The risk of long-term bowel dysfunction after resection for sigmoid adenocarcinoma: a cross-sectional survey comparing complete mesocolic excision with conventional surgery.

AIM: To investigate whether complete mesocolic excision (CME) might carry a higher risk of bowel dysfunction and subsequent reduction in quality of life compared with conventional resection. METHOD: A cross-sectional questionnaire study based on data from a national survey regarding long-term bowel function and a population-based cohort study comparing CME (study group) with conventional resection (control group). A total of 622 patients undergoing elective resection for Stage I-III sigmoid adenocarcinoma at four university colorectal centres between June 2008 and December 2014 were eligible to receive the questionnaire in mid-November 2015. Primary outcomes were four or more bowel movements daily, nocturnal bowel movements, unproductive call to stool, obstructive sensation and impact of bowel function on quality of life (QOL). RESULTS: One hundred and twenty-seven (69.0%) and 289 (66.0%) patients in the study and control groups, respectively, responded to the questionnaire after medians of 4.41 [interquartile range (IQR) 2.50, 5.83] and 4.57 (IQR 3.15, 5.82) years, respectively (P = 0.048). CME was not associated with: increased risk of four or more bowel movements daily [adjusted OR 1.14 (95% CI 0.59-2.14; P = 0.68)], nocturnal bowel movements [adjusted OR 1.31 (0.66-2.53; P = 0.43)], unproductive call to stool [adjusted OR 0.99 (0.54-1.77; P = 0.97)] or obstructive sensation [adjusted OR 1.01 (0.56-1.78; P = 0.96)]. While one in five patients in both groups had moderate to severe impact of bowel function on QOL, there was no association with CME. CONCLUSION: For patients with sigmoid cancer, CME is associated with neither higher risk of bowel dysfunction nor impaired QOL.

The effect of a multidisciplinary regional educational programme on the quality of colon cancer resection.

AIM: Mesocolic plane surgery with central vascular ligation produces an oncologically superior specimen following colon cancer resection and appears to be related to optimal outcomes. We aimed to assess whether a regional educational programme in optimal mesocolic surgery led to an improvement in the quality of specimens. METHOD: Following an educational programme in the Capital and Zealand areas of Denmark, 686 cases of primary colon cancer resected across six hospitals were assessed by grading the plane of surgery and undertaking tissue morphometry. These were compared to 263 specimens resected prior to the educational programme. RESULTS: Across the region, the mesocolic plane rate improved from 58% to 77% (P < 0.001). One hospital had previously implemented optimal surgery as standard prior to the educational programme and continued to produce a high rate of mesocolic plane specimens (68%) with a greater distance between the tumour and the high tie (median for all fresh cases: 113 vs 82 mm) and lymph node yield (33 vs 18) compared to the other hospitals. Three of the other hospitals showed a significant improvement in the plane of surgical resection. CONCLUSION: A multidisciplinary regional educational programme in optimal mesocolic surgery improved the oncological quality of colon cancer specimens as assessed by mesocolic planes; however, there was no significant effect on the amount of tissue resected centrally. Surgeons who attempt central vascular ligation continue to produce more radical specimens suggesting that such educational programmes alone are not sufficient to increase the amount of tissue resected around the tumour.

Incidence of venous thromboembolic events in enhanced recovery after surgery for colon cancer: a retrospective, population-based cohort study.

