Search

While particle carriers have potential to revolutionize disease treatment, using these carriers requires knowledge of spatial and temporal biodistribution. The goal of this study was to track orally administered particle uptake and trafficking through the murine gastrointestinal (GI) tract using multispectral optoacoustic tomography (MSOT). Polylactic acid (PLA) particles encapsulating AlexaFluor 680 (AF680) dye conjugated to bovine serum albumin (BSA) were orally gavaged into mice. Particle uptake and trafficking were observed using MSOT imaging with subsequent confirmation of particle uptake via fluorescent microscopy. Mice treated with PLA-AF680-BSA particles exhibited MSOT signal within the small bowel wall at 1 and 6 h, colon wall at 6, 12, and 24 h, and mesenteric lymph node 24 and 48h. Particle localization identified using MSOT correlated with fluorescence microscopy. Despite the potential of GI tract motion artifacts, MSOT allowed for teal-time tracking of particles within the GI tract in a non-invasive and real-time manner. Future use of MSOT in conjunction with particles containing both protein-conjugated fluorophores as well as therapeutic agents could allow for non-invasive, real time tracking of particle uptake and drug delivery. Citation Format: Neal Bhutiani, Abhilash Samykutty, Kelly McMasters, Nejat Egilmez, Lacey R. McNally. Tracking of orally-administered particles within the gastrointestinal tract of murine models using multispectral optoacoustic tomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1954.

9519 Background: A 31-GEP test is a validated prognostic tool for predicting the risk of metastasis in CM, classifying patients (pts) as Class 1 (low risk) or Class 2 (high risk). Here we report updated survival analysis from two clinical registry studies (NCT02355574/NCT02355587) designed to prospectively evaluate outcomes in patients for whom the GEP test was part of their clinical care. Methods: Eleven US dermatologic and surgical centers participated using IRB-approved protocols. Participants were CM pts ≥16 years old who had successful 31-GEP test results. Recurrence-free (RFS), distant metastasis-free (DMFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox regression analysis. Results: At data censoring, 340 pts were accrued who had completed at least one follow-up visit. Median age was 58 years (range 18-87), 53.5% were male, median Breslow thickness was 1.2mm (range 0.2-12mm), 18.2% (62/340) were ulcerated, and 11.2% (38/340) had a positive sentinel lymph node (SLN). Median follow-up was 3.2 years for pts without an event. Six percent (16/265) of Class 1 pts had a recurrence compared to 33% (25/75) of Class 2 pts (p < 0.001). Three-year RFS was 96%, 91%, 80%, and 62% for Class 1A, 1B, 2A, and 2B, respectively (p < 0.001). Three-year DMFS was 97%, 93%, 84%, and 80% for Class 1A, 1B, 2A, and 2B, respectively (p < 0.001). Three-year OS was 98%, 90%, 96%, and 74% for Class 1A, 1B, 2A, and 2B, respectively (p < 0.001). Class 2 was an independent predictor of RFS and OS in multivariate analysis (respective HRs: 2.28 and 3.70, p < 0.05). Conclusions: Consistent with results from previous studies, this analysis demonstrates that the GEP test complements conventional staging and improves the ability to identify high-risk CM pts. These results support use of the test for guiding decisions related to follow-up, surveillance, and treatment in CM pts. Clinical trial information: NCT02355574/NCT02355587.

Central venous pressure (CVP) is the standard method of volume status evaluation during hepatic resection. CVP monitoring requires preoperative placement of a central venous catheter (CVC), which can be associated with increased time, cost, and adverse events. Stroke volume variation (SVV) is a preload index that can be used to predict an individual's fluid responsiveness through an existing arterial line. The purpose of this study was to determine if SVV is as safe and effective as CVP in measuring volume status during hepatic resection.Two cohorts of 40 consecutive patients (80 total) were evaluated during hepatic resection between December 2010 and August 2012. The initial evaluation group of 40 patients had continuous CVP monitoring and SVV monitoring performed simultaneously to establish appropriate SVV parameters for hepatic resection. A validation group of 40 patients was then monitored with SVV alone to confirm the accuracy of the established SVV parameters. Type of hepatic resection, transection time, blood loss, complications, and additional operative and postoperative factors were collected prospectively. SVV was calculated using the Flotrac™/Vigileo™ System.The evaluation group included 40 patients [median age 62 (29-82) years; median body mass index (BMI) 27.7 (16.5-40.6)] with 18 laparoscopic, 22 open, and 24 undergoing major (≥3 segments) hepatectomy. Median transection times were 43 (range 20-65) min, median blood loss 250 (range 20-950) cc, with no Pringle maneuver utilized. In this evaluation group, a CVP of -1 to 1 significantly correlated to a SVV of 18-21 (R (2) = 0.85, p 0.001). The validation group included 40 patients [median age 61 (35-78) years; median BMI 28.1 (17-41.2)], with 24 laparoscopic, 16 open, and 33 undergoing major hepatectomy. Using a SVV goal of 18 to 21, median transection time was 55 (25-78) min, median blood loss of 255 (range 100-1,150) cc, again without the use of a Pringle maneuver.SVV can be used safely as an alternative to CVP monitoring during hepatic resection with equivalent outcomes in terms of blood loss and parenchymal transection time. Using SVV as a predictor of fluid status could prove to be advantageous by avoiding the need for CVC insertion and therefor eliminating the risk of CVC related complications in patients undergoing hepatic resection.

Background This study sought to determine clinical and molecular factors related to recurrence and survival in patients with ICC following hepatectomy. Methods Database review identified 34 patients. Molecular markers (Ki67, p53, beta-catenin) and standard pathological evaluations were performed. Results The most common resections were right (n = 11), extended right (n = 8), and left hepatectomy (n = 7). The 30- and 90 -day mortality rates were 5.9% and 11.8%. The median tumor size was 7.8 cm. Nine patients (26.5%) had positive lymph nodes and ten patients (29.4%) received adjuvant therapy. Median follow up was 33.5 months. The median disease-free interval was 6 months. The median overall survival was 37.9 months. Univariate predictors of recurrence were tumor size (P = 0.02) and differentiation (P = 0.05). On multivariate analysis, differentiation (P = 0.03; OR = 0.38; 95% CI: 0.17–0.89) remained significant. Univariate predictors of survival were tumor size (P = 0.02), lymphovascular invasion (P = 0.02), satellite nodules (P = 0.006), beta-catenin expression (P = 0.008), and recurrence (P = 0.026). On multivariate analyses, satellite lesions (P = 0.05, OR = 3.15, 95% CI: 0.96–10.4) and beta-catenin (P = 0.04, OR = 3.23; 95% CI: 1.1–9.7) remained significant and differentiation (P = 0.045; OR = 0.42; 95% CI: 0.18–0.98) was an additional predictor. Conclusion Future clinical trials could include certain molecular and pathologic factors to assist in determining the necessity and type of adjuvant therapy. J. Surg. Oncol. 2014 109:98–103. © 2013 Wiley Periodicals, Inc.

