from nationwide projects and multi-centre studies. RESULTS: The 5-yr OS and RS were 46.6% and 58.5%, respectively. For patients with stage I-III tumours 5-yr OS was 57.1% and 5-yr RS 70.1%. Adjuvant or neo-adjuvant treatment was given in 54.8% stage II-III patients who were < 70 years old. There were marked differences between the provinces in the use of radiotherapy for stage II-III patients and in 5-yr RS for all stages. In stage IV, the median OS was 13 months and the 2-yr OS was 28%. Comparison with recent multi-centre trials indicates significant potential benefits from the PROCARE project: an absolute increase of the 5-yr OS by 10 to 20% after chemoradiotherapy and TME in stage II-III patients 75 years old or less, a 7-month increase of the median OS and an absolute 15% increase of the 2-yr OS in unresectable stage IV patients with combined chemotherapy. CONCLUSION: Significant improvement seems to be achievable. Implementation of the PROCARE guidelines with quality assurance through prospective registration in a specific database, however, is a crucial prerequisite for credible audit of performance and feedback to individual teams.

Adolescent↗

The potential for the improvement of the nutritive value of soya-bean meal by different proteases in broiler chicks and broiler cockerels.

1. The potential for improving the nutritive value of commercial solvent-extracted, heat-treated soya-bean meal (SBM) by protease treatment was measured using growing broiler chicks and tube-fed broiler cockerels. 2. SBM was pre-treated (50 degrees C for 2 h) with water alone; at alkaline pH (initial pH 8.25) with and without protease P1 (isolated from a Bacillus species) or at acid pH (initial pH 4.5) with and without protease P2 (isolated from an Aspergillus species) and incorporated into diets (290 g SBM/kg diet) for broiler chicks (20 chicks/treatment). Only protease P2 treatment improved chick performance; from 7 to 28 d of age, chicks fed on treated SBM had greater feed intakes and gained more weight than chicks fed on untreated SBM. Both proteases P1 and P2 significantly reduced chick serum anti-soya antibodies while protease P2 treatment increased apparent ileal nitrogen (N) digestibility and apparent N retention across the whole digestive tract. 3. Two tube-feeding experiments established that, of the treated SBMs used in experiment 1, only protease P2 treatment improved apparent N digestibility and true metabolisable energy. Also it was shown that increasing the temperature at which treated SBM was dried to 60 degrees C, compared with freeze-drying or drying at 50 degrees C reduced apparent N digestibility and true metabolisable energy of SBM with no significant interactions between enzyme treatment and drying temperature for both apparent N digestibility and TME. 4. It is concluded that, overall, the nutritional value of SBM assayed in a growth trial and by tube feeding was improved by treatment with protease P2 and not by treatment with protease P1.

Animal Feed↗

Influence of level of feed input and procedure on metabolisable energy and endogenous energy loss (EEL) with adult cockerels.

1. Two experiments were performed to study the relationship between apparent metabolisable energy (AME) and true metabolisable energy (TME) values at different feed intakes. Rhode Island Red (RIR) adult cockerels were used in two bioassays, under standard conditions. 2. In the first experiment (precision feeding) the birds were not fed for 24 h and then various quantities of maize were fed. There were 6 replicates per treatment. Droppings voided during the 48 h of the experimental period were collected and assayed for gross energy and nitrogen. 3. In the second experiment, each bird was given a 3-d adaptation period, fasted for 24 h and then given maize as an admixture (conventional addition method: CAM) to the same rations as those used in the first experiment. During the 3 d of the experimental period, droppings were collected and frozen for chemical analysis. 4. The results showed that mean metabolisable energy (ME) values obtained by the precision-feeding procedure were higher than those obtained by CAM. The endogenous energy loss (EEL) (FEm + UEe) determined by precision feeding was lower than that given by CAM. 5. It was concluded that the method of feeding does not influence ME of maize at different feed inputs. However, differences among intercepts of the regression between ME and feed input suggest that EEL varies at different maize inputs. 6. The optimum maize quantity was approximately 35 to 40 g for adult RIR cockerels by both procedures.

Animal Feed↗

Endogenous losses of energy and amino acids in birds and their effect on true metabolisable energy values and availability of amino acids in maize.

1. Endogenous losses of amino acids (EAAL) and energy (EEL) were determined in unfed adult cockerels. The intercepts of linear regression analysis were determined using 44 birds precision-fed on maize. During the experimental period (48 h), excreta of birds were collected, and the samples of maize and the excreta were dried, ground and assayed for gross energy and amino acids. 2. The EAAL and EEL in unfed cockerels influenced true available amino acid (TAAA) values. Therefore, the intercept of regressions showed an increase in TAAA values of maize. 3. The results indicated that there was no significant difference between the data obtained for EEL from the unfed birds and from regression analysis so, the figure from regression analysis could be used for calculating the true metabolisable energy (TME) value of maize. 4. The calculated EAAL from regression analysis caused an increase in the TAAA value in maize. The amounts of metabolic and endogenous amino acid excretions varied in voided excreta from unfed birds. These differences would be related to genetics, age, sex and environmental temperatures.