AIM: Both the Danish and the National Institute of Clinical Excellence (NICE) guidelines recommend prolonged thromboprophylaxis (PT) with low-molecular-weight heparin (LMWH) for 28 days postoperatively after elective surgery for colon cancer. The evidence relies on data from two randomized clinical trials (RCTs) that included not only colon cancers but also other abdominal cancers or benign colorectal diseases. Neither of those studies investigated the risk of venous thromboembolism (VTE) under enhanced recovery after surgery (ERAS). We aim to describe the risk of VTE and estimate the cost of preventing one case of VTE by PT under ERAS. METHOD: This was a retrospective study of 2230 patients undergoing elective surgery for colon cancer Stage I-III in the Capital Region of Denmark, 1 June 2008 to 31 December 2013. Patients who were discharged on postoperative day 28 or later, died during admission or were discharged with a vitamin K antagonist, novel oral anticoagulants or LMWH were excluded. Patients with rectal cancer only were not included. End-points were symptomatic VTE diagnosed within 60 days postoperatively. RESULTS: Three-hundred and thirty patients were excluded. For the remaining 1893, the median length of stay (LOS) was 4 [interquartile range (IQR): 3-5] days. Of these 1893 patients, four (0.20%) experienced a nonfatal symptomatic VTE. All four patients had other postoperative complications before the VTE. The cost of each symptomatic VTE prevented is estimated to be between £63 709 and £111 455 when medication and home-care nursing are included. CONCLUSION: The risk of symptomatic VTE after uncomplicated, elective surgery for colon cancer with ERAS seems negligible and the cost-effectiveness of PT to prevent one symptomatic VTE seems questionable.

Short-term outcomes after complete mesocolic excision compared with 'conventional' colonic cancer surgery.

BACKGROUND: Complete mesocolic excision (CME) seems to be associated with improved oncological outcomes compared with 'conventional' surgery, but there is a potential for higher morbidity. METHODS: Data for patients after elective resection at the four centres in the Capital Region of Denmark (June 2008 to December 2013) were retrieved from the Danish Colorectal Cancer Group database and medical charts. Approval from a Danish ethics committee was not required (retrospective study). RESULTS: Some 529 patients who underwent CME surgery at one centre were compared with 1701 patients undergoing 'conventional' resection at the other three hospitals. Laparoscopic CME was performed in 258 (48·8 per cent) and laparoscopic 'conventional' resection in 1172 (68·9 per cent). More extended right colectomy procedures were done in the CME group (17·4 versus 3·6 per cent). The 90-day mortality rate in the CME group was 6·2 per cent versus 4·9 per cent in the 'conventional' group (P = 0·219), with a propensity score-adjusted logistic regression odds ratio (OR) of 1·22 (95 per cent c.i. 0·79 to 1·87). Laparoscopic surgery was associated with a lower risk of mortality at 90 days (OR 0·63, 0·42 to 0·95). Intraoperative injury to other organs was more common in CME operations (9·1 per cent versus 3·6 per cent for 'conventional' resection; P < 0·001), including more splenic (3·2 versus 1·2 per cent; P = 0·004) and superior mesenteric vein (1·7 versus 0·2 per cent; P < 0·001) injuries. Rates of sepsis with vasopressor requirement (6·6 versus 3·2 per cent; P = 0·001) and postoperative respiratory failure (8·1 versus 3·4 per cent; P < 0·001) were higher in the CME group. CONCLUSION: CME is associated with more intraoperative organ injuries and severe non-surgical complications than 'conventional' resection for colonic cancer.

Can the quality of colonic surgery be improved by standardization of surgical technique with complete mesocolic excision?

AIM: we analysed the influence of standardization of colon cancer surgery with complete mesocolic excision (CME) on the quality of surgery measured by the pathological end-points of number of harvested lymph nodes, high tie of supplying vessels, plane of mesocolic resection and rate of R0 resection. METHOD: One hundred and ninety-eight patients with colonic carcinoma who underwent radical surgery between September 2007 and February 2009 were divided into two groups, including those undergoing surgery before (93) or after (105) 1 June 2008, when complete mesocolic excision (CME) was introduced as standard in our hospital. RESULTS: The overall mean high tie increased from 7.1 (CI, 6.5-7.6) to 9.6 (8.9-10.3) cm (P<0.0001) and the mean number of harvested lymph nodes from 24.5 (22.8-26.2) to 26.7 (24.6-28.8) (P=0.0095). There were no significant increases in these end-points in open right hemicolectomy, and in laparoscopic sigmoid resection the number of lymph nodes did not increase significantly. The plane of mesocolic resection, the rate of R0 resection and the risk of complications did not change significantly. The median (range) length of hospital stay increased from 4 (2-62) to 5 (2-71) days (P=0.04). CONCLUSION: Standardization of colonic cancer surgery with CME seems to improve the quality of surgery without increasing the risk of complications.

