Passive immunization against tumor necrosis factor partially abrogates interleukin 2 toxicity.

Passive immunization against TNF allowed non-tumor-bearing C3H/HEN mice and tumor-bearing C57BL/6 mice to tolerate significantly more doses of IL-2 before death (p less than 0.005 and p less than 0.001, respectively). The antitumor effect of IL-2 against both 3-d and 10-d pulmonary metastases was maintained in mice treated concurrently with neutralizing antibodies to TNF. In one experiment with 10-d pulmonary metastases, increased administration of IL-2 made possible by passive immunization against TNF significantly improved the antitumor response compared to equitoxic doses of IL-2 and control antibody. The results indicate that TNF is a mediator of IL-2 toxicity but contributes minimally to the antitumor effects of IL-2. Strategies to inhibit TNF may improve the therapeutic index of IL-2 as a neoplastic agent.

Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis.

Tumor necrosis factor (TNF) is a peptide secreted by macrophages in response to endotoxin that can produce many of the changes seen in septic shock. After cecal ligation and puncture (CLP) rats gradually develop tachycardia, hypotension, tachypnea, and hypothermia. At 5 h post-CLP, rats have a peak in serum levels of endotoxin and 60% of rats have blood cultures that grow Gram-negative rods (Escherichia coli and Klebsiella pneumonia). At 20 h post-CLP all rats develop positive blood cultures. Serum levels of TNF are not reproducibly measurable in rats following CLP. Rats undergoing CLP have a 50-80% mortality with deaths usually occurring 24-72 h postinjury. Repetitive (twice daily x 6 d) i.p. injection of sublethal doses of recombinant human TNF-alpha (100 micrograms/kg) to rats undergoing CLP 1 d after the treatment period resulted in a significant reduction in mortality compared to control rats previously unexposed to rTNF (P less than 0.03). Animals treated with rTNF had no hypotension or hypothermia after CLP and regained normal food intake faster than control rats. 12 h after CLP the gene expression for manganous superoxide dismutase (MnSOD), an inducible mitochondrial metalloenzyme responsible for cellular resistance to injury from toxic reactive oxygen species, was higher in livers of rats treated with rTNF suggesting that the TNF treatment augmented expression of this protective enzyme. Unlike MnSOD, expression of the gene for copper-zinc SOD was not affected by CLP or rTNF treatment. The results suggest that prior treatment with recombinant TNF can ameliorate the lethality, hypotension, hypothermia, and anorexia of Gram-negative sepsis in rats and that the mechanism may be related to enhanced hepatic expression of the gene for MnSOD. Repeated administration of recombinant TNF may be a strategy to minimize mortality and morbidity of Gram-negative sepsis.

Prolonged survival of tumor-bearing rats with repetitive low-dose recombinant tumor necrosis factor.

Tumor necrosis factor may be a mediator of the syndrome of cancer cachexia. Tachyphylaxis or tolerance to the cachectic effects of recombinant tumor necrosis factor (rTNF) has been previously described. In this study, we investigate whether repetitive exposure to rTNF can induce similar tolerance in tumor-bearing (TB) rats and ameliorate cachexia induced by the tumor. In experiment 1, non-tumor-bearing (NTB) and TB rats were randomized to either escalating low doses of rTNF or saline i.p. twice daily for 9 consecutive days. NTB rats treated with rTNF demonstrated a significant decline in food intake and weight change (P less than 0.00001) but soon developed tolerance to the cachectic effects of rTNF; they consumed significantly more food than on the first day of treatment and had weight change similar to NTB rats treated with saline. TB rats treated with rTNF showed a similar significant decline in food intake and weight change (P less than 0.0001) and also demonstrated similar tolerance to the cachectic effects of rTNF with continued treatment. Following treatment, TB rats that had been treated with rTNF ate significantly more and lost less weight than TB rats that had been treated with saline (P less than 0.00001). rTNF treatment of TB rats also demonstrated antineoplastic activity, as estimated tumor weight of tumors from rats treated with rTNF were significantly less than controls (P = 0.003). The anticachexia and antineoplastic effects of rTNF resulted in prolonged survival of TB rats treated with rTNF compared to control TB rats (P = 0.015). Experiment 2 utilized two different rTNF treatment regimens in TB rats: one group received 12 days of escalating doses of rTNF, and another group received 15 days of rTNF treatment. TB rats treated with rTNF again had a significantly greater food intake (P less than 0.00001) and delayed weight loss (P = 0.0001) posttreatment that was further augmented by additional doses of rTNF. Antineoplastic activity of rTNF was less clear, and overall tumor growth curves were not affected by rTNF treatment. Survival of TB rats treated with rTNF was again significantly increased in a dose-dependent manner (P = 0.006). Repeated administration of low doses of rTNF to TB rats induces mild reduction in tumor growth, tolerance to the cachectic effects of rTNF that results in tolerance to the cachectic effects of tumor, and prolongation of survival.

