Obstructive Colorectal Cancer Research Articles

Oxidative Stress and the Epigenome in Human Disease

Epigenetics refers to the study of the changes in gene expression that occur without changes in the DNA sequence. There is growing evidence that epigenetic modifications such as changes in the levels of DNA methylation or post-translational histone modifications are involved in the pathogenesis of many human diseases including cancer. Oxidative stress as a result of metabolic or environmental factors leads to excessive production of reactive oxygen species (ROS). ROS plays a role in many human diseases including cancer and pulmonary and cardiovascular diseases by promoting DNA damage and/or altering signaling pathways. This review article summarizes the most recent reports linking both oxidative stress and epigenetic mechanisms in the pathogenesis of chronic obstructive pulmonary disease (COPD), cardiovascular disease, and lung, prostate and colorectal cancers. Here, we emphasize the importance that future studies should focus on epigenetic intervention strategies to treat diseases associated with oxidative stress.

Self-Expandable Metal Stent Placement as a Bridge to Laparoscopic or Open Surgery for Obstructive Colorectal Cancer: Short-Term Outcomes of Nineteen Consecutive Cases

Purpose Laparoscopic colorectal resection is a feasible and less invasive procedure with short-term advantages compared with open surgery; however, the evidence for its efficacy for treating obstructive colorectal cancer (CRC) is lacking. In this study, we aimed to determine short-term outcomes of SEMS placement for obstructive CRC followed by laparoscopic colorectal resection. Methods As of August 2013, 51 patients with obstructive CRC underwent stent insertion. Thirty-two patients received palliation therapy not intended for tumor resection. After decompression of the proximal intestine, nine and 10 patients underwent laparoscopic and open surgery, respectively. Clinicopathological, intraoperative, and postoperative data were retrospectively collected. Results There were no differences in resection rates and curabilities between the two groups. All surgeries were performed with a single-stage anastomosis, and no anastomotic leakage was observed. There was one patient with abdominal morbidity in the open group (Open) and none in the Lap group. There was no mortality in either group. Time to flatus (3.4 ± 1.8 days, Lap; 2.6 ± 1.1 days, Open) and time to oral intake (7.9 ± 2.5 days, Lap; 7.7±1.9 days, Open) were similar between the groups. Postoperative hospitalization times for the Lap group were shorter, but the difference was not statistically significant (15.2 ± 3.9 days, Lap; 21 ± 11.7 days, Open, p = 0.21). Conclusion Our findings indicate that laparoscopic surgery combined with preoperative stent placement is feasible as well as safe compared with open surgery for obstructive CRC.

The role of primary colectomy after successful endoscopic stenting in patients with obstructive metastatic colorectal cancer.

Although the initial clinical efficacy of self-expandable metal stents is acceptable, doubt still remains about long-term clinical outcomes and complications. The aim of this study was to evaluate the stoma formation rate and risk factors for complications after successful stenting in patients with obstructive metastatic colorectal cancer. This was a tertiary-care center retrospective study. From January 2000 to December 2010, 130 patients with unresectable obstructive colorectal cancer received successful self-expandable metal stent placement. Among them, 14 patients received primary colectomy after successful stenting. Self-expandable metal stent placement and primary colectomy were performed. The stoma formation rate and complications were measured. In patients with successful stenting, stoma formation rates at 1 and 2 years were 15.6% (95% CI, 8.74-22.4) and 24.4% (95% CI, 13.8-35.0), and the median patency duration was 157 days (range, 2-1590 days). However, long-term complications occurred in 58 patients (44.6%), including reobstruction (32.6%), stent migration (10.3%), and perforation (7.8%), and a large number of reinterventions (45.7%) and hospitalizations (37/9%) were needed to manage complications. In multivariate analysis, primary colectomy after successful endoscopic stenting was a negative predictive factor for reobstruction (OR, 0.12; 95% CI, 0.02-0.99; p = 0.04). This was a retrospective, single-center study. To reduce stent-related late complications, primary colectomy after successful endoscopic stenting could be a therapeutic option in patients who have unresectable colorectal cancer with obstruction, especially in those who expect long-term survival.

