Diagnosis and management of recurrent colorectal cancer.

Justification for the management of recurrent colorectal cancer begins with proof that the ultimate outcome measured by survival can be influenced. To do this, we must prove there is value to follow-up of colorectal cancer patients. Without followup, the management of recurrent cancer is limited.

The prognostic impact of the time interval to recurrence for the mortality in recurrent colorectal cancer.

OBJECTIVE: The risk of a cancer recurrence has been correlated with the stage of the primary tumour at the time of presentation. However, once a recurrence has developed, the primary tumour stage may not be the determining prognostic factor anymore. The objective of this study was (i) to evaluate the association between the recurrence interval and the outcome of the recurrence, and (ii) to determine whether that interval was affected by the use of adjuvant radiation and/or chemotherapy. METHOD: This retrospective study analysed 212 patients who developed recurrent colorectal cancer from 1987 to 1993. Primary parameters such as age, gender, primary tumour site and stage, and use of postoperative adjuvant treatment were correlated with the recurrence interval, the type and site of the recurrence (i.e. locoregional vs distant metastases), and the outcome. Uni- and multivariate analysis was used to compare the recurrence interval and survival between different subgroups as defined by risk factors. RESULTS: The mean time between the primary and the recurrent tumour was 25 months (range 1-252 months) with 82% of the recurrences developing within 3 years after surgery. The recurrence interval was inversely correlated with the initial tumour stage. Poor survival was associated with a short recurrence interval (less than 12 months) and a distant recurrence site. Even after adjusting for the initial tumour stage, the use of adjuvant treatment did not prolong the interval, i.e. delay the onset of recurrent cancer. CONCLUSION: The recurrence interval of colorectal cancer is a prognostic factor. However, the use of adjuvant therapy did not prolong that interval.

A survey of perceptions and attitudes among European surgeons towards the clinical impact and management of postoperative ileus.

OBJECTIVE: Postoperative ileus (POI) can negatively affect patient recovery and morbidity, yet the lack of an internationally accepted definition and clinical management pathway for this condition suggest POI may be under-recognized as a clinical problem. The purpose of this survey was therefore to assess current attitudes of surgeons towards the clinical impact and management of POI. SUBJECTS AND METHODS: Telephone interviews were conducted with 230 surgeons from hospitals in the UK, France, Germany, Italy and Spain. RESULTS: Across Europe, there are differences in the terms surgeons use to refer to delayed recovery of gastrointestinal (GI) function and the symptoms, concerns and risks they associate with this condition. Furthermore, there is marked variation in the attitudes of European surgeons towards minimizing the risk of delayed recovery of GI function and in the strategies to manage POI. Additionally, some of the measures applied most commonly by European surgeons are in contrast to evidence in the literature indicating that they have no benefit for quicker resolution of GI function. CONCLUSION: The results suggest that there is a need for clearer definition of the factors that constitute POI, increased recognition of the impact of this condition and improved understanding of the most effective peri-/postoperative care for surgical patients.

Surgical management of ulcerative colitis.

As long as our understanding of ulcerative colitis is too limited to allow a more specific, disease-targeted treatment, surgery will play an important role in the management of these patients. Careful interdisciplinary evaluation and counselling of patients with ulcerative colitis will permit to achieve the goals on an individual basis with maximum safety. Restorative proctocolectomy with an IPAA has evolved as the procedure of choice among four basic surgical options because it appears to be safe and carries a low mortality. Although the associated morbidity is not negligible, functional results are generally good and patient satisfaction is high.

Effects of topical tumoricidal agents on port-site recurrence of colon cancer: an experimental study in rats.

