Sentinel lymph node positivity in melanoma: Which risk prediction tool is most accurate?

BACKGROUND: Sentinel lymph node biopsy for melanoma determines treatment and prognostic factors and improves disease-specific survival. To risk-stratify patients for sentinel lymph node biopsy consideration, Memorial Sloan Kettering Cancer Center and Melanoma Institute Australia developed nomograms to predict sentinel lymph node positivity. We aimed to compare the accuracy of these 2 nomograms. METHODS: A multi-institutional study of patients with melanoma receiving sentinel lymph node biopsy between September 2018 and December 2022 was performed. The accuracy of the 2 risk prediction tools in determining a positive sentinel lymph node biopsy was analyzed using receiver operating characteristic curves and area under the curve. RESULTS: In total, 532 patients underwent sentinel lymph node biopsy for melanoma; 98 (18.4%) had positive sentinel lymph node. Increasing age was inversely related to sentinel lymph node positivity (P < .01); 35.7% of patients ≤30 years had positive sentinel lymph node compared with 9.7% of patients ≥75 years. When we analyzed the entire study population, accuracy of the 2 risk prediction tools was equal (area under the curveMemorial Sloan Kettering Cancer Center: 0.693; area under the curveMIA: 0.699). However, Memorial Sloan Kettering Cancer Center tool was a better predictor in patients aged ≥75 years (area under the curveMemorial Sloan Kettering Cancer Center: 0.801; area under the curveMelanoma Institute Australia: 0.712, P < .01) but Melanoma Institute Australia tool performed better in patients with a higher mitotic index (mitoses/mm2 ≥2; area under the curveMemorial Sloan Kettering Cancer Center: 0.659; area under the curveMelanoma Institute Australia: 0.717, P = .027). Both models were poor predictors of sentinel lymph node positivity in young patients (age ≤30 years; area under the curveMemorial Sloan Kettering Cancer Center: 0.456; area under the curveMelanoma Institute Australia: 0.589, P = .283). CONCLUSION: The current study suggests that the 2 risk stratification tools differ in their abilities to predict sentinel lymph node positivity in specific populations: Memorial Sloan Kettering Cancer Center tool is a better predictor for older patients, whereas Melanoma Institute Australia tool is more accurate in patients with a higher mitotic index. Both nomograms performed poorly in predicting sentinel lymph node positivity in young patients.

Implications of Postoperative Complications for Survival After Cytoreductive Surgery and HIPEC: A Multi-Institutional Analysis of the US HIPEC Collaborative.

BACKGROUND: Postoperative complications (POCs) are associated with worse oncologic outcomes in various cancer histologies. The impact of POCs on the survival of patients with appendiceal or colorectal cancer after cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is unknown. METHODS: The US HIPEC Collaborative (2000-2017) was reviewed for patients who underwent CCR0/1 CRS/HIPEC for appendiceal/colorectal cancer. The analysis was stratified by noninvasive appendiceal neoplasm versus invasive appendiceal/colorectal adenocarcinoma. The POCs were grouped into infectious, cardiopulmonary, thromboembolic, and intestinal dysmotility. The primary outcomes were overall survival (OS) and recurrence-free survival (RFS). RESULTS: Of the 1304 patients, 33% had noninvasive appendiceal neoplasm (n = 426), and 67% had invasive appendiceal/colorectal adenocarcinoma (n = 878). In the noninvasive appendiceal cohort, POCs were identified in 55% of the patients (n = 233). The 3-year OS and RFS did not differ between the patients who experienced a complication and those who did not (OS, 94% vs 94%, p = 0.26; RFS, 68% vs 60%, p = 0.15). In the invasive appendiceal/colorectal adenocarcinoma cohort, however, POCs (63%; n = 555) were associated with decreased 3-year OS (59% vs 74%; p < 0.001) and RFS (32% vs 42%; p < 0.001). Infectious POCs were the most common (35%; n = 196). In Multivariable analysis accounting for gender, peritoneal cancer index (PCI), and incomplete resection (CCR1), infectious POCs in particular were associated with decreased OS compared with no complication (hazard ratio [HR] 2.08; p < 0.01) or other types of complications (HR, 1.6; p < 0.01). Similarly, infectious POCs were independently associated with worse RFS (HR 1.61; p < 0.01). CONCLUSION: Postoperative complications are associated with decreased OS and RFS after CRS/HIPEC for invasive histology, but not for an indolent disease such as noninvasive appendiceal neoplasm, and this association is largely driven by infectious complications. The exact mechanism is unknown, but may be immunologic. Efforts must target best practices and standardized prevention strategies to minimize infectious postoperative complications.

