Patterns of failure and predictors of outcome in cutaneous malignant melanoma of the scalp.

BACKGROUND: Patients with melanoma of the scalp may have higher failure (recurrence) rates than melanoma of other body sites. OBJECTIVE: We sought to characterize survival and patterns of failure for patients with scalp melanoma. METHODS: Between 1998 and 2010, 250 nonmetastatic patients underwent wide local excision of a primary scalp melanoma. Kaplan-Meier analyses were performed to evaluate overall survival, scalp control, regional neck control, distant metastases-free survival, and disease-free survival. RESULTS: Five-year overall survival was 86%, 57%, and 45% for stages I, II, and III, respectively, and 5-year scalp control rates were 92%, 75%, and 63%, respectively. Five-year distant metastases-free survival for these stages were 92%, 65%, and 45%, respectively. Of the 74 patients who recurred, the site of first recurrence included distant disease in 47%, although 31% recurred in the scalp alone. LIMITATIONS: This is a retrospective review. CONCLUSION: Distant metastases-free survival and overall survival for stage II and III patients with scalp melanoma are poor, and stage III patients experience relatively high rates of scalp failure suggesting that these patients may benefit from additional adjuvant systemic and local therapy. Further research is needed to characterize the environmental, microenvironmental, and genetic causes of the increased aggressiveness of scalp melanoma and to identify more effective treatment and surveillance methods.

Age-related telomere uncapping is associated with cellular senescence and inflammation independent of telomere shortening in human arteries.

Arterial telomere dysfunction may contribute to chronic arterial inflammation by inducing cellular senescence and subsequent senescence-associated inflammation. Although telomere shortening has been associated with arterial aging in humans, age-related telomere uncapping has not been described in non-cultured human tissues and may have substantial prognostic value. In skeletal muscle feed arteries from 104 younger, middle-aged, and older adults, we assessed the potential role of age-related telomere uncapping in arterial inflammation. Telomere uncapping, measured by p-histone γ-H2A.X (ser139) localized to telomeres (chromatin immunoprecipitation; ChIP), and telomeric repeat binding factor 2 bound to telomeres (ChIP) was greater in arteries from older adults compared with those from younger adults. There was greater tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence, measured by P53 bound to P21 gene promoter (ChIP), and greater expression of P21, interleukin 8, and monocyte chemotactic protein 1 mRNA (RT-PCR) in arteries from older adults compared with younger adults. Telomere uncapping was a highly influential covariate for the age-group difference in P53/P21-induced senescence. Despite progressive age-related telomere shortening in human arteries, mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence. Collectively, these findings demonstrate that advancing age is associated with greater telomere uncapping in arteries, which is linked to P53/P21-induced senescence independent of telomere shortening.

Diversity of stage III melanoma in the era of sentinel lymph node biopsy.

BACKGROUND: Sentinel lymph node (SLN) biopsy for melanoma often detects minimal nodal tumor burden. Although all node-positive patients are considered stage III, there is controversy regarding the necessity of adjuvant therapy for all patients with tumor-positive SLN. METHODS: Post hoc analysis was performed of a prospective multi-institutional study of patients with melanoma ≥ 1.0 mm Breslow thickness. All patients underwent SLN biopsy; completion lymphadenectomy was performed for patients with SLN metastasis. Kaplan-Meier analysis of disease-free survival (DFS) and overall survival (OS) was performed. Univariate and multivariate Cox regression analyses were performed. Classification and regression tree (CART) analysis also was performed. RESULTS: A total of 509 patients with tumor-positive SLN were evaluated. Independent risk factors for worse OS included thickness, age, gender, presence of ulceration, and tumor-positive non-SLN (nodal metastasis found on completion lymphadenectomy). As the number of tumor-positive SLN and the total number of tumor-positive nodes (SLN and non-SLN) increased, DFS and OS worsened on Kaplan-Meier analysis. On CART analysis, the 5-year OS rates ranged from 84.9% (women with thickness < 2.1 mm, age < 59 years, no ulceration, and tumor-negative non-SLN) to 14.3% (men with thickness ≥ 2.1 mm, age ≥ 59 years, ulceration present, and tumor-positive non-SLN). Six distinct subgroups were identified with 5-year OS in excess of 70%. CONCLUSIONS: Stage III melanoma in the era of SLN is associated with a very wide range of prognosis. CART analysis of prognostic factors allows discrimination of low-risk subgroups for which adjuvant therapy may not be warranted.