The roles of gamma-interferon and tumor necrosis factor alpha in an experimental rat model of cancer cachexia.

Administration of repetitive sublethal doses of either recombinant human tumor necrosis factor (TNF) or recombinant murine gamma-interferon (IFN) to non-tumor-bearing (NTB) rats caused a significant decline in food intake and body weight. After 3 days rats became resistant to the anorectic and weight loss effects of TNF but maintained persistent diminished food intake and diminished body weight gain while receiving recombinant murine IFN. Passive immunization against recombinant rat gamma-interferon allowed cachectic tumor-bearing (TB) rats to eat more food, have a lesser decline in body weight, live longer, and tolerate larger tumors than similar TB rats given nonspecific control antibody. TB rats treated with an antisera to recombinant murine TNF, which was 100% protective when given to NTB rats 6 h before a lethal endotoxin challenge, did not differ significantly from TB rats treated with control antibody with respect to food intake, body weight, survival, or tumor size. Serum levels of TNF or IFN were not detectable in cachectic tumor-bearing rats. The data indicate that the administration of exogenous IFN can simulate cachexia in NTB rats and that passive immunization against it can partially reverse the cachectic changes associated with cancer and prolong survival. These findings suggest that gamma-interferon may be an important mediator of cachexia in this rat tumor model.

The utility of circulating levels of human pancreatic polypeptide as a marker for islet cell tumors.

The measurement of plasma levels of human pancreatic polypeptide (hPP) has been reported to be clinically useful in predicting the existence of pancreatic islet cell neoplasms in patients with familial multiple endocrine neoplasia type 1 (FMEN-I) and the possible presence of metastatic disease in patients with islet cell tumors. However, these studies have not been prospective and involve small numbers of patients. In this study, fasting plasma samples from 36 patients with biopsy-proved islet cell tumors were analyzed for hPP by radioimmunoassay and compared with age-matched control subjects. Of 13 patients with FMEN-I who had islet cell tumors, 7 (54%) had elevated plasma hPP levels before surgery. After resection of all islet cell tumors, 4 of 12 patients evaluated after surgery still had elevated levels. Fifteen patients had islet cell tumors that were localized (seven insulinomas and eight gastrinomas), but none of these patients had elevated hPP levels, either before or after surgery. Nine patients, including one with FMEN-I, with metastatic islet cell tumors to the liver were studied; three with more advanced disease had elevated hPP levels before surgery. Each of the nine patients underwent resection of all gross disease and the three patients with elevated preoperative levels had normal postoperative hPP levels. Our results indicate that basal plasma levels of hPP were not clinically useful. The hPP levels did not reliably predict the presence of islet cell tumors in patients with FMEN-I, because 46% of patients with tumors did not have elevated plasma levels, and in those with elevated values hPP levels did not reliably predict the resection of all tumor. Plasma levels of hPP have no utility in patients with localized sporadically occurring islet cell tumors and limited utility (33%) in predicting the presence of metastatic islet cell tumors to the liver.

A randomized, prospective trial of postoperative somatostatin analogue in patients with neuroendocrine tumors of the pancreas.