Impact of Neoadjuvant Chemotherapy on the Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: A Multi-Institutional Retrospective Review.

Cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with improved survival for patients with colorectal peritoneal metastases (CR-PM). However, the role of neoadjuvant chemotherapy (NAC) prior to CRS-HIPEC is poorly understood. A retrospective review of adult patients with CR-PM who underwent CRS+/-HIPEC from 2000-2017 was performed. Among 298 patients who underwent CRS+/-HIPEC, 196 (65.8%) received NAC while 102 (34.2%) underwent surgery first (SF). Patients who received NAC had lower peritoneal cancer index score (12.1 + 7.9 vs. 14.3 + 8.5, p = 0.034). There was no significant difference in grade III/IV complications (22.4% vs. 16.7%, p = 0.650), readmission (32.3% vs. 23.5%, p = 0.114), or 30-day mortality (1.5% vs. 2.9%, p = 0.411) between groups. NAC patients experienced longer overall survival (OS) (median 32.7 vs. 22.0 months, p = 0.044) but similar recurrence-free survival (RFS) (median 13.8 vs. 13.0 months, p = 0.456). After controlling for confounding factors, NAC was not independently associated with improved OS (OR 0.80) or RFS (OR 1.04). Among patients who underwent CRS+/-HIPEC for CR-PM, the use of NAC was associated with improved OS that did not persist on multivariable analysis. However, NAC prior to CRS+/-HIPEC was a safe and feasible strategy for CR-PM, which may aid in the appropriate selection of patients for aggressive cytoreductive surgery.

What is the Optimal Preoperative Imaging Modality for Assessing Peritoneal Cancer Index? An Analysis From the United States HIPEC Collaborative.

BACKGROUND: Radiographic prediction of peritoneal carcinomatosis index (PCI) can improve patient selection for cytoreductive surgery. We aimed to determine the correlation of computed tomography (CT)-predicted PCI (CT-PCI) and magnetic resonance imaging (MRI)-predicted PCI (MRI-PCI) with intraoperative-PCI, and if a preoperative-PCI cutoff is associated with incomplete cytoreduction. PATIENTS AND METHODS: Patients from the US HIPEC Collaborative (2000-2017) with appendiceal, colorectal, or peritoneal mesothelioma (PM) histology who underwent cytoreductive surgery were included. Pearson correlation coefficients were used to determine correlation between preoperative and intraoperative-PCI values. Fisher r-to-z transformation was used to compare correlations. RESULTS: A total of 488 patients were included. Of these, 34% had noninvasive appendiceal, 30% invasive appendiceal, 28% colorectal, and 8% PM histology. CT-PCI was correlated with intraoperative-PCI for patients with noninvasive and invasive appendiceal and colorectal histologies (r = 0.689, 0.554, and 0.571; all P < .001), but not PM (r = 0.188; P = .295). MRI-PCI was correlated with intraoperative-PCI for all histologies (non-invasive appendiceal: r = 0.591; P = .002; invasive appendiceal: r = 0.848; P < .001; colorectal: r = 0.729; P < .001; PM: r = 0.890; P = .007). Comparing CT and MRI, correlations were similar in noninvasive appendiceal and colorectal histologies; MRI was better for invasive appendiceal and PM (P = .005 and P = .021, respectively). Twenty-eight (6%) patients underwent an incomplete cytoreduction (cytoreduction score, 2-3). PCI greater than 15 was associated with cytoreduction score of 2 to 3 for both CT and MRI (CT-PCI: odds ratio, 3.0; P = .033; MRI-PCI: odds ratio, 7.6; P = .071). CONCLUSIONS: In this multi-institutional cohort, CT and MRI-PCI correlate well with intraoperative-PCI. MRI appears to be superior for invasive appendiceal and peritoneal mesothelioma. External validation in a larger population is needed.

Is Obesity Protective in Thoracoabdominal Penetrating Trauma?

