Robert J. Canter

Mitotic rate as a predictor of sentinel lymph nodepositivity in patients with thin melanomas

BackgroundLymphatic mapping and sentinel lymphadenectomy (LM/SL) provide important prognostic information for patients with early-stage melanoma. Although the use of this technique in patients with thin melanomas (≤1.00 mm) is not routine, risk factors that may predict sentinel lymph node (SLN) positivity in this patient population are under investigation. We sought to determine whether mitotic rate (MR) is associated with SLN positivity in thin-melanoma patients and, therefore, whether it may be used to risk-stratify and select patients for LM/SL.MethodsClinical and histopathologic variables were reviewed for 181 patients with thin melanomas who underwent LM/SL from January 1996 through January 2004. Univariate and multivariate logistic regression analyses were performed to identify factors associated with SLN positivity. Risk groups were defined on the basis of the development of a classification tree.ResultsThe overall SLN positivity rate was 5%. All patients with positive SLNs had an MR of >0. By univariate analysis, MR and thickness were significant predictors of SLN positivity. The association between MR and SLN positivity remained significant controlling for each of the other variables evaluated. On the basis of a classification tree, patients with an MR >0 and tumor thickness ≥.76 mm were identified as a higher-risk group, with an SLN positivity rate of 12.3%.ConclusionsIn patients with thin melanomas, MR >0 seems to be a significant predictor of SLN positivity that may be used to risk-stratify and select patients for LM/SL. To confirm these results, the predictive value of MR for SLN positivity needs to be validated in other populations of thin-melanoma patients.

A synovial sarcoma-specific preoperative nomogram supports a survival benefit to ifosfamide-based chemotherapy and improves risk stratification for patients.

Purpose: To identify prognostic factors related to outcome in 255 patients with synovial sarcoma and to construct a preoperative nomogram to predict the risk of disease-specific death. Design: Between July 1982 and June 2006, 301 patients underwent treatment at our institution for primary synovial sarcoma of all anatomic sites and 255 patients with localized disease at presentation were resected with curative intent. Data were collected prospectively and analyzed retrospectively. Results: Five-, 10-, and 15-year disease-specific survival (DSS) was 72%, 60%, and 53%, respectively. Multivariate analysis revealed size and primary tumor site as the only independent adverse predictors of disease-specific death. A nomogram based on preoperative data for surgical patients not receiving anthracycline-ifosfamide (AI) chemotherapy (n = 196) estimates 3- and 5-year DSS with a concordance index of 77.3%. For the first 3 years following diagnosis, the observed DSS for patients treated with AI chemotherapy (n = 59) was greater than that predicted by the preoperative nomogram based on patients not receiving AI chemotherapy. SYT-SSX fusion transcript data were available for 132 patients. Multivariate analysis of this subset showed that SYT-SSX1 fusion type was predictive of early, but not late, distant recurrence. Conclusion: Size and location govern prognosis in primary synovial sarcoma resected with curative intent. A nomogram based on preoperative variables provides individualized patient survival estimates and shows an early survival benefit to chemotherapy that may dissipate over time. This nomogram may improve decision-making with regards to selecting patients most likely to benefit from neoadjuvant/adjuvant chemotherapy.

Surgical Resident Involvement Is Safe for Common Elective General Surgery Procedures

BACKGROUND Outcomes of surgical resident training are under scrutiny with the changing milieu of surgical education. Few have investigated the effect of surgical resident involvement (SRI) on operative parameters. Examining 7 common general surgery procedures, we evaluated the effect of SRI on perioperative morbidity and mortality and operative time (OpT). STUDY DESIGN The American College of Surgeons National Surgical Quality Improvement Program database (2005 to 2007) was used to identify 7 cases of nonemergent operations. Cases with simultaneous procedures were excluded. Logistic regression was performed across all procedures and within each procedure incorporating SRI, OpT, and risk-stratifying American College of Surgery National Surgical Quality Improvement Program morbidity and mortality probability scores, which incorporate multiple prognostic individual patient factors. Procedure-specific, SRI-stratified OpTs were compared using Wilcoxon rank-sum tests. RESULTS A total of 71.3% of the 37,907 cases had SRI. Absolute 30-day morbidity for all cases with SRI and without SRI were 3.0% and 1.0%, respectively (p < 0.001); absolute 30-day mortality for all cases with SRI and without SRI were 0.1% and 0.08%, respectively (p < 0.001). After multivariate analysis by specific procedure, SRI was not associated with increased morbidity but was associated with decreased mortality during open right colectomy (odds ratio 0.32; p = 0.01). Across all procedures, SRI was associated with increased morbidity (odds ratio 1.14; p = 0.048) but decreased mortality (odds ratio 0.42; p < 0.001). Mean OpT for all procedures was consistently lower for cases without SRI. CONCLUSIONS SRI has a measurable impact on both 30-day morbidity and mortality and OpT. These data have implications to the impact associated with surgical graduate medical education. Further studies to identify causes of patient morbidity and prevention strategies in surgical teaching environments are warranted.