Tu1029 Endoscopic and Surgical Treatment of Malignant Colorectal Polyps: A Population-Based Comparative Study

Background: Self-expanding metal stents (SEMS) used as a bridge to surgery for obstructive colorectal cancer (CRC) have fallen under suspicion for inducing tumor dissemination and thereby increasing CRC recurrence and long-term mortality, but data regarding these risks are sparse. Several attempts to compare SEMS with acute surgery in randomized settings have failed and the existing evidence from observational studies is based primarily on singlecenter studies conducted in highly specialized settings with little or no information on potential confounding factors.Methods:We conducted a nationwide population-based cohort study using Danish medical registries (2005-2010) by comparing overall mortality and recurrence after CRC resection in patients with preoperative stenting (n=581) to patients undergoing urgent (n=3,333) or elective resection (n=13,722). For patients surviving the first 30 days after CRC resection, we used the Kaplan Meier method to compute absolute survival. For CRC patients with localized and regional disease, the risk of CRC recurrence was estimated treating death as a competing risk. We computed mortality rate ratios (MRRs) and cause specific hazard ratios of recurrence within 5 years, using Cox regression with adjustment for important covariates. Results: Crude 5-year survival was 49% (95% CI: 43%55%) among patients with preoperative SEMS, 40% (95% CI: 38%-43%) among patients undergoing urgent resection, and 65% (95% CI: 64%-66%) among patients with elective resection. For SEMS vs. urgent resection, the adjusted MRR was 0.99 (95% CI: 0.91-1.07) and for SEMS vs. elective resection, the adjusted MRR was 1.39 (95% CI: 1.19-1.62). The 5-year recurrence risk was 39% (95% CI: 31%-46%) after preoperative SEMS, 30% (95% CI: 27%-32%) after urgent resection, and 22% (95% CI: 21%-24%) after elective surgery. The adjusted cause-specific hazard ratios for recurrence were 1.13 (95% CI: 0.99-1.28) for SEMS vs. urgent resection and 1.81 (95% CI: 1.44-2.28) for SEMS vs. elective resection. Conclusions: Long-term mortality associated with use of SEMS as a bridge to surgery was comparable to that of urgent resection, but higher than that observed following elective resection. SEMS use may be associated with an increased risk of CRC recurrence.

Tu1026 Mortality and Recurrence After Colorectal Cancer Resection With Preoperative Stenting -A Danish Nationwide Cohort Study

Background: Self-expanding metal stents (SEMS) used as a bridge to surgery for obstructive colorectal cancer (CRC) have fallen under suspicion for inducing tumor dissemination and thereby increasing CRC recurrence and long-term mortality, but data regarding these risks are sparse. Several attempts to compare SEMS with acute surgery in randomized settings have failed and the existing evidence from observational studies is based primarily on singlecenter studies conducted in highly specialized settings with little or no information on potential confounding factors.Methods:We conducted a nationwide population-based cohort study using Danish medical registries (2005-2010) by comparing overall mortality and recurrence after CRC resection in patients with preoperative stenting (n=581) to patients undergoing urgent (n=3,333) or elective resection (n=13,722). For patients surviving the first 30 days after CRC resection, we used the Kaplan Meier method to compute absolute survival. For CRC patients with localized and regional disease, the risk of CRC recurrence was estimated treating death as a competing risk. We computed mortality rate ratios (MRRs) and cause specific hazard ratios of recurrence within 5 years, using Cox regression with adjustment for important covariates. Results: Crude 5-year survival was 49% (95% CI: 43%55%) among patients with preoperative SEMS, 40% (95% CI: 38%-43%) among patients undergoing urgent resection, and 65% (95% CI: 64%-66%) among patients with elective resection. For SEMS vs. urgent resection, the adjusted MRR was 0.99 (95% CI: 0.91-1.07) and for SEMS vs. elective resection, the adjusted MRR was 1.39 (95% CI: 1.19-1.62). The 5-year recurrence risk was 39% (95% CI: 31%-46%) after preoperative SEMS, 30% (95% CI: 27%-32%) after urgent resection, and 22% (95% CI: 21%-24%) after elective surgery. The adjusted cause-specific hazard ratios for recurrence were 1.13 (95% CI: 0.99-1.28) for SEMS vs. urgent resection and 1.81 (95% CI: 1.44-2.28) for SEMS vs. elective resection. Conclusions: Long-term mortality associated with use of SEMS as a bridge to surgery was comparable to that of urgent resection, but higher than that observed following elective resection. SEMS use may be associated with an increased risk of CRC recurrence.

