Predisposing factors of diminished survival in simultaneous liver/kidney transplantation.

Since the adoption of the Model for End-Stage Liver Disease, simultaneous liver/kidney transplants (SLKT) have substantially increased. Recently, unfavorable outcomes have been reported yet contributing factors remain unclear. We retrospectively reviewed 74 consecutive adult SLKT performed at our center from 2000 to 2010 and compared with kidney transplant alone (KTA, N = 544). In SLKT, patient and death-censored kidney graft survival rates were 64 ± 6% and 81 ± 5% at 5 years, respectively (median follow-up, 47 months). Multivariable analyses revealed three independent risk factors affecting patient survival: hepatitis C virus positive (HCV+, hazard ratio [HR] 2.9, 95% confidence interval [CI] 1.1-7.9), panel reactive antibody (PRA) > 20% (HR 2.8, 95% CI 1.1-7.2) and female donor gender (HR 2.9, 95% CI 1.1-7.9). For death-censored kidney graft survival, delayed graft function was the strongest negative predictor (HR 8.3, 95% CI 2.5-27.9), followed by HCV+ and PRA > 20%. The adjusted risk of death-censored kidney graft loss in HCV+ SLKT patients was 5.8 (95% CI 1.6-21.6) compared with HCV+ KTA (p = 0.008). Recurrent HCV within 1 year after SLKT correlated with early kidney graft failure (p = 0.004). Careful donor/recipient selection and innovative approaches for HCV+ SLKT patients are critical to further improve long-term outcomes.

Thin-layer ablation of human esophageal epithelium using a bipolar radiofrequency balloon device.

BACKGROUND: The goal of this study was to determine the optimal treatment parameters for the ablation of human esophageal epithelium using a balloon-based bipolar radiofrequency (RF) energy electrode. METHODS: Immediately prior to esophagectomy, subjects underwent esophagoscopy and ablation of two separate, 3-cm long, circumferential segments of non-tumor-bearing esophageal epithelium using a balloon-based bipolar RF energy electrode (BARRX Medical, Inc., Sunnyvale, CA, USA). Subjects were randomized to one of three energy density groups: 8, 10, or 12 J/cm2. RF energy was applied one time (1x) proximally and two times (2x) distally. Following resection, sections from each ablation zone were evaluated using H&E and diaphorase. Histological endpoints were complete epithelial ablation (yes/no), maximum ablation depth, and residual ablation thickness after tissue slough. Outcomes were compared according to energy density group and 1x vs 2x treatment. RESULTS: Thirteen male subjects (age, 49-85 years) with esophageal adenocarcinoma underwent the ablation procedure followed by total esophagectomy. Complete epithelial removal occurred in the following zones: 10 J/cm2 (2x) and 12 J/cm2 (1x and 2x). The maximum depth of injury was the muscularis mucosae: 10 and 12 J/cm2 (both 2x). A second treatment (2x) did not significantly increase the depth of injury. Maximum thickness of residual ablation after tissue slough was only 35 microm. CONCLUSIONS: Complete removal of the esophageal epithelium without injury to the submucosa or muscularis propria is possible using this balloon-based RF electrode at 10 J/cm2 (2x) or 12 J/cm2 (1x or 2x). A second application (2x) does not significantly increase ablation depth. These data have been used to select the appropriate settings for treating intestinal metaplasia in trials currently under way.

Gastric carcinoids: a temporal increase with proton pump introduction.

BACKGROUND: Recent reports have indicated a rising incidence of gastric carcinoids. This study aimed to evaluate the incidence pattern of gastric carcinoids in two large population-based cancer registries. METHODS: The Florida Cancer Data System (FCDS), Florida's statewide cancer registry, and the Surveillance, Epidemiology, and End Results (SEER) program were used. The study population was defined as all cases of gastric carcinoid identified in either database from January 1981 to December 2000. Descriptive statistics and age-adjusted incidence rates were calculated. RESULTS: There were 326 (FCDS) and 594 (SEER) cases of invasive gastric carcinoid during the 20-year study period. The mean age of the patients was 65 years (range, 21-96 years), and the male:female ratio was 1:1. The age-adjusted incidence rate in FCDS increased from 0.04 (per 100,000 age-adjusted to the 2000 U.S. standard population) to 0.18 in the year 2000. The estimated annual percentage change in incidence was 8.17 in FCDS and 9.17 in SEER (p < 0.05). A decrease in gastric cancer was noted during this same period (from 8.64 to 11.14 cases per 100,000 in FCDS and from 11.14 to 8.06 cases per 100,000 in SEER). CONCLUSIONS: This study documented a statistically significant eight- or ninefold increase in the incidence of gastric carcinoids in two large databases. The temporal increase in incidence correlates with the introduction and widespread use of proton pump inhibitors since the late 1980s. Other explanations include improved detection with wider application of upper endoscopy. Further epidemiologic studies are warranted.