Negligible Effect of Selective Preoperative Biliary Drainage on Perioperative Resuscitation, Morbidity, and Mortality in Patients Undergoing Pancreaticoduodenectomy

OBJECTIVE To examine the effect of selective preoperative biliary drainage (BD) on perioperative resuscitation, morbidity, and mortality in patients undergoing pancreaticoduodenectomy. Biliary drainage prior to pancreaticoduodenectomy remains controversial. Proponents argue that it facilitates referral to high-volume tertiary centers, while detractors maintain that it increases surgical morbidity and mortality. DESIGN Retrospective analysis of single-institution tumor registry database. SETTING University medical center. PATIENTS From October 1, 2003, to May 31, 2008, 90 patients underwent pancreaticoduodenectomy for periampullary mass lesions. MAIN OUTCOME MEASURES Clinicopathologic data were reviewed and analyzed among patients who did and did not receive BD for their association with perioperative outcomes. chi(2) Analysis, independent-samples t tests, and Mann-Whitney U tests were used as appropriate. RESULTS Fifty-six patients (62%) underwent BD, and 34 (38%) did not. Intraoperative bile cultures were positive for 1 or more species of microorganisms in 88% of stented patients (35 of 40). There were no significant differences in fluid requirements, transfusion requirements, or surgery duration between patients who did and did not undergo BD. Estimated blood loss was increased in patients who received BD (625 mL vs 525 mL in patients who did not undergo BD; P = .03), while reoperation was significantly more common in nonstented patients (4% vs 15% in patients who did not undergo BD; P = .02). Intensive care unit stay, overall length of stay, pancreatic leak/abscess/fistula, infectious complications, postoperative percutaneous drainage, hospital readmission, and 30- and 90-day mortality were not significantly different between the 2 groups. CONCLUSIONS Although preoperative biliary stents may complicate the intraoperative management and lessen the postoperative complications of patients undergoing pancreaticoduodenectomy, only estimated blood loss and reoperation were significantly different in this cohort. Further study may reveal patient subgroups who may specifically benefit or suffer from preoperative biliary stenting. Currently, selective preoperative BD appears appropriate in the multidisciplinary management of patients with periampullary lesions.

NK Cells Preferentially Target Tumor Cells with a Cancer Stem Cell Phenotype

Increasing evidence supports the hypothesis that cancer stem cells (CSCs) are resistant to antiproliferative therapies, able to repopulate tumor bulk, and seed metastasis. NK cells are able to target stem cells as shown by their ability to reject allogeneic hematopoietic stem cells but not solid tissue grafts. Using multiple preclinical models, including NK coculture (autologous and allogeneic) with multiple human cancer cell lines and dissociated primary cancer specimens and NK transfer in NSG mice harboring orthotopic pancreatic cancer xenografts, we assessed CSC viability, CSC frequency, expression of death receptor ligands, and tumor burden. We demonstrate that activated NK cells are capable of preferentially killing CSCs identified by multiple CSC markers (CD24+/CD44+, CD133+, and aldehyde dehydrogenasebright) from a wide variety of human cancer cell lines in vitro and dissociated primary cancer specimens ex vivo. We observed comparable effector function of allogeneic and autologous NK cells. We also observed preferential upregulation of NK activation ligands MICA/B, Fas, and DR5 on CSCs. Blocking studies further implicated an NKG2D-dependent mechanism for NK killing of CSCs. Treatment of orthotopic human pancreatic cancer tumor-bearing NSG mice with activated NK cells led to significant reductions in both intratumoral CSCs and tumor burden. Taken together, these data from multiple preclinical models, including a strong reliance on primary human cancer specimens, provide compelling preclinical evidence that activated NK cells preferentially target cancer cells with a CSC phenotype, highlighting the translational potential of NK immunotherapy as part of a combined modality approach for refractory solid malignancies.