The Barcelona Clinic Liver Cancer (BCLC) staging classification is commonly used for staging hepatocellular carcinoma (HCC). This system assumes the coexistence of cirrhosis; however, a significant proportion of patients with HCC present without cirrhosis. Recently, an alternative system was proposed that stratifies patients according to alpha-fetoprotein (AFP) level. The aim of this study was to apply the AFP staging system to noncirrhotic patients with HCC and evaluate its ability to predict overall survival (OS). A prospective hepatopancreatobiliary database was reviewed for all patients with a diagnosis of HCC. Patients were staged based on BCLC classification as well as by AFP stage according to four levels: less than 10 ng/mL, 10 to 150 ng/mL, 150 to 500 ng/mL, and greater than 500 ng/mL. Cirrhotic patients were compared with noncirrhotic patients in terms of patient demographics and HCC stage. Kaplan-Meier (KM) analysis of OS was performed for noncirrhotic patients according to BCLC and AFP staging systems. Cirrhotic and noncirrhotic patients differed significantly in terms of median age at presentation (64 vs 70 years, P < 0.001) and gender (76 vs 65% male, P = 0.006). BCLS staging classification did not distinguish between cirrhotics and noncirrhotics ( P = 0.733), whereas AFP staging demonstrated a significant difference between the two groups ( P < 0.0001). KM analysis of OS for noncirrhotic patients with HCC was significant for both the BCLC and the AFP staging systems ( P = 0.003 vs P < 0.0001, respectively). Patients presenting with HCC in the absence of cirrhosis appear to have different characteristics than patients with cirrhosis. Staging according to AFP level is an appropriate predictor of prognosis in noncirrhotic patients with HCC.

Hepatectomy is an accepted treatment modality for large (greater than 5 cm) colorectal liver metastases (CLM). Recently, laparoscopic hepatectomy has emerged as a viable option; however, its use for patients with large CLM is undefined. A retrospective analysis of a single institution's prospective database was performed for patients with large CLM resected between 1995 and 2010. Patients were stratified by operative approach. Patient characteristics, tumor burden, operative factors, hospital course, and long-term outcomes were compared using nonparametric, Fisher's exact, and Kaplan-Meier testing. Eighty-four patients were identified. Eight patients (9.5%) underwent laparoscopic resection. Age (59.5 vs 60 years), body mass index (26.8 vs 27.5 kg/m2), size of largest tumor (6.8 vs 7.5 cm), R0 resection (100 vs 89.5%), hepatic recurrence (25 vs 43.4%), and transfusion rate (14.3 vs 30.9%) of laparoscopic compared with open resection were similar. However, complication rate (12.5 vs 60.5%; P = 0.0192), blood loss (225 vs 400 mL; P = 0.0427), and length of stay (3.5 vs 7.0 days; P = 0.0005) were significantly higher in the open resection cohort. Median disease-free survival was 14.4 and 13.2 months for laparoscopic and open patients, respectively. Laparoscopic resection appears to be a safe approach for resecting large CLM. Tumor size does not preclude laparoscopic hepatectomy.

There is a growing body of evidence suggesting the equivalence and in some cases superiority of laparoscopic liver resection versus open resection. Fewer data exist regarding the financial impact of laparoscopic liver resection. Retrospective review of 98 consecutive patients at a single institution from 2007 through 2011 undergoing first time hepatic resection was performed. Laparoscopic and open cases were compared primarily on OR and hospital charges. Deviation-based cost modeling and weighted average mean cost for the two procedures were used to determine both financial and clinical efficacy on the basis of differences in length of stay, complications, and charges. There were 57 laparoscopic and 41 open cases included in the study. Right hepatectomy was the most common procedure performed in both the laparoscopic (n = 23, 40.4 %) and open (n = 22, 53.7 %) groups. Patients in the laparoscopic group were significantly more likely to have an “on course” postoperative hospitalization (73.7 vs. 26.8 %; p

To compare clinicopathologic and prognostic factors associated with scalp melanomas and nonscalp melanomas of the head and neck (HN).Post hoc analysis of the database from a multi-institutional, prospective, randomized study.Clinicopathologic factors were assessed and correlated with survival and recurrence. Univariate and multivariate analysis of prognostic factors affecting disease-free survival and overall survival were performed.Of 405 patients with HN melanomas ≥1.0 mm Breslow thickness, 109 patients had melanoma of the scalp. All were Caucasian (100%), with most being male (79.5%) with a mean age of 49.8 years. The mean Breslow thickness was 2.4 mm; 25% had signs of ulceration. Sentinel lymph node (SLN) positivity was seen in 20.9% of scalp melanoma patients, and was more likely in younger patients (44.7 vs. 50.8 years, P = .04) and in those with a Breslow thickness of 2 to 4 mm (P = .005). The incidence of locoregional and distant recurrence were similar. Overall survival for scalp melanoma patients was significantly impacted by SLN positivity (P = .03), whereas Breslow thickness and ulceration status predicted poorer survival in nonscalp melanoma patients (P = .005, P.0001, respectively).In the Sunbelt Melanoma Trial, SLN status was the strongest predictor of overall survival in scalp melanoma. Tumor thickness and ulceration correlated with poorer overall survival in nonscalp HN melanoma. The prognostic significance of SLN status in the HN may vary with the melanoma site.

Background Resection margin status has been shown to impact outcomes for pancreatic adenocarcinoma (PAC), yet it remains unknown whether margin status is a reflection of tumor biology or surgical technique. Methods Two hundred eighty-three consecutive patients with pancreatic adenocarcinoma were identified in a prospectively maintained database. Only patients with R0 (n = 207) or R1 (n = 76) tumors were included. Each operative surgeon's first 50 cases were excluded to control for technical inexperience. Univariable and multivariable analyses of clinicopathologic and intra-operative factors were performed. Results The median follow-up for the cohort was 30.3 months with a median overall survival (OS) of 19.0 months. The R1 group had a higher rate of lymph node ratio >0.2 (41% vs. 25%; P = 0.013), and more microvascular invasion (64% vs. 44%; P = 0.007). R0 resections had both improved overall survival (22.7 months vs. 15.0 months, P = 0.004) and disease free survival (13.5 months vs. 10.7 months, P = 0.026). Factors independently associated with overall survival were microvascular invasion (HR 2.26; P = 0.001), pre-existing pulmonary disease (HR 2.18, P = 0.043), and cardiac disease (HR 1.78, P = 0.033). Conclusion Factors associated with an R1 resection reflect a biologically more aggressive tumor, with a higher likelihood of microvascular invasion and increased positive lymph node ratio. J. Surg. Oncol. 2013;107:602–607. © 2013 Wiley Periodicals, Inc.

Background Combined pancreatic and liver resection for hepato-pancreatico-biliary disease is generally considered contraindicated since it is thought to provide little if any survival benefit with high risk of morbidity. Our goal was to review our experience with combined pancreatic and liver resections to better define characteristics that increase risk for perioperative complications after combined resections. Methods A review of prospectively collected IRB approved hepato-pancreatico-biliary database was performed from October 2002 to April 2012. Results Twenty-one cases were identified including all histologies. Perioperative outcomes were examined and the overall mean length of stay was 12.1 days (range: 6–26 days) and no perioperative mortalities ( 25 and risk of Grade 3 complications (P = 0.149). The median survival following operation was 11 months (range: 3–148 months). Conclusion Combined pancreas and liver resection for metastatic disease should only be considered in highly selected patients. Tumor histology as well as BMI > 25 (overweight and obese patients) should be considered in the decision making process in an effort to minimize surgical morbidity while potentially improving survival. J. Surg. Oncol. 2013;107:709–712. © 2013 Wiley Periodicals, Inc.