The incidence of obesity has been increasing in the United States, and the medical care of obese patients after injury is complex. Obesity has been linked to increased morbidity after blunt trauma. Whether increased girth protects abdominal organs from penetrating injury or complicates management from obesity-associated medical comorbidities after penetrating injury has not been well defined. All patients admitted with penetrating injury between January 1, 2010, and December 31, 2013, at a university-affiliated Level I center trauma center were reviewed. Primary endpoints for analysis were the presence of significant injuries requiring operative intervention and outcomes, including inpatient complications. Logistic regression, chi-squared tests, and the Kruskal-Wallis test were used to compare groups. Five hundred patients were included in the study; 225 with stabs and 275 with gunshot wounds (GSWs). In each group, there was no major difference between obese and nonobese patients in regard to injury location, operative approach, or postoperative outcomes. Unadjusted odds ratios comparing both overweight and obese individuals to normal BMI patients did not suggest a decreased rate of therapeutic operations for either population after stabs or GSWs. In obese or overweight patients, there is no difference in the rate of operative intervention for significant injuries after penetrating axial trauma compared with a normal BMI population. On the other hand, obesity was not associated with prolonged length of stay, increased complications, or death after penetrating injuries.

Influence of carcinoid syndrome on the clinical characteristics and outcomes of patients with gastroenteropancreatic neuroendocrine tumors undergoing operative resection.

BACKGROUND: The incidence, clinical characteristics, and long-term outcomes of patients with gastroenteropancreatic neuroendrocrine tumors and carcinoid syndrome undergoing operative resection have not been well characterized. METHODS: Patients undergoing resection of primary or metastatic gastroenteropancreatic neuroendrocrine tumors between 2000 and 2016 were identified from an 8-institution collaborative database. Clinicopathologic and postoperative characteristics as well as overall survival and disease-free survival were compared among patients with and without carcinoid syndrome. RESULTS: Among 2,182 patients who underwent resection, 139 (6.4%) had preoperative carcinoid syndrome. Patients with carcinoid syndrome were more likely to have midgut primary tumors (44.6% vs 21.4%, P < .001), lymph node metastasis (63.4% vs 44.3%, P < .001), and metastatic disease (62.8% vs 26.7%, P < .001). There was no difference in tumor differentiation, grade, or Ki67 status. Perioperative carcinoid crisis was rare (1.6% vs 0%, P < .01), and the presence of preoperative carcinoid syndrome was not associated with postoperative morbidity (38.8% vs 45.5%, P = .129). Substantial symptom improvement was reported in 59.5% of patients who underwent curative-intent resection, but occurred in only 22.7% who underwent debulking. Despite an association on univariate analysis (P = .04), carcinoid syndrome was not independently associated with disease-free survival after controlling for confounding factors (hazard ratio 0.97, 95% confidence interval 0.64-1.45). Preoperative carcinoid syndrome was not associated with overall survival on univariate or multivariate analysis. CONCLUSION: Among patients undergoing operative resection of gastroenteropancreatic neuroendrocrine tumors, the prevalence of preoperative carcinoid syndrome was low. Although operative intervention with resection or especially debulking in patients with carcinoid syndrome was disappointing and often failed to improve symptoms, after controlling for markers of tumor burden, carcinoid syndrome was not independently associated with worse disease-free survival or overall survival.

The impact of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio among patients with intrahepatic cholangiocarcinoma.