BACKGROUND: Reports of metastatic spread of colon and rectal cancer to port sites after laparoscopic resection of potentially curable lesions has raised doubt regarding the efficacy and safety of laparoscopic technology in cancer surgery. Experimental study in animals has led us to believe that the mode of spread of these metastases is via the direct route. We hypothesized, therefore, that we could decrease the rate of trocar-site recurrences by treating the individual port sites with a topical tumoricidal agent. MATERIALS AND METHODS: Male BD-IX rats weighing 240 to 360 g were injected with syngeneic colon cancer to simulate free intraperitoneal cancer spread to trocar sites. All rats were subjected to a sham laparoscopic operation after 2 x 10(5) viable cancer cells had been injected into their peritoneal cavities. Five-millimeter trocars were inserted into each rat after abdominal insufflation to 10 mm Hg. Pneumoperitoneum was maintained for 10 minutes before the trocars were removed simultaneously. Trocar sites were then subjected to one of three treatments, with each animal receiving a maximum of two different treatments. Sites were treated with 70% ethanol (N = 42), povidine/ iodine (N = 40), or no topical treatment (N = 46). Three weeks later, the animals were euthanized and autopsied. Subcutaneous tumors at trocar sites or tumors with >50% volume within the wound were considered implants. RESULTS: Control sites revealed a metastasis rate of 41% (19/46). The tumor implant rate was 36% (15/42) at alcohol-treated sites and 20% (8/40) at sites treated with povidone-iodine (P < 0.05). CONCLUSION: Topical administration of povidone-iodine to trocar wounds after laparoscopic surgery can significantly reduce the incidence of port-site metastasis in a syngeneic animal model of colon cancer.

The WAND local anesthetic delivery system: a more pleasant experience for anal anesthesia.

PURPOSE: The WAND is a computer-controlled local anesthetic delivery system. Its use has been proven to be more comfortable for dental patients. The purpose of this study is to explore its applicability to anal procedures. Our hypothesis is that the WAND will provide greater comfort during anesthesia delivery while achieving the same anesthetic effect as traditional syringe technique. METHODS: Twenty patients with painless anal pathology were randomized to receive anal anesthesia using either the WAND or traditional syringe technique to a randomly selected half of the anoderm (right or left). The opposite side was then anesthetized by the alternate method, allowing patients to act as their own control. Objective and subjective pain scores were obtained from the patient after each mode of delivery. An independent observer interpreted the patient's tolerance by giving a subjective pain score. The volume of anesthetic used was recorded. Adequacy of anesthesia was tested by a pinch test. RESULTS: Sixteen (80 percent) of the 20 patients preferred the use of the WAND. Objective and subjective pain scores per the patients and subjective pain scores per the observer were significantly lower for the WAND than for traditional syringe technique (P < 0.05). The mean volume of local anesthetic used with the WAND was 1.7 ml compared with 3.2 ml for traditional syringe technique (P < 0.005). Anesthesia achieved with the WAND was as good as that achieved with traditional syringe technique when the pinch test was used. CONCLUSION: The WAND is as effective as the traditional syringe technique in the delivery of anal anesthesia while providing a more comfortable experience for the patient.

Systemic administration of a matrix-targeted retroviral vector is efficacious for cancer gene therapy in mice.

Targeting cytocidal vectors to tumors and associated vasculature in vivo is a long-standing goal of human gene therapy. In the present study, we demonstrated that intravenous infusion of a matrix (i.e., collagen)-targeted retroviral vector provided efficacious gene delivery of a cytocidal mutant cyclin G1 construct (designated Mx-dnG1) in human cancer xenografts in nude mice. A nontargeted CAE-dnG1 vector (p = 0.014), a control matrix-targeted vector bearing a marker gene (Mx-nBg; p = 0.004), and PBS served as controls (p = 0.001). Enhanced vector penetration and transduction of tumor nodules (35.7 +/- 1.4%, mean +/- SD) correlated with therapeutic efficacy without associated toxicity. Kaplan-Meier survival studies were conducted in mice treated with PBS placebo, the nontargeted CAE-dnG1 vector, and the matrix-targeted Mx-dnG1 vector. Using the Tarone log-rank test, the overall p value for comparing all three groups simultaneously was 0.003, with a trend that was significant to a level of 0.004, indicating that the probability of long-term control of tumor growth was significantly greater with the matrix-targeted Mx-dnG1 vector than with the nontargeted CAE-dnG1 vector or PBS placebo. The present study demonstrates that a matrix-targeted retroviral vector deployed by peripheral vein injection (1) accumulated in angiogenic tumor vasculature within 1 hr, (2) transduced tumor cells with high-level efficiency, and (3) enhanced therapeutic gene delivery and long-term efficacy without eliciting appreciable toxicity.

Design, expression, and renaturation of a lesion-targeted recombinant epidermal growth factor-von Willebrand factor fusion protein: efficacy in an animal model of experimental colitis.

