A Historical Cohort in Kidney Transplantation: 55-Year Follow-Up of 72 HLA-Identical, Donor-Recipient Pairs.

The impact of HLA matching on graft survival has been well characterized in renal transplantation, with a higher degree of matching associated with superior graft survival. Additionally, living donor grafts are known to confer superior survival compared to those from deceased donors. The purpose of this study is to report our multi-decade institutional experience and outcomes for patients who received HLA-identical living donor grafts, which represent the most favorable scenario in kidney transplantation. We conducted a retrospective analysis of these graft recipients performed at a Duke University Medical Center between the years of 1965 and 2002. The recipients demonstrated excellent graft and patient survival outcomes, superior to a contemporary cohort, with median patient and graft survival of 24.2 and 30.9 years, respectively, among Duke recipients vs. 16.1 and 16.0 years in a cohort derived from national data. This study offers a broad perspective on the importance of HLA matching and graft type, and demonstrates a historical best-case-scenario in renal transplantation.

Does protected research time during general surgery training contribute to graduates' career choice?

A number of general surgery training programs offer a dedicated research experience during the training period. There is much debate over the importance of these experiences with the added constraints placed on training surgeons including length of training, Accreditation Council of Graduate Medical Education limitations, and financial barriers. We seek to quantify the impact of a protected research experience on graduates of a university-affiliated general surgery training program. We surveyed all graduates of a single university-affiliated general surgery training program who completed training from 1989 to 1999. Data was obtained for 100 per cent of the subjects. Most graduates (72/73; 98.6%) completed a dedicated research experience (range: 1-5 years). Presently, 72.6 per cent (53/73) are practicing academic surgery and 82.5 per cent (60/73) are engaged in research activities. Fifty-one of 73 graduates (69.5%) have current research funding including 32.9 per cent (24/73) with National Institutes of Health funding. Of all graduates, 42.5 per cent (31/73) have become full professors with 20.2 per cent (15/73) division/section chiefs and 14.3 per cent (10/73) department chairmen or vice chairmen. Those trainees achieving a career in academic surgery were statistically more likely to have committed 2 or more years to a protected research experience during training (P < 0.05), fellowship training after general surgery residency (P < 0.01), and a first job at an academic institution upon completion of training (P < 0.001). Understanding the importance of resident research experiences while highlighting critical factors during the formative training period may help to ensure continued academic interest and productivity of future trainees.

Pediatric melanoma: a single-institution experience of 150 patients.

PURPOSE: Differentiating pigmented skin lesions from malignant melanoma in the pediatric population has been a challenge. Despite guidelines describing clinical features and histopathologic criteria to distinguish these lesions, misdiagnoses still occur. We report our experience over 30 years in a pediatric population with malignant melanoma. METHODS: We performed a retrospective review of 150 pediatric patients treated for malignant melanoma between 1973 and 2007 at our institution. Outcomes measured included age, Breslow thickness, Clark level of invasion, tumor location, local and distant failure rates, and overall survival. RESULTS: One hundred fifty pediatric patients were evaluated. The mean age was 15.1 years. The mean Breslow thickness was 2.05 mm and corresponding Clark level of invasion was 3.47. There were 43 known recurrences (29%); 29 distant, 14 nodal, and 7 local. Overall survival was 84% with a mean follow-up of 8.5 years. Sixteen patients (10.7%) were incorrectly diagnosed on initial pathologic examination. Overall survival in the misdiagnosed group was 66%. CONCLUSION: Pigmented skin lesions in the pediatric population represent a diagnostic challenge to pathologists and clinicians. Improvements in diagnostic techniques with rigorous characterization, as well as increased physician awareness, should lead to a reduction in errors of diagnosis.

Improved survival with pulmonary metastasectomy: an analysis of 1720 patients with pulmonary metastatic melanoma.