BACKGROUND: Neutrophil-to-lymphocyte ratio and platelets-to-lymphocyte ratio may be host factors associated with prognosis. We sought to determine whether neutrophil-to-lymphocyte and platelets-to-lymphocyte ratio were associated with overall survival among patients undergoing surgery for intrahepatic cholangiocarcinoma. METHODS: Patients who underwent resection for intrahepatic cholangiocarcinoma between 1990 and 2015 were identified from 12 major centers. Clinicopathologic factors and overall survival were compared among patients stratified by neutrophil-to-lymphocyte ratio and platelets-to-lymphocyte ratio. Risk factors identified on multivariable analysis were included in a prognostic model and the discrimination was assessed using Harrell's concordance index (C index). RESULTS: A total of 991 patients were identified. Median neutrophil-to-lymphocyte ratio and platelets-to-lymphocyte ratio were 2.7 (interquartile range [IQR]: 2.0-4.0) and 109.6 (IQR: 72.4-158.8), respectively. Preoperative neutrophil-to-lymphocyte ratio was elevated (≥5) in 100 patients (10.0%) and preoperative platelets-to-lymphocyte ratio (≥190) in 94 patients (15.2%). Patients with low and high neutrophil-to-lymphocyte ratio and platelets-to-lymphocyte ratio generally had similar baseline characteristics with regard to tumor characteristics. Overall survival was 37.7 months (95% confidence interval [CI]: 32.7-42.6); 1-, 3-, and 5-year overall survival was 78.8%, 51.6%, and 39.3%, respectively. Patients with an neutrophil-to-lymphocyte ratio <5 had a median survival of 47.1 months (95% CI: 37.9-53.3) compared with a median survival of 21.9 months (95% CI: 4.8-39.1) among patients with an neutrophil-to-lymphocyte ratio ≥5 (P = .001). In contrast, patients who had a platelets-to-lymphocyte ratio <190 vs platelets-to-lymphocyte ratio ≥190 had comparable long-term survival (P > .05). On multivariable analysis, an elevated neutrophil-to-lymphocyte ratio was independently associated with decreased overall survival (hazard ratio: 1.04, 95% CI: 1.01-1.07; P = .002). Patients could be stratified into low- versus high-risk groups based on standard tumor-specific factors such as lymph node status, tumor size, number, and vascular invasion (C index 0.62). When neutrophil-to-lymphocyte ratio was added to the prognostic model, the discriminatory ability of the model improved (C index 0.71). CONCLUSION: Elevated neutrophil-to-lymphocyte ratio was independently associated with worse overall survival and improved the prognostic estimation of long-term survival among patients with intrahepatic cholangiocarcinoma undergoing resection.

The Cost of Failure: Assessing the Cost-Effectiveness of Rescuing Patients from Major Complications After Liver Resection Using the National Inpatient Sample.

OBJECTIVE: To estimate the cost of rescue and cost of failure and determine cost-effectiveness of rescue from major complications at high-volume (HV) and low-volume (LV) centers METHODS: Ninety-six thousand one hundred seven patients undergoing liver resection were identified from the Nationwide Inpatient Sample (NIS) between 2002 and 2011. The incremental cost of rescue and cost of FTR were calculated. Using propensity-matched cohorts, a cost-effectiveness analysis was performed to determine the incremental cost-effectiveness ratio (ICER) between HV and LV hospitals. RESULTS: Ninety-six thousand one hundred seven patients were identified in NIS. The overall mortality was 2.3% and was lowest in HV centers (HV 1.4% vs. MV 2.1% vs. LV 2.6%; p < 0.001). Major complications occurred in 14.9% of hepatectomies and were comparable regardless of volume (HV 14.2% vs. MV 14.3% vs. LV 15.4%; p < 0.001). The FTR rate was substantially lower among HV centers (HV 7.7%, MV 11%, LV 12%; p < 0.001). At a willingness to pay benchmark of $50,000 per year of life saved, both HV (ICER = $3296) and MV (ICER = $4182) centers were cost-effective at rescuing patients from a major complication compared to LV hospitals. CONCLUSION: Not only was FTR less common at HV hospitals, but the management of most major complications was cost-effective at higher volume centers.

Surgical approaches for the treatment of perihilar cholangiocarcinoma.

INTRODUCTION: Since their initial description, perihilar cholangiocarcinoma (pCCA) has remained one of the more clinically challenging scenarios encountered by hepatobiliary surgeons. Surgery remains the only potentially curative therapy, but requires complex, technically demanding operations with high associated morbidity and mortality. Over the last several decades, advances in surgical technique and perioperative management have improved patient outcomes. Areas covered: Achievement of optimal outcomes requires a multidisciplinary approach from a team of providers with expertise in hepatobiliary and oncologic surgery, medical oncology, radiation oncology, and advanced gastroenterology. We herein report a comprehensive review on pCCA with an emphasis on surgical strategies and perioperative management. Expert commentary: Despite incremental improvements from advances in surgical technique and perioperative management, outcomes remain poor due to the aggressive systemic nature of this disease and the tendency for locoregional and distant recurrence. The marginal benefit observed with traditional systemic therapies continues to be a key weakness in current management. However, improved understanding of the genetic alterations and pathways that drive tumorigenesis has the potential to dramatically alter the way in which we care for these patients.

Perioperative complications and the cost of rescue or failure to rescue in hepato-pancreato-biliary surgery.