Sentinel lymph node localization in early breast cancer.

METHODS: Thirty-two patients with clinical node-negative breast cancer underwent sentinel node localization study as part of a National Cancer Institute-sponsored multicenter trial. Anatomical and histopathologic characteristics of sentinel lymph node (SLN) and a kinetic analysis of nodal uptake were studied. Patients were injected with 1 mCi/4 ml unfiltered 99mTc-sulfur colloid in four divided doses around the palpable lesion or immediately adjacent to the excision cavity if prior biopsy was performed. SLN biopsy was performed 1.5-6 hr (mean = 3 hr) postinjection. Intraoperative localization was performed using a gamma probe. All patients underwent complete axillary dissection. RESULTS: SLN was identified in 30 of 32 (94%) patients. There were no false-negative SLN biopsies. CONCLUSION: This study supports the clinical validity of SLN biopsy in breast cancer and confirms that, unlike the blue dye technique, the learning curve with unfiltered 99mTc-sulfur colloid and the gamma detection probe is short, and SLN localization is achievable in over 90% of cases by surgeons with modest experience. The use of unfiltered 99mTc-sulfur colloid (larger particle size) with larger injected volume permits effective localization of SLNs.

A subcutaneous or subfascial jejunostomy is beneficial in the surgical management of extrahepatic bile duct cancers.

BACKGROUND: Extrahepatic bile duct cancers are rare tumors with a dismal prognosis. Even after a resection, obstructive cholestasis and other biliary complications are the rule. To facilitate retrograde access to the biliary tree for treatment of such biliary complications, a modified Roux-en-Y hepaticojejunostomy is constructed such that the afferent limb is brought up as a subcutaneous or subfascial jejunostomy (SJ). The safety and utility of construction of an SJ was evaluated in patients with extrahepatic cholangiocarcinoma. METHODS: From 1985 to 1997, 24 patients with extrahepatic bile duct cancers received an SJ as part of their management. Demographic data, operative data, tumor characteristics, and postoperative courses were retrospectively reviewed. All but 3 patients were followed to the time of death. RESULTS: The average age of the patients was 62 +/- 9 years. The tumor was resected in 17 patients. Major complications occurred in 5 patients (21%). There was 1 operative death (4%). None of the complications could be attributed to construction of the SJ, although 1 patient had a soft tissue infection at the site of the percutaneous access of the SJ. Frequent dilatations of biliary strictures were required in 5 patients, and 1 patient eventually required insertion of an internal biliary stent. These procedures could all be accomplished through the SJ. CONCLUSIONS: The SJ is a technically simple and safe addition to the management of resectable and unresectable extrahepatic bile duct cancers, particularly proximal lesions. The procedure facilitates brachytherapy if indicated, and it allows convenient management of postoperative biliary complications, including recurrent strictures.

Giant acquired tracheoesophageal fistulas: strategy for successful management.

Giant tracheoesophageal fistulas (TEF) present a significant management problem for the head and neck surgeon. Chronic aspiration and sepsis are associated complications that occur in these patients, who are frequently already debilitated from pre-existing medical calamities. The combination results in prolonged morbidity and frequent mortality. Recently, we have managed two patients with this difficult problem. The first patient was managed using conventional methods well described in the literature with an unsuccessful outcome. The second was managed differently using a two-stage approach. The esophageal stream was first excluded from the respiratory system via a surgical approach, which to the best of our knowledge has not been previously described in the literature. After a period of convalescence, the patient's alimentary tract is reconstituted with a gastric pull-up, reversed gastric tube, or colon interposition. We propose this as an alternative method of management for TEF.

Large cystic lesions of the liver in adults: a 15-year experience in a tertiary center.