Tu1027 Assessing Barriers for Screening Colonoscopy in an Urban Underserved Population

Background: Self-expanding metal stents (SEMS) used as a bridge to surgery for obstructive colorectal cancer (CRC) have fallen under suspicion for inducing tumor dissemination and thereby increasing CRC recurrence and long-term mortality, but data regarding these risks are sparse. Several attempts to compare SEMS with acute surgery in randomized settings have failed and the existing evidence from observational studies is based primarily on singlecenter studies conducted in highly specialized settings with little or no information on potential confounding factors.Methods:We conducted a nationwide population-based cohort study using Danish medical registries (2005-2010) by comparing overall mortality and recurrence after CRC resection in patients with preoperative stenting (n=581) to patients undergoing urgent (n=3,333) or elective resection (n=13,722). For patients surviving the first 30 days after CRC resection, we used the Kaplan Meier method to compute absolute survival. For CRC patients with localized and regional disease, the risk of CRC recurrence was estimated treating death as a competing risk. We computed mortality rate ratios (MRRs) and cause specific hazard ratios of recurrence within 5 years, using Cox regression with adjustment for important covariates. Results: Crude 5-year survival was 49% (95% CI: 43%55%) among patients with preoperative SEMS, 40% (95% CI: 38%-43%) among patients undergoing urgent resection, and 65% (95% CI: 64%-66%) among patients with elective resection. For SEMS vs. urgent resection, the adjusted MRR was 0.99 (95% CI: 0.91-1.07) and for SEMS vs. elective resection, the adjusted MRR was 1.39 (95% CI: 1.19-1.62). The 5-year recurrence risk was 39% (95% CI: 31%-46%) after preoperative SEMS, 30% (95% CI: 27%-32%) after urgent resection, and 22% (95% CI: 21%-24%) after elective surgery. The adjusted cause-specific hazard ratios for recurrence were 1.13 (95% CI: 0.99-1.28) for SEMS vs. urgent resection and 1.81 (95% CI: 1.44-2.28) for SEMS vs. elective resection. Conclusions: Long-term mortality associated with use of SEMS as a bridge to surgery was comparable to that of urgent resection, but higher than that observed following elective resection. SEMS use may be associated with an increased risk of CRC recurrence.

Tu1436 K-RAS Mutation Status and Anti-Tumoral Therapies Do Not Influence the Risk of Adverse Events in Patients With Obstructive Colorectal Cancer Palliated by Self-Expandable Metallic Stents

Tu1436 K-RAS Mutation Status and Anti-Tumoral Therapies Do Not Influence the Risk of Adverse Events in Patients With Obstructive Colorectal Cancer Palliated by Self-Expandable Metallic Stents

Tu1433 Is Endoscopic Colorectal Stenting As a Bridge to Surgery Really Useful for For Obstructive Colorectal Cancer?

Endoscopic colorectal stenting in malignant colorectal obstruction has been reported to have the advantages such as high successful primary anastomosis and low overall stoma rate as a bridge to surgery, shorter hospital stay and cost effectiveness. But recent studies reported that colorectal stenting was no more effective and safe compared to emergency surgery in clinical success rate and overall complication rate. The aim of this study was to compare the outcomes between operation after colorectal stenting and surgery only for curative purpose in patients with colorectal obstruction.

Experts reviews of the multidisciplinary consensus conference colon and rectal cancer 2012

The first multidisciplinary consensus conference on colon and rectal cancer was held in December 2012, achieving a majority of consensus for diagnostic and treatment decisions using the Delphi Method. This article will give a critical appraisal of the topics discussed during the meeting and in the consensus document by well-known leaders in surgery that were involved in this multidisciplinary consensus process. Scientific evidence, experience and opinions are collected to support multidisciplinary teams (MDT) with arguments for medical decision-making in diagnosis, staging and treatment strategies for patients with colon or rectal cancer. Surgery is the cornerstone of curative treatment for colon and rectal cancer. Standardizing treatment is an effective instrument to improve outcome of multidisciplinary cancer care for patients with colon and rectal cancer. In this article, a review of the following focuses; Perioperative care, age and colorectal surgery, obstructive colorectal cancer, stenting, surgical anatomical considerations, total mesorectal excision (TME) surgery and training, surgical considerations for locally advanced rectal cancer (LARC) and local recurrent rectal cancer (LRRC), surgery in stage IV colorectal cancer, definitions of quality of surgery, transanal endoscopic microsurgery (TEM), laparoscopic colon and rectal surgery, preoperative radiotherapy and chemoradiotherapy, and how about functional outcome after surgery?