BACKGROUND: It is unclear how either the successful or failed rescue of hepato-pancreato-biliary (HPB) patients from complications impacts costs. METHODS: A retrospective cohort study of HPB surgical patients was performed using claims data from 2013 to 2015 in the Medicare Provider Analysis and Review (MEDPAR) database. Patient demographics, characteristics, outcomes and risk-adjusted Medicare payments were compared. RESULTS: 11,596 patients were identified. Over half of the patients (n = 5,810, 50.1%) underwent liver surgery, while 42% (n = 4892) had pancreatic and 8% (n = 894) had biliary operations. The overall complication rate varied (liver: 19.6%; pancreas: 20.3%; biliary: 25.2%, p = 0.001). In general, both minor and serious complications resulted in higher Medicare payments. Failed rescue led to higher average Medicare payments during index hospitalization compared to successful rescue ($53,476 versus $44,636, p < 0.001). The reverse was true on readmission; successful rescue was associated with higher average Medicare payments ($25,746 versus $15,654, p < 0.001). Taken together (index plus readmission), total hospitalization payments were higher for failed compared to successful rescue ($66,604 versus $52,143, p < 0.001). CONCLUSION: Following HPB surgery, there is a significant cost associated with both rescue and failure-to-rescue from perioperative complications. Total hospitalization cost was highest for patients who experienced failure-to-rescue.

Unique Genes in Tumor-Positive Sentinel Lymph Nodes Associated with Nonsentinel Lymph Node Metastases in Melanoma.

BACKGROUND: Current risk assessment tools to estimate the risk of nonsentinel lymph node metastases after completion lymphadenectomy for a positive sentinel lymph node (SLN) biopsy in cutaneous melanoma are based on clinical and pathologic factors. We identified a novel genetic signature that can predict non-SLN metastases in patients with cutaneous melanoma staged with a SLN biopsy. METHODS: RNA was collected for tumor-positive SLNs in patients staged by SLN biopsy for cutaneous melanoma. All patients with a tumor-positive SLN biopsy underwent completion lymphadenectomy. A 1:10 case:control series of positive and negative non-SLN patients was analyzed by microarray and quantitative RT-PCR. Candidate differentially expressed genes were validated in a 1:3 case:control separate cohort of positive and negative non-SLN patients. RESULTS: The 1:10 case:control discovery set consisted of 7 positive non-SLN cases matched to 70 negative non-SLN controls. The cases and controls were similar with regards to important clinicopathologic factors, such as gender, primary tumor site, age, ulceration, and thickness. Microarray and RT-PCR identified six potential differentially expressed genes for validation. In the 40-patient separate validation set, 10 positive non-SLN patients were matched to 30 negative non-SLN controls based on gender, ulceration, age, and thickness. Five of the six genes were differentially expressed. The five gene panel identified patients at low (7.1%) and high risk (66.7%) for non-SLN metastases. CONCLUSIONS: A novel, non-SLN gene score based on differential expressed genes in a tumor-positive SLN can identify patients at high and low risk for non-SLN metastases.

Longer Time Intervals from Diagnosis to Surgical Treatment in Breast Cancer: Associated Factors and Survival Impact.

Time interval (TI) from breast cancer diagnosis to definitive surgery is increasing, but the impact on outcomes is not well understood. TI longer than 30 days is associated with a greater chance of delay of chemotherapy, which may impact survival. We sought to identify factors associated with longer TI and the influence on outcome measures. METHODS: We examined TI for stage 0-III breast cancer patients treated between 2006 and 2015 at a university-based cancer center. Univariate and multivariate analyses were used to study factors associated with TI <30, 30 to 60, and >60 days. Kaplan-Meier plots were used to examine the effect of different TI on overall survival, disease-specific survival, and recurrence-free survival. RESULTS: 1589 patients were included with a median follow-up of 47 months. Median TI was 32 days. Median TI increased in patients from 2011 to 2015 compared with those from 2006 to 2010 (35 vs 30 days, P < 0.001). On multivariate analysis, mastectomy (with or without reconstruction), MRI use, and increasing age were independent predictors of TI >30 days . There were no significant differences in overall survival, disease-specific survival, or recurrence-free survival. There was no association between TI >30 days and a subsequent delay >60 days to adjuvant chemotherapy (OR 1.04, 95% CI 0.72-1.52). CONCLUSIONS: TI has increased in the last five years. Patient characteristics, tumor biology, and stage do not influence TI, whereas age, mastectomy, and MRI use were all associated with longer TI. Longer TI does not appear to significantly delay adjuvant chemotherapy or influence short-term outcomes.