BACKGROUND: Pancreatic surgery is not uncommonly complicated by prolonged pancreatic drainage and fistula. Octreotide decreases pancreatic exocrine function and has been reported to improve closure of pancreatic and intestinal fistulae. This randomized, prospective trial was designed to evaluate the efficacy of postoperative octreotide in reducing pancreatic drainage and complications after resection of neuroendocrine tumors of the pancreas. METHODS: Patients with neuroendocrine tumors of the pancreas were entered into the study and randomized after operation to receive octreotide 150 micrograms subcutaneously every 8 hours or saline solution subcutaneously every 8 hours in a double-blinded fashion. Daily pancreatic drainage, total drainage, number of days to drain removal, and complications were recorded. RESULTS: Ten patients were given octreotide; eleven patients were given saline solution. The number of days to drain removal, daily drainage, and total drainage were not significantly different. Complications related to pancreatic drainage were not significantly different. CONCLUSIONS: Octreotide is not indicated for the routine postoperative management of patients with neuroendocrine tumors of the pancreas.

Role of tumor necrosis factor in oxygen toxicity.

mRNA from lungs of mice exposed to high-dose oxygen (greater than 95%) for 3 days demonstrated increased expression of the genes for tumor necrosis factor (TNF), interleukin-1, and interleukin-6 compared with mRNA from lungs of mice exposed to room air. Daily treatment of mice exposed to high-dose oxygen with an antibody to TNF improved survival compared with mice receiving a similar dose of control immunoglobulin G. Pretreatment of mice with repetitive sublethal intraperitoneal doses of recombinant human TNF for 3 days or a single intravenous dose followed by exposure to high-dose oxygen afforded a significant survival advantage compared with high-dose oxygen-exposed mice pretreated with vehicle or interleukin-1. The repetitive intraperitoneal TNF pretreatment reduced the development of interstitial pneumonitis, pulmonary edema, and lung weight gain associated with oxygen toxicity and enhanced expression of the gene for the free radical protective enzyme manganous superoxide dismutase in lung tissue, a gene that is augmented as mice are exposed to high-dose oxygen. Furthermore a single intravenous dose of TNF 24 h after oxygen exposure was still protective. The results suggest that the toxicity of oxygen therapy can be partially ameliorated by either treatment with anti-TNF antibody or pretreatment and early treatment with TNF. These findings are consistent with the hypothesis that oxygen exposure induces TNF, which causes part of the toxicity of high-dose oxygen, and that pretreatment or early treatment with TNF induces the gene for an enzyme that recently has been shown to be very effective in protecting mice from the toxicity of oxygen.

Mechanisms of cancer cachexia.

It is currently hypothesized that the mechanisms of cancer cachexia involve the host's production of inflammatory cytokines, which in turn orchestrate a series of complex interrelated steps that ultimately lead to a chronic state of wasting, malnourishment, and death (see Fig. 1). The metabolic changes seen in the tumor-bearing host are similar, but not identical, to those seen in sepsis and inflammation and appear to result from a generalized response of the host to the stimulus of invasion--the tumor. Although there are likely to be several humoral factors, of either host or tumor origin (see Fig. 1), involved in cancer cachexia, recombinant DNA methodology has provided sufficient amounts of only a few cytokines to enable careful investigation of their cachectic potential. TNF/cachectin has been most extensively studied and appears to play a clear role, because administration of low-dose continuous or escalating doses simulates changes associated with cancer cachexia. In addition, these cachectic changes have been blocked by a specific antisera. IL-1, IL-6, and interferon-gamma all have potential as mediators of cancer cachexia and more work is clearly indicated. It is possible that, given our current understanding of the mechanisms of cancer cachexia, it can be theorized that TNF, which causes many of the manifestations of cancer cachexia, and IL-1 are released by macrophages in response to tumor (see Fig. 1). Interferon-gamma appears to potentiate these effects and may also be necessary for the complete syndrome of cancer cachexia. IL-6 probably is released as another mediator, principally mediating the acute phase response seen in cancer cachexia. Other factors are certain to be involved. Further study into the mechanisms and possible treatment of cancer cachexia is needed, because a large proportion of cancer patients who are incurable by current therapies continue to suffer from this lethal wasting diathesis. Furthermore, specific strategies to reverse the cachectic changes associated with cancer will likely improve antitumor treatment.