Amino Acids↗

Effect of feeding technique, ad libitum, dry or wet force feeding, on the metabolisable energy values of raw materials for poultry.

1. Metabolisable energy values (AME, AMEn, TME and TMEn) of three raw materials (maize, sunflower meal and soyabean meal) were determined in adult cockerels using two classical feeding e techniques (ad libitum and force-feeding of dry food) and a new one in which birds were force-fed wet diets. 2. In the wet force-feeding assay nitrogen balances and food intakes were similar to those achieved with ad libitum feeding. The duration of the assay using wet force-feeding was only 2 d as compared to the 3 or 7 d experimental periods for the dry or the ad libitum assays respectively. 3. TMEn values were not dependent on the feeding technique used; AME and AMEn data obtained in the ad libitum and wet force-feeding assays were close to TMEn values. As expected, these values were underestimated in the dry force-feeding assay.

Animal Feed↗

True metabolisable energy values of some feedingstuffs.

1. The apparent metabolisable energy (AME) and the true metabolisable energy (TME) contents of some feedingstuffs were determined with cockerels. The test materials consisted of feed-grade lentil, lentil bran and wild vetch seed. 2. The average values of nitrogen lost, endogenous energy losses (EEL) and endogenous energy losses corrected to zero-nitrogen balance (EELN) were found to be 1.18 g, 62.13 kJ and 21.51 kJ/bird/48h, respectively, from adult cockerels given an energy supply as 50 g glucose during starvation. 3. The nitrogen-corrected apparent metabolisable energy (AME(N)) values for feed-grade lentil, lentil bran and wild vetch seed, respectively, were 6.84, 3.05 and 14.31 kJ/g dry matter. The nitrogen-corrected true metabolisable energy (TMEN) values for the respective feedingstuffs were 7.44, 3.65 and 14.90 kJ/g dry matter.

Animal Feed↗

A simple and sensitive radioimmunoassay for adenosine.

We developed a simple and sensitive radioimmunoassay (RIA) for adenosine. The RIA is based on the double antibody method with adenosine 2', 3'-0-disuccinyl-3-[125I]-iodotyrosine methyl ester (diSc-adenosine-[125I]-TME) as a tracer. Anti-adenosine antiserum for the RIA was raised in rabbits immunized with diSc-adenosine conjugated to human serum albumin (diSc-adenosine-HSA). All samples and standards were succinylated prior to assay. The present immunoassay allows detection of 6.25-400 pmol/ml of adenosine in sample. Values obtained by the RIA and by a HPLC analysis showed a high correlation with correlation coefficient of 0.997. In order to determine adenosine in plasmas, blood cells must be separated in the presence of 6 mM EDTA, 0.006% dipyridamole (Dip) and 23 microM 2'-deoxycoformycin (dCF) at 2 degrees C. Adenosine in plasma could be accurately determined by the proposed method even without any pretreatments by deproteinizing. The adenosine levels with or without EDTA-treated normal human plasmas determined were 26.2 +/- 7.26 and 100 +/- 3.62 pmol/ml (mean +/- SEM), respectively.

Adenosine↗

Preoperative radiotherapy for rectal cancer--is 5 x 5 Gy a good or a bad schedule?

Preoperative radiotherapy substantially lowers local failure rates after rectal cancer surgery, an effect that is seen whether surgery is optimized, total mesorectal excision (TME), or not. Preoperative radiotherapy also slightly improves survival. Postoperative radiotherapy also decreases local recurrence rates, but the relative reduction is less pronounced even when higher doses are used. Preoperatively, a high-dose, short-term schedule, 5 x 5 Gy in one week, has been used in several randomised trials. This is a convenient schedule and has low toxicity if properly conducted. In trials where the radiation technique has been simplified, resulting in large irradiated volumes, unacceptable acute and late toxicities have been seen. It has not yet been possible to detect any late toxicity in trials where the treatment was given using techniques avoiding the irradiation of unnecessarily large tissue volumes outside the target volume. The relative advantages of using this short-term schedule relative to a conventional irradiation for about 5 weeks are discussed.

Dose Fractionation, Radiation↗

Quality of treatment in routine care in a population sample of rectal cancer patients.

