Bart C. Vrouenraets

Isolated limb perfusion with tumor necrosis factor-α and melphalan for patients with unresectable soft tissue sarcoma of the extremities

Since 1992, isolated limb perfusion (ILP) with tumor necrosis factor‐α (TNFα) and melphalan has been used for the treatment of patients with unresectable soft tissue sarcomas of the extremities. The authors retrospectively studied the results of limb salvage surgery using TNFα‐ILP at their institution.

Toxicity and morbidity of isolated limb perfusion

Because a relationship between toxicity and treatment outcome has never been demonstrated for isolated limb perfusion (ILP) with melphalan, it is important to keep the side-effects of the procedure restricted to a minimum. Risk factors for more severe acute regional toxicity have recently been identified with tissue temperature above 40 degrees C and a high melphalan peak concentration being the most important. Acute regional toxicity should be mild taking into account these factors and maintaining the normal physiological conditions in the limb during ILP. This should also decrease the incidence of long-term morbidity, especially ankle stiffness and muscle atrophy, since a relation between the severity of the acute regional tissue reactions and long-term morbidity has been demonstrated. Lymphedema is strongly linked to a concomitant regional lymph node dissection and this operation may be delayed until the acute regional tissue reactions have faded. It is not yet clear whether the addition of tumor necrosis factor-alpha (TNF-alpha) to melphalan increases regional toxicity. In the absence of melphalan leakage to the systemic circulation, systemic toxicity is minimal; this is also true with TNF-alpha. Compared to ILP with melphalan +/- TNF-alpha, ILP with other drugs is less effective and often is associated with increased regional toxicity.

Relation between limb toxicity and treatment outcomes after isolated limb perfusion for recurrent melanoma.

BACKGROUND The optimal toxic reaction of the normal tissues in perfused limbs after isolated limb perfusion (ILP) is unknown. Theoretically, more severe limb toxicity could reflect a concomitant increased toxic effect to the tumor and improved outcomes. We determined whether there is a relation between limb toxicity and treatment outcomes after ILP for recurrent limb melanoma. STUDY DESIGN Among 252 patients with recurrent melanoma of the limbs, treatment outcomes in 192 patients (76%) with no or mild acute limb toxicity were compared with those in 60 (24%) with more severe reactions. Multivariate analysis was used to identify prognostic factors for complete response, limb recurrence-free interval, and survival. RESULTS Among 112 patients with measurable disease, 65 patients (58%) had a complete response and 27 (42%) experienced a relapse in the perfused limb. For complete response, uninvolved regional lymph nodes (p = 0.0025) and ILP using tumor necrosis factor-alpha (p = 0.0076) appeared to be favorable prognostic factors in multivariate analysis. There was no evidence of a relation between limb toxicity and complete response either in univariate (p = 0.16) or multivariate analysis (p = 0.46). For limb recurrent-free interval, only the number of lesions was a significant prognostic factor (p = 0.047); limb toxicity was not (p = 0.095). In 140 patients with recurrent melanoma excised before or at the moment of ILP, independent prognostic factors for survival were gender, the number of positive nodes, and stage of disease. There was no relation between limb toxicity and survival in either univariate (p = 0.53) or multivariate analysis (p = 0.94). Forty-eight (34%) of the 140 patients had a relapse in the perfused limb. No prognostic factors for limb recurrent-free interval could be identified; limb toxicity was not related to relapse time in univariate or multivariate analyses (p = 0.16 and p = 0.14, respectively). CONCLUSIONS More severe acute limb toxicity is not associated with improved outcomes. One should aim at grade II toxicity (slight erythema or edema, compatible with complete recovery) at the most to increase the therapeutic ratio of ILP.

Safety and efficacy of isolated limb perfusion in elderly melanoma patients.