Anastomotic leakage after curative anterior resection for rectal cancer: short and long-term outcome.

OBJECTIVE: The influence of symptomatic anastomotic leakage (AL) after anterior resection (AR) for rectal cancer on short and long-term mortality and local and distant recurrence was analysed. METHOD: All patients with a first diagnosis of rectal carcinoma were prospectively registered in a national database. This comprised 1494 Danish citizens who had had a curative AR between May 2001 and December 2004. Data on survival and recurrence were obtained from the National Patient Register. Multivariate analyses were performed. RESULTS: Anastomotic leakage increased the 30-day mortality [odds ratio (OR) 4.01 (95% CI 2.24-7.17)]. Of other possible risk factors, only age had a significant interaction with leakage, as the risk of death within 30 days of AR decreased with increasing age. Long-term survival decreased significantly after AL [hazard ratio (HR) of 1.63, CI 1.21-2.19]. A total of 97 (6.7%) and 258 (18.0%) patients had local and distant recurrence respectively in the follow-up period. The risk of local and distant recurrence after AL was not different with HR of 1.50 (CI 0.84-2.69) and 1.13 (CI 0.76-1.69) respectively. No other factors influenced the risk of recurrence due to AL. CONCLUSION: Anastomotic leakage after AR for rectal cancer increases the 30-day and long-term mortality, but AL did not increase the risk of local and distant recurrence.

Anastomotic leakage after anterior resection for rectal cancer: risk factors.

OBJECTIVE: The study aimed to identify risk factors for clinical anastomotic leakage (AL) after anterior resection for rectal cancer in a consecutive national cohort. METHOD: All patients with an initial first diagnosis of colorectal adenocarcinoma were prospectively registered in a national database. The register included 1495 patients who had had a curative anterior resection between May 2001 and December 2004. The association of a number of patient- and procedure-related factors with clinical AL after anterior resection was analysed in a cohort design. RESULTS: Anastomotic leakages occurred in 163 (11%) patients. In a multivariate analysis, the risk of AL was significantly increased in patients with tumours located below 10 cm from the anal verge if no faecal diversion was undertaken (OR 5.37 5 cm (tumour level from anal verge), 95% CI 2.10-13.7, OR 3.57 7 cm, CI 1.81-7.07 and OR 1.96 10 cm, CI 1.22-3.10), in male patients (OR 2.36, CI 1.18-4.71), in smokers (OR 1.88, CI 1.02-3.46), and perioperative bleeding (OR 1.05 for intervals of 100 ml blood loss, CI 1.02-1.07). CONCLUSION: Anastomotic leakage after anterior resection for low rectal tumours is related to the level, male gender, smoking and perioperative bleeding. Faecal diversion is advisable after total mesorectal excision of low rectal tumours in order to prevent AL.

[Estrogen replacement in women treated for breast cancer]. / Ostrogensubstitution til kvinder behandlet for mammacancer.

Oestrogen replacement therapy in women with a history of breast cancer has long been considered contraindicated. However, the literature does not indicate an increased risk of recurrent breast cancer in postmenopausal women receiving oestrogen replacement therapy. We advocate that women with a history of breast cancer without nodal involvement could be offered oestrogen replacement therapy and thereby benefit from prevention of cardiovascular disease and osteoporosis. But the patients must accept a potentially increased risk of recurrence. We emphasize the need for randomized prospective studies.

[Estrogen replacement to women treated for endometrial cancer]. / Ostrogensubstitution til kvinder behandlet for endometriecancer.

Oestrogen replacement therapy in women treated for endometrial cancer has long been considered contra-indicated. Based on a review of the literature, which shows a low risk of recurrence during oestrogen replacement therapy in women treated for low-risk endometrial cancer, we advocate that this group of patients could be offered oestrogen replacement therapy and be provided with the benefits of prevention of cardiovascular disease and osteoporosis. Further studies are needed to investigate the survival and recurrence rates of high-risk patients treated with oestrogen replacement therapy.