Variations in compliance with rectal cancer treatment guidelines and the effect of quality indicators on long-term outcomes were investigated with data from the Munich Cancer Registry. Patients diagnosed between 1996 and 1998 with an invasive primary rectal tumor which was resected were included in these analyses (n=884). Median follow up was 5.7 years. Relative and overall survival was examined. Adjusted survival was predicted by UICC stage, grade, age, local recurrence, and residual tumor status. UICC III patients receiving the recommended adjuvant therapy had a significant survival advantage in the multivariate model; UICC II patients did not. Even if there were no significant survival differences there were significant treatment and outcome (regarding local recurrence) variations between hospitals. The variations between hospitals refer to different quality indicators in the individual hospitals. The outcome (regarding survival) appears good in Munich and is comparable with other population studies. Fewer local recurrences, better reporting of the TME technique, greater use of combined therapy and fewer stomas, however, may improve the quality of care in Munich. Variations in care between hospitals should therefore be monitored and controlled. Detailed and frequent feedback to the clinicians is vital to improve quality of care and is possible with cancer registries.

Aged↗

Regional micrometastasis of low rectal cancer in mesorectum: a study utilizing HE stain on whole-mount section and ISH analyses on tissue microarray.

AIM: To investigate the regional spread of microscopic tumor nodules in the mesorectum of patients with low rectal cancer, and to provide further pathological evidence for optimal procedure selection of radical resection for rectal cancer. METHODS: Sixty-two patients with low rectal cancer underwent low anterior resection and total mesorectal excision (TME). Surgical specimens were sliced transversely on serial embedded blocks at 2.5-mm intervals, and stained with hematoxylin and eosin (HE). On whole-mount sections the mesorectum was divided into 3 regions: the outer region of the mesorectum (ORM), the middle region of the mesorectum (MRM), and the inner region of the mesorectum (IRM). Microscopic metastatic foci were investigated for metastatic mesorectal region, frequency, types, involvement of the lymphatic system, and correlation with the primary tumor. Tumor-suspect nodules previously considered disease free by HE stain on whole-mount section were examined by in situ hybridization (ISH) on tissue microarray (TMA) through detecting mRNAs of CEA and CK20 with non radioactive biotin-tagged oligonucleotide probes. RESULTS: Microscopic spread of the tumor was observed in 50.0 percent of patients (31 out of 62, 24 by HE stain on whole-mount section and 7 by ISH on TMA) and that in the ORM was observed in 38.7 percent of the patients (24 out of 62, 16 observed by HE stain on whole-mount section and 8 by ISH on TMA). Microscopic tumor foci spread in the circumferential resection margin (CRM) occurred in 8.1 percent of the patients (5 out of 62, 4 observed by HE stain on whole-mount section and one by ISH on TMA), and distal mesorectum (DMR) involvement was detected in 6.5 percent (4 out of 62, all observed by HE stain on whole-mount section), with the spread extending to within 3 cm from the lower margin of the tumor. Most (26 of 31) of the patients with microscopic spread in mesorectum had TNM Stage III diseases. CONCLUSIONS: The results of the present study support the theory that complete excision of the mesorectum without destruction of the ORM is essential for surgical management of low rectal cancer, and an optimal DMR clearance resection margin of no less than 4 cm was referenced. Five patients with microscopic tumor nodule spread in the CRM observed in the study suggested that microscopic metastases exist in pelvic lateral areas and in the mesorectum simultaneously, indicating the significance of preoperative and/or postoperative radiochemotherapy.

Adenocarcinoma↗

Development and validation of a novel risk stratification signature derived from migrasome and tumor microenvironment-related genes for molecular subtyping and improving clinical outcomes in head and neck squamous cell carcinoma.

BACKGROUND: The tumor microenvironment (TME) and migrasomes released by tumor cells significantly influence carcinogenesis and immune evasion. However, our understanding of the prognostic and therapeutic implications of migrasome and tumor microenvironment-related genes (mtmRGs) in head and neck squamous cell carcinoma (HNSCC) remains limited. METHODS: We explored the relationship between mtmRGs and HNSCC prognosis by utilizing The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Subsequently, we developed an innovative prognostic signature, and assessed its prognostic significance using the Kaplan-Meier method, time-dependent receiver operating characteristic (ROC), and Cox regression analyses. To explore the underlying mechanisms, we conducted gene set variation analysis (GSVA), gene set enrichment analysis (GESA), and immune infiltration analysis. A nomogram was developed to estimate the overall survival (OS) rates for HNSCC patients. Lastly, we chose P4HA1, which was part of the signature, for additional experimental validation in vitro and in vivo. RESULTS: The mtmRGs signature effectively classifies HNSCC patients into two distinct risk subgroups, with the high-risk cohort demonstrating significantly poorer OS. The risk score serves as an independent prognostic factor for HNSCC patients; those with lower risk scores are more likely to exhibit favorable responses to immunotherapy, particularly with CTLA4 inhibitors. Furthermore, a lower risk score is significantly correlated with the sensitivity of HNSCC patients to cyclophosphamide, gemcitabine, and axitinib. CONCLUSION: This study presents an innovative gene signature associated with mtmRGs, which may be utilized both for predicting survival and directing personalized chemotherapy and immunotherapy regiments for patients with HNSCC.

Humans↗