Short-term outcomes of laparoscopic surgery after insertion of self-expandable metallic stent as a “bridge to surgery” for left-sided obstructive colorectal cancer.

643 Background: Safety and validity of performing laparoscopic surgery after preoperative lavege using the self-expandable metallic stent (SEMS) for left-sided obstructive colorectal cancer were examined. We evaluated the short-term outcome of SEMS insertion compared with laparoscopic surgery without SEMS. Methods: Patients with left-sided colorectal cancer treated by either laparoscopic surgery with stent placement (n = 8) or laparoscopic surgery only (n = 42) in our hospital between April, 2012 and January, 2013 were registered. Short-term outcomes were compared with the two groups about patient characteristics (sex, age, American Society of Anesthesiologists Physical Status, body mass index, prior abdominal surgery), pathological data of patients (tumor location, size of tumor , tumor differentiation, number of harvested lymph nodes, pTNM classification, UICC pathological stage), and operative and post operative results (procedures, conversion, operative time, blood loss, morbidity, solid food intake, postoperative hospital stay, total hospital stay). Results: Except for tumor size in the patient characteristic parameters, there were no statistically significant difference between the two groups. Conversion rate to laparotomy was higher in the stent group (2 versus 1, p = 0.013). There was no difference in operation time, blood loss and postoperative complications between the two groups. Conclusions: Although the long-term oncological result requires further investigation, laparoscopic surgery after self-expandable metallic stent is a safe and feasible treatment as a “brige to surgery” for left-sided obstructive colorectal cancer.

The role of colorectal stent placement in the management of acute malignant obstruction

In recent decades, the use of colorectal stents for palliation or as a bridge to surgery in acute malignant colorectal obstruction has increased. We aimed to evaluate the technical and clinical efficacy, safety and clinical outcomes of endoscopic stenting for the relief of acute colorectal obstruction secondary to cancer. From March 2006 to December 2012, among 100 patients with acute malignant colorectal obstruction, stenting procedures were performed on 42 patients for relief of obstruction. Uncovered self-expanding metal stents (SEMS) were placed endoscopically under fluoroscopic guidance in all patients. Using the patient database, a review was conducted to determine the effectiveness of the procedure and the short- and long-term complications. Stent placement was technically successful in 39/42 (92.8%) and clinically successful in 38/42 (90.4%) patients. Sixteen patients later underwent an elective surgical resection, and in 26 patients with metastatic disease or comorbidity, stent placement was palliative. Complications occurred in 10 (23.8%) patients, and the most common was tenesmus (n=3). Migration, bleeding, and recto-sigmoid perforation occurred in two patients each. Stent obstruction due to fecal impaction was seen in one case. Stent placement for colorectal obstruction is an effective and relatively safe procedure, with minor complications. It not only allows subsequent elective resection, but is also definitive for palliative treatment in patients with obstructive colorectal cancer.

Assessment of Postoperative Gastrointestinal Motility in Patients with Obstructive Colorectal Cancer

Assessment of Postoperative Gastrointestinal Motility in Patients with Obstructive Colorectal Cancer

A Case of Septic Shock due to Bacterial Translocation from Obstructive Colorectal Cancer

A Case of Septic Shock due to Bacterial Translocation from Obstructive Colorectal Cancer

Comparative study of postoperative complications in patients with and without an obstruction who had left-sided colorectal cancer and underwent a single-stage operation after mechanical bowel preparation.