Influence of complete revascularization on long-term survival after coronary artery bypass surgery.

To evaluate the influence of complete coronary revascularization after coronary artery bypass grafting (CABG) on long-term survival, we reviewed the records, including reports of coronary angiography, of 198 patients (25 women). Coronary artery bypass grafting was performed in the period 1973-1982, when the patients' mean age was 52.5 years. No significant (p < 0.05) difference in survival in the first 15 postoperative years was found between the patients judged to have complete revascularization at coronary angiography 6 months after CABG and the general Danish population. Complete revascularization by extensive grafting should improve survival of patients treated for angina. If the revascularization remains complete at coronary angiography assessment 6 months postoperatively, the 15-year survival rate can be expected to equal that in the general population.

[Leiomyosarcoma of the spermatic cord]. / Leiomyosarkom i funiculus spermaticus.

Sarcoma of the spermatic cord is a rare disease with less than 300 cases reported in the literature. A case of leiomyosarcoma is presented, and an analysis of the therapeutic approaches of radical orchidectomy, and in some cases retroperitoneal lymph node dissection, chemotherapy and radiation is given. The total numbers of different types of sarcomas in the spermatic cord, reported to The Danish Department of Cancer Registration are briefly presented as well.

[A 20-year follow-up of Danish coronary artery bypass patients]. / Tyve års opfølgning af danske koronararteriebypass-patienter.

This study describes the influence of complete revascularization on the long term survival of patients following coronary artery bypass surgery. The patient population consists of 100 consecutive patients discharged from our department after undergoing a coronary bypass operation between November 1973 and July 1978. Patients who survived less than 30 days postoperatively are excluded from the study. The patient population consists of 87 males and 13 females. Mean age was 52.2 years at time of surgery. The rate of revascularization was estimated by coronary angiography, performed between one and 34 months postoperatively, in contrast to other similar studies found in the literature, where such estimation was performed peroperatively. Twenty-five of 86 patients were completely revascularized at postoperative angiographic estimation. Long term survival for the patient population and for the group of completely revascularized patients were compared to the expected survival of the Danish background population (comparable age and sex). Long term survival for the patient population as a whole was similar to that found in similar studies. There was an expected increased mortality compared to the Danish background population.

Analysis of the clinical utility of a predictive chemosensitivity assay.

We present an elementary statistical analysis for quantifying the clinical utility of a predictive chemosensitivity assay based on retrospective data. An assay predictive of patient response could possibly improve response rates and reduce morbidity by individualizing chemotherapy for each patient. An analysis of retrospective data can suggest appropriate patient populations and sample sizes for study in prospective trials using the chemosensitivity assay. We provide an example with data from a clonogenic assay collected on melanoma patients.

Evolution and clinical application of a rapid chemosensitivity assay.

The clinical usefulness of the soft agar colony-formation assay of in vitro chemosensitivity developed by Hamburger and Salmon is limited by long turnaround time (2-3 weeks), low success rate for small specimens, and clumping artifacts that can lead to erroneous predictions of resistance (false-negative errors). An improved technique was developed for measuring in vitro growth by incorporation of tritiated thymidine that can be performed in 5 days. With this rapid assay, 819 tumors were processed, with an overall success rate of 59.3%. This result compared favorably to the overall success rate of 58.2% for 1591 colony-formation assays because more small specimens could be submitted for the rapid assay. Melanoma and ovarian cancer specimens grew particularly well (76% and 75% successful, respectfully). Sixty-five correlations of in vitro and in vivo responses are available to date. None of 30 tumors, predicted to be resistant in vitro responded to chemotherapy clinically. Patients whose tumors were predicted to be sensitive in vitro had a 43% clinical response rate. The assay appears to be particularly accurate for predicting clinical resistance to chemotherapy, possibly because clumping artifacts do not occur in this system and peak achievable plasma concentrations of chemotherapeutic agents can be used. Optimal in vitro drug concentrations and culture conditions are still being defined, and improved success rates are being seen with more recent specimens. The introduction of this technique underscores the fact that in vitro chemosensitivity tests must continuously evolve to maximize their clinical application.