Sentinel lymph node biopsy for melanoma in pregnant women.

BACKGROUND: The incidence of melanoma is rising in young women of childbearing age. Melanoma diagnosed during pregnancy presents unique challenges. This study was conducted to determine the effect of sentinel lymph node biopsy (SLNB) for melanoma on maternal and fetal outcomes in pregnant women. METHODS: A prospective melanoma database was retrospectively queried for women diagnosed with melanoma during or immediately before pregnancy as well as SLNB in pregnant women. The outcomes of SLNB for the mothers and fetuses were evaluated. RESULTS: Fifteen pregnant women underwent wide local excision (WLE) and SLNB for melanoma from 1997 to 2012. The median gestational age was 20 weeks. More than half of the women noticed changes in the primary melanoma lesion during the pregnancy. The median Breslow thickness was 1.00 mm. Lymphatic mapping and SLNB were performed with some combination of radiocolloid or vital blue dye without adverse effects. Three patients had micrometastatic disease and underwent a completion lymphadenectomy. Sixteen children were born at a median gestational age of 39 weeks. The median 1- and 5-minute Apgar scores were 8 and 9, respectively. At a median follow-up of 54.4, months none of the patients had experienced recurrence, and all children were healthy and free of melanoma. CONCLUSIONS: In this series of pregnant women with melanoma, SLNB was performed safely during pregnancy without adverse effects to the mothers and fetuses. We recommend that clinicians explain the risks and benefits of the SLNB procedure to pregnant women so an informed decision can be made about the procedure.

α1-Adrenergic responsiveness in human skeletal muscle feed arteries: the impact of reducing extracellular pH.

Graded exercise results not only in the modulation of adrenergic mediated smooth muscle tone and a preferential increase in blood flow to the active skeletal muscle termed 'functional sympatholysis', but is also paralleled by metabolically induced reductions in pH. We therefore sought to determine whether pH attenuates α(1)-adrenergic receptor sensitivity in human feed arteries. Feed arteries (560 ± 31 µm i.d.) were harvested from 24 humans (55 ± 4 years old) and studied using the isometric tension technique. Vessel function was assessed using KCl, phenylephrine (PE), ACh and sodium nitroprusside (SNP) concentration-response curves to characterize non-receptor-mediated and receptor-mediated vasocontraction, as well as endothelium-dependent and -independent vasorelaxation, respectively. All concentration-response curves were obtained from (originally contiguous) vessel rings in separate baths with a pH of 7.4, 7.1, 6.8 or 6.5. Reduction of the pH, via HCl, reduced maximal PE-induced vasocontraction (pH 7.4 = 85 ± 19, pH 7.1 = 57 ± 16, pH 6.8 = 34 ± 15 and pH 6.5 = 16 ± 5% KCl(max)), which was partly due to reduced smooth muscle function, as assessed by KCl (pH 7.4 = 88 ± 13, pH 7.1 = 67 ± 8, pH 6.8 = 67 ± 9 and pH 6.5 = 58 ± 8% KCl(max)). Graded acidosis had no effect on maximal vasorelaxation. In summary, these data reveal that reductions in extracellular pH attenuate α(1)-mediated vasocontraction, which is partly explained by reduced smooth muscle function, although vasorelaxation in response to ACh and SNP remained intact. These findings support the concept that local acidosis is likely to contribute to functional sympatholysis and exercise hyperaemia by opposing sympathetically mediated vasoconstriction while not impacting vasodilatation.

Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline.

PURPOSE: The American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) sought to provide an evidence-based guideline on the use of lymphatic mapping and sentinel lymph node (SLN) biopsy in staging patients with newly diagnosed melanoma. METHODS: A comprehensive systematic review of the literature published from January 1990 through August 2011 was completed using MEDLINE and EMBASE. Abstracts from ASCO and SSO annual meetings were included in the evidence review. An Expert Panel was convened to review the evidence and develop guideline recommendations. RESULTS: Seventy-three studies met full eligibility criteria. The evidence review demonstrated that SLN biopsy is an acceptable method for lymph node staging of most patients with newly diagnosed melanoma. RECOMMENDATIONS: SLN biopsy is recommended for patients with intermediate-thickness melanomas (Breslow thickness, 1-4 mm) of any anatomic site; use of SLN biopsy in this population provides accurate staging. Although there are few studies focusing on patients with thick melanomas (T4; Breslow thickness, >4 mm), SLN biopsy may be recommended for staging purposes and to facilitate regional disease control. There is insufficient evidence to support routine SLN biopsy for patients with thin melanomas (T1; Breslow thickness, <1 mm), although it may be considered in selected patients with high-risk features when staging benefits outweigh risks of the procedure. Completion lymph node dissection (CLND) is recommended for all patients with a positive SLN biopsy and achieves good regional disease control. Whether CLND after a positive SLN biopsy improves survival is the subject of the ongoing Multicenter Selective Lymphadenectomy Trial II.