Background The importance of the lymph node ratio (LNR) after regional lymphadenectomy for cutaneous melanoma is unknown. Materials and methods A post hoc analysis was performed for patients after the completion of lymphadenectomy for cutaneous melanoma. LNR was calculated as the number of tumor-positive nodes divided by the total number of lymph nodes. Comparison of disease-free survival (DFS) and overall survival (OS) and univariate and multivariate analyses with regard to LNR was performed. Comparison of the performance of LNR to other measurements of lymph node disease was performed. Results A LNR of 0.10 was a significant cutoff point for determining DFS and OS. On multivariate analysis, LNR >0.10 was an independent predictor of DFS and OS without other measures of lymph node disease burden. Patients with LNR >0.10 had worse DFS and OS. Absolute counts of tumor-positive lymph nodes differentiated survival differences better than LNR. LNR was not a significant predictor of survival in patients with neck or axillary dissections but was for inguinal dissections. In multivariate analysis of alternative nodal measures, LNR was an inferior prognostic factor. Conclusions A LNR >0.10 has a negative prognostic significance when it is the only measurement of lymph node disease considered but is an inferior prognostic factor to alternative measures of lymph node disease.

There has been conflicting evidence regarding negative effects of blood transfusion in oncology patients. This study was undertaken to determine any negative effects of specific blood product transfusion after resection of hepatic colorectal metastases (CRM). Retrospective review of patients undergoing hepatectomy for CRM from 1995 to 2009 at a single institution was performed. Specific attention was paid to the effect of blood transfusion within 30 days of operation on overall survival, disease-free survival (DFS), and complications. To mitigate the bias introduced by complications that require blood transfusion to treat, only nonbleeding complications were considered. Complications were analyzed with univariate and multivariate logistic regression. Survival was analyzed according to Kaplan-Meier and Cox proportional hazards. There were 239 patients included in the study. There were 64 (26.8%) receiving a transfusion of any kind with 25.5 per cent getting red cells (PRBCs), 7.11 per cent getting fresh-frozen plasma, and 3.77 per cent getting platelets. Multivariate analysis revealed only PRBC transfusion to be independently associated with nonbleeding complications (odds ratio, 1.980; 95% confidence interval, 1.094 to 3.582; P = 0.0239). There was no significant adverse effect of transfusion with any product on overall or DFS. PRBC transfusion appears to increase the risk of postoperative complications; thus, strategies to minimize blood use may be warranted.

Background This study was performed to identify clinicopathologic factors associated with survival in acral lentiginous melanoma. Methods A post hoc analysis of a prospective clinical trial and local database was performed in all patients with acral lentiginous melanomas. Multivariate analyses of factors associated with a tumor-positive sentinel lymph node (SLN) biopsy, disease-free survival (DFS), overall survival (OS), and local and in-transit recurrence-free survival (LITRFS) were performed. Kaplan–Meier survival analyses were performed. Results Eighty-five patients were identified. Age younger than 59 years and Breslow thickness (BT) of 2.0 mm or greater were independent risk factors for a positive SLN. SLN status was the only independent risk factor for DFS and LITRFS on multivariate analysis. A BT of 2.0 mm or greater was the only independent risk factor for OS. SLN status distinguished differences in DFS, OS, and LITRFS on Kaplan–Meier analysis. Conclusions SLN status is the dominant factor for recurrence and survival in acral lentiginous melanoma. BT and ulceration are less important in this histologic subtype.

Background We have previously reported favorable response and survival rates using drug-eluting beads loaded with doxorubicin (DEBDOX) for unresectable hepatic metastases. This study investigates the quality of life (QoL) impact of DEBDOX for the treatment of unresectable hepatic metastases from melanoma. Methods A multi-center, prospective, non-controlled clinical trial was reviewed. QoL was assessed at baseline and after each treatment, and doxorubicin-specific effects were assessed after each treatment. Results Twenty patients received 61 DEBDOX treatments. After each treatment, at least 83% of patients reported “little” to “none” doxorubicin-related symptoms. For the 8 FACT-Hep subscales, QoL scores were unchanged through 3 treatments for 18 of 24 total time points by ANOVA, with a small-to-moderate ES change through the last treatment in 36 of 40 time points. Conclusions Hepatic arterial therapy with DEBDOX is safe with minimal QOL changes in treating unresectable liver-dominant melanoma metastasis. Clinical trial NCT01010984.

Introduction Accessory spleens located within the pancreatic parenchyma (intrapancreatic accessory spleen, IPAS) pose a unique clinical challenge. In many cases, despite imaging and other diagnostic studies, malignancy cannot be excluded and patients are subjected to pancreatic resection. We review our experience with the presentation, diagnosis, and treatment of patients with IPAS to provide insight into improving pre-operative evaluation of these patients Methods A retrospective chart review identified seven patients who underwent surgical resection of an intrapancreatic spleen at University of Louisville Hospital between 2004 and 2015. Charts were analyzed for presenting symptoms, pre-operative imaging, operative therapy, and final pathologic evaluation. Patients were included in the study if they underwent pancreatic resection for a pancreatic mass and were diagnosed with an IPAS on final pathologic evaluation. Results Patient age ranged from 38 to 72 with a median age of 62.5, including five males and two females. Lesions ranged from 1.4 to 7.4 cm in maximal diameter (mean 3.8 cm). All lesions were identified as round, hypervascular, well-circumscribed masses in the pancreatic tail. The most common pre-operative diagnosis was a non-functioning pancreatic neuroendocrine tumor (NF-PNET). The most common operative approach was laparoscopic distal pancreatectomy and splenectomy. Conclusion IPAS are benign tumors commonly mistaken for pancreatic neoplasms such as NF-PNET. A combination of CT, MRI and nuclear medicine examinations can confirm the diagnosis of IPAS and prevent unnecessary surgical resection.

The multimodality approach has significantly improved outcomes for hepatic malignancies. Microwave ablation is often used in isolation or succession, and seldom in combination with resection. Potential benefits and pitfalls from combined resection and ablation therapy in patients with complex and extensive bilobar hepatic disease have not been well defined.A review of the University of Louisville prospective Hepato-Pancreatico-Biliary Patients database was performed with multi-focal bilobar disease that underwent microwave ablation with resection or microwave only included.One hundred and eight were treated with microwave only (MWA, n = 108) or combined resection and ablation (CRA, n = 84) and were compared with similar disease-burden patients undergoing resection only (n = 84). The groups were comparable except that the MWA group was older (p = .02) and with higher co-morbidities (diabetes, hepatitis). The resection group had larger tumours (4 vs. 3.2 and 3 cm) but the CRA group had more numerous lesions (4 vs. 3 and 2, p = .002). Short-term outcomes including morbidity (47.6% vs. 43%, p = .0715) were similar between the CRA and resection only groups. Longer operative time (164 vs. 126 min, p = .003) and need for blood transfusion (p = .001) were independent predictors of complications. Survival analyses for colorectal metastasis patients (n = 158) demonstrated better overall survival (OS) (43.9 vs. 37.6 and 30.5 months, p = .035), disease-free survival (DFS) (38 vs. 26.6 and 16.9 months, p = .028) and local recurrence-free survival (LRFS) (55.4 vs. 17 and 22.9 months, p .001) with resection only.The use of microwave ablation in addition to surgical resection did not significantly increase the morbidities or short-term outcomes. In combination with systemic and other local forms of therapy, combined resection and ablation is a safe and effective procedure.