Lymphadenectomy for Intrahepatic Cholangiocarcinoma: Has Nodal Evaluation Been Increasingly Adopted by Surgeons over Time?A National Database Analysis.

BACKGROUND: Surgical management of intrahepatic cholangiocarcinoma routinely includes resection of the hepatic parenchyma, yet the role of lymphadenectomy (LND) is more controversial. The objective of the current study was to define overall utilization, as well as temporal trends, in the utilization of LND among patients undergoing curative-intent hepatectomy for ICC using a nationwide database. MATERIALS AND METHODS: One thousand four hundred ninety-six patients who underwent curative-intent resection for ICC were identified using the SEER database from 2000 to 2013. The utilization of LND was assessed over time and by geographic region. LND utilization and the incidence of lymph node metastasis (LNM) were evaluated relative to AJCC T categories. RESULTS: At the time of surgery, slightly over one-half of patients (n = 784, 52.4%) had at least one LN evaluated. Specifically, 613 (41.0%) patients had 1-5 LNs evaluated, whereas 171 (11.4%) patients had ≥ 6 LNs evaluated. The proportion of patients who had at least one LN evaluated at the time of surgery did not change with time (2000-2004: 50.5% vs. 2005-2009: 52.0% vs. 2010-2013: 53.7%) (p = 0.636). In contrast, the proportion of patients who had ≥ 6 LNs examined did increase (2000-2004: 6.9% vs. 2005-2009: 10.6% vs. 2009-2013: 14.3%) (p = 0.003). The risk of LNM was higher among patients with advanced T category tumors (Referent T1; T2a: OR 4.2, 95% CI 2.0-8.8, p < 0.001; T2b: OR 2.4, 95% CI 1.1-4.9, p = 0.018; T3: OR 3.6, 95% CI 1.6-7.9, p = 0.001; T4: OR 2.2, 95% CI 1.0-4.9, p = 0.049). In addition, the portion of patients with LNM varied among the different T categories (T1, 23.2%, T2a, 55.3%, T2b, 42.0%, T3, 51.4%, and T4, 39.5%; p = 0.001). CONCLUSIONS: Utilization of LND in the surgical management of ICC across the USA remained relatively low and did not change over the last decade. Selective utilization of LND may be problematic as T-stage was not a reliable predictor of nodal status with almost a quarter of patients with early stage disease having LNM.

Danger on the Farm: A Comparison of Agricultural and Animal-Related Injuries.

Animal-related injuries are common in rural areas. Agricultural workers can suffer severe injuries involving farm machinery or falls. The spectrum of injuries related to rural activities is poorly defined and characterizing these injuries will improve injury prevention efforts. Records for injured patients admitted between 2010 and 2013 were retrospectively reviewed. Patients with a mechanism of injury involving a large animal or with the injury site listed as "farm" were included. Patients with agricultural injuries (n = 85) were older with more multisystem injuries than patients injured by animals (n = 132) but the Injury Severity Score was equivalent. There was no difference in intensive care unit length of stay, ventilator days, or mortality. There was no difference in frequency of solid organ injury, pelvic fractures, rib fractures, or hemo- or pneumothorax between groups. Animal injuries had more frequent traumatic brain injuries (22.4% vs 10.5%, P = 0.03), whereas agricultural injuries had more vertebral fractures (20.5% vs 9.2%). Of toxicology screens performed, 25 per cent (22/88) were positive. No significant differences were found between occupational versus recreational animal injuries. Agricultural and animal-related injuries have different characteristics but Injury Severity Score and mortality were similar. Severe injuries from both mechanisms are common in rural communities and injury prevention activities are needed in both settings.

Molecular Staging of Sentinel Lymph Nodes Identifies Melanoma Patients at Increased Risk of Nodal Recurrence.