OBJECTIVES: The outcomes of patients with metastatic melanoma are poor. Although prognostic models have been developed to predict the occurrence of pulmonary metastasis from cutaneous melanoma, few data exist to define the outcomes of these patients once metastasis has occurred. The objective of this study was to discriminate predictors of survival for patients with pulmonary metastatic melanoma. METHODS: We found 1720 patients with pulmonary metastasis listed in a prospective comprehensive cancer center database of 14,057 consecutive patients with melanoma (Jan 1, 1970-June 1, 2004). Demographic and histopathologic data, time and location of recurrences, number of pulmonary nodules, and subsequent therapies were collected. Univariate and multivariate Cox proportional hazards models were used to identify predictors of survival for patients with pulmonary metastatic melanoma. RESULTS: The median survival was 7.3 months after development of pulmonary metastasis. Significant predictors of survival from the multivariate model included nodular histologic type (P = .033), disease-free interval (P < .001), number of pulmonary metastases (P = .012), presence of extrathoracic metastasis (P < .001), and performance of pulmonary metastasectomy (P < .001). Interactions were identified between metastasectomy and disease-free interval and presence of extrathoracic metastasis. Surgery was associated with a survival advantage of 12 months for patients with a disease-free interval longer than 5 years (19 vs 7 months, P < .01) and of 10 months for patients without extrathoracic metastasis (18 vs 8 months, P < .01). CONCLUSIONS: When all other identified risk factors were controlled for mathematically, metastasectomy maintained a significant survival advantage for patients with pulmonary metastatic melanoma. These data support the role of surgery for a select subset of patients with pulmonary metastasis.

The Kraske procedure: a critical analysis of a surgical approach for mid-rectal lesions.

BACKGROUND AND OBJECTIVES: To analyze the Kraske procedure as an approach to mid-rectal disease. METHODS: Twenty-two patients underwent a Kraske procedure at either Duke University Medical Center, the Durham Veterans Administration Medical Center, or the Durham Regional Hospital between 1992 and 1997. The clinical and pathologic characteristics of these patients were retrospectively analyzed and compared with previous published series. RESULTS: Of the 22 patients, 13 underwent resection of an adenocarcinoma and 9 underwent resection of a villous adenoma. Post-operative complications included four fecal fistulas (two of which required a temporary diverting colostomy), two wound infections, two cases of urinary retention, and one case of transient fecal incontinence. CONCLUSIONS: The Kraske procedure minimizes exposure of mid-rectal lesions without the morbidity of a major laparotomy. However, it does carry a moderate complication rate and thus should be utilized selectively in managing patients with mid-rectal tumors not amenable to other treatment options.

Melanoma of the ear: treatment and survival probabilities based on 199 patients.

BACKGROUND: In 2005, it is now estimated that one in 62 Americans have a lifetime risk of developing invasive melanoma. Melanoma of the ear accounts for 1% of all cases of melanoma and 14.5% of all head and neck melanomas. With this increase in incidence, plastic surgeons will likely have to treat and manage more of these patients in the future. METHODS: A retrospective chart review was performed on 199 patients diagnosed with primary melanoma of the ear. Specimens were reviewed by same center dermatopathologists (Duke University Medical Center, Durham, NC) for standardization of histologic criteria in all but 10 patients. Surgical treatment and outcomes were reviewed and survival rates based on thickness and stage were calculated. Metastases information, anatomic location on the ear, and histologic subtype were recorded and analyzed. RESULTS: The median length of follow up was 3.3 years with a range of 0.4 to 24.9 years. Eighty-six patients were known to be dead at the last known follow-up date. The median survival time among these patients was 7.9 years. The most common histologic classification of the lesions were superficial spreading type (45.2%) and were most likely to be localized to the anterior helix (49.3%). One hundred sixty-one of 199 (80.9%) patients underwent wide local excision with local recurrence rate of 10.6%. Overall, 43.2% of patients developed a local recurrence or metastatic spread. Ulceration, thickness, and stage all negatively affected survival. CONCLUSIONS: This is the largest review of primary ear melanoma cases reported to date. Survival probabilities at 2, 5, and 10 years for melanoma of the ear based on thickness and stage are presented. Ulceration adversely affected survival probability (P < 0.003). Lesion excision with confirmed negative margins on permanent section pathology should be the goal of initial surgical therapy, and there is no apparent role for elective lymph node dissection in treatment of melanoma of the ear.

Histopathologic characteristics, recurrence patterns, and survival of 129 patients with desmoplastic melanoma.