Oncolytic adenoviruses (Ads) have been shown to be safe and have great potential for the treatment of solid tumors. However, the therapeutic efficacy of Ads is antagonized by limited spread within solid tumors. To develop Ads with enhanced spread, viral particles of an E1-wildtype Ad5 dl309 was repeatedly treated with UV type C irradiation and selected for the efficient replication and release from cancer cells. After 72 cycles of treatment and cancer selection, AdUV was isolated. This vector has displayed many favorable characteristics for oncolytic therapy. AdUV was shown to lyse cancer cells more effectively than both E1-deleted and E1-wildtype Ads. This enhanced cancer cell lysis appeared to be related to increased AdUV replication in and release from infected cancer cells. AdUV-treated A549 cells displayed greater expression of the autophagy marker LC3-II during oncolysis and formed larger viral plaques upon cancer cell monolayers, indicating increased virus spread among cancer cells. This study indicates the potential of this approach of irradiation of entire viral particles for the development of oncolytic viruses with designated therapeutic properties.

The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma.

Melanoma is generally resistant to chemotherapy, which may be related to defects in death receptor signaling and to defects in induction of apoptosis. Forkhead family transcription factors induce the expression of death receptor ligands such as Fas ligand (Fas-L) resulting in apoptosis. We therefore investigated whether a triple mutant form of forkhead transcription factor FKHRL1 (FKHRL1/TM) can enhance Fas-L mediated-apoptosis in melanoma cells. Two melanoma cells A2058 or DM6 were tested for their sensitivity to agonistic anti-Fas antibody (CH-11); adenovirus expressing FKHRL1/TM (Ad-FKHRL1/TM) was assessed for its capability to induce activation of the caspase pathway; the role of Fas-L in the Ad-FKHRL1/TM mediated-cell death was also assessed in vitro. Ad-FKHRL1/TM antitumor activity in vivo was also evaluated in a mouse melanoma xenograft model. We found that DM6 melanoma cells were more resistant to Fas/Fas-L-mediated apoptosis induced by agonistic anti-Fas antibody than A2058 melanoma cells. Ectopic expression of FKHRL1/TM in melanoma cells upregulated Fas-L expression, decreased procaspase-8 levels, and significantly increased Fas/FasL-mediated cell death in both cells lines; this induced cell death was partially blocked by a Fas/Fas-L antagonist. Importantly, Ad-FKHRL1/TM treatment of subcutaneous melanoma xenografts in mice resulted in approximately 70% decrease in tumor size compared with controls. These data indicate that overexpression of FKHRL1/TM can induce the Fas-L pathway in melanoma cells. Ad-FKHRL1/TM therefore might represent a promising vector for melanoma treatment.

This study was undertaken to assess the safety and efficacy of laparoscopic versus open resection of hepatic colorectal metastases (CRM).We reviewed retrospectively of all patients undergoing initial resection of CRM at a single institution between 1995 and 2010. The study cohort consisted of all patients undergoing laparoscopic resection and a cohort of patients undergoing open resection matched on a 4:1 basis by propensity scoring. Variables analyzed included patient and tumor characteristics, short-term outcomes, and OS and disease-free (DFS) survivals.The 35 patients in the laparoscopic cohort and 140 patients in the open cohort were equivalent in terms of age, Charlson Comorbidity Index, tumor characteristics, and Clinical Risk Score. Similar proportions of patients in the laparoscopic and open groups underwent synchronous colectomy (9% in both; P = .976) and major hepatectomy (54% vs 51%; P = .705). Blood loss (202 vs 385 mL; P.001), complications (23% vs 50%; P = .004), and duration of stay (4.8 vs 8.3 days; P.001) were less in the laparoscopic cohort. Five-year OS (36% vs 42%; P = .818) and DFS (15% vs 22%; P = .346) were also similar in the laparoscopic and open groups.Laparoscopic resection of hepatic CRM seems to be a beneficial alternative to open surgery in appropriately selected patients.

Purpose The American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) sought to provide an evidence-based guideline on the use of lymphatic mapping and sentinel lymph node (SLN) biopsy in staging patients with newly diagnosed melanoma. Methods A comprehensive systematic review of the literature published from January 1990 through August 2011 was completed using MEDLINE and EMBASE. Abstracts from ASCO and SSO annual meetings were included in the evidence review. An Expert Panel was convened to review the evidence and develop guideline recommendations. Results Seventy-three studies met full eligibility criteria. The evidence review demonstrated that SLN biopsy is an acceptable method for lymph node staging of most patients with newly diagnosed melanoma. Recommendations SLN biopsy is recommended for patients with intermediate-thickness melanomas (Breslow thickness, 1 to 4 mm) of any anatomic site; use of SLN biopsy in this population provides accurate staging. Although there are few studies focusing on patients with thick melanomas (T4; Breslow thickness, > 4 mm), SLN biopsy may be recommended for staging purposes and to facilitate regional disease control. There is insufficient evidence to support routine SLN biopsy for patients with thin melanomas (T1; Breslow thickness, < 1 mm), although it may be considered in selected patients with high-risk features when staging benefits outweigh risks of the procedure. Completion lymph node dissection (CLND) is recommended for all patients with a positive SLN biopsy and achieves good regional disease control. Whether CLND after a positive SLN biopsy improves survival is the subject of the ongoing Multicenter Selective Lymphadenectomy Trial II. Copyright © 2012 American Society of Clinical Oncology and Society of Surgical Oncology. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission by the American Society of Clinical Oncology and Society of Surgical Oncology.

This analysis was performed to compare differences in clinicopathologic factors, sentinel lymph node (SLN) status, and survival between upper extremity (UE) and lower extremity (LE) melanoma patients. Post hoc analysis of a prospective clinical trial was performed of all patients with extremity melanomas with complete data. Survival was evaluated with Kaplan-Meier analysis. Univariate and multivariate analyses were performed. A total of 1115 patients aged 18 to 70 years with extremity melanomas ≥ 1.0 mm Breslow thickness were analyzed; all underwent SLN biopsy with completion lymphadenectomy for a tumor-positive SLN. Compared with UE patients, LE melanoma patients were younger, predominantly female, and had a higher rate of SLN metastasis. Kaplan-Meier analysis revealed worse 5-year disease-free survival (DFS) and worse local and in-transit recurrence-free survival in LE versus UE melanoma patients, but no difference in overall survival (OS). Subgroup analysis revealed that older patients (age > 51 years) with LE melanomas had worse DFS, local and in-transit recurrence-free-survival, and OS. LE tumor location was not an independent risk factor for OS or DFS. Compared with UE melanoma patients, those with LE melanomas have a greater risk of tumor-positive SLN and local/in-transit recurrence.