BACKGROUND: Molecular staging of sentinel lymph nodes (SLNs) may identify patients who are node-negative by standard microscopic staging but are at increased risk for regional nodal recurrence; such patients may benefit from completion lymph node dissection (CLND). STUDY DESIGN: In a multicenter, randomized clinical trial, patients with tumor-negative SLNs by standard pathology (hematoxylin and eosin [H and E] serial sections and immunohistochemistry [IHC]) underwent reverse transcriptase polymerase chain reaction (PCR) analysis of SLNs for melanoma-specific mRNA. Microscopically negative/PCR+ patients were randomized to observation, CLND, or CLND with high-dose interferon (HDI). For this post-hoc analysis, clinicopathologic features and survival outcomes, including overall survival (OS) and disease-free survival (DFS), were compared between PCR+ patients who underwent CLND vs observation. Microscopic and molecular node-negative (PCR-) patients were included for comparison. RESULTS: A total of 556 patients were PCR+: 180 underwent observation, and 376 underwent CLND. An additional 908 PCR- patients were observed. Median follow-up was 72 months. Disease-free survival (DFS) was significantly better for PCR+ patients who underwent CLND compared with observation (p = 0.0218). No statistically significant differences in OS or distant disease-free survival (DDFS) were seen. Regional lymph node recurrence-free survival (LNRFS) was improved in PCR+ patients with CLND compared to observation (p = 0.0065). The PCR+ patients in the observation group had the worst DFS; those with CLND had similar DFS to that in the PCR- group (p = 0.9044). CONCLUSIONS: Patients with microscopically negative/PCR+ SLN have an increased risk of nodal recurrence that was mitigated by CLND. Although CLND did not affect OS, these data suggest that molecular detection of melanoma-specific mRNA in the SLN predicts a greater risk of nodal recurrence and deserves further study.

Melanoma Patient-Reported Quality of Life Outcomes Following Sentinel Lymph Node Biopsy, Completion Lymphadenectomy, and Adjuvant Interferon: Results from the Sunbelt Melanoma Trial.

BACKGROUND: Quality of life (QOL) and physical condition (PC) outcomes after sentinel lymph node biopsy (SLNB), completion lymph node dissection (CLND), and adjuvant therapy with interferon alfa-2b (IFN) were evaluated in this study. METHODS: Self-reported QOL and PC scores were evaluated in patients enrolled in a prospective, multicenter, randomized, clinical trial evaluating adjuvant IFN. After SLN biopsy, patients with a positive SLN underwent CLND then were randomized to adjuvant IFN or observation. QOL and PC scores were compared between patients who underwent SLNB alone, CLND without IFN, and CLND with IFN. Time to return to baseline QOL and PC scores reported at the time of SLNB was recorded and compared. RESULTS: There were statistically significant differences in time to return to baseline QOL (p = 0.0018) and PC (p = 0.0018) scores across the three treatment groups. The time to return to baseline QOL and PC scores was similar for SLND and CLND alone. Differences in time to return to baseline QOL and PC were sustained when stratified by recurrence status but did not differ significantly for different lymph node regions. There was a delay in return to baseline QOL and PC condition scores that was sustained beyond the cessation of IFN therapy. CONCLUSIONS: CLND is well-tolerated with a similar effect on self-reported QOL outcomes in both the short- and long-term compared with SLNB alone. IFN therapy is associated with worse QOL outcomes compared with SLNB and CLND, an effect that may be sustained following cessation of adjuvant IFN.

Tumor specific liposomes improve detection of pancreatic adenocarcinoma in vivo using optoacoustic tomography.

BACKGROUND: Pancreatic cancer often goes undiagnosed until late stage disease due in part to suboptimal early detection. Our goal was to develop a Syndecan-1 tagged liposome containing fluorescent dye as an improved contrast agent for detection of pancreatic adenocarcinoma in vivo using multispectral optoacoustic tomography. RESULTS: The diagnostic capabilities and specificity to pancreatic adenocarcinoma of Syndecan-1 targeted liposomes were evaluated both in vitro and in vivo. Immunocytochemistry showed that liposomes preferentially bound to and released their contents into cells expressing high levels of insulin-like growth factor 1 receptor. We determined that the contents of the liposome were released into the cell as noted by the change in propidium iodide fluorescence from green to red based upon nucleic acid binding. In an orthotopic mouse model, the liposomes preferentially targeted the pancreatic tumor with little off-target binding in the liver and spleen. Peak accumulation of the liposomes in the tumor occurred at 8 h post-injection. Multispectral optoacoustic tomographic imaging was able to provide high-resolution 3D images of the tumor and liposome location. Ex vivo analysis showed that non-targeted liposomes accumulated in the liver, suggesting that specificity of the liposomes for pancreatic adenocarcinoma was due to the presence of the Syndecan-1 ligand. CONCLUSIONS: This study demonstrated that Syndecan-1 liposomes were able to release cargo into IGF1-R expressing tumor cells. The Syndecan-1 liposomes demonstrated tumor specificity in orthotopic pancreatic cancer as observed using multispectral optoacoustic tomography with reduced kidney and liver uptake. By targeting the liposome with Syndecan-1, this nanovehicle has potential as a targeted theranostic nanoparticle for both drug and contrast agent delivery to pancreatic tumors.