Human skeletal muscle feed arteries studied in vitro: the effect of temperature on α(1)-adrenergic responsiveness.

Heat and cold exposure can decrease and increase total peripheral resistance, respectively, in humans. With unique access to human skeletal muscle feed arteries, we sought both to characterize these vessels and to determine the interaction between temperature and α(1)-adrenergic receptor responsiveness. We hypothesized that α(1)-mediated vasocontraction of human feed arteries would be attenuated in response to 39 or 35°C. Skeletal muscle feed arteries were harvested from thirty-two human volunteers and studied using isometric techniques. Vessel function was assessed using KCl, sodium nitroprusside (SNP), phenylephrine (PE) and ACh dose-response curves to characterize non-receptor- and receptor-mediated vasocontraction and vasorelaxation. Single doses of PE (1 mm) and KCl (100 mm) were administered at 37°C and then, in a balanced design, repeated at both 35 and 39°C. The KCl and PE dose-response curves elicited significant vasocontraction (2009 ± 407 and 1974 ± 508 mg developed tension, respectively), whereas SNP and ACh induced the expected vasorelaxation (102 ± 6 and 73 ± 10% relaxation, respectively). Altering the temperature had no effect on inherent smooth muscle function (KCl response), but both a reduction (35°C) and an increase in temperature (39°C) decreased the vasocontractile response to 1 mm PE (37°C, 1478 ± 338 mg; 35°C, 546 ± 104 mg; and 39°C, 896 ± 202 mg; P < 0.05) or across PE dose (P < 0.05, 35 and 39 versus 37°C). Despite clear heterogeneity between both the human volunteers and the feed arteries themselves, this novel approach to the procurement of human vessels revealed a robust 'inverted U' response to altered temperature, such that α(1)-mediated vasocontraction was attenuated with either warming or cooling.

Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial.

BACKGROUND: Sentinel-lymph-node (SLN) surgery was designed to minimise the side-effects of lymph-node surgery but still offer outcomes equivalent to axillary-lymph-node dissection (ALND). The aims of National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-32 were to establish whether SLN resection in patients with breast cancer achieves the same survival and regional control as ALND, but with fewer side-effects. METHODS: NSABP B-32 was a randomised controlled phase 3 trial done at 80 centres in Canada and the USA between May 1, 1999, and Feb 29, 2004. Women with invasive breast cancer were randomly assigned to either SLN resection plus ALND (group 1) or to SLN resection alone with ALND only if the SLNs were positive (group 2). Random assignment was done at the NSABP Biostatistical Center (Pittsburgh, PA, USA) with a biased coin minimisation approach in an allocation ratio of 1:1. Stratification variables were age at entry (≤ 49 years, ≥ 50 years), clinical tumour size (≤ 2·0 cm, 2·1-4·0 cm, ≥ 4·1 cm), and surgical plan (lumpectomy, mastectomy). SLN resection was done with a blue dye and radioactive tracer. Outcome analyses were done in patients who were assessed as having pathologically negative sentinel nodes and for whom follow-up data were available. The primary endpoint was overall survival. Analyses were done on an intention-to-treat basis. All deaths, irrespective of cause, were included. The mean time on study for the SLN-negative patients with follow-up information was 95·6 months (range 70·1-126·7). This study is registered with ClinicalTrials.gov, number NCT00003830. FINDINGS: 5611 women were randomly assigned to the treatment groups, 3989 had pathologically negative SLN. 309 deaths were reported in the 3986 SLN-negative patients with follow-up information: 140 of 1975 patients in group 1 and 169 of 2011 in group 2. Log-rank comparison of overall survival in groups 1 and 2 yielded an unadjusted hazard ratio (HR) of 1·20 (95% CI 0·96-1·50; p=0·12). 8-year Kaplan-Meier estimates for overall survival were 91·8% (95% CI 90·4-93·3) in group 1 and 90·3% (88·8-91·8) in group 2. Treatment comparisons for disease-free survival yielded an unadjusted HR of 1·05 (95% CI 0·90-1·22; p=0·54). 8-year Kaplan-Meier estimates for disease-free survival were 82·4% (80·5-84·4) in group 1 and 81·5% (79·6-83·4) in group 2. There were eight regional-node recurrences as first events in group 1 and 14 in group 2 (p=0·22). Patients are continuing follow-up for longer-term assessment of survival and regional control. The most common adverse events were allergic reactions, mostly related to the administration of the blue dye. INTERPRETATION: Overall survival, disease-free survival, and regional control were statistically equivalent between groups. When the SLN is negative, SLN surgery alone with no further ALND is an appropriate, safe, and effective therapy for breast cancer patients with clinically negative lymph nodes. FUNDING: US Public Health Service, National Cancer Institute, and Department of Health and Human Services.

