Size of sentinel node metastases predicts other nodal disease and survival in malignant melanoma.

BACKGROUND: A positive sentinel lymph node (SLN) biopsy is an indication for completion lymph node dissection (CLND) in malignant melanoma; however, most CLNDs are negative. We hypothesized SLN metastatic size of < or =2 mm would predict CLND status and prognosis. METHODS: We evaluated 80 consecutive patients undergoing CLND for positive SLNs over a 10-year period. Incidence of positive nonsentinel nodes and survival were compared for patients with SLN metastases < or =2 mm and >2 mm. RESULTS: Of 504 patients undergoing SLN biopsy, 49 patients had SLN deposits < or =2 mm and a 6% incidence of positive CLNDs. Five-year survival was 85%, essentially the same as negative SLN biopsies. In contrast, 31 had SLN metastases >2 mm, a 45% incidence of addition disease at CLND, and 5-year survival of 47% (P < .0001). CONCLUSION: An SLN metastatic cut point of 2 mm is an efficient predictor of CLND status and survival in malignant melanoma.

Nonaccidental trauma is a major cause of morbidity and mortality among patients at a regional level 1 pediatric trauma center.

BACKGROUND: Traumatic injuries are a major cause of morbidity and mortality in children. The purpose of the present study was to determine the incidence of nonaccidental trauma (NAT) and to compare the outcomes of accidental trauma (AT) patients with NAT patients at a large pediatric trauma center. METHODS: A retrospective chart review of 6186 trauma patients younger than 18 years evaluated during the period of 1996 to 2004. RESULTS: During the period of study, NAT accounted for 7.3% (n = 453) of trauma evaluations (n = 6186). Compared to AT, the NAT patient was younger, 12 vs 76 months (P < .05); were more severely injured, injury severity score 18 vs 9 (P < .05); and required both longer intensive care unit stay, 2 vs 1 day (P < .05), and overall hospital stay, 6 vs 3 days (P < .05). Craniotomy was required in 4.4% of NAT patients compared with 2.7 % of AT patients (P < .05). Abdominal exploration was necessary in 3.5% of NAT patients compared to 1.6% of AT patients. The mortality rate for NAT was 9.7% compared to 2.2% for AT (P < .05). CONCLUSIONS: The surgeon caring for children must appreciate the high incidence of NAT with its increased morbidity and mortality relative to AT patients. A surgical evaluation should be performed promptly in NAT patients because of their frequent need for emergent intervention.

Positioning for the Nuss procedure: avoiding brachial plexus injury.

BACKGROUND: In 1987, Nuss developed a minimally invasive technique for the treatment of pectus excavatum. The procedure has had excellent results with minimal complications. Anesthetic concerns include risks of cardiothoracic injuries, dysrythmias, pneumothorax, pleural effusions, and hemorrhage. In addition, we identified a risk of brachial plexus injury that can occur secondary to patient positioning. We report our experience with the Nuss procedure and modified patient positioning. METHODS: A retrospective chart review was performed on 95 children or adolescents who underwent a Nuss procedure at the Children's Hospital in Denver, CO, USA. The first group of patients (58) was positioned with their arms extended above their heads at a 90 degrees angle at the shoulder. The second group of patients (37) was positioned in an arthroscopy sling in a neutral position utilizing a right angled suspension device attached to the operating room bed. RESULTS: In the first group of patients, three of 58 (5.2%) children had transient brachial plexus injuries. To date, in the second group of patients, there have been no brachial plexus injuries using the suspension device. CONCLUSIONS: We found that patients are at risk of transient brachial plexus injury during the Nuss procedure due to positioning of the arms. A readily available device that permits the extremity to be maintained in a neutral position but also allows intraoperative manipulation during critical aspects of the Nuss procedure eliminates transient brachial plexus palsy.

Visceral injuries in nonaccidental trauma: spectrum of injury and outcomes.

BACKGROUND: Nonaccidental trauma (NAT) causes significant morbidity and mortality in children. The purpose of this study was to characterize visceral injuries associated with NAT and the management and outcomes of children with these injuries. METHODS: During a 7-year period, children admitted to our regional pediatric trauma center with a diagnosis of NAT were identified and their injuries characterized. RESULTS: NAT accounted for 7% (n = 265 of 3705) of all trauma admissions during the period of study. Visceral injuries were diagnosed in 9% (n = 24 of 265) of NAT patients. Compared with the remaining NAT population, children with visceral injuries were similar in age and sex but had higher injury severity scores (21 vs. 17, P < .05). There was a high coincidence of thoracic trauma and nonburn integumental injuries in abdominally injured NAT patients. Children with visceral injuries were more likely to undergo emergent operations (46% [11 of 24] vs. 5% [15 of 241], P < .0001) than those without. However, there was no difference in Intensive Care Unit stay, hospital stay, or overall mortality for children with visceral injuries compared with those without. CONCLUSIONS: Visceral injuries are not uncommon in NAT, and these injuries often require emergent operative intervention. Thus, prompt evaluation and treatment by a surgeon remains a critical step in the management of children with NAT.