BACKGROUND: Desmoplastic melanoma (DM) has been associated with higher local recurrence rates than other types of cutaneous melanoma. Current controversies regarding locoregional treatment strategies warrant further investigation. METHODS: Retrospective review of a prospectively maintained melanoma database identified 129 patients with DM out of >12,500 melanoma patients referred for treatment from 1980 to 2003. Clinical and histopathologic characteristics, recurrence, and survival were analyzed. RESULTS: The median follow-up was 4.0 years. Of the 129 patients identified, 82 (63.6%) were male, and the median age was 55.2 years. American Joint Committee on Cancer staging was I, II, and III in 25.6%, 68.0%, and 6.4% of patients, respectively, and the mean tumor thickness was 4.42 mm. Overall survival was 76% at 5 years and 64% at 10 years; median survival was 13.0 years. A total of 51 patients (39.5%) experienced disease recurrence, with a median time to recurrence of 1.3 years. The first recurrence was local in 18 patients (14.0%), nodal in 18 patients (14.0%), and distant in 15 patients (11.6%), with median survivals of 6.7, 7.8, and 1.8 years, respectively. Statistically significant predictors of recurrence were a final positive margin status and stage, and predictors of overall survival were patient age and stage. CONCLUSIONS: Compared with other types of melanoma, DMs do demonstrate a tendency toward local recurrence, thus suggesting that narrower excision margins may not be appropriate in this population. Scrutiny of final surgical margins is critical to the local management of DM. In addition, the potential for regional nodal involvement must be considered at the time of diagnosis and during surveillance for disease recurrence.

Pathologic nodal status predicts disease-free survival after neoadjuvant chemoradiation for gastroesophageal junction carcinoma.

BACKGROUND: The incidence of carcinoma of the gastroesophageal junction (GEJ) is rapidly increasing, and the prognosis remains poor. We examined outcomes in patients who received neoadjuvant chemoradiation for GEJ tumors to identify factors that predict disease-free (DFS) and overall (OS) survival. METHODS: A retrospective analysis was performed of 101 consecutive patients who received chemoradiation and surgery for GEJ carcinoma between 1992 and 2001. RESULTS: The median DFS and OS of all patients were 16 and 25 months, respectively. Twenty-eight patients with a complete histological response (T0N0) experienced greater DFS compared with all others (P = .02). Node-negative patients, regardless of T stage, experienced improved median DFS (24 months) compared with N1 patients (9 months; P = .01). Preoperative stage, age, tumor location, or Barrett's esophagus did not independently predict OS by univariate analysis. Multivariate analysis demonstrated that only posttreatment nodal status (P = .03)-not the degree of primary tumor response-predicted DFS. CONCLUSIONS: The nodal status of patients with GEJ tumors after neoadjuvant therapy is predictive of DFS after resection. The poor outcome in node-positive patients supports postneoadjuvant therapy nodal staging, because surgical aggressiveness should be tempered by the realization that cure is unlikely and median survival is short.

Melanoma, a tumor based on a mutant stem cell?

Stem cells play a critical role in normal tissue maintenance, and mutations in these stem cells may give rise to cancer. We hypothesize that melanoma develops from a mutated stem cell and therefore residual stem cell characteristics should be able to be identified in melanoma cell lines. We studied three metastatic melanoma cell lines that exhibited multiple morphologic forms in culture and demonstrated the capacity to pigment. We used the ability to efflux Hoechst 33342 dye, a technique known to enrich for stem cells in many tissues, to segregate cell populations. The cells with the greatest ability to efflux the dye were (1) small in size, (2) had the capacity to give rise to larger cell forms, and (3) had the greatest ability to expand in culture. The small cells were found to have a decreased proliferative rate and were less melanized. Large dendritic cells that appeared to be nonproliferative were identified in cultures. Treatment with cytosine beta-D-arabinofuranoside hydrochloride (Ara-C) expanded the large cell population but the residual proliferative capacity, both in vitro and in vivo, remained concentrated in the smaller cell fraction. Antigenic staining patterns were variable and heterogeneous. Nestin (a neural stem cell marker) and gp100 (premelanosomal marker) favored the smaller cell population, while nerve growth factor receptor often labeled larger cells. Morphologic and antigenic heterogeneity remained intact after clonal purification. These findings are consistent with the behavior expected for a tumor based on stem cell biology; this finding has diagnostic and therapeutic implications for melanocytic neoplasias.