BackgroundOlder patients are assumed to have a higher risk of complications from isolated limb perfusion (ILP). A study was performed evaluating the safety and efficacy of ILP in patients older than 75 years with advanced melanoma of the limbs.MethodsA total of 218 therapeutic ILPs with melphalan with or without tumor necrosis factor α were performed in 202 patients with advanced measurable melanoma and were analyzed retrospectively. Fifty-three patients (28%) were 75 years or older.ResultsComplete response rates were 56% for those older than 75 years and 58% for the younger group (P=.79). Locoregional relapse occurred in 56% of the older group versus 51% in the younger group (P=.61). Limb toxicity, systemic toxicity, local complications, and long-term morbidity were similar in both age groups. Perioperative mortality was low, with one procedure-related death in the older group. Older patients stayed in the hospital for a median of 23 days (younger patients, 19 days;P<.01).ConclusionsILP results in similar response rates in the elderly with recurrent melanoma, without increased toxicity, complications, or long-term morbidity compared with younger patients. Older age in itself is not a contraindication for ILP.

Esophageal Perforation Associated with Cervical Spine Surgery: Report of Two Cases and Review of the Literature

Background/Aims: Esophageal perforation after anterior cervical spine surgery is a rare complication with various clinical presentations and treatments. Methods: Two cases of esophageal perforation after anterior cervical spine surgery are described, one occurring in the immediate postoperative period and one several years after plate stabilization of the cervical spine. Results: Primary suturing of the acute perforation and diversion of the salivary flow by means of T-tube placement after delayed presentation allowed successful healing of the esophageal defects. Conclusion: When encountering acute dysphagia after cervical spine surgery, one should think of an esophageal perforation and install immediate further diagnostics and therapy. Treatment depends on the time of detection and size of the perforation. In early stages, with vital tissues, primary suturing is the treatment of choice. If presentation is late, it seems advisable to limit the procedure to simple drainage after removal of foreign bodies.

Systemic toxicity after isolated limb perfusion with melphalan for melanoma

Systemic exposure to melphalan is minimized during isolated limb perfusion (ILP) by isolating a limb from the rest of the body. Consequently, there should be no toxicity to vital organs. At present systemic toxicity after ILP has not been studied in detail. Therefore, the incidence, nature and risk factors of systemic toxicity was retrospectively studied in 368 patients who underwent a single ILP with melphalan between 1978-1990. Some form of systemic toxicity occurred in 98 patients (27%). Nausea and vomiting after the 1st post-ILP day was seen in 73 patients (20%), and in seven (2%) treatment was required. Bone marrow depression was encountered in seven patients (2%): WHO grade II in five, and grade III in two. Miscellaneous systemic side-effects, including fever and minimal scalp hair loss, occurred in 19 patients (5%). Leakage from the isolated circuit to the systemic circulation was measured with radioactive tracers. Mean cumulative leakage during ILP was 0.9%. Systemic toxicity was not increased in patients with leakage greater than 1% or 5%. Female sex was associated with an increased incidence of systemic toxicity (P<0.05). Age over 60 years (P<0.05) and more severe acute regional toxicity (P<0.05) were correlated with nausea and vomiting. The miscellaneous systemic side-effects were more frequently encountered in women than in men (P<0.05). In conclusion, systemic toxicity was rarely severe, with nausea and vomiting being the most frequently encountered side-effects. Age over 60 years, female sex and more severe acute regional toxic reactions were correlated with an increased incidence of systemic side-effects. Systemic leakage during ILP was not associated with toxicity, probably due to the low incidence of significant leakage.

Evidence-Based Surgical Treatment of Esophageal Cancer: Overview of High-Quality Studies

Evidence-based medicine is the conscientious, explicit, and judicious use of best available evidence in making decisions for individual patient care. The present review gives an evidence-based review of esophageal cancer surgery. The literature search was restricted to the highest level of evidence on the surgical treatment of esophageal cancer.