PurposeThe purpose of this study is to compare postoperative complications for single-stage surgery after mechanical bowel preparation in patients who experienced obstruction and those who did not.MethodsFrom 2000 to 2011, 1,224 patients underwent a single-stage operation for left colorectal cancer after bowel preparation. Nonobstruction (NOB) and obstruction (OB) colorectal cancer patients were 1,053 (86.0%) and 171 (14.0%), respectively. Postoperative morbidity and mortality were compared between groups.ResultsThe OB group had poor preoperative conditions (age, white blood cell, hemoglobin, albumin level, and advanced tumor stage) compared with the NOB group (P < 0.05). Mean on-table lavage time for the OB group was 17.5 minutes (range, 14-60 minutes). Mean operation time for the OB group was statistically longer than that of the NOB group (OB: 210 minutes; range, 120-480 minutes vs. NOB: 180 minutes; range, 60-420 minutes; P < 0.001). Overall morbidity was similar between groups (NOB: 19.7% vs. OB: 23.4%, P = 0.259). Major morbidity was more common in the OB group than in the NOB group, but the difference was without significance (OB: 11.7% vs. NOB: 7.6%, P = 0.070). Postoperative death occurred in 16 patients (1.3%), and death in the OB group (n = 7) was significantly higher than it was in the NOB group (n = 9) (4.1% vs. 0.9%, P = 0.001). Twelve patients had surgical complications, which were the leading cause of postoperative death: postoperative bleeding in five patients and leakage in seven patients.ConclusionPostoperative morbidity for a single-stage operation for obstructive left colorectal cancer is comparable to that for NOB, regardless of poor conditions of the patient.

Surgical management of obstructed and perforated colorectal cancer: still debating and unresolved issues

SUMMARY Emergency surgery for obstruction and perforation from colorectal cancer (CRC) predicts poorer outcomes compared with elective surgery. For obstructed cancers, the evidence suggests significantly poorer outcomes with multistaged procedures compared with single-stage procedures in this group. Stenting remains an attractive option as a ‘bridge-to-surgery’, with multiple single-center studies demonstrating excellent short-term outcomes. However, contradictory evidence from three randomized trials casts doubts on stenting as the preferred modality for initial management of all curative obstructed CRCs. Results from a UK multicenter randomized controlled trial are still awaited. Palliative stenting shows predominantly positive results and is a valuable option for nonresectable or incurable CRCs. All authors agree on emergency surgery as the primary modality of treatment for perforated malignancies. Short-term outcomes are markedly poorer than the elective surgery group and correlate with the degree of peritoneal contamination. Long-term outcomes are comparable to elective surgery when perioperative deaths are excluded.

Late complications related to palliative stenting in patients with obstructing colorectal cancer

Introduction: Self-expanding metal stents (SEMSs) are increasingly used for the palliative treatment of incurable obstructing colorectal cancer. The aim of the current study was to evaluate clinical outcome, including technical and clinical success of stenting, and to identify factors associated with late complications of SEMS in palliation of incurable obstructing colorectal cancer. Material and methods: Between 2003 and 2010 details of 56 patients who underwent an attempt of SEMS insertion for obstructive incurable colorectal cancer at Turku University Hospital were recorded to our database prospectively and analyzed retrospectively. Results: Technical success was achieved in 42 patients (75%) and clinical success in 39 patients (70%). Late complications related to SEMS occurred in 13 patients (31%). Ten patients (24%) needed re-intervention because of a complication: Eight ostomies, one Hartmann´s procedure due to late perforation and one re-stenting because of stent migration. Three patients with stent-related complications were treated conservatively. Chemotherapy and prolonged survival were risk factors for SEMS-related late complications and re-intervention. Conclusion: SEMS insertion is a feasible procedure for the palliative treatment of obstructing colorectal cancer in patients with severe comorbidities and short life expectancy. However, for patients who are candidates for chemotherapy and have a longer life expectancy, other treatment options such as palliative tumor resection should also be considered.

Comparison of short-term outcomes after elective surgery following endoscopic stent insertion and emergency surgery for obstructive colorectal cancer

PurposeThe aim of this study was to compare short-term morbidities and mortalities of elective surgery after stent insertion and emergency surgery in obstructive colorectal cancer. MethodsWe retrospectively reviewed 77 patients with obstructive colorectal cancer that underwent elective surgery after stenting (stent group: SG, n = 49) or emergent surgery (emergency group: EG, n = 28) from January 2000 to July 2010. ResultsThe American Society of Anesthesiologists (ASA) score of SG was lower than that of EG (p = 0.015). The percentages of open and laparoscopic surgery in SG were 73.5% (36/49) and 26.5% (13/49), respectively, whereas surgery in EG was performed using an open technique (p = 0.003). The rate of primary anastomosis, without constructing a stoma, was 87.8% in SG and 42.9% in EG (p < 0.001). There was no difference in a postoperative complication. Anastomotic leakage according to time between stent placement and surgery in SG were 3 cases for 1–9 days and 0 for more than 10 days (p = 0.037). Three-year overall survival rates were 68.8% and 51.3% (p = 0.430), respectively. ConclusionPreoperative stent insertion in obstructive colorectal cancer seems to be safe and feasible, and may decrease second stage procedure. Waiting 10 days after stent placement may be a more optimal time for surgical intervention. Further prospective randomized studies are needed to determine the proper time bridge to surgery following stent insertion in obstructive colorectal cancer.