In the present study, the mature epidermal growth factor (EGF) protein was engineered to incorporate a high affinity collagen-binding domain (CBD) derived from co-agulation von Willebrand factor, to specifically target EGF to colonic lesions. The fusion protein was expressed in an E. coli bacterial expression system, purified by metal chelate chromatography, and renatured by oxidative refolding into a soluble biologically active growth factor. The EGF-CBD fusion protein bound tightly to collagen matrices under conditions in which native non-targeted EGF was washed away. In biologic assays, the EGF-CBD fusion protein stimulated NIH3T3 cell proliferation with near wild-type biological activity. In vivo binding studies showed that the collagen-targeted EGF, but not the non-targeted EGF, accumulated at areas of exposed collagen on the luminal surface of the inflamed colon. Finally, a single colonic instillation of the collagen-targeted EGF-induced a more rapid regeneration of intestinal crypts 24 h after treatment (no. of crypts = 89.2+/-8.1) compared to the non-targeted EGF (no. of crypts = 52.2+/-29.8; p=0.027), and the PBS control (no. of crypts = 24. 0+/-22.9; p=0.001). Taken together, these findings indicate that intracolonic delivery of collagen-targeted EGF represents a potentially effective therapeutic strategy for acute or chronic inflammatory bowel disease.

Follow-up: does it work? Can we afford it?

Follow-up of patients with colorectal cancer has been controversial. This is largely because studies have been small and inadequate to assess results. A recently performed meta-analysis confirms a very significant benefit to the follow-up of patients following curative resection of colorectal cancer. This article outlines the rationale and cost-effectiveness of a follow-up policy.

Inhibition of metastatic tumor growth in nude mice by portal vein infusions of matrix-targeted retroviral vectors bearing a cytocidal cyclin G1 construct.

Tumor invasion and associated angiogenesis evoke a remodeling of extracellular matrix components. Retroviral vectors bearing auxiliary matrix-targeting motifs (ie., collagen-binding polypeptides) accumulate at sites of newly exposed collagen, thus promoting tumor site-specific gene delivery. In this study, we assessed the antitumor effects of serial portal vein infusions of matrix-targeted vectors bearing a mutant cyclin G1 (dnG1) construct in a nude mouse model of liver metastasis. The size of tumor foci was dramatically reduced in dnG1 vector-treated mice compared with that in control vector- or PBS-treated animals (P = 0.0002). These findings represent a definitive advance in the development of targeted injectable vectors for metastatic cancer.

Incorporation of tumor vasculature targeting motifs into moloney murine leukemia virus env escort proteins enhances retrovirus binding and transduction of human endothelial cells.

Adhesion receptors expressed on the surfaces of tumor-activated endothelial cells provide an advantageous locus for targeting gene therapy vectors to angiogenic tissues and/or tumor vasculature. In this study, we engineered a series of Asn-Gly-Arg (NGR)-containing congeners of the presumptive cell binding motif contained within the ninth type III repeat of fibronectin and displayed these tumor vasculature targeting motifs (TVTMs) within the context of Moloney murine leukemia envelope "escort" proteins. Comparative studies of envelope incorporation into viral particles and evaluation of the cell binding properties of the targeted vectors revealed critical structural features, thus identifying a subset of optimal TVTMs. Utilizing a modified ELISA to evaluate viral binding to target cells, we observed a significant down-regulation of TVTM-virion binding to human endothelial cells following sustained (48-h) exposure to VEGF. Normalized for equivalent titers (10(6) CFU/ml), as assayed on NIH 3T3 cells, vectors displaying TVTM escort proteins significantly enhanced the transduction efficiency from 12.2 to 37.4% in human KSY-1 endothelial cell cultures (P < 0.001) and from 0.4 to 4.1% in human umbilical vein endothelial cell (HUVEC) cultures (P < 0.001). In summary, these studies utilized an engineering approach to identify a subset of TVTMs that are stably incorporated as envelope "escort" proteins into retroviral vectors and that, by functioning to improve the binding efficiency and transduction of both HUVEC and KSY1 endothelial cells, may have therapeutic potential for targeting gene delivery to the tumor-associated vasculature.

Molecular engineering of matrix-targeted retroviral vectors incorporating a surveillance function inherent in von Willebrand factor.