Breast cancers: estrogen and progesterone receptor status as a predictor of in vitro chemotherapeutic response.

Although clinical observations have shown that estrogen receptor-positive (ER+) breast tumors are more responsive to hormonal therapy than ER-negative (ER-) tumors, it remains controversial whether ER status can predict chemotherapeutic response. To determine if there was any correlation between estrogen and progesterone values and in vitro chemosensitivity to various anticancer drugs, clonogenic (CA), estrogen (ERA), and progesterone (PRA) assays on breast cancers were performed on 100 patients. Clonogenic assays were performed using the double-layer soft agar technique with continuous drug exposures. ERAs and PRAs were performed using the charcoal-coated dextran method. Chemosensitivity was defined as 50% inhibition of colony formation. ERA was considered positive if greater than or equal to 5 fmole/mg cytosol and PRA positive if greater than or equal to 10 fmole/mg cytosol. Significant tumor growth (greater than 30 colonies/plate) was achieved in 81/100 assays. ERA and PRA values were not predictive of colony formation in vitro. Of all agents or combinations of agents tested (L-PAM, 5-FU, MTX, adriamycin, vinblastine, cis-plat, FAC, CMF), only the response to 5-FU correlated significantly with ERA. Eight of 11 (73%) of the ER- tumors were sensitive to 5-FU, whereas only 6/20 (30%) of ER+ tumors were sensitive (P less than 0.05). ER- tumors were also more likely to be sensitive to CMF (P = 0.09) and adriamycin (P = 0.07) than ER+ tumors. PRA values were not predictive of chemosensitivity, nor did combining PRA and ERA enhance the predictive value of ERA alone.

Clinical correlations with chemosensitivities measured in a rapid thymidine incorporation assay.

A rapid assay for in vitro chemosensitivity testing measuring [3H]thymidine incorporation has been developed. Results of this assay correlate highly with chemosensitivities determined by the soft-agar clonogenic assay. A correlative study was carried out on 219 solid tumor specimens to assess the ability of the rapid assay to predict clinical response to antineoplastic therapy. One hundred forty-two of 219 tumors (65%) yielded chemosensitivity data. Of these, 33 were evaluable for in vitro-in vivo correlations. In vitro sensitivity (greater than or equal to 80% inhibition of thymidine uptake) was associated with clinical response in 6 of 13 patients. In vitro resistance was associated with progressive disease in 20 of 20 patients. The rapid assay offers several advantages over the soft-agar clonogenic assay, including higher success rate, avoidance of clumping artifact, shorter time course (5 days), and very low false-negative rate. Further refinement may be necessary, but the rapid assay appears to have potential for individualizing solid tumor chemotherapy.

Chemosensitivity testing of human solid tumors. A review of 1582 assays with 258 clinical correlations.

To improve clinical interpretation and use of in vitro clonogenic assay results, the authors reviewed their experience to date with chemosensitivity testing of over 1500 solid tumors. All clonogenic assays were performed using a double-layer-soft-agar system with continuous exposure of cells to one concentration of standard anticancer drugs. Significant growth was defined as greater than or equal to 30 colonies/control plate. Clinical responses were determined according to standard criteria. Data were analyzed using two different criteria of in vitro sensitivity (greater than or equal to 50% and greater than or equal to 75% inhibition of colony formation) and independently for each histologic type of tumor. Overall, 68% of specimens plated produced significant growth in vitro. Cloning ability varied from 57% to 82% depending on tumor histology. The assay was 57% reliable for predicting in vivo sensitivity, and 92% reliable for in vivo resistance. Predictive accuracy for sensitivity varied from 30% to 86%, depending on the tumor histology. Use of greater than or equal to 50% ICF (inhibition of colony formation) as criteria for differentiating sensitivity from resistance proved most reliable, although criteria should be individualized for each tumor type to maximize predictive accuracy.