Tumour necrosis factor mediates the survival benefit of interleukin 2 in a murine pulmonary metastases model.

Antibody to tumour necrosis factor (TNF Ab) markedly decreases the toxicity of systemic interleukin-2 (IL-2) in mice but does not completely abrogate the anti-tumour response in terms of number of pulmonary metastases. Experiments were performed with a murine model of pulmonary metastases treated with high-dose IL-2 and concomitant TNF Ab or control antibody (CON Ab) to determine the effects of TNF Ab on survival. Mice were given either equal doses of IL-2 and TNF Ab or CON Ab or equitoxic doses of IL-2. In four consecutive experiments mice given TNF Ab tolerated 5 to 6 additional IL-2 doses (a 40-60% increase in total doses) in the equitoxic IL-2 dose group compared to the maximally tolerated dose with CON Ab. In all four experiments TNF Ab-treated mice had decreased survival compared to the CON Ab group given equal doses of IL-2 and in two of four experiments this difference was statistically significant (P2 < 0.01). Mice given 40-60% additional doses of IL-2 with TNF Ab had no improvement in survival compared with equitoxic doses of IL-2 with CON Ab in three of four experiments (P2 = 0.32, P2 = 0.67, P2 = 0.69). The TNF Ab preparation had no direct inhibition of IL-2 activity in an in vitro IL-2 proliferation bioassay. TNF Ab consistently blocks IL-2 toxicity and it also abrogates IL-2 therapeutic efficacy such that survival parallels treatment toxicity in this experimental model.

MR imaging of the muscular component of myocutaneous flaps in the head and neck.

BACKGROUND AND PURPOSE: Myocutaneous flaps are commonly used for reconstruction in head and neck surgery. The purpose of this study was to characterize the MR imaging findings of the muscular component of these flaps, with an emphasis on enhancement patterns. Recognition of these imaging findings is important in differentiating postoperative changes from recurrent tumor. METHODS: MR studies were evaluated in 25 patients who had undergone 27 flap reconstructions after resection of a head and neck tumor. Twenty were free flaps and seven were pedicled rotation flaps, and a dominant component of all flaps was muscle. MR images were reviewed for signal intensity, enhancement characteristics, and morphology over a period of 7 to 79 months. RESULTS: On baseline postoperative images, 21 flaps showed moderate or intense enhancement of the muscular graft component relative to nonenhancing native muscle, three flaps showed mild enhancement, and three showed no enhancement. On follow-up images, 18 flaps that initially had intense enhancement showed persistent intense enhancement, and three showed decreasing enhancement. Two flaps with initial mild enhancement were unchanged on follow-up, and one became nonenhancing. None of the initially nonenhancing flaps subsequently enhanced. T1 signal intensity of muscular graft components was always isointense with normal muscle, whereas T2 signal intensity was variable and tended to be stable. Ninety-three percent of our muscular flap components showed striations typical of normal muscle and were best identified on T1-weighted images. No significant imaging differences were found between pedicled and free flaps. CONCLUSION: Most muscular flap components show moderate or intense enhancement on fat-suppressed contrast-enhanced MR images that may persist for many months and be quite striking. Radiologists should be familiar with the typical postoperative appearance of predominantly muscular flaps to avoid misdiagnosis as tumor extension or recurrence.

Coverage of skull base defects.

Successful reconstruction of the cranial base requires a knowledge of this complex anatomic area, a careful assessment of the defect, a healthy respect for the potential for ascending infection and meningitis, and reliable techniques to effectively contain the intracranial space with vascularized tissue. The first step in reconstruction is a secure dural repair, which must be covered by a healthy vascularized layer. The scalp contains galeal and pericranial flaps, which are usually incorporated into the reconstruction. Sometimes, along with local muscles such as the temporalis, these local tissues are all that is needed to complete the reconstruction. When the defects are larger and in irradiated beds, free tissue transfer has emerged as the most reliable method to bolster the dural repair.

How to use a gel template for an exact facial flap transfer.