Ulceration as a predictive marker for response to adjuvant interferon therapy in melanoma.

OBJECTIVE: This analysis was performed to investigate the hypothesis that ulceration predicts improved response to adjuvant interferon (IFN) therapy. SUMMARY BACKGROUND DATA: Several studies have demonstrated that adjuvant therapy for high-risk melanoma patients with IFN alfa-2b improves disease-free survival (DFS), although the impact on overall survival (OS) is controversial. Recent data have suggested that IFN therapy may preferentially benefit patients with ulcerated primary melanomas. METHODS: Post hoc analysis was performed by a prospective multi-institutional randomized study of observation versus adjuvant IFN therapy for melanoma. All patients underwent sentinel lymph node biopsy; completion lymphadenectomy was performed for patients with sentinel lymph node metastasis. Patients were stratified by Breslow thickness, ulceration, and nodal status. Kaplan-Meier analysis of DFS and OS was performed and included univariate and multivariate analyses. RESULTS: A total of 1769 patients were analyzed (1311 without ulceration, 458 with ulceration) with a median follow-up of 71 months. Ulceration was associated with significantly worse DFS and OS in both node-negative and node-positive patients. Kaplan-Meier analysis of node-negative and node-positive patients by ulceration status revealed that the only significant impact of interferon was improved DFS in the ulcerated node-positive patients (P = 0.0169). IFN therapy had no significant impact on OS regardless of ulceration status, however. On multivariate analysis, IFN treatment was a significant independent predictor of DFS among ulcerated patients (odds ratio, 0.51; 95% confidence interval, 0.30-0.83; P = 0.0053), but not among patients without ulceration. CONCLUSIONS: These data support the conclusion that ulceration is a predictive marker for response to adjuvant IFN therapy. Future studies to evaluate specifically the differential effect of IFN on patients with ulcerated melanomas may allow us to focus this therapy on patients most likely to benefit from it.

The prognostic significance of nonsentinel lymph node metastasis in melanoma.

BACKGROUND: We hypothesized that metastasis beyond the sentinel lymph nodes (SLN) to the nonsentinel nodes (NSN) is an important predictor of survival. MATERIALS AND METHODS: Analysis was performed of a prospective multi-institutional study that included patients with melanoma ≥ 1.0 mm in Breslow thickness. All patients underwent SLN biopsy; completion lymphadenectomy was performed for all SLN metastases. Disease-free survival (DFS) and overall survival (OS) were computed by Kaplan-Meier analysis; univariate and multivariate analyses were performed to identify factors associated with differences in survival among groups. RESULTS: A total of 2335 patients were analyzed over a median follow-up of 68 months. We compared 3 groups: SLN negative (n = 1988), SLN-only positive (n = 296), and both SLN and NSN positive (n = 51). The 5-year DFS rates were 85.5, 64.8, and 42.6% for groups 1, 2, and 3, respectively (P < 0.001). The 5-year OS rates were 85.5, 64.9, and 49.4%, respectively (P < 0.001). On univariate analysis, predictors of decreased OS included: SLN metastasis, NSN metastasis, increased total number of positive LN, increased ratio of positive LN to total LN, increased age, male gender, increased Breslow thickness, presence of ulceration, Clark level ≥ IV, and axial primary site (in all cases, P < 0.01). When the total number of positive LN and NSN status were evaluated using multivariate analysis, NSN status remained statistically significant (P < 0.01), while the total number of positive LN and LN ratio did not. CONCLUSIONS: NSN melanoma metastasis is an independent prognostic factor for DFS and OS, which is distinct from the number of positive lymph nodes or the lymph node ratio.