Melanoma arising in a skin graft.

Cutaneous melanoma remains an ongoing public health threat, and the cornerstone of management continues to be early diagnosis and treatment. Unfortunately, primary melanomas may have atypical presentations, making early diagnosis difficult and causing significant treatment delays. In this report, an unusual case is presented in which a patient experienced the synchronous development of a melanoma in situ within a skin graft donor site and an invasive melanoma within the recipient skin graft site. This exceptional presentation of cutaneous melanoma is discussed to highlight key principles of skin grafting in relation to the management of malignant melanoma.

A Phase I trial of preoperative eniluracil plus 5-fluorouracil and radiation for locally advanced or unresectable adenocarcinoma of the rectum and colon.

PURPOSE: Eniluracil, an effective inactivator of dihydropyrimidine dehydrogenase, allows for oral dosing of 5-fluorouracil (5-FU), which avoids the morbidity of continuous infusion 5-FU. We addressed the safety of oral eniluracil and 5-FU combined with preoperative radiotherapy and determined the recommended Phase II dose and dose-limiting toxicity in patients with locally advanced rectal and colon cancer. METHODS AND MATERIALS: Patients with TNM Stage II or III rectal cancer and residual or recurrent colon cancer received eniluracil (starting at 6.0 mg/m(2) every 12 h) and 5-FU (starting at 0.6 mg/m(2) every 12 h). Eniluracil and 5-FU were given with a 5-week course of preoperative radiotherapy of 4500 cGy, with a possible 540-cGy boost. Surgery was performed approximately 4 weeks after completion of chemoradiotherapy. RESULTS: Twenty-two patients were enrolled; 1 patient was withdrawn owing to noncompliance. Chemotherapy was completed in all patients; radiotherapy was completed in 20 patients. The recommended Phase II dose of eniluracil and 5-FU was 8 mg/m(2) every 12 h and 0.8 mg/m(2) every 12 h, respectively. Diarrhea was the dose-limiting toxicity. Eleven of the 17 patients with primary rectal cancer underwent a sphincter-sparing procedure. One patient had a pathologic complete response. CONCLUSION: Preoperative chemoradiotherapy with oral eniluracil and 5-FU is feasible and well tolerated. Additional investigation is warranted.

Thin melanomas: predictive lethal characteristics from a 30-year clinical experience.

OBJECTIVE: To guide treatment and clinical follow-up by defining the natural history of thin melanomas and identifying negative prognostic characteristics that may delineate high-risk patients. SUMMARY BACKGROUND DATA: In following > 10,000 patients with cutaneous melanoma over the past 30 years, our institution has observed nodal or metastatic disease in approximately 15% of patients with a thin (<1 mm) primary lesion. METHODS: A database query of patients with cutaneous melanoma returned 1158 patients with primary lesion < or = 1 mm thick and who received their initial treatment at a single institution. Median follow-up was 11 years (range, 1 to 34 years). Patient and melanoma characteristics as well as outcomes were recorded and statistically analyzed. RESULTS: 6.6% of patients had nodal or distant disease at presentation. Over time, an additional 9.4% developed metastases, including nodal and distal recurrences. Overall incidence of advanced disease was 15.3%. Univariate analysis identified male gender (P = 0.01), advanced age (>45 years; P = 0.05), and Breslow thickness (>0.75 mm; P = 0.008) as significant negative prognostic characteristics. Of patients with these 3 high-risk characteristics, 19.7% developed advanced disease (likelihood ratio 6.3; P = 0.007 versus nonhigh-risk patients). This group had more than twice the incidence of nodal recurrences. Patients with recurrence had significantly decreased 10-year survival (82% versus 45%; P < 0.0001). Surprisingly, neither ulceration nor Clark level predicted advanced disease. CONCLUSIONS: Thin melanomas are potentially lethal lesions. Long-term follow-up identified a high-risk population of older males with tumors between 0.75 mm and 1.0 mm whose risk of recurrent disease approaches 20%. Traditionally accepted negative prognostic factors such as ulceration and discordant Clark levels are not predictive for metastasis in this population. Given the poor prognosis associated with recurrent disease, we recommend close clinical evaluation and follow-up to maximize accurate staging and therapeutic options.