Clinical and oncologic safety of laparoscopic surgery for obstructive left colorectal cancer following transanal endoscopic tube decompression

Little information has been available concerning the safety of laparoscopic resection of obstructive colorectal cancer after transanal endoscopic tube decompression (TETD). The aim of this study was to assess the short- and long-term outcomes of laparoscopic surgery following TETD for such advanced colorectal cancer. A retrospective review was performed of 40 patients with obstructive left colorectal cancer whose distended bowels were treated with TETD before laparoscopic surgery, between January 2001 and March 2011 (TETD group). The elective surgery resulted in potentially curative resection of the tumor in all cases. Their clinical records were compared to those of 80 matched controls with nonobstructive left colorectal cancer resected laparoscopically during the same period (control group). Operative time, blood loss, and the rate of conversion to laparotomy were comparable between the two groups. There were no significant between-group differences in morbidity rates. Five-year overall survival rates in the TETD and control groups were 71.9 and 75.4%, respectively, with no statistical difference. Disease-free survival rates after 5 years were also similar (TETD group, 64.5% vs. control group, 66.3%). There were no significant differences between the two groups in recurrence rates and patterns. These results suggest that laparoscopic surgery following TETD is clinically and oncologically safe and could be a treatment of choice for obstructive left colorectal cancer.

Oncologic safety of stent as bridge to surgery compared to emergency radical surgery for left-sided colorectal cancer obstruction

There are still concerns about the oncologic safety of stent insertion for colorectal cancer obstruction. This study investigated whether the use of stents as a bridge to surgery negatively affect the long-term outcome compared to curative surgery for left-sided colorectal cancer obstruction. Between January 2004 and December 2009, patients with left-sided colorectal cancer obstruction without distant metastasis were retrospectively reviewed. Forty-three patients underwent radical resection after preoperative stent insertion (stent group), whereas 48 underwent emergency surgery with curative intent (surgery group). The short- and long-term outcomes between the two groups were compared. The stent and surgery groups had similar demographics. There were no significant differences in primary anastomosis, laparoscopic-assisted surgery, operation time, time until first defecation and oral intake after surgery, postoperative hospital stay, and reoperation. The stent group had an average hospital stay 7 days longer than the surgery group. During the median follow-up period of 48.1 months, the 5-year disease-free survival rates were not significantly different between the stent and surgery groups (47.2 vs. 48.9%, respectively; p = 0.499). Overall, the 5-year survival rate was also similar in the two groups (70.4 vs. 76.4%, respectively; p = 0.941). For left-sided colorectal cancer obstruction, stent insertion followed by surgery showed short-term advantages and similar oncologic outcomes compared to surgery without preoperative intervention. Stent insertion as a bridge to surgery is a safe and feasible treatment option for patients with colorectal cancer obstruction.

Outcome of emergency one-stage resection and anastomosis procedure for patients with obstructed colorectal cancer

The purpose of this study was to verify the outcome of the emergency one stage resection and anastomosis procedure for patients with obstructed colorectal cancer. An emergency one stage resection and anastomosis procedure was performed for 40 patients with obstructive colorectal cancer. The outcome was verified and compared dividing into two groups. 17 patients under the age of 70 in (Group A), 23 patients 70 years and over in (Group B). The operative mortality rate in both groups was 0%. As a result, postoperative complications were not significantly different between the two groups. The overall survival rate after a 5-year period in both groups was 41.8%, regarding all patients and the survival curves for the two groups, was not significantly different. The 5 year survival rate in stage II or III showed no differences between the two groups. The one-stage resection and anastomosis of the large bowel could be applied safely to emergency patients, which in turn allows for excellent short-term operative results in both groups mentioned. This particular procedure should be positively enforced, even in elderly patients in their 70's.