Second primary melanomas: incidence and outcome.

The objective of this study was to determine the incidence of multiple primary melanomas (MPM) and other cancers types among patients with melanoma. Factors associated with development of MPM were assessed in a post hoc analysis of the database from a multi-institutional prospective randomized trial of patients with melanoma aged 18 to 70 years with Breslow thickness 1 mm or greater. Disease-free survival (DFS) and overall survival (OS) were evaluated by Kaplan-Meier analysis. Forty-eight (1.9%) of 2506 patients with melanoma developed additional primary melanomas. Median follow-up was 66 months. Except in one patient, the subsequent melanomas were thinner (median, 0.32 mm vs. 1.50 mm; P < 0.0001). Compared with patients without MPM, patients with MPM were more likely to be older (median age, 54.5 vs. 51.0 years; P = 0.048), to have superficially spreading melanomas (SSM) (P = 0.025), to have negative sentinel lymph nodes (P = 0.021), or to lack lymphovascular invasion (LVI) (P = 0.008) with the initial tumor. On multivariate analysis, age (P = 0.028), LVI (P = 0.010), and SSM subtype of the original melanoma (P = 0.024) were associated with MPM. Patients with MPM and patients with single primary melanoma had similar DFS (5-year DFS 88.7 vs. 81.3%, P = 0.380), but patients with MPM had better OS (5-year OS 95.3 vs. 80.0%, P = 0.005). Nonmelanoma malignancies occurred in 152 patients (6.1%). Ongoing surveillance of patients with melanoma is important given that a significant number will develop additional melanoma and nonmelanoma tumors. With close follow-up, second primary melanomas are usually detected at an early stage.

Recurrence risk of early-stage melanoma of the external ear: an investigation of surgical approach and sentinel lymph node status.

Surgical management of external ear melanoma presents unique technical challenges based on the unique anatomy and reconstruction concerns. Surgical technique, including preservation of cartilage, is variable and impact on recurrence is unclear. Our goal was to investigate surgical approach, including extent of surgical resection and sentinel lymph node biopsy (SLNB), and the impact on recurrence. In this retrospective review of primary clinical stage 1/2 external ear melanoma, demographics, tumor characteristics, surgical resection technique (including cartilage-sparing vs. cartilage removal), and SLNB results were evaluated for recurrence risk. One hundred and fifty-six patients total had an average follow-up of 5.6 years. Twenty-nine (18.6%) patients underwent cartilage-sparing surgery and 99 (63.5%) patients underwent SLNB, 14.1% of whom had micrometastatic disease. Ten (6.4%) patients recurred loco-regionally. Recurrence was associated with Breslow depth, initial stage at diagnosis, and SLNB status. Cartilage-sparing surgery was not associated with increased recurrence. Sentinel lymph node identification rate was 100% based on clinical detection with use of lymphoscintigraphy. In addition to confirming established risk factors for melanoma recurrence, we confirm the feasibility of SLNB in stratifying recurrence risk. Although we did not see an increased recurrence risk with surgical technique and cartilage-sparing approaches, these findings are limited by small sample size.

Predictive factors of regional toxicity and serum creatine phosphokinase levels after isolated limb infusion for melanoma: a multi-institutional analysis.

BACKGROUND: Isolated limb infusion (ILI) is a minimally invasive technique delivering regional chemotherapy to treat in-transit extremity melanoma. Determining perioperative factors that could predict toxicity is important to optimize strategies to improve clinical outcomes after regional chemotherapy in melanoma. METHODS: Perioperative factors from 171 ILI patients performed at eight centers from 2001 to 2008 were reviewed. The Wieberdink limb toxicity scale and creatine phosphokinase (CK) levels were used to measure toxicity. Logistic regression analysis was used to estimate the association between toxicity and perioperative parameters. RESULTS: Mild (grades I-II) and severe (grades >or=III) limb toxicity developed in 68% and 32% of patients, respectively. Melphalan adjusted for ideal body weight (aIBW) and papaverine were used in 47% and 63% of patients, respectively. Median peak CK for all patients was 563 U/l, and median peak occurred at postoperative day 4. On univariate analysis, papaverine and high CK levels (>563 U/l) were significantly associated with higher toxicity. On the contrary, aIBW was significantly associated with a lower risk of severe toxicity. Perfusate blood gas at 30 min [pH, PaO(2), and base excess (BE) ], limb temperature, and ischemia time were not predictive of limb toxicity. On multivariate analysis, severe toxicity was associated with female sex (P = 0.01), papaverine (P = 0.01), and high peak CK levels (P < 0.01). Independent predictors of high CK levels included younger age, unadjusted melphalan dose, and low PaO(2) at 30 min. CONCLUSIONS: ILI can be performed with an acceptable morbidity. Papaverine use, female gender, and high peak CK were associated with higher limb toxicity. CK levels can be diminished significantly with aIBW.