A variety of materials have been used as template materials to aid in the design of local facial flaps. The biggest criticism of these materials is that they do not conform sufficiently to complex defects. This report describes the use of a hydrogel sheet wound dressing (ClearSite, NDM, Akron, Ohio) as a template material. ClearSite appears to make an ideal template material because it is thin, pliable, transparent, and inexpensive. This gel template adequately conforms to irregular three-dimensional shapes. It has the added beneficial ability to "lift" marking pen lines, which can then be transferred as an exact replica of the defect size. A case is presented in which a ClearSite template directed the transfer of the exact amount of forehead tissue following excision of a complex congenital nevus of the nose. Use of the ClearSite template seems well suited to help in local facial flaps and is likely to simplify the design of many distant flaps as well.

Incidence of hematoma associated with ketorolac after TRAM flap breast reconstruction.

Ketorolac is frequently used as an adjunct for postoperative pain relief, especially by anesthesiologists during the immediate postoperative period. It can be used alone as an analgesic but is more often used to potentiate the actions of narcotics such as morphine or meperidine in an attempt to reduce the total dose and side effects of those drugs. The manufacturer of ketorolac cautions against its use in patients who have a high risk of postoperative bleeding, for fear of increasing the risk of hematoma, but the risk in transverse rectus abdominis musculocutaneous (TRAM) flap patients has never been reported. In a study of 215 patients who had undergone TRAM flap breast reconstruction, it was determined that patients who received intravenous ketorolac (n = 65) as an adjunct to their treatment with morphine administered by use of a patient-controlled analgesia device required less morphine (mean cumulative dose, 1.39 mg/kg) than did patients who did not receive ketorolac (n = 150; mean cumulative dose, 1.75 mg/kg; p = 0.02). There was no increase in the incidence of hematoma in patients who were treated with ketorolac. The data presented in this study suggest that the use of intravenous ketorolac does reduce the need for narcotics administration in patients undergoing TRAM flap breast reconstruction, without significantly increasing the risk of hematoma.

Postoperative morphine requirements of free TRAM and DIEP flaps.

In a review of the charts of 158 patients who had undergone breast reconstruction with free transverse rectus abdominis musculocutaneous (TRAM) or deep inferior epigastric perforator (DIEP) flaps and who were treated for postoperative pain with morphine administered by a patient-controlled analgesia pump, the total dose of morphine administered during hospitalization for the flap transfer was measured. Patients whose treatment was supplemented by other intravenous narcotics were excluded from the study. The mean amount of morphine per kilogram required by patients who had reconstruction with DIEP flaps (0.74 mg/kg, n = 26) was found to be significantly less than the amount required by patients who had reconstruction with TRAM flaps (1.65 mg/kg; n = 132; p < 0.001). DIEP flap patients also remained in the hospital less time (mean, 4.73 days) than did free TRAM flap patients (mean, 5.21 days; p = 0.026), but the difference was less than one full hospital day. It was concluded that the use of the DIEP flap does reduce the patient requirement for postoperative pain medication and therefore presumably reduces postoperative pain. It may also slightly shorten hospital stay.

Reconstructive management of cranial base defects after tumor ablation.