BACKGROUND: Cystic lesions of the liver consist of a heterogeneous group of disorders and may present a diagnostic and therapeutic challenge. Large hepatic cysts tend to be symptomatic and can cause complications more often than smaller ones. STUDY DESIGN: We performed a retrospective review of adults diagnosed with large (> or = 4 cm) hepatic cystic lesions at our center, over a period of 15 years. Polycystic disease and abscesses were not included. RESULTS: Seventy-eight patients were identified. In 57 the lesions were simple cysts, in 8 echinococcal cysts, in 8 hepatobiliary cystadenomas, and in 1 hepatobiliary cystadenocarcinoma. In four patients, the precise diagnosis could not be ascertained. Mean size was 12.1 cm (range, 4 to 30 cm). Most simple cysts were found in women (F:M, 49:8). Bleeding into a cyst (two patients) and infection (one patient) were rare manifestations. Percutaneous aspiration of 28 simple cysts resulted in recurrence in 100% of the cases within 3 weeks to 9 months (mean 4(1/2) months). Forty-eight patients were treated surgically by wide unroofing or resection (laparoscopically in 18), which resulted in low recurrence rates (11% for laparoscopy and 13% for open unroofing). Four of the eight patients with echinococcal cysts were symptomatic. All were treated by open resection after irrigation of the cavity with hypertonic saline. There was no recurrence during a followup period of 2 to 14 years. Hepatobiliary cystadenomas occurred more commonly in women (F:M, 7:1) and in the left hepatic lobe (left:right, 8:0). Seven were multiloculated. All were treated by open resection, with no recurrence, and none had malignant changes. Cystadenocarcinoma was diagnosed in a 77-year-old man, and was treated by left hepatic lobectomy. CONCLUSIONS: Large symptomatic simple cysts invariably recur after percutaneous aspiration. Laparoscopic unroofing can be successfully undertaken, with a low recurrence rate. Open resection after irrigation with hypertonic saline is a safe and effective treatment for echinococcal cysts. Hepatobiliary cystadenomas have predilection for women and for the left hepatic lobe. Malignant transformation is an uncommon but real risk. Open resection is a safe and effective treatment for hepatobiliary cystadenoma, and is associated with a low recurrence rate.

Metastasectomy as a cytoreductive strategy for treatment of isolated pulmonary and hepatic metastases from breast cancer.

The authors sought to examine the utility of resection in conjunction with adjuvant chemotherapy for treatment of metastases from breast cancer isolated to the liver or lungs. Limitations of regional therapy were examined and potential agents for systemic therapy were reviewed. As resection of metastases is a controversial therapeutic approach, no clinical trials are available for review. Rather, evidence for a potential role for surgery rests on retrospective studies of small series of patients. Technical advances have rendered resection of liver and lung metastases safe. Long-term results as reported by other investigators support the role of metastasectomy in selected patients. The site of failure following ablation of liver metastases is usually in the liver. Following resection of lung metastases, nonpulmonary and disseminated recurrences are most common. Adjuvant therapy with docetaxel or any other agent or combination with significant activity against visceral metastases might potentiate long-term results.

Extent of resection in the management of duodenal adenocarcinoma.

BACKGROUND: It has been postulated that segmental duodenal resection (SR) is not an adequate operation for patients with adenocarcinoma of the duodenum and that pancreaticoduodenectomy (PD) is the procedure of choice, regardless of the tumor site. However, data from previous studies do not clearly support this position. METHODS: We reviewed the records of 63 patients treated for duodenal adenocarcinoma from 1979 through 1998. Perioperative outcome, patient survival, and extent of lymphadenectomy were compared in patients who underwent PD and SR. RESULTS: The overall morbidity for PD and SR was 27% and 18%, respectively (not significant [NS]). Patients who underwent SR had a 5-year survival of 60% versus 30% for patients who underwent PD (NS). Lymph node status was a prognostic factor for survival (P = 0.014). The mean number of lymph nodes in the specimens was 9.9 +/- 2.1 for PD and 8.3 +/- 4.4 for SR (NS). CONCLUSIONS: Segmental duodenal resection for patients with duodenal adenocarcinoma is associated with acceptable postoperative morbidity and long-term survival. The procedure is especially well suited for distal duodenal tumors. Clearance of lymph nodes and outcome are comparable to PD.

Portal hypertension. A fifteen year perspective.