Outcomes of 1,327 patients operated on through twelve multispecialty surgical volunteerism missions: A retrospective cohort study.

BACKGROUND: Surgical volunteer missions (SVMs) have become a popular approach for reducing the burden of surgical disease worldwide. The aim of this study was to evaluate the outcomes of 12 surgical missions between 2006 and 2018 from the mission entitled "Operation Giving Back Bohol" Tagbilaran, Philippines and discuss the lessons learned during these missions in particular seven challenges that every volunteer surgeon should be familiar with. METHODS: This was a retrospective descriptive study of prospectively collected data on all patients treated during one SVM. The data collected included gender, age, diagnosis, types of surgeries performed, and perioperative adverse events. RESULTS: During the study period 1327 operations were performed (842 females (63.4%) and 485 males (36.6%); (male-to-female ratio 0.59); mean age 37 ±â€¯18 years. The majority of operations were for thyroid disease (31.6%), followed by hernia (17.3%), hysterectomies/salpingo-oophorectomies (12.2%), soft tissue tumors (9.9%), cleft lip/palate repairs (7.2%), breast (6.4%), gallbladder disease (4.7%), cataract (2.9%), parotid masses (1.4%) and others (6.4%). For each mission, there were an average 5.5 days of operating, performing a median of 105.5 (80-148) cases per mission. There were 27 complications (2%), of which, 22 were postoperative bleeding and two temporary tracheostomies. The mortality rate was 0.15% (2/1327). In one patient, the family withdrew care following compassionate last ditch effort thyroidectomy for advanced cancer and one patient died as a result of intracranial bleeding from a brain tumor, which was unrecognized before mastectomy. CONCLUSIONS: Surgical volunteerism missions are safe and valuable in lessening the burden of surgical disease globally when performed in an organized fashion and with continuity of care. However, there is need for standardization of surgical care provided during SVMs and creation of a world-wide database of all SVMs, and each surgeon and others who participate in these mission should be familiar with critical elements and challenges for the successful mission.

Population-based analysis of prognostic factors and survival in familial melanoma.

PURPOSE: Familial melanoma patients are reported to present with thinner melanomas, to be younger at the time of diagnosis, and to have a greater likelihood of developing multiple primary tumors. We sought to determine whether melanomas that occur in a familial setting demonstrate different prognostic and survival statistics relative to sporadic melanoma. PATIENTS AND METHODS: This population-based study used the Utah Cancer Registry and Utah Population Database to objectively evaluate prognostic and survival statistics of the familial melanoma population. From 1973 to 1999, there were 7,785 cases of invasive melanoma identified through the Utah Cancer Registry. These were linked to the Utah Population Database, resulting in 2,659 subjects with family-history information from which a familiality score could be calculated. Cases scored in the top ninth percentile were assigned as high familial risk, and the remaining 91% were considered low familial risk. RESULTS: Multivariate logistic-regression analysis found no association between sex, Breslow depth, Clark level, or survival and the familial status. Age at first diagnosis of invasive melanoma was slightly lower in the high-familial-risk group (57 v 60 years; P = .03). High-familial-risk subjects had more melanomas diagnosed at age 30 or younger (12% v 6%; P < .001). A significant difference in the overall number of individuals with two or more primary malignant melanomas was not detected among the groups (P = .2). CONCLUSION: These data suggest that melanomas occurring in the context of an underlying inherited susceptibility do not have a significantly different biologic behavior.

Final Results of the Sunbelt Melanoma Trial: A Multi-Institutional Prospective Randomized Phase III Study Evaluating the Role of Adjuvant High-Dose Interferon Alfa-2b and Completion Lymph Node Dissection for Patients Staged by Sentinel Lymph Node Biopsy.