Resveratrol decreases nitric oxide production by hepatocytes during inflammation.

INTRODUCTION: The production of excessive amounts of nitric oxide (NO) through inducible nitric oxide synthase (iNOS) contributes to organ injury, inflammation, and mortality after shock. Resveratrol (RSV) is a natural polyphenol that decreases shock-induced hepatic injury and inflammation. We hypothesized that RSV would mediate these effects by decreasing hepatocyte iNOS production. METHODS: Rat hepatocytes were isolated, cultured with varying concentrations of RSV, and then stimulated to induce iNOS with interleukin-1 and interferon. Induction of iNOS protein was measured by Western blot, iNOS mRNA by polymerase chain reaction, and NO production was measured by culture supernatant nitrite. Activation of intracellular signaling pathways involving Akt, c-Jun N-terminal kinase (JNK), and nuclear factor κB (NF-κB) were measured by Western blot using isoform-specific antibodies. RESULTS: RSV decreased the expression of iNOS mRNA, protein, and supernatant nitrite in a dose-dependent manner. Our previous work demonstrated that Akt and JNK both inhibit hepatic iNOS production, whereas NF-κB increases iNOS expression. Analysis of signaling pathways in this study demonstrated that RSV increased JNK phosphorylation but decreased Akt phosphorylation and increased NF-κB activation. CONCLUSION: RSV decreases cytokine-induced hepatocyte iNOS expression, possibly through up-regulation of the JNK signaling pathway. RSV merits further investigation to determine its mechanism as a compound that can decrease inflammation after shock.

Targeting Acidity in Pancreatic Adenocarcinoma: Multispectral Optoacoustic Tomography Detects pH-Low Insertion Peptide Probes In Vivo.

BACKGROUND: pH-low insertion peptides (pHLIP) can serve as a targeting moiety that enables pH-sensitive probes to detect solid tumors. Using these probes in conjunction with multispectral optoacoustic tomography (MSOT) is a promising approach to improve imaging for pancreatic cancer. METHODS: A pH-sensitive pHLIP (V7) was conjugated to 750 NIR fluorescent dye and evaluated as a targeted probe for pancreatic adenocarcinoma. The pH-insensitive K7 pHLIP served as an untargeted control. Probe binding was assessed in vitro at pH 7.4, 6.8, and 6.6 using human pancreatic cell lines S2VP10 and S2013. Using MSOT, semiquantitative probe accumulation was then assessed in vivo with a murine orthotopic pancreatic adenocarcinoma model. RESULTS: In vitro, the V7-750 probe demonstrated significantly higher fluorescence at pH 6.6 compared with pH 7.4 (S2VP10, P = 0.0119; S2013, P = 0.0160), whereas no difference was observed with the K7-750 control (S2VP10, P = 0.8783; S2013, P = 0.921). In the in vivo S2VP10 model, V7-750 probe resulted in 782.5 MSOT a.u. signal compared with 5.3 MSOT a.u. in K7-750 control in tumor (P = 0.0001). Similarly, V7-750 probe signal was 578.3 MSOT a.u. in the S2013 model compared with K7-750 signal at 5.1 MSOT a.u. (P = 0.0005). There was minimal off-target accumulation of the V7-750 probe within the liver or kidney, and probe distribution was confirmed with ex vivo imaging. CONCLUSIONS: Compared with pH-insensitive controls, V7-750 pH-sensitive probe specifically targets pancreatic adenocarcinoma and has minimal off-target accumulation. The noninvasive detection of pH-targeted probes by means of MSOT represents a promising modality to improve the detection and monitoring of pancreatic cancer.