Two hundred six consecutive patients were followed from 5 to 15 years after a distal splenorenal shunt operation. Nonalcoholic patients demonstrated nearly twice the survival rate when compared with alcoholic patients. The mean duration of life for the surviving nonalcoholics was 10 years and for the alcoholics, 9 years. We predict that approximately a third of the nonalcoholics will enjoy long-term survival. The operative mortality rate was similar in both groups, being about 4 percent. The risk of liver cancer was highest in the male alcoholics, and long-term survival was greater for women in both the alcoholic and nonalcoholic groups.

Percutaneous dilatation of biliary strictures through the afferent limb of a modified Roux-en-Y choledochojejunostomy or hepaticojejunostomy.

BACKGROUND: This report is a 13-year prospective evaluation of percutaneous balloon dilatation of benign biliary strictures through the subcutaneous or subfascially positioned afferent limb of a choledocho or hepaticojejunostomy in 30 patients. DATA SOURCE: Twenty-seven strictures developed after a common duct injury sustained at the time of cholecystectomy, two after hepatectomy reconstruction for trauma and one following a gastrectomy. Twelve injuries (40%) were recognized at operation. Of the 18 patients where the injury was unrecognized at the time of operation, 8 had not been reoperated at the time of referral, 7 had late repairs by the referring physician, and 3 had late repairs at our institution. The follow-up is 1 to 13 years. RESULTS: There has been 1 late death and 6 patients are lost alive. The jejunal-limb was accessed 50 times with two minor and no major complications. There have been two parajejunal hernia repairs, but there have not been any reoperations for recurrent biliary strictures. CONCLUSIONS: Benign biliary strictures can be effectively managed by repeat balloon dilatations thru the afferent limb of a choledocho or hepaticojejunostomy, thus eliminating the need for repeat surgical interventions.

Reconstruction of the stenotic hypopharynx and cervical esophagus without total laryngectomy.

Reconstruction for severe stenosis of the hypopharynx, laryngeal inlet, and/or cervical esophagus is a challenging problem for the surgeon and his patient who want to avoid total laryngectomy. We reviewed the case records of eight patients and the relevant published literature in an effort to define the requirements for success and the causes of failure. A variety of surgical techniques were used. Seven of 8 patients eat a normal or near normal diet. Two of 4 patients, who sustained laryngeal damage at the time of initial injury, required total laryngectomy because of persistent aspiration. The 2 remaining patients and the 4 patients, who did not sustain laryngeal damage at the time of injury, speak with a good voice. Total laryngectomy should be reserved for those patient who cannot be rehabilitated following optimal reconstruction.

A phase II trial of recombinant leukocyte interferon plus doxorubicin in patients with hepatocellular carcinoma.

A Phase II trial of combination therapy with recombinant leukocyte interferon (alpha IFN) and doxorubicin was performed in patients with unresectable hepatocellular carcinoma. alpha IFN was administered at a starting dose of 20 x 10(6) U/m2 intramuscularly or subcutaneously with doxorubicin 20 mg/m2 intravenously weekly x 3 weeks followed by a 2-week period rest. There were 22 patients entered into the study. Among the 21 patients, there were 2 partial responses (10%), one minor response, and one patient had stable disease. Toxicity was generally tolerable, with fever, fatigue, and myelosuppression being the most common side effects. This combination of weekly recombinant leukocytic interferon and doxorubicin has modest and limited activity in hepatocellular carcinoma.

A phase I study of chemoembolization with cisplatin, thiotepa, and lipiodol for primary and metastatic liver cancer.

Thirty patients with primary hepatocellular carcinoma or liver metastases were entered into a program of chemoembolization with cisplatin, lipiodol, and escalating doses of thiotepa. Doses of cisplatin were 100/m2, and thiotepa doses ranged from 9 mg/m2 to 24 mg/m2. Two of three patients with ocular melanoma had partial responses in the liver metastases for 3+ and 16 months. In patients with either hepatocellular carcinoma (15 patients) or primary cholangiocarcinoma of the liver (three patients), there were two partial responses, for 22 and 33 months. Five patients had minor responses: four with a 40% reduction in tumor and one with a mixed response. There were four early deaths, which involved sepsis in two patients, respiratory failure in one, and acute myocardial infarction in one. Otherwise, toxicity was tolerable and reversible and included abdominal pain and transient elevation of serum creatinine, bilirubin, and transaminases. Less common toxicities included ototoxicity and peripheral neuropathy. Chemoembolization of the liver with cisplatin, thiotepa, and lipiodol can produce responses, but toxicity can be significant. The recommended starting phase II dose for future studies is thiotepa 24 mg/m2 and cisplatin 100 mg/m2.