PURPOSE: The Sunbelt Melanoma Trial is a prospective randomized trial evaluating the role of high-dose interferon alfa-2b therapy (HDI) or completion lymph node dissection (CLND) for patients with melanoma staged by sentinel lymph node (SLN) biopsy. PATIENTS AND METHODS: Patients were eligible if they were age 18 to 70 years with primary cutaneous melanoma ≥ 1.0 mm Breslow thickness and underwent SLN biopsy. In Protocol A, patients with a single tumor-positive lymph node after SLN biopsy underwent CLND and were randomly assigned to observation versus HDI. In Protocol B, patients with tumor-negative SLN by standard histopathology and immunohistochemistry underwent molecular staging by reverse transcriptase polymerase chain reaction (RT-PCR). Patients positive by RT-PCR were randomly assigned to observation versus CLND versus CLND+HDI. Primary end points were disease-free survival (DFS) and overall survival (OS). RESULTS: In the Protocol A intention-to-treat analysis, there were no significant differences in DFS (hazard ratio, 0.82; P = .45) or OS (hazard ratio, 1.10; P = .68) for patients randomly assigned to HDI versus observation. In the Protocol B intention-to-treat analysis, there were no significant differences in overall DFS (P = .069) or OS (P = .77) across the three randomized treatment arms. Similarly, efficacy analysis (excluding patients who did not receive the assigned treatment) did not demonstrate significant differences in DFS or OS in Protocol A or Protocol B. Median follow-up time was 71 months. CONCLUSION: No survival benefit for adjuvant HDI in patients with a single positive SLN was found. Among patients with tumor-negative SLN by conventional pathology but with melanoma detected in the SLN by RT-PCR, there was no OS benefit for CLND or CLND+HDI.

Metastatic melanoma in pregnancy: risk of transplacental metastases in the infant.

PURPOSE: Although metastases to the fetus via the placenta are rare, melanoma is the most common culprit. When it occurs, maternally derived melanoma metastasis in the infant is almost invariably fatal. PATIENTS AND METHODS: This article reviews current guidelines for placental evaluation in pregnant women with metastatic melanoma and presents surveillance recommendations for their infants. Comprehensive literature reviews were performed on melanoma in pregnancy and melanoma metastasis to the placenta and fetus. The use of interferon alfa in the pediatric population was also reviewed. A comprehensive search of the MEDLINE database (1966 to 2002) was performed. Articles were reviewed and additional references were obtained from the bibliographies. Translation of non-English articles was performed, and authors of previous publications were contacted. RESULTS: Eighty-seven patients with placental or fetal metastasis were identified. Twenty-seven occurrences were attributed to melanoma (31%). The fetus was affected in six of 27 melanoma patients (22%), with five of six infants dying of disease. The use of high-dose interferon alfa adjuvant therapy in pediatric patients has not been reported. CONCLUSION: The placentas of women with known or suspected metastatic melanoma should be carefully examined grossly and histologically by pathologists. With placental involvement, fetal risk of melanoma metastasis is approximately 22%. Neonates delivered with concomitant placental involvement should be considered a high-risk population. The risk-benefit ratio of adjuvant treatment for a potentially affected infant should be carefully weighed.

Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: overall results of a randomized trial of the Southwest Oncology Group.

PURPOSE: Patients with clinically negative nodes constitute over 85% of new melanoma cases. There is no adjuvant therapy for intermediate-thickness, node-negative melanoma patients. PATIENTS AND METHODS: The Southwest Oncology Group conducted a randomized phase III trial of an allogeneic melanoma vaccine for 2 years versus observation in patients with intermediate-thickness (1.5 to 4.0 mm or Clark's level IV if thickness unknown), clinically or pathologically node-negative melanoma (T3N0M0). RESULTS: Six hundred eighty-nine patients were accrued over 4.5 years; 89 patients (13%) were ineligible. Surgical node staging was performed in 24%, the remainder were clinical N0. Thirteen eligible patients refused assigned treatment: seven on the observation arm and six on the vaccine arm. Most vaccine patients experienced mild to moderate local toxicity, but 26 (9%) experienced grade 3 toxicity. After a median follow-up of 5.6 years, there were 107 events (tumor recurrences or deaths) among the 300 eligible patients randomized to vaccine compared with 114 among the 300 eligible patients randomized to observation (hazard ratio, 0.92; Cox-adjusted P(2) = 0.51). There was no difference in vaccine efficacy among patients with tumors < or = 3 mm or > 3 mm. CONCLUSION: This represents one of the largest randomized, controlled trials of adjuvant vaccine therapy in human cancer reported to date. Compliance with randomization was excellent, with only 2% refusing assigned therapy. There is no evidence of improved disease-free survival among patients randomized to receive vaccine, although the power to detect a small but clinically significant difference was low. Future investigations of adjuvant vaccine approaches for patients with intermediate-thickness melanoma should involve larger numbers of patients and ideally should include sentinel node biopsy staging.