Successful reconstruction after cranial base tumor ablation is paramount in preventing potentially life-threatening complications. The purpose of this study was to evaluate experiences of cranial base reconstruction and to identify reconstructive management principles that may assist in achieving successful cranial base reconstruction. All cranial base reconstructions performed by the Department of Plastic Surgery at the University of Texas M. D. Anderson Cancer Center between January of 1993 and September of 1999 were reviewed. Analyses were performed to assess the impact of location of defect, type of reconstruction, type of dural repair, and history of preoperative radiation and chemotherapy on rates of complications, and patient survival. The 77 patients who underwent cranial base reconstruction after tumor ablation during the study period had a mean age of 52 years (6 to 84 years). The mean follow-up period was 28.7 months (1 to 76 months). Squamous cell carcinoma, the most common histopathologic type, was present in 24 patients (31 percent), and 35 patients (45 percent) presented with recurrent disease. Location of defects involved region I (anterior) in 31 patients (40 percent), region II (anterior-lateral) in 18 (23 percent), region III (lateral-posterior) in six (8 percent), and more than one region in 22 (29 percent). Reconstructive methods included free flaps in 52 patients (68 percent), temporalis muscle flaps in 14 (18 percent), pericranial flaps in eight (10 percent), and other local flaps (two galeal, one scalp) in three (4 percent). Of the 52 free flaps, 18 (35 percent) were used in region I, 14 (27 percent) in region II, six (12 percent) in region III, and 14 (27 percent) in defects involving more than one region. Of the 14 temporalis muscle flaps, 13 (93 percent) were used for defects involving regions I or II and one (7 percent) was used for a defect involving region III. Of the 11 pericranial and other local flaps, nine (82 percent) were used in region I, one (9 percent) in region II, and one (9 percent) in a combination of regions II and III. Complications occurred in 21 patients (27 percent): three total flap losses (4 percent), three partial flap losses (4 percent), two cerebrospinal fluid leaks (3 percent), two cases of meningitis (3 percent), two abscesses (3 percent), five cases of delayed wound healing (6 percent), two hematomas (3 percent), one wound infection (1 percent), and one cerebrovascular accident (1 percent). Overall survival was 77 percent at 2 years and 58 percent at 4 years. The type of reconstruction, location of defect, type of dural repair, and history of preoperative radiation and chemotherapy had no significant association with the incidence of complications. Neither the type of reconstruction nor the location of defect showed a significant effect on patient survival. In this experience, local flaps, such as pericranial or temporalis muscle flaps, are good choices for reconstruction of smaller anterior or lateral cranial base defects. For defects that require larger amounts of soft tissue, free flaps are appropriate. With proper patient selection, successful cranial base reconstruction can be performed with either local or free flaps with a low incidence of complications.

Comparison of cost for DIEP and free TRAM flap breast reconstructions.

A recent article by Kaplan and Allen suggested that deep inferior epigastric perforator (DIEP) flap breast reconstruction was less expensive than reconstruction performed with free transverse rectus abdominis musculocutaneous (TRAM) flaps. To test that hypothesis, a series of patients who had undergone unilateral breast-mound reconstruction by the first author using DIEP or free TRAM flaps between November 1, 1996, and March 30, 2000, were reviewed. Bilateral reconstructions and reconstructions performed by other surgeons in the department were excluded to eliminate all variables except the choice of flap. All hours in the operating room and days in the hospital until discharge were included. Early readmissions for the treatment of complications were included, as were the costs of the mastectomy in the case of immediate reconstructions, but late revisions and nipple reconstructions were not. The totals were then converted into resource costs in 1999 dollars, and the DIEP and free TRAM flap groups compared. There were 21 DIEP flaps and 24 free TRAM flaps in the series. In this series, there was no significant difference between the cost of DIEP and free TRAM flap breast reconstruction.

Effect of obesity on flap and donor-site complications in free transverse rectus abdominis myocutaneous flap breast reconstruction.