Transhiatal versus transthoracic esophagectomy: complication and survival rates.

The classic approach for esophagectomy is via a combined thoracic and abdominal approach. Concerns persist regarding the adequacy of this approach as a cancer operation. A study was carried out to compare these approaches, with particular reference to complication rates and long-term survival. The charts of all adult patients undergoing esophagectomy for carcinoma at the University of Miami/Jackson Memorial Hospital between July 1991 and June 1996 were reviewed. Patients who had transabdominal resections alone or colon interpositions were excluded. Of 65 esophageal resections, 38 (58%) were performed transhiatally (THE) and 27 (42%) were performed via the transthoracic (TTE) route. Treatment groups were matched for age and site, stage, and histology of tumor. Similarly, the treatment groups were homogeneous with respect to distribution of neoadjuvant chemotherapy/radiation. The number of patients experiencing any postoperative complication was similar in both treatment groups, occurring in 22 THE (58%) and 17 TTE (63%) patients (P>0.05). Anastomotic leak occurred in five THE patients (13%) and one TTE patient (4%) (P>0.05). The single TTE patient with a leak died within 3 months without leaving the hospital. All five THE patients who developed a leak left the hospital. Although there was a tendency toward a higher percentage of patients in the TTE group to suffer respiratory failure and sepsis and a higher percentage of THE patients to experience anastomotic leak, these did not reach statistical significance. Again, although perioperative mortality tended to be higher in the TTE group, this did not reach statistical significance. Four and 5-year survival rates were similar in both groups. Whereas a 4-year cumulative survival difference of 42% for THE patients and 31% in TTE patients extended at 58 months to 28% and 8%, respectively, these did not reach statistical significance. Similarly, analysis by stage and preoperative treatment type (+/- neoadjuvant chemotherapy/radiation) failed to demonstrate any survival difference between the two groups. These findings demonstrate that there is little difference in operative morbidity and mortality between THE and TTE routes. Anastomotic leaks that occur after cervical anastomosis tend to run a more benign course. Survival data do not support routine TTE as a superior oncological operation, despite the theoretical benefit of better lymphatic clearance. We continue to advocate THE because it allows a cervical anastomosis without thoracotomy and we feel it is better tolerated by patients.

Neoadjuvant therapy for esophageal cancer: standard of care or elusive myth?

Although surgical resection as the sole treatment modality for esophageal carcinoma has historically been associated with poor survival rates, improvements have recently been reported using varied neoadjuvant chemo-radiation protocols. This study evaluates the outcome of patients undergoing surgery for esophageal carcinoma at the University of Miami/Jackson Memorial Hospital between July 1991 and June 1996. Seventy-two patients underwent esophageal resection; 51 males and 21 females with a median age of 62.5 years (range = 42-82). Histology was equally distributed between adenocarcinoma (36 patients; 50%) and squamous cell carcinoma (36 patients; 50%). Pathological stage distribution consisted of 6 stage 0 (8%), 10 stage I (14%), 23 stage II (32%), 31 stage III (43%), and 2 stage IV (3%) lesions. Patients were divided into three groups according to the type of preoperative treatment; Group 1 (n = 44); surgery alone; Group 2 (n = 18); neoadjuvant 5-fluorouracil based chemotherapy, and Group 3 (n = 9); neoadjuvant 5-fluorouracil based chemotherapy in conjunction with external beam radiation (XRT). One patient received preoperative XRT alone. All survivors were followed for a minimum of 1 year and statistical analysis was performed using Kaplan-Meier curves, log-rank, and chi-square tests. In the 28 patients receiving any form of neoadjuvant therapy only one patient had a pathological complete response (CR) (3.5%). The overall 5 year and median survival rates were 18 per cent and 20.5 months (range = 0-73), respectively. Individual treatment group survival rates at 5 years were 28% for Group 1; 21% for Group 2; and 0% for Group 3, showing no survival difference between Groups 1 and 2; Group 3 fared significantly worse than the other two, probably as a result of the high operative mortality in this group. These results indicate that surgical resection continues to be an important treatment modality for esophageal carcinoma. Neoadjuvant chemotherapy in our experience failed to improve these survival rates and pre-operative chemoradiation was associated with a high perioperative mortality rate. Chemotherapy regimens with higher CRs may further improve these survival rates.