The seventh edition of the American Joint Committee on Cancer esophageal cancer staging system classifies nodal status by the number of malignant nodes (LNMs) found. This may be confounded by variations in lymphadenectomy and specimen review. The ratio of lymph nodes containing metastases to the total nodes excised (LNR) has been suggested as an alternative. We seek to validate the use of LNR for staging and determine the effect of the total lymph node yield (LNY) on its accuracy. A review of our prospective esophageal database identified 94 patients who underwent esophagectomy for cancer at out institution from 1992 until 2010. Univariate and multi-variate analyses were performed. The mean age of our patients was 59.4 years. Transthoracic esophagectomy was performed in all but three instances. The majority of tumors were adenocarcinoma, 76 per cent. Overall survival at 2 and 5 years was 52 and 29 per cent, respectively. LNY correlated with LNM ( r = 0.302, P = 0.001) but not LNR ( r = 0.012, P = 0.912). Using Kaplan-Meier analysis, LNR had no effect on disease-specific (DS) survival ( P = 0.803). However, a Cox proportional hazards regression model showed LNR to be a significant predictor of DS mortality (hazard ratio, 9.47; P = 0.049). The lack of correlation between LNR and LNY suggests that LNR may be a more robust staging method when LNY is low. Furthermore, LNR was found to be a significant predictor of DS mortality when controlling for other factors influencing survival. However, neither a staging system based on LNR nor its efficacy compared with the current system could be determined from these data.

Background We found that a computer model developed by the American Joint Committee on Cancer (AJCC) melanoma staging committee had limitations for predicting prognosis of patients staged by sentinel lymph node (SLN) biopsy. We sought to develop a model that more accurately predicts prognosis in this population. Study Design Using a data set obtained from a prospective multi-institutional study of 2,507 patients with clinically node-negative melanomas ≥1.0 mm Breslow thickness, we developed a prognostic model using a Cox regression formula incorporating a number of significant clinicopathologic factors. The AJCC model and our model were used to predict 5-year survival from this test data set. The concordance correlation coefficient (CCC) was determined and chi-square tests were performed. Our new prognostic model was validated using an independent data set of 1,001 patients. Results Using the test data set, the CCC for the AJCC model was 0.875; chi-square tests demonstrated statistically significant differences between observed and predicted survivals for numerous clinicopathologic factors. The CCC for our model was 0.976 and none of the chi-square tests was statistically significant. Our model performed similarly well in SLN-negative patients (CCC 0.929) and SLN-positive patients (CCC 0.889). The AJCC model performed well in SLN-negative patients (CCC 0.854), but not in SLN-positive patients (CCC 0.626). Using the validation data set, similar findings were obtained. Conclusions Our prognostic model provides superior survival estimates compared with the AJCC model for patients undergoing SLN biopsy. This online tool is available at www.melanomacalculator.com, and will provide important information that can be used to guide adjuvant therapy decisions and stratification in clinical trials.

hpb_432 228..235 Background: The effect of diabetes on survival after resection pancreatic ductal carcinoma (PDAC) is unclear. The present study was undertaken to determine whether pre-operative diabetes has any predictive value for survival. Methods: A retrospective review from seven centres was performed. Metabolic factors, tumour char- acteristics and outcomes of patients undergoing resection for PDAC were collected. Univariate and multivariable analyses were performed to determine factors associated with disease-free (DFS) and overall survival (OS). Results: Of the 509 patients in the present study, 31.2% had diabetes. Scoring systems were devised to predict OS and DFS based on a training set (n = 245) and were subsequently tested on an independent set (n = 264). Pre-operative diabetes (P 2c m (P = 0.001), metastatic nodal ratio >0.1 (P < 0.001) and R1 margin (P < 0.001) all correlated with DFS and OS on univariate analysis. Scoring systems were devised based on multivariable analysis of the above factors. Diabetes and the metastatic nodal ratio were the most important factors in each system, earning two points for OS and four points for DFS. These scoring systems significantly correlated with both DFS (P < 0.001) and OS (P < 0.001). Conclusion: Pre-operative diabetes status provides useful information that can help to stratify patients in terms of predicted post-operative OS and DFS.

Psychological distress and coping related to a breast cancer diagnosis can profoundly affect psychological adjustment, possibly resulting in the disruption of circadian rest/activity and cortisol rhythms, which are prognostic for early mortality in metastatic colorectal and breast cancers, respectively. This study aims to explore the relationships of cancer-specific distress and avoidant coping with rest/activity and cortisol rhythm disruption in the period between diagnosis and breast cancer surgery. Fifty-seven presurgical breast cancer patients provided daily self-reports of cancer-specific distress and avoidant coping as well as actigraphic and salivary cortisol data. Distress and avoidant coping were related to rest/activity rhythm disruption (daytime sedentariness, inconsistent rhythms). Patients with disrupted rest/activity cycles had flattened diurnal cortisol rhythms. Maladaptive psychological responses to breast cancer diagnosis were associated with disruption of circadian rest/activity rhythms. Given that circadian cycles regulate tumor growth, we need greater understanding of possible psychosocial effects in cancer-related circadian disruption.

E2F-1-deleted mutant, ‘truncated E2F’ (E2Ftr, E2F-1[1–375]), lacking the carboxy-terminal transactivation domain, was shown to be more potent at inducing cancer cell apoptosis than wild-type E2F-1 (wtE2F-1; full-length E2F-1). Mechanisms by which wtE2F-1 and E2Ftr induce apoptosis, however, are not fully elucidated. Our study demonstrates molecular effects of pro-apoptotic BH3-only Bcl-2 family member Harakiri (Hrk) in wtE2F-1- and E2Ftr-induced melanoma cell apoptosis. We found that Hrk mRNA and Harakiri (HRK) protein expression was highly up-regulated in melanoma cells in response to wtE2F-1 and E2Ftr overexpression. HRK up-regulation did not require the E2F-1 transactivation domain. In addition, Hrk gene up-regulation and HRK protein expression did not require p53 in cancer cells. Hrk knockdown by Hrk siRNA was associated with significantly reduced wtE2F-1- and E2Ftr-induced apoptosis. We also found that an upstream factor, ‘downstream regulatory element antagonist modulator’ (DREAM), may be involved in HRK-mediated apoptosis in response to wtE2F-1 and E2Ftr overexpression. DREAM expression levels increased following wtE2F-1 and E2Ftr overexpression. Western blotting detected increased DREAM primarily in dimeric form. The homodimerization of DREAM resulting from wtE2F-1 and E2Ftr overexpression may contribute to the decreased binding activity of DREAM to the 3′-untranslated region of the Hrk gene as shown by electromobility shift assay. Results showed wtE2F-1- and E2Ftr-induced apoptosis is partially mediated by HRK. HRK function is regulated in response to DREAM. Our findings contribute to understanding the mechanisms that regulate wtE2F-1- and E2Ftr-induced apoptosis and provide insights into the further evaluation of how E2Ftr-induced apoptosis may be used for therapeutic gain.

ObjectivesIn laparoscopic liver resection, multiple options for parenchymal transection techniques exist; however, none have emerged as superior. The aim of this study was to compare operative characteristics and outcomes between bipolar compression and ultrasonic devices used for parenchymal transection during laparoscopic liver resection.MethodsA review of a prospective hepatopancreatobiliary database from December 2002 to August 2009 identified 54 patients who underwent laparoscopic liver resection with parenchymal division using either a bipolar compression (n= 35) or an ultrasonic (n= 19) device. Operative data, histology and 90-day complication rates were compared between the groups using analysis of variance (anova) and Pearson's chi-squared test.ResultsThe two groups did not differ significantly in terms of age, body mass index, parenchymal steatosis/inflammation or number of segments resected. A shorter time of parenchymal transection was noted for the bipolar compression device (median: 35min; range: 20–65min) vs. the ultrasonic device (median: 55min; range: 29–75min) (P < 0.001). Median total operative time was also shorter using the bipolar compression device (130min) than the ultrasonic device (180min) (P= 0.050). No significant differences between device groups were noted for estimated blood loss, complications of any type or liver-specific complications.ConclusionsBipolar compression devices may offer advantages over ultrasonic devices in terms of decreased transection time and total operative time. No differences in postoperative complications in laparoscopic liver resection emerged between patients operated using the devices.