Sarcopenia: Current Concepts and Imaging Implications

OBJECTIVE The purpose of this article is to review the nomenclature, clinical impact, and diagnostic techniques characterizing sarcopenia. CONCLUSION Sarcopenia-defined as significant loss of muscle-is associated with cachexia and frailty. Specific diagnostic criteria for sarcopenia continue to evolve, but imaging can play a role in the detection and quantification of muscle depletion. Emerging evidence indicates that sarcopenia is a relevant predictor of quality and quantity of life, particularly in patients who are elderly, have cancer, or undergo surgery.

Predicting Survival for Well-Differentiated Liposarcoma: The Importance of Tumor Location

BACKGROUND Although well-differentiated liposarcoma (WD Lipo) is a low grade neoplasm with a negligible risk of metastatic disease, it can be locally aggressive. We hypothesized that survival for WD Lipo varies significantly based on tumor location. METHODS We identified 1266 patients with WD Lipo in the Surveillance, Epidemiology, and End Results database from 1988-2004. After excluding patients diagnosed by autopsy only, those lacking histologic confirmation, those lacking data on tumor location, and those with metastatic disease or unknown staging information, we arrived at a final study cohort of 1130 patients. Clinical, pathologic, and treatment variables were analyzed for their association with overall survival (OS) and disease-specific survival (DSS) using Kaplan-Meier analysis and Cox proportional hazards multivariate models. RESULTS Mean age was 61 y (± 14.6), 72.2% were white, and 60.4% were male. Eighty-one percent of patients were treated with surgical therapy alone, 4.6% were treated with radiotherapy (RT) alone, and 12.9% were treated with both surgery and RT. Extremity location was most common (41.6%), followed by trunk (29%), retroperitoneal/intra-abdominal (RIA, 21.6%), thorax (4.2%), and head/neck (3.6%). With a median follow-up of 45 mo, median OS was 115 mo (95% confidence interval [CI] 92-138 mo) for RIA tumors compared to not reached for other tumor locations (P = 0.002). On multivariate analysis, increasing age and RIA location both predicted worse OS and DSS while tumor size, race, sex, receipt of RT, and Surveillance, Epidemiology, and End Results (SEER) stage did not. Tumor size became a significant predictor of worse DSS, but not OS, only when site, SEER stage, and extent of resection were removed from the multivariate model. Non-RIA locations, including extremity, experienced statistically similar OS, but 5-y DSS for trunk location was intermediate [92.3%, (95% CI 88.5%-96.1%) compared with 98.0% (95% CI, 96.2%-99.8%) for extremity and 86.6 (95% CI 81.1%-92.1%) for RIA, P < 0.001]. CONCLUSIONS Among patients with WD Lipo, RIA location is associated with significantly worse outcomes independent of tumor size. Future studies should focus on the anatomic and biologic reasons for these differences.

Tumor necrosis factor-alpha damages tumor blood vessel integrity by targeting VE-cadherin.

Background:Isolated limb perfusion using high-dose human tumor necrosis factor-alpha with melphalan is effective therapy for bulky extremity in-transit melanoma and sarcoma. Objective:While it is widely accepted that melphalan is a DNA alkylating agent, the mechanism of selective antitumor effect of tumor necrosis factor-alpha is unclear. Methods and Results:Electron microscopic analyses of human melanoma biopsies, pre- and post-melphalan perfusion, showed that the addition of tumor necrosis factor-alpha caused gapping between endothelial cells by 3 to 6 hours post-treatment followed by vascular erythrostasis in treated tumors. In human melanoma xenografts raised in mice, tumor necrosis factor-alpha selectively increased tumor vascular permeability by 3 hours and decreased tumor blood flow by 6 hours post-treatment relative to treated normal tissue. In an in vitro tumor endothelial cell model, tumor necrosis factor-alpha caused vascular endothelial adherens junction protein, VE-cadherin, to relocalize within the cell membrane away from cell-cell junctions leading to gapping between endothelial cells by 3 to 6 hours post-treatment. Phosphotyrosinylation was a prerequisite for movement of VE-cadherin away from endothelial cell junctions and for gapping between endothelial cells. Clinical isolated limb perfusion tumor specimens, at 3 hours postperfusion, showed a discontinuous and irregular pattern of VE-cadherin expression at endothelial cell junctions when compared with normal (skin) or pretreatment tumor tissue. Conclusions:Together, the data suggest that tumor necrosis factor-alpha selectively damages the integrity of tumor vasculature by disrupting VE-cadherin complexes at vascular endothelial cell junctions leading to gapping between endothelial cells, causing increased vascular leak and erythrostasis in tumors. VE-cadherin appears to be a potentially good target for selective antitumor therapy.