Balloon dilatation through the subcutaneously placed afferent limb of a hepaticojejunostomy in patients with resected Klatskin tumors.

It is generally conceded that palliation for proximal bile duct tumors (Klatskin) is exceptional if obstruction and the resultant infections can be prevented. Our experience with balloon dilatations thru the subcutaneously placed afferent limb of a choledocho or hepatico jejunostomy in patients with benign strictures suggests that this approach will be effective in patients with malignancies and thus provide long-term control of the obstruction without the need for external tubes. This is a report on one patient who, following a resected Klatskin tumor with positive margins, was treated with transhepatic internal external stents and was converted to a subcutaneous limb following numerous bouts of cholangitis. A schedule for repeat dilatations thru the jejunal limb was established. The patient has remained afebrile with a normal bilirubin and a moderately elevated alkaline phosphatase. Recurrent tumors or postirradiation strictures in patients with resected Klatskin tumors can be effectively controlled by repeated balloon dilatation without the need for external stents.

Management of hilar bile duct carcinoma.

BACKGROUND/AIMS: Hilar cholangiocarcinoma is a rare tumor with a dismal prognosis. Because proximal bile duct cancers are uncommon, outcomes related to various therapeutic interventions are not well defined. METHODOLOGY: Between 1985 and 1997, 55 patients with bile duct cancers involving the proximal third of the extrahepatic bile ducts were seen. The management of patients with resectable and unresectable disease was retrospectively reviewed. All but four patients were followed until the time of death. RESULTS: Forty patients underwent laparotomy following preoperative assessment of extent of disease and 19 patients (35%) ultimately underwent resection with curative intent. Survival was significantly longer in patients who underwent resection (2-year survival 47% vs. 18%; P = 0.027). Of those patients whose disease was resected, 11 patients received adjuvant radiotherapy. Survival for this group was not significantly different from that seen in patients who did not receive adjuvant radiotherapy. Similarly, in patients with unresectable disease, administration of radiotherapy was not associated with an improved outcome. CONCLUSIONS: Locoregional extent of disease is the greatest problem in cases of proximal bile duct cancers. Resection provides the best hope for long-term survival, but new adjuvant strategies are needed.

Activation of Notch1 signaling in stromal fibroblasts inhibits melanoma growth by upregulating WISP-1.

The tumor microenvironment is emerging as an important target for cancer therapy. Fibroblasts (Fbs) within the tumor stroma are critically involved in promoting tumor growth and angiogenesis through secretion of soluble factors, synthesis of extracellular matrix and direct cell-cell interaction. In this work, we aim to alter the biological activity of stromal Fbs by modulating the Notch1 signaling pathway. We show that Fbs engineered to constitutively activate the Notch1 pathway significantly inhibit melanoma growth and tumor angiogenesis. We determine that the inhibitory effect of 'Notch-engineered' Fbs is mediated by increased secretion of Wnt-induced secreted protein-1 (WISP-1) as the effects of Notch1 activation in Fbs are reversed by shRNA-mediated blockade of WISP-1. When 'Notch-engineered' Fbs are co-grafted with melanoma cells in SCID mice, shRNA-mediated blockade of WISP-1 reverses the tumor-suppressive phenotype of the 'Notch-engineered' Fbs, significantly increases melanoma growth and tumor angiogenesis. Consistent with these findings, supplement of recombinant WISP-1 protein inhibits melanoma cell growth in vitro. In addition, WISP-1 is modestly expressed in melanoma-activated Fbs but highly expressed in inactivated Fbs. Evaluation of human melanoma skin biopsies indicates that expression of WISP-1 is significantly lower in melanoma nests and surrounding areas filled with infiltrated immune cells than in the adjacent dermis unaffected by the melanoma. Overall, our study shows that constitutive activation of the Notch1 pathway confers Fbs with a suppressive phenotype to melanoma growth, partially through WISP-1. Thus, targeting tumor stromal Fbs by activating Notch signaling and/or increasing WISP-1 may represent a novel therapeutic approach to combat melanoma.