Anal malignant melanoma (AMM) is a rare tumor with poor prognosis. We performed a systematic review of reports on wide local excision (WLE) and abdominoperineal resection (APR) for treatment of AMM in an attempt to define a precise set of reporting measures for outcomes of treatment of AMM. A systematic review of the literature was performed. Demographic data, surgical treatment, pathology, and survival rates were recorded. We compared WLE versus APR in terms of the overall survival time, the disease-free survival, and overall survival at 60 months. Twenty-one reports met the inclusion criteria. Notably, of these, 10 did not specify thickness of the primary melanoma. Interestingly, groin lymph node status was described in 19 of 21 reports, whereas location was specified in only 12 papers and thickness (depth in mm) in only 11. The median survival times of patients undergoing WLE (n = 324) and those undergoing APR (n = 369) are comparable (20 and 21 months, respectively). The mean median survival at 60 months was 15 per cent for WLE and 14 per cent for APR. The mean disease-free survival at 60 months was found to be 10 per cent for WLE and 6 per cent for APR. Patient selection for such a rare neoplasm yields very similar outcomes for both conservative and radical treatments. There is a wide variation in the reporting of both clinical and treatment outcomes. More uniformity of reporting of pathologic features and node status is essential before rational assessment of results can be done.

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.

To prospectively evaluate predictive factors of hospital readmission rates in patients undergoing abdominal surgical procedures.Recommendations from MedPAC that the Centers for Medicare and Medicaid Services (CMS) report upon and determine payments based in part on readmission rates have led to an attendant interest by payers, hospital administrators and far-sighted physicians.Analysis of 266 prospective treated patients undergoing major abdominal surgical procedures from September 2009 to September 2010. All patients were prospectively evaluated for underlying comorbidities, number of preop meds, surgical procedure, incision type, complications, presence or absence of primary and/or secondary caregiver, their education level, discharge number of medications, and discharge location. Univariate and multivariate analyses were performed.Two hundred twenty-six patients were reviewed with 48 (18%) gastric-esophageal, 39(14%) gastrointestinal, 88 (34%) liver, 58 (22%) pancreas, and 33 (12%) other. Seventy-eight (30%) were readmitted for various diagnoses the most common being dehydration (26%). Certain preoperative and intraoperative factors were not found to be significant for readmission being, comorbidities, diagnosis, number of preoperative medications, patient education level, type of operation, blood loss, and complications. Significant predictive factors for readmission were age (≥69 years), number of discharged (DC) meds (≥9 medications), ≤50% oral intake (52% vs. 23%), and DC home with a home health agency (62% vs. 11%)Readmission rates for surgeons WILL become a quality indicator of performance. Quality parameters among Home Health agencies are nonexistent, but will reflect on surgeon’s performance. Greater awareness regarding predictors of readmission rates is necessary to demonstrate improved surgical quality.

We sought to determine if there was a difference in outcomes in African-American compared with Caucasian women with hormone-responsive breast cancer, and whether this was related to race or other tumor and treatment variables.We included 1,205 patients with hormone-responsive breast cancer were identified in the Kentucky Cancer Registry (1996-2007). The effect of race on survival was evaluated using Kaplan-Meier and Cox regression methodologies.In this cohort, 76.9% were Caucasian and 21.7% were African American. Compared with Caucasians, African-American women were older (57 vs 55 years; P = .032) and more likely to have larger tumors (19 vs 17 mm; P = .009). No significant racial differences in grade, operative, or systemic treatment were noted. Univariate analysis found no significant differences in disease-specific overall survival (DSS) or disease-free survival (DFS) between Caucasians and African Americans (5-year actuarial DSS, 93.6% vs 90.7%, respectively; P = .205; 5-year actuarial DFS, 91.5% vs 90.4%, respectively; P = .829). On multivariate analysis, only tumor size remained an independent predictor of DSS (odds ratio [OR], 1.021; 95% confidence interval [CI], 1.013-1.028; P.001). Controlling for age, tumor size, and insurance status, race did not influence DSS or DFS (P = .913 and P = .857).African Americans present with larger tumors than Caucasians; treatment is similar. Tumor size, not race, affects disease-specific outcomes in patients with breast cancer.

Background and Objectives Patients with peri-hilar cholangiocarcinoma who undergo R1 resection with curative intent will have an improved survival compared to patients who were not resected. Methods Review of a prospective hepatobiliary database identified 130 patients. Survival was compared using the log-rank test. Results Seventy-nine patients (61%) were resected while 51 (49%) patients were not. Forty-two patients (54%) had an R0 resection. There was no difference in mean age (69 vs. 67; P = 0.8), BMI (27.8 vs. 27.9; P = 1.0), gender (73% vs. 43% male; P = 0.1), presence of jaundice (77% vs. 64%; P = 0.5), vascular involvement on pre operative imaging (77% vs. 64%; P = 0.5), stent (73.1% vs. 64.3%; P = 0.72), and lobar atrophy (27% vs. 7%, P = 0.2) in the resected versus non-resected patients. All patients underwent chemotherapy and/or radiation therapy. After a median follow up of 35.6 months the median OSl for all peri-hilar patients was 16.2 months (95% CI = 11.2–23.4). The median OS for resected patients was 18.9 months (95% CI = 12.5–24.7) versus 5.0 months (95% CI = 0–6.9) for patients not resected (P

The prognostic significance of lymphovascular invasion (LVI) in melanoma remains controversial. Clinicopathologic data from a prospective trial of patients with melanoma were analyzed with respect to LVI. Disease-free survival and overall survival (OS) were evaluated by Kaplan-Meier (KM) analysis. Univariate and multivariate analyses were performed to evaluate factors predictive of tumor-positive sentinel nodes (SLN) and survival. A total of 2183 patients were included in this analysis; 171 (7.8%) had LVI. Median follow-up was 68 months. Factors associated with LVI included tumor thickness, ulceration, and histologic subtype ( P < 0.05). LVI was associated with a greater risk of SLN metastasis ( P < 0.05). By KM analysis, LVI was associated with worse OS ( P = 0.0009). On multivariate analysis, age, gender, thickness, ulceration, anatomic location, and SLN status were predictors of OS; however, LVI was not an independent predictor of OS. Among patients with regression, the 5-year OS rate was 49.4 per cent for patients with LVI versus 81.1 per cent for those with no LVI ( P < 0.0001). LVI is associated with a greater risk of SLN metastasis. Although LVI is not an independent predictor of OS in general, it is a powerful predictor of worse OS among patients who have evidence of regression of the primary tumor.