Heterotopic ossification in rectal cancer: Rare finding with a novel proposed mechanism.

The rare finding of heterotopic ossification in a case of primary rectal adenocarcinoma is described along with a review of the literature. Immunohistochemistry for a bone morphogenic protein (BMP-2) and fibroblast growth factor (FGF-2), both of which induce and stimulate bone formation, was performed and revealed overexpression of BMP-2 by the tumor cells, elucidating a possible mechanism which up to now had been based merely on speculation.

The long-term clinical course of patients with cutaneous melanoma.

BACKGROUND: The clinical course of cutaneous melanoma is associated with pathologic and clinical factors, such as thickness, ulceration, and location of tumor and gender of the patient. The authors used a parametric survival model that incorporated a cured fraction of patients to translate these factors into specific estimates of long-term outcome. METHODS: A cohort study was conducted of 5837 patients who were treated for localized cutaneous melanoma between 1978 and 1990 at the Duke Comprehensive Cancer Center. Of these, 495 patients were excluded because the survival status or one or more of the prognostic factors was unknown. Maximum follow-up was 22 years. The primary outcome measures examined were cured fraction (probability of cure), median tumor specific survival (i.e., median time to death from tumor), and the probability of tumor-related survival at fixed intervals after treatment. RESULTS: For an example of a class of patients with a relatively good prognosis, consider women with nonulcerated lesions measuring 0.5 mm thick on an extremity. The probability of cure (+/- standard error) for these patients was estimated at 80.8% +/- 2.0%, and the median tumor specific survival was 10.0 years +/- 0.8 years. This suggests that, in these patients, half of the deaths from melanoma will occur more than 10 years after treatment, barring death from other causes. Conversely, men with ulcerated lesions measuring 8.00 mm thick on the trunk have a relatively poor prognosis. The probability of cure for these patients was 16.8% +/- 2.4%, and the median tumor specific survival was 2.7 years +/- 0.2 years. Despite this poor initial prognosis, the conditional probability of cure increased to 90%; after 15 years of recurrence free survival. CONCLUSIONS: Parametric statistical analysis provides quantitative measures of long-term survival. These measures show that late recurrence-longer than a decade after treatment-is to be expected in a significant portion of patients, although the probability of cure increases with progressively longer recurrence free survival.

Mutations of the BRAF gene in human cancer.

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.

Poor outcome and quality of life in female patients undergoing secondary surgery for recurrent peptic ulcer disease.

Secondary peptic ulcer surgery is uncommon given the success of a wide variety of medical therapies, plus the good outcome expected after primary peptic ulcer surgery. Early reports of secondary peptic ulcer surgery in the 1950s and 1960s suggested good long-term outcome in most patients; however, recent data suggest that patients operated in the Helicobacter pylori era have a worse outcome. We have attempted to quantify the poor outcome in these patients and measure the effect of sex, a previously unrecognized risk factor for poor outcome after peptic ulcer surgery. We reviewed the outcomes of 35 patients who underwent secondary peptic ulcer surgery for symptoms of persistent or recurrent peptic ulcer symptoms or complications of the condition. These patients were compared to a "control" group of patients to determine long-term quality of life as measured by the SF-36 and Visick scores (average follow-up 60 months). Visick and SF-36 scores were obtained through telephone interviews. The two groups of patients were age matched to eliminate age as a variable in the SF-36 results. There were more females than males in the secondary peptic ulcer surgery group (4.5/1 female-to-male ratio). Although perioperative mortality was zero for both groups, patients undergoing secondary peptic ulcer surgery had a high number of complications (57% of patients had complications). Patients undergoing secondary peptic ulcer surgery scored lower in seven of the eight subclasses of the SF-36 questionnaire compared to their age-matched cohorts. In contrast, average Visick scores showed slight improvement for three out of four symptoms reported. Immediate postoperative complications were not related to long-term quality of life issues. Secondary peptic ulcer surgery is more prevalent in females than in males. Although secondary peptic ulcer surgery is partially effective in alleviating symptoms, quality of life is poor.