The purpose of this study was to assess the effect of obesity on flap and donor-site complications in patients undergoing free transverse rectus abdominis myocutaneous (TRAM) flap breast reconstruction. All patients undergoing breast reconstruction with free TRAM flaps at our institution from February 1, 1989, through May 31, 1998, were reviewed. Patients were divided into three groups based on their body mass index: normal (body mass index <25), overweight (body mass index 25 to 29), obese (body mass index > or =30). Flap and donor-site complications in the three groups were compared. A total of 936 breast reconstructions with free TRAM flaps were performed in 718 patients. There were 442 (61.6 percent) normal-weight, 212 (29.5 percent) overweight, and 64 (8.9 percent) obese patients. Flap complications occurred in 222 of 936 flaps (23.7 percent). Compared with normal-weight patients, obese patients had a significantly higher rate of overall flap complications (39.1 versus 20.4 percent; p = 0.001), total flap loss (3.2 versus 0 percent; p = 0.001), flap seroma (10.9 versus 3.2 percent; p = 0.004), and mastectomy flap necrosis (21.9 versus 6.6 percent; p = 0.001). Similarly, overweight patients had a significantly higher rate of overall flap complications (27.8 versus 20.4 percent; p = 0.033), total flap loss (1.9 versus 0 percent p = 0.004), flap hematoma (0 versus 3.2 percent; p = 0.007), and mastectomy flap necrosis (15.1 versus 6.6 percent; p = 0.001) compared with normal-weight patients. Donor-site complications occurred in 106 of 718 patients (14.8 percent). Compared with normal-weight patients, obese patients had a significantly higher rate of overall donor-site complications (23.4 versus 11.1 percent; p = 0.005), infection (4.7 versus 0.5 percent; p = 0.016), seroma (9.4 versus 0.9 percent; p <0.001), and hernia (6.3 versus 1.6 percent; p = 0.039). Similarly, overweight patients had a significantly higher rate of overall donor-site complications (19.8 versus 11.1 percent; p = 0.003), infection (2.4 versus 0.5 percent; p = 0.039), bulge (5.2 versus 1.8 percent; p = 0.016), and hernia (4.3 versus 1.6 percent; p = 0.039) compared with normal-weight patients. There were no significant differences in age distribution, smoking history, or comorbid conditions among the three groups of patients. Obese patients, however, had a significantly higher incidence of preoperative radiotherapy and preoperative chemotherapy than did patients in the other two groups. A total of 23.4 percent of obese patients had preoperative radiation therapy compared with 12.3 percent of overweight patients and 12.4 percent of normal-weight patients; 34.4 percent of obese patients had preoperative chemotherapy compared with 24.5 percent of overweight patients and 17.7 percent of normal-weight patients. Multiple logistic regression analysis was used to determine the risk factors for flap and donor-site complications while simultaneously controlling for potential confounding factors, including the incidence of preoperative chemotherapy and radiotherapy. In summary, obese and overweight patients undergoing breast reconstruction with free TRAM flaps had significantly higher total flap loss, flap hematoma, flap seroma, mastectomy skin flap necrosis, donor-site infection, donor-site seroma, and hernia compared with normal-weight patients. There were no significant differences in the rate of partial flap loss, vessel thrombosis, fat necrosis, abdominal flap necrosis, or umbilical necrosis between any of the groups. The majority of overweight and even obese patients who undertake breast reconstruction with free TRAM flaps complete the reconstruction successfully. Both such patients and surgeons, however, must clearly understand that the risk of failure and complications is higher than in normal-weight patients. Patients who are morbidly obese are at very high risk of failure and complications and should avoid any type of TRAM flap breast reconstruction.

Effect of smoking on complications in patients undergoing free TRAM flap breast reconstruction.

Free pedicled transverse rectus abdominis myocutaneous (TRAM) flap breast reconstruction is often advocated as the procedure of choice for autogenous tissue breast reconstruction in high-risk patients, such as smokers. However, whether use of the free TRAM flap is a desirable option for breast reconstruction in smokers is still unclear. All patients undergoing breast reconstruction with free TRAM flaps at our institution between February of 1989 and May of 1998 were reviewed. Patients were classified as smokers, former smokers (patients who had stopped smoking at least 4 weeks before surgery), and nonsmokers. Flap and donor-site complications in the three groups were compared. Information on demographic characteristics, body mass index, and comorbid medical conditions was used to perform multivariate statistical analysis. A total of 936 breast reconstructions with free TRAM flaps were performed in 718 patients (80.9 percent immediate; 23.3 percent bilateral). There were 478 nonsmokers, 150 former smokers, and 90 smokers. Flap complications occurred in 222 (23.7 percent) of 936 flaps. Smokers had a higher incidence of mastectomy flap necrosis than nonsmokers (18.9 percent versus 9.0 percent; p = 0.005). Smokers who underwent immediate reconstruction had a significantly higher incidence of mastectomy skin flap necrosis than did smokers who underwent delayed reconstruction (21.7 percent versus 0 percent; p = 0.039). Donor-site complications occurred in 106 (14.8 percent) of 718 patients. Donor-site complications were more common in smokers than in former smokers (25.6 percent versus 10.0 percent; p = 0.001) or nonsmokers (25.6 percent versus 14.2 percent; p = 0.007). Compared with nonsmokers, smokers had significantly higher rates of abdominal flap necrosis (4.4 percent versus 0.8 percent; p = 0.025) and hernia (6.7 percent versus 2.1 percent; p = 0.016). No significant difference in complication rates was noted between former smokers and nonsmokers. Among smokers, patients with a smoking history of greater than 10 pack-years had a significantly higher overall complication rate compared with patients with a smoking history of 10 or fewer pack-years (55.8 percent versus 23.8 percent; p = 0.049). In summary, free TRAM flap breast reconstruction in smokers was not associated with a significant increase in the rates of vessel thrombosis, flap loss, or fat necrosis compared with rates in nonsmokers. However, smokers were at significantly higher risk for mastectomy skin flap necrosis, abdominal flap necrosis, and hernia compared with nonsmokers. Patients with a smoking history of greater than 10 pack-years were at especially high risk for perioperative complications, suggesting that this should be considered a relative contraindication for free TRAM flap breast reconstruction. Smoking-related complications were significantly reduced when the reconstruction was delayed or when the patient stopped smoking at least 4 weeks before surgery.