Controversy exists regarding the prognostic implications of regression in patients with cutaneous melanoma. Some consider regression to be an indication for sentinel lymph node (SLN) biopsy because regression may result in underestimation of the true Breslow thickness. Other data support regression as a favorable prognostic indicator, representing immune system recognition of the primary tumor. This analysis was performed to determine whether regression predicts nodal metastasis, disease-free survival (DFS), or overall survival (OS). Post hoc analysis was performed of a multicenter prospective randomized trial that included patients aged 18 to 70 years with cutaneous melanomas 1 mm or greater Breslow thickness. All patients underwent SLN biopsy; those with tumor-positive SLN underwent completion lymphadenectomy. Kaplan-Meier analysis of survival, univariate analysis, and multivariate analysis were performed. A total of 2220 patients (261 with regression; 1959 without regression) were included in this analysis with a median follow-up of 68 months. Patients with regression were more likely to be male, older than 50 years old, and have lower median Breslow thickness, superficial spreading histologic subtype, and a non-extremity anatomic location ( P < 0.05 in all cases). Regression was not significantly associated with Clark level, ulceration, lymphovascular invasion, number of SLNs removed, or SLN metastasis. On multivariate analysis, factors independently predictive of DFS included Breslow thickness, ulceration, and SLN status ( P < 0.05 in all cases); the same factors along with age, gender, and anatomic tumor location were significantly associated with OS ( P < 0.05 in all cases). Regression was not significantly associated with DFS (risk ratio [RR], 0.94; 95% confidence interval [CI], 0.67-1.27; P = 0.68) or OS (RR, 1.01; 95% CI, 0.76-1.32; P = 0.93). These data suggest that regression is not a significant prognostic factor for patients with cutaneous melanoma and should not be used to guide clinical decision-making for such patients.

Background and Objectives The aim of this study was to determine the safety and efficacy of hepatic metastasectomy in elderly patients with colorectal liver metastases (CLM). Methods A retrospective review of a hepatobiliary database was performed on consecutive patients treated with metastasectomy for CLM. Patients were stratified by age (

Hepatocellular carcinoma (HCC) is a challenging malignancy as a result of the advanced course at presentation. Recent interventional advances have improved treatment of lesions unamenable to resection using drug-eluting microbeads delivered into the hepatic circulation. We hypothesize that the use of hepatic arterial therapy (HAT) will safely identify appropriate patients who can proceed to ablation and/or transplantation. We evaluated our open-label, multicenter, multinational, single-arm study including 240 patients with intermediate-staged HCC who received drug-eluting beads and were not initial candidates for transplantation or resection. We reviewed the resulting clinical data to determine factors leading to possible ablation or transplant. Of 240 patients undergoing HAT, 14 (5.8%) received ablation or transplant. We compared those receiving ablation or transplant with those receiving only HAT. Groups were similar regarding sex, age, median number of tumors (one; range, 1 to 25), Child's score, tobacco and alcohol abuse, and treatment type. Patients who were downstaged were more likely to have: hepatitis-related tumors (76 to 66%, P = 0.02), distinct lesions on imaging (92 to 76%, P = 0.004), and less than 25 per cent parenchymal involvement (84 to 59%, P = 0.0001). These patients typically had one tumor frequently in the left lobe (58.8 vs 30.9%, P = 0.0001), accessible through segmental arteries (47 vs 17%, P = 0.001), with increased segmental branch occlusion (57 vs 39%, P = 0.02). HAT should be considered a potential bridging therapy to eventual ablation or transplant in the multimodal treatment of HCC.

Lymphovascular invasion (LVI) is not uniformly found or reported in breast cancer tumor reports. We sought to determine the impact of the finding of LVI on various parameters of lymph node status in patients with breast cancer. A chart review was performed of 400 node-positive patients from a cohort of patients in a prospective multicenter national sentinel node registry. The finding of LVI was then correlated to number of positive sentinel nodes, the number of positive non-sentinel nodes, the lymph node ratio, and the size of the largest metastatic deposit. Of the 400 patients, data regarding LVI were missing in 98 (24.5%) cases. Although all of these patients were node-positive, LVI was noted to be present in 155 patients (38.8%) and absent in 147 (36.8%). LVI was found to correlate with more positive sentinel nodes (mean, 1.72 vs 1.35; P < 0.001), more positive nonsentinel nodes (mean, 2.16 vs 0.54; P < 0.001), and a higher lymph node ratio (0.29 vs 0.16; P < 0.001). LVI also correlated with size of largest metastatic deposit ( P = 0.002). Although LVI is known to be associated with lymph node status, it is not frequently noted on pathology reports. Given its prognostic value, LVI should be carefully evaluated and reported.

Purpose The aim of this study was to assess the independent prognostic value of primary tumor mitotic rate compared with other clinical and pathologic features of stages I and II melanoma. Methods From the American Joint Committee on Cancer (AJCC) melanoma staging database, information was extracted for 13,296 patients with stages I and II disease who had mitotic rate data available. Results Survival times declined as mitotic rate increased. Ten-year survival ranged from 93% for patients whose tumors had 0 mitosis/mm2 to 48% for those with ≥ 20/mm2 (P < .001). Mean number of mitoses/mm2 increased as the primary melanomas became thicker (1.0 for melanomas ≤ 1 mm, 3.5 for 1.01 to 2.0 mm, 7.3 for 3.01 to 4.0 mm, and 9.6 for > 8 mm). Ulceration was also associated with a higher mitotic rate; 59% of ulcerated melanomas had ≥ 5 mitoses/mm2 compared with 16% of nonulcerated melanomas (P < .001). In a multivariate analysis of 10,233 patients, the independent predictive factors for survival in order of statistical significance were as follows: tumor thickness (χ2 = 104.9; P < .001), mitotic rate (χ2 = 67.0; P < .001), patient age (χ2 = 48.2; P < .001), ulceration (χ2 = 46.4; P < .001), anatomic site (χ2 = 34.6; P < .001), and patient sex (χ2 = 33.9; P < .001). Clark level of invasion was not an independent predictor of survival (χ2 = 3.2; P = .37). Conclusion A high mitotic rate in a primary melanoma is associated with a lower survival probability. Among the independent predictors of melanoma-specific survival, mitotic rate was the strongest prognostic factor after tumor thickness.

Background Low platelet count is a marker of portal hypertension but is not routinely included in the standard preoperative evaluation of patients with hepatocellular carcinoma (HCC) because it pertains to liver function (Child/model for end-stage liver disease [MELD] score) and tumor burden (Milan criteria). We hypothesized that low platelet count would be independently associated with increased perioperative morbidity and mortality after resection. Study Design Patients treated with liver resection for HCC between January 2000 and January 2010 at 3 institutions were eligible. Preoperative platelet count, Child/MELD score, and tumor extent were recorded. Low preoperative platelet count (LPPC) was defined as 3 /μL. Postoperative liver insufficiency (PLI) was defined as peak bilirubin >7 mg/dL or development of ascites. Univariate and multivariate regression was performed for predictors of major complications, PLI, and 60-day mortality. Results A total of 231 patients underwent resection, of whom 196 (85%) were classified as Child A and 35 (15%) as Child B; median MELD score was 8. Overall, 168 (71%) had tumors that exceeded Milan criteria and 134 (58%) had major hepatectomy (≥3 Couinaud segments). Overall and major complication rates were 55% and 17%, respectively. PLI occurred in 25 patients (11%), and 21 (9%) died within 60 days of surgery. Patients with LPPC (n = 50) had a significantly increased number of major complications (28% versus 14%, p=0.031), PLI (30% versus 6%, p=0.001), and 60-day mortality (22% versus 6%, p=0.001). When adjusted for Child/MELD score and tumor burden, LPPC remained independently associated with increased number of major complications (odds ratio [OR] 2.8, 95% confidence intervals [CI] 1.1 to 6.8, p=0.026), PLI (OR 4.0, 95% CI 1.4 to 11.1, p=0.008), and 60-day mortality (OR 4.6, 95% CI 1.5 to 14.6, p=0.009). Conclusions LPPC is independently associated with increased major complications, PLI, and mortality after resection of HCC, even when accounting for standard criteria, such as Child/MELD score and tumor extent, used to select patients for resection. Patients with LPPC may be better served with transplantation or liver-directed therapy.