Interaction of Histologic Subtype and Histologic Grade in Predicting Survival for Soft-Tissue Sarcomas

BACKGROUND Histologic grade is considered the paramount prognostic factor in predicting survival for soft-tissue sarcomas (STS). Increasing data suggest that histologic type substantially impacts STS behavior. STUDY DESIGN The Surveillance, Epidemiology, and End Results program was used to identify 17,364 cases of STS diagnosed between 1988 and 2004. Using death from STS as 1 of the outcomes variables, histologic types were grouped into 3 categories: favorable (survival >or= 20% above the mean), neutral (survival within 20% of the mean), and unfavorable (survival >or= 20% below the mean). The effect of histology on survival was analyzed stratified by tumor grade. Five-year survival was calculated using Kaplan-Meier analysis. RESULTS Among 73 histologic types, malignant fibrous histiocytoma (24.1%); leiomyosarcoma, not otherwise specified (14.8%); sarcoma, not otherwise specified (12.8%); and myxoid liposarcoma (5.9%) were the most prevalent. Grade distribution was as follows: low, 12.6%; intermediate, 14.9%; high, 37.1%; and unknown, 35.4%. Risk of death from STS increased with increasing grade: 8.0% for low, 25.9% for intermediate, and 38.3% for high. Among low-grade tumors, risk of death from STS ranged from 4.3% for favorable types to 15.3% for unfavorable types. Among intermediate-grade tumors, risk of death from STS ranged from 6.0% for favorable types to 45.4% for unfavorable types. Among high-grade tumors, risk of death from STS ranged from 24.3% for favorable types to 58.9% for unfavorable types. CONCLUSIONS Within categories of STS grade, there are substantial differences in survival, depending on histologic type. Histologic type is an important predictor of biologic behavior in STS.

Text Messaging Among Residents and Faculty in a University General Surgery Residency Program: Prevalence, Purpose, and Patient Care

BACKGROUND There is little information about the use of text messaging (texting) devices among resident and faculty physicians for patient-related care (PRC). OBJECTIVE To determine the prevalence, frequency, purpose, and concerns regarding texting among resident and attending surgeons and to identify factors associated with PRC texting. DESIGN E-mail survey. SETTING University medical center and its affiliated hospitals. PARTICIPANTS Surgery resident and attending staff. OUTCOME MEASURES Prevalence, frequency, purpose, and concerns regarding patient-related care text messaging. RESULTS Overall, 73 (65%) surveyed physicians responded, including 45 resident (66%) and 28 attending surgeons (62%). All respondents owned a texting device. Majority of surgery residents (88%) and attendings (71%) texted residents, whereas only 59% of residents and 65% of attendings texted other faculty. Most resident to resident text occurred at a frequency of 3-5 times/d (43%) compared with most attending to resident texts, which occurred 1-2 times/d (33%). Most resident to attending (25%) and attending to attending (30%) texts occurred 1-2 times/d. Among those that texted, PRC was the most frequently reported purpose for resident to resident (46%), resident to attending (64%), attending to resident (82%), and attending to other attending staff (60%) texting. Texting was the most preferred method to communicate about routine PRC (47% of residents vs 44% of attendings). Age (OR: 0.86, 95% CI: 0.79-0.95; p = 0.003), but not sex, specialty/clinical rotation, academic rank, or postgraduate year (PGY) level predicted PRC texting. CONCLUSIONS Most resident and attending staff surveyed utilize texting, mostly for PRC. Texting was preferred for communicating routine PRC information. Our data may facilitate the development of guidelines for the appropriate use of PRC texting.