Survival after attempted surgical resection and intraoperative radiation therapy for pancreatic and periampullary adenocarcinoma.

PURPOSE: To evaluate a single institution's experience with intraoperative radiation therapy (IORT) in combination with attempted surgical resection for pancreatic and periampullary adenocarcinoma. METHODS AND MATERIALS: From May 1986 until June 2001, 77 patients at LDS Hospital underwent attempted surgical resection and IORT for pancreatic or periampullary adenocarcinoma. A potentially curative resection was defined as surgery with negative or microscopic positive margins. No patients had metastatic disease at the time of surgery and IORT. Forty-four patients with tumors located in the pancreas and 9 patients with periampullary tumors underwent potentially curative surgical resection and IORT. Twenty-four patients had pancreatic tumors deemed unresectable and underwent surgical bypass and IORT. Actuarial survival was calculated from the date of IORT until last follow-up or death by use of the Kaplan-Meier method. RESULTS: Patients undergoing a potentially curative resection and IORT for periampullary adenocarcinoma had a median survival of 167 months and a 56% 5-year actuarial survival, compared with a median survival of 16 months and a 19% 5-year actuarial survival for patients undergoing the same treatment for pancreatic adenocarcinoma (p = 0.03). Patients with unresectable disease who underwent bypass and IORT had a median survival of 11 months and a 0% 3-year survival, significantly worse than patients able to undergo surgical resection and IORT (p = 0.0002). The operative mortality for all patients undergoing potentially curative resection and IORT was 3.7%. CONCLUSIONS: Intraoperative radiation therapy is well tolerated and does not increase the morbidity or mortality of potentially curative surgical resection for pancreatic or periampullary adenocarcinoma. Patients with periampullary adenocarcinoma have a better prognosis than those with pancreatic adenocarcinoma, and patients with unresectable pancreatic disease fared worse.

Is incisional biopsy of melanoma harmful?

BACKGROUND: In the era of sentinel lymph node (SLN) biopsy, there has been concern that manipulation, injection, and massage of intact primary melanomas (after incisional or shave biopsy) could lead to an artifactual increased rate of SLN micrometastases or an actual increased risk of recurrence. The aim of this study was to evaluate the difference in the incidence of SLN metastasis, locoregional recurrence (LRR), disease-free survival (DFS), distant disease-free survival (DDFS), or overall survival (OS) for patients who undergo excisional versus incisional versus shave biopsy. METHODS: Analysis of database from a multicenter prospective randomized study from centers across the United States and Canada. Eligible patients were 18 to 71 years old, with cutaneous melanoma > or = 1.0 mm Breslow thickness. All patients underwent SLN biopsy using blue dye and radioactive colloid injection. SLNd were evaluated by serial histological sections with S100 immunohistochemistry. Statistical analysis was performed using univariate and multivariate analyses with a significance level of P < .05; survival analysis was performed by the Kaplan-Meier method with the log-rank test. RESULTS: A total of 2,164 patients were evaluated; 382 patients were excluded for lack of biopsy information. Positive SLNs were found in 220 of 1,130 (19.5%), 58 of 281 (20.6%), and 67 of 354 (18.9%) of patients with excisional, incisional, or shave biopsy, respectively (no significant difference). There were significant differences among the 3 biopsy types in ulceration (P = .018, chi2) and regression (P = .022, chi2); there were no differences in age, gender, Breslow thickness, Clark level, lymphovascular invasion, tumor location, or histologic subtype. Biopsy type did not significantly affect LRR, DFS, DDFS, or OS. CONCLUSIONS: The concern that incomplete excision of primary melanomas may result in an increased incidence of SLN micrometastases, artifactual or real, is unfounded. Similarly, there is no evidence that biopsy type adversely affects locoregional or distant recurrence. Although shave biopsy is generally discouraged because it may lead to inaccurate tumor thickness measurements, it does not appear to affect overall patient outcome.