Survival in sentinel lymph node-positive pediatric melanoma.

BACKGROUND: Sentinel lymph node (SLN) status is the strongest predictor of survival in adult melanoma. However, the prognostic value of SLN status in children and adolescents with melanoma is unknown. METHODS: Records of 327 patients aged 12 to 86 years undergoing SLN biopsy for melanoma or other melanocytic lesions were reviewed. A literature search identified additional patients younger than 21 years undergoing SLN biopsy for the same indications and these patients were combined with our series for meta-analysis. RESULTS: Sentinel lymph node metastases were found in 8 (40%) of 20 patients aged 12 to 20 years compared with 55 (18%) of 307 adults (P < .05). Median follow-up was 35 and 17 months for the groups, respectively. Sentinel lymph node-positive pediatric patients did not recur, whereas 14 (25%) adults recurred within this period. Of the 55 adults, 5 (9.1%) have died of disease. Of the combined SLN-positive children and adolescents from the literature (total n = 25), only a single (4%) child recurred at 6 months. The difference in survival for adult and pediatric patients was significant. CONCLUSION: Pediatric patients have a higher incidence of SLN metastases than adults yet have a lower incidence of recurrence. Sentinel lymph node status does not predict early recurrence in pediatric patients with melanoma or atypical Spitz nevi.

Sentinel lymph node biopsy for melanoma and other melanocytic tumors in adolescents.

BACKGROUND/PURPOSE: Melanoma is rare, accounting for only 1% of all pediatric malignancies. The management of pediatric melanoma is controversial but largely parallels that of an adult occurrence. Sentinel lymph node biopsy (SLNBX) has become a standard of care for adults with melanoma, but the role of this procedure in the staging of pediatric patients remains to be established. The goal of this study was to determine outcomes and complications of children and adolescent patients undergoing SLNBX at the authors' institution. METHODS: A retrospective review of patients younger than 21 years (N = 20) undergoing SLNBX for melanoma or other melanocytic skin lesions at the University of Colorado Health Science Center between 1996 and 2003 was conducted. RESULTS: Sentinel lymph node biopsy was successful in all 20 patients, and 8 patients (40%) were found to have metastases within the sentinel node. As in adults, the sentinel node status correlates with primary tumor depth. No complications occurred in patients undergoing SLNBX, but 4 clinically significant complications (57%) occurred in the 7 patients undergoing a completion lymph node dissection. At 33 months median follow-up, all patients were disease free. CONCLUSIONS: Sentinel lymph node biopsy can be successfully and safely performed in pediatric patients for melanoma and atypical nevi. However, the prognostic information and therapeutic implications of SLNBX results for children and adolescents remain unclear. Completion lymph node dissection for microscopic disease is a morbid procedure with uncertain benefit to pediatric or adult patients with a positive SLNBX result. Long-term follow-up data are needed before SLNBX can become a standard of care in pediatric melanoma or as a diagnostic tool to distinguish the atypical Spitz nevus from melanoma.

Identifying risk factors for complications following sentinel lymph node biopsy for melanoma.

BACKGROUND: Sentinel lymph node biopsy has become routine in the staging of patients with cutaneous melanoma and is presumed to have fewer complications than elective regional lymph node dissection (RLND). However, little information is available to refute or support this assumption. HYPOTHESIS: Risk factors for complications following sentinel lymph node biopsy (SLNBX) can be identified. DESIGN: Retrospective medical record review. PATIENTS AND METHODS: The medical records of 339 consecutive patients undergoing SLNBX for melanoma between 1996 and 2003 at our institution were reviewed for complications. RESULTS: In our series of 339 patients, 20 complications (5.9%) were observed following SLNBX compared with 15 (19.5%) of 77 patients undergoing RLND during the same period (P<.001). Seroma formation, transient nerve injuries, and minor wound infections were the most frequently observed complications in patients undergoing SLNBX. In contrast, chronic lymphedema and wound infections were the most frequent complications observed in patients undergoing RLND. Patients with comorbid medical conditions had more complications following either SLNBX or RLND than those without. The number of lymph nodes excised and the placement of closed-suction drainage were associated with an increased incidence of complications following SLNBX but not RLND. The incidence of annual complications inversely correlated with the cumulative number of SLNBXs performed during this period. CONCLUSIONS: Sentinel lymph node biopsy can be performed with a low incidence of complications. Experience with SLNBX decreases complications. Patients with more than 1 sentinel lymph node excised or a closed-suction drain placed at the time of SLNBX are at an increased risk of complications.