Radiological evaluation of colorectal anastomoses

Background and aimsThe purpose of this study was to determine the accuracy, interobserver variability, timing and discordance with relaparotomy of postoperative radiological examination of colorectal anastomoses.Patient/methodsFrom 2000 to 2005, 429 patients underwent an ileocolonic, colo-colonic, or colorectal anastomosis. Radiological examination of the anastomosis was not performed routinely, but only when there were clinically signs of leakage. Radiological imaging was reviewed by an independent radiologist and medical records were retrospectively analyzed. Clinical anastomotic leakage was the standard of reference and defined as leakage confirmed during relaparotomy, drainage of pus per anum or as an anastomotic defect identified at digital examination.ResultsRadiological evaluation of the anastomosis was performed in 91 patients (21%): CT in 27 patients, contrast radiography in 40, and both imaging modalities in 24 patients. The interobserver variability of CT and contrast radiography was 10% and 14%, respectively. The sensitivity and negative predictive value of imaging of the anastomosis was 65% and 73%, respectively. Anastomotic leakage was found in 11 of 21 patients (52%) who underwent relaparotomy despite negative imaging. Three of 36 patients (8%) with a diagnosis of anastomotic leakage based on radiological examination had an intact anastomosis at relaparotomy.ConclusionRadiological imaging of the anastomosis after colorectal surgery should be restrictively applied and interpreted with caution because of the high false-negative rate and the substantial interobserver variability.

Isolated Limb Perfusion Prolongs the Limb Recurrence-Free Interval After Several Episodes of Excisional Surgery for Locoregional Recurrent Melanoma

BackgroundThe influence of isolated limb perfusion (ILP) on the limb recurrence-free interval (LRFI) and the number of lesions per recurrence was studied for patients with frequently recurring regional in-transit metastases previously managed by excisional surgery.MethodsAll 43 patients who had their first ILP for a third or further limb recurrence were selected from our computer database of 451 patients who underwent therapeutic ILP for recurrent extremity melanoma in our centers. Eighteen patients had resectable and 25 had locally unresectable lesions at the time of ILP. The patients had a total of 269 intervals between treatment of their primary melanoma and last recurrence or last follow-up. Median follow-up was 35 months (interquartile range, 14–64 months).ResultsThe median LRFI decreases over time from primary melanoma to the third or further recurrence for which ILP was performed (P < 0.001). The median LRFI is 4.7 times longer (95% confidence interval [CI], 2.8–7.9; P < 0.001) after ILP in comparison with the last interval before ILP. Patients with resectable lesions have a median LRFI that is 5.9 times longer (95% CI, 2.7–13; P < 0.001). In all patients, the number of lesions increases by 22% per recurrence number (95% CI, 10%–35%; P = 0.02). At the same recurrence number, patients before ILP have a 2.6-fold higher (95% CI, 1.6–4.5) mean number of lesions than do patients after ILP (P < 0.001).ConclusionsILP lengthens the LRFI and decreases the number of lesions per recurrence significantly in patients with repeatedly recurrent limb melanoma. Therefore, ILP could be a valuable adjunct to excisional surgery for in-transit metastases in these patients whose LRFIs tend to shorten over time.

Incidence and risk factors of delirium in the elderly general surgical patient

BACKGROUND This study evaluates the incidence of delirium and risk factors associated with delirium in elderly patients admitted to a general surgical ward. METHODS Patients aged over 60 years who were admitted with an acute or elective general surgical diagnosis were eligible for this prospective cohort study. Risk factors associated with delirium were analyzed using univariate and multivariate analysis to identify those independently associated with delirium. RESULTS A total of 209 patients were included in the study. The incidence of delirium was 16.9% (23.2% for acute admission, P < .001). Variables associated with delirium were dementia, presence of an urinary catheter, cognitive decline at admission measured with the mini-mental state examination, white blood cell count >10.0 × 10(9)/L, and urea >7.5 mmol/L. Median length of hospital stay was 13 days (range 3-85) for patients with delirium versus 7 (range 1-54) for patients without (P = .002). CONCLUSIONS The incidence of delirium is high in elderly patients, especially after an acute admission, leading to an increase in length of hospital stay. To minimize delirium, associated risk factors must be identified and, if possible, treated.