A major obstacle that limits the potential of human gene therapy is the inefficiency of gene delivery to appropriate sites in vivo. Previous studies demonstrated that the physiological surveillance function performed by von Willebrand factor (vWF) could be incorporated into retroviral vectors by molecular engineering of the MuLV ecotropic envelope (Env) protein. To advance the application of vWF targeting technology beyond laboratory animals, we prepared an extensive series of Env proteins bearing modified vWF-derived matrix-binding sequences and assembled these chimeric proteins into targeted vectors that are capable of transducing human cells. Initially, a dual envelope configuration was utilized, which required coexpression of a wild-type amphotropic Env. Subsequently, streamlined "escort" Env proteins were constructed wherein the inoperative receptor-binding domain of the targeting partner was replaced by the vWF-derived collagen-binding motif. Ultimately, an optimal construct was developed that exhibited properties of both extracellular matrix (ECM)-targeting and near wild-type amphotropic infectivity, and could be arrayed as a single envelope on a retroviral particle. On intraarterial instillation, enhanced focal transduction of neointimal cells (approximately 20%) was demonstrated in a rat model of balloon angioplasty. Moreover, transduction of tumor foci (approximately 1-3%) was detected after portal vein infusion of a matrix-targeted vector in a nude mouse model of liver metastasis. We conclude that the unique properties of these targeted injectable retroviral vectors would be suitable for improving therapeutic gene delivery in numerous clinical applications, including vascular restenosis, laser and other surgical procedures, orthopedic injuries, wound healing, ischemia, arthritis, inflammatory disease, and metastatic cancer.

Abdominal insufflation does not cause hematogenous spread of colon cancer.

BACKGROUND AND PURPOSE: Previous investigators have suggested that port-site recurrences are possibly a result of abdominal insufflation, forcing viable cancer cells into the circulation to metastasize and thrive in areas of trauma. Using a syngeneic animal cancer model, we tested the hypothesis that pneumoperitoneum increases the incidence of wound metastasis by a blood-borne mechanism. METHODS: Male BD IX rats (N = 150) were injected intraperitoneally with 2 x 10(5) viable syngeneic 1,2-dimethylhydralazine-induced colon cancer cells (DHD-K12). Animals were divided into three groups: A (abdominal insufflation with 3-cm incision on the back into muscle remote from the peritoneum); B (3-cm back incision alone); and C (control group with 3-cm midline abdominal incision). Three weeks after surgery, the animals were euthanized and autopsied. RESULTS: In the two groups with back wounds, the incidence of cancer growth at the incision was zero, as demonstrated grossly and by histologic sample (A: 0/47, B: 0/43). In contrast, the autopsied control group had a 42% incidence of metastasis to the wound (25/59). There seemed to be no difference in the distribution of intra-abdominal disease between those rats that underwent insufflation and those that did not. CONCLUSION: It is unlikely that pneumoperitoneum promotes hematogenous wound implantation of free intraperitoneal cancer cells.

Follow-up of colorectal cancer: a meta-analysis.

PURPOSE: The value of intensive follow-up for patients after resection of colorectal cancer remains controversial. This study reviews all randomized and prospective cohort studies to assess the value of aggressive follow-up. METHODS: The literature was searched from the years 1972 to 1996 for studies reporting on the follow-up of patients with colorectal cancer. Randomized and comparative-cohort studies that included history, physical examination, and carcinoembrionic antigen values at least three times a year for at least two years were included in a meta-analysis. Single-cohort studies with intensive follow-up and traditional follow-up were also included in a two-group comparative analysis for each outcome indicator. Outcome indicators were 1) curative resection rates after recurrent cancer, 2) survival rates of curative re-resections, 3) length of survival after recurrence, and 4) cumulative five-year survival. RESULTS: Two randomized and three comparative-cohort studies met these criteria and included 2,005 patients, which were evaluated in the meta-analysis. The cumulative five-year survival was 1.16 times higher in the intensively followed group (P = 0.003). Two and one-half times more curative re-resections were performed for recurrent cancer in those patients undergoing intensive follow-up (P = 0.0001). Those patients in the intensive follow-up group with a recurrence had a 3.62-times higher survival rate than the control (P = 0.0004). Fourteen single-cohort studies were also included in the comparative analysis of 6,641 patients. The findings from these aggregated studies support the results of the meta-analysis. CONCLUSION: Our study concludes that intensive follow-up detects more recurrent cancers at a stage amenable to curative resection, resulting in an improvement in survival of recurrences and an increased overall five-year cumulative rate of survival.