Novel extranuclear-targeted anthracyclines override the antiapoptotic functions of Bcl-2 and target protein kinase C pathways to induce apoptosis.

Bcl-2 inhibits apoptosis induced by numerous antitumor drugs, including doxorubicin and daunorubicin and is, thus, a major impediment to successful cancer chemotherapy. Here, we report the ability of a novel family of nonnuclear targeted anthracyclines to induce rapid apoptosis in cells despite Bcl-2 or Bcl-X(L) expression. Typified by N-benzyladriamycin-14-valerate (AD 198) and N-benzyladriamycin-14-pivalate (AD 445), this family of compounds binds to the C1 regulatory domain of protein kinase C (PKC), competitively inhibits phorbol ester binding in cell-free studies, and induces PKC translocation in intact cells. PKC-delta has an established role as a pro-apoptotic protein through the association of the holoenzyme or catalytic fragment with mitochondria. In proliferating 32D.3 myeloid cells, or in 32D.3 cells engineered to overexpress Bcl-2, substantial levels of PKC-delta are associated with mitochondria. However, after a 1-h exposure to 5 microM AD 198, cytochrome c release, caspase-3 activation, poly(ADP-ribose) polymerase (PARP) cleavage, PKC-delta cleavage, and DNA fragmentation are observed. Pretreatment of 32D.3 cells with the selective PKC-delta inhibitor, rottlerin, but not the general PKC inhibitor, GF 109203X, or PKC-alpha and -beta inhibitor, Gö 6976, delayed the 50% cell kill to >24 h for control and Bcl-2 overexpressing 32D.3 cells treated with 5 microM AD 198. Rottlerin delayed PKC-delta and PARP cleavage to >20 h post-drug exposure and also delayed mitochondrial membrane depolarization. In contrast, the pan-caspase inhibitor Z-Val-Ala-Asp-CH2F blocked PKC-delta and PARP cleavage, but not mitochondrial membrane depolarization. These results suggest that AD 198 induces mitochondrial-dependent apoptosis in 32D.3 cells by activating PKC-delta holoenzyme on mitochondria, which, in turn, overrides the antiapoptotic effects of Bcl-2.

Interaction of the novel anthracycline antitumor agent N-benzyladriamycin-14-valerate with the C1-regulatory domain of protein kinase C: structural requirements, isoform specificity, and correlation with drug cytotoxicity.

Anthracycline antibiotics like doxorubicin (DOX) are known to exert their antitumor effects primarily via DNA intercalation and topoisomerase II inhibition. By contrast, the noncross-resistant cytoplasmically localizing DOX analogue, N-benzyladriamycin-14-valerate (AD 198), only weakly binds DNA and does not inhibit topoisomerase II, yet it displays superior antitumor activity, strongly suggesting a distinct cytotoxic mechanism. In recent modeling studies, we reported a structural similarity between AD 198 and commonly accepted ligands for the C1-domain of protein kinase C (PKC), and we hypothesized that the unique biological activity of AD 198 may derive, in part, through this kinase. Consistent with this hypothesis, the present biochemical studies demonstrate that AD 198 competes with [3H]phorbol-12,13-dibutyrate ([3H]PDBu) for binding to phorbol-responsive PKC isoforms, the isolated C1b domain of PKC-delta (delta C1b), and the nonkinase phorbol ester receptor, beta2-chimaerin. In NIH/3T3 cells, AD 198 competitively blocks PKC activation by C1-ligands. Importantly, neither DOX nor N-benzyladriamycin, the principal AD 198 metabolite, inhibits basal or phorbol-stimulated PKC activity or appreciably competes for [3H]PDBu binding. In CEM cells, structure activity studies with 14-acyl congeners indicate that the rapid induction of apoptosis correlates with competition for [3H]PDBu binding, strongly implicating phorbol-binding proteins in drug activity. Collectively, these studies support the conclusion that AD 198 is a C1-ligand and that C1-ligand receptors are selective drug targets. These studies provide the impetus for continuing efforts to understand the molecular basis for the unique biological activity of AD 198 and provide for the design of analogues with improved affinity for C1-domains and potentially greater antitumor activity.