Reconstruction of large sacral defects following total sacrectomy.

Total sacrectomies for cancer ablation often result in extensive defects that are challenging to reconstruct. In an effort to elucidate the criteria to select the most effective reconstructive options, we reviewed our experience with the management of large sacral wound defects. All patients who had a sacral defect reconstruction after a total sacrectomy at our institution between January of 1993 and August of 1998 were reviewed. The size of the defect, the type of reconstruction, postoperative complications, and functional outcome in each patient were assessed. A total of 27 flaps were performed in 25 patients for sacral defect reconstruction after a total sacrectomy. Diagnoses consisted of chordoma (n = 13), giant cell carcinoma (n = 2), sarcoma (n = 5), rectal adenocarcinoma (n = 4), and radiation induced necrosis (n = 1). The size of sacral defects ranged from 18 to 450 cm2 (mean, 189.8 cm2). Ten patients, including five who had preoperative radiation therapy, underwent transpelvic vertical rectus abdominis myocutaneous (VRAM) flap reconstruction for sacral defects with a mean size of 203.3 cm2. Of these, five patients (50 percent) had complications (four minor wound dehiscences and one seroma). Eight patients, including one who had preoperative radiation therapy, underwent bilateral gluteal advancement flap reconstruction for sacral defects with a mean size of 198.0 cm2. They had no complications. Two patients, both of whom had preoperative radiation therapy, underwent gluteal rotation flap reconstruction for sacral defects of 120 cm2 and 144 cm2. Both patients had complications (one partial flap loss and one nonhealing wound requiring a free flap). Three patients, including one who had preoperative radiation therapy, underwent reconstruction with combined gluteal and posterior thigh flaps for sacral defects with a mean size of 246 cm2; two of these patients had partial necrosis of the posterior thigh flaps. Three patients, all of whom had preoperative radiation therapy, underwent free flap reconstruction for sacral defects with a mean size of 144.3 cm2. They had no complications. Our experience suggests that there are three reliable options for the reconstruction of large sacral wound defects: bilateral gluteal advancement flaps, transpelvic rectus myocutaneous flaps, and free flaps. In patients with no preoperative radiation therapy and intact gluteal vessels, the use of bilateral gluteal advancement flaps should be considered. In patients with a history of radiation to the sacral area and in patients whose gluteal vessels have been damaged, the use of the transpelvic VRAM flap should be considered. If the transpelvic VRAM flap cannot be used because of previous abdominal surgery, a free flap should be considered as a last option.

Malignant melanoma arising within a burn scar case report and review of the literature.

Burn scar carcinomas, also called Marjolin's ulcers, are uncommon tumors that arise from an antecedent burn. Most burn scar carcinomas are diagnosed about 30 years after the burn, and most are well-differentiated squamous cell carcinomas. We report a case in which a squamous cell carcinoma developed within a burn scar on the cheek and then a malignant melanoma arose within the burn scar after the squamous cell carcinoma had been excised. We also review the available literature on burn scar carcinoma, covering the demographics, pathogenesis, diagnosis, prognosis, and treatment of the disease. Given the multifocality of this disease process, we advocate aggressive resection of the entire burn scar, as well as the tumor, to prevent the development of further cancers within the wound.