Background Many surgeons are reluctant to use esophageal stents during neoadjuvant therapy for esophageal cancer because of concerns about nutritional status, stent-related complications, or added difficulties during esophagogastrectomy. We hypothesized that esophageal stenting during neoadjuvant therapy allows for optimal nutritional intake without adversely affecting perioperative outcomes. Study Design This study is a prospective, dual-institution, single-arm, phase II evaluation of esophageal cancer patients undergoing neoadjuvant therapy before resection. All patients had a self-expanding polymer stent placed before neoadjuvant therapy. We monitored dysphagia symptoms, nutritional status, stent-related complications, and perioperative complications during the course of therapy and 90 days postoperatively. Results We enrolled 32 patients with dysphagia and weight loss who were eligible for neoadjuvant therapy. After stent placement, 2 patients had stent migrations requiring replacement. No erosive complications were observed. During the course of neoadjuvant therapy, we noted improvement in dysphagia, mild weight loss, and maintenance of performance status. At a median of 50 days (range 18 to 92 days) after completion of neoadjuvant therapy, 20 patients underwent margin-negative esophagogastrectomy (16 Ivor Lewis, 4 minimally invasive) without problems with stent removal or difficulty in surgical dissection. Twelve patients did not undergo resection due to development of metastases (n = 8) or rapid decline in functional status (n = 4). Major perioperative complications included pulmonary embolism (n = 2), chyle leak (n = 1), and bronchial injury (n = 1). No surgical complications were attributed to stent placement. Conclusions Use of esophageal stents during neoadjuvant therapy is safe and results in resolution of dysphagia, mild weight loss, and maintenance of performance status without an effect on intraoperative dissection, perioperative complications, or delay in resection after neoadjuvant therapy.

BackgroundThe use of hepatic arterial therapy (HAT) with either yttrium-90 or drug-eluting bead therapy for initially unresectable hepatic malignancies has risen significantly. The safety of hepatic resection after hepatic arterial therapy (HAT) is not established.ObjectiveThe present study evaluates the safety profile for hepatic resection after HAT.MethodsWe identified 840 patients undergoing hepatectomy for primary or metastatic lesions. Forty patients underwent HAT before hepatectomy (pre-HAT). A 1 : 4 case-matched analysis compared three groups: (i) pre-HAT and pre-operative chemotherapy (n = 40); (ii) pre-operative chemotherapy (n = 160); and (iii) no pre-operative therapy (n = 640). Controls were matched for age, resection type, maximal tumour size and magnitude of resection. Morbidity and mortality among groups were compared using a graded complication scale.ResultsThere were no differences in post-operative complications, grade of complication or liver-specific complications among the groups. A proportional hazards model for all patients did not demonstrate any association between increased complications and either pre-HAT or pre-operative chemotherapy when compared with patients without pre-operative therapy (P = 0.7).ConclusionsPre-HAT demonstrated similar morbidity, liver-specific morbidity and intra-operative complications when compared with patients undergoing pre-operative chemotherapy alone or without pre-operative chemotherapy. These results suggest that pre-HAT is safe and should not preclude hepatectomy in carefully selected patients.

The prognostic significance of tumor infiltrating lymphocyte (TIL) response in cutaneous melanoma is controversial. This analysis of data from a prospective, randomized trial included patients with cutaneous melanoma ≥ 1.0 mm Breslow thickness who underwent wide local excision and sentinel lymph node (SLN) biopsy. Univariate and multivariate analyses were performed to determine factors associated with TIL response, disease-free survival (DFS), and overall survival (OS). A total of 515 patients were included; TIL response was classified as “brisk” (n = 100; 19.4%) or “non-brisk” (n = 415; 80.6%). Patients in the nonbrisk TIL group were more likely to have tumor-positive SLN (17.6% vs 7%; P = 0.0087). On multivariate analysis, nonbrisk TIL response, increased tumor thickness, and ulceration were significant independent predictors of tumor-positive SLN. By Kaplan-Meier analysis, 5-year DFS rate was 91 per cent for those with a brisk TIL response compared with 86 per cent in the nonbrisk group ( P = 0.41). The 5-year OS rates were 95 per cent versus 84 per cent in the brisk versus nonbrisk TIL groups, respectively ( P = 0.0083). However, on multivariate analysis, TIL response was not a significant independent factor predicting DFS or OS. TIL response is a significant predictor of SLN metastasis but is not a major predictor of DFS or OS.

Intraoperative autotransfusion (IOAT) has been avoided in oncologic surgery because of possible tumor cell dissemination. Through a prior Phase I study, we demonstrated that malignant cells are not present in blood filtered for IOAT. We hypothesized that autotransfusion could be safely used for patients undergoing major oncologic procedures and reduce the need for allogeneic blood. A Phase II, IRB-approved, prospective evaluation was conducted of patients undergoing gastrointestinal oncologic procedures. All procedures were conducted with blood salvaged for IOAT, and the collected volume was autotransfused if it was >100 ml. Quality of life (QoL) was assessed by questionnaire at regular intervals. A total of 92 patients were enrolled with median age of 56 years. The most commonly performed procedures were hepatectomy (47%) and pancreaticoduodenectomy (26%). The median preoperative hemoglobin (Hgb) was 13.1 (range, 9–16), and the median estimated blood loss was 350 ml (range, 20–4000 ml). Of the 92 total patients, 32 (35%) received IOAT with a median volume of 255 ml (range, 117–1499 ml). Multivariate analysis identified that patients with preoperative Hgb >11 g/dl (P = .02), and blood loss of 400–900 ml (P = .03) benefited from IOAT with a reduction in postoperative blood transfusion rate. Patients with discharge Hgb >10 g/dl showed higher mean QoL scores throughout their recovery. At a median follow-up of 18 months, the rates of recurrence in the IOAT and the non-IOAT groups were equivalent (38 vs. 39%, P = .9). Intraoperative autotransfusion can be used safely and effectively for major oncologic procedures. Furthermore, degree of discharge anemia is associated with lower quality of life in patients undergoing oncologic gastrointestinal surgery.

Background Men have a higher lifetime incidence of melanoma than women. Methods Data from the 2005 Health Interview Survey were analyzed for sex differences in response to sun exposure and reported preventive measures among adults. Results There were 31,428 people surveyed representing the US population. Although women were more likely to burn after 1 hour of sun (8.7% vs 5.4%), they also reported fewer sunburns than men (mean .7 vs .9). Women were also more likely stay in the shade (11.2% vs 6.2%) and always use sunscreen. However, women used a tanning bed more than men (2.1 vs .6 times per year) and were less likely to wear protective clothing when in the sun than men. After controlling preventive behaviors, men were 1.4 times more likely to have had a sunburn during the last 12 months. Conclusions Although men more often wear protective clothing and are less likely to use a tanning bed, women are more likely to avoid sun exposure and use sunscreen. The higher incidence of melanoma in men may be explained, in part, by an increased incidence of preventive measures taken by women.