Adam C. Berger

Colon Cancer Survival Is Associated With Decreasing Ratio of Metastatic to Examined Lymph Nodes

PURPOSE Colorectal cancer is the second leading cause of cancer deaths in the United States, with poor survival predicted by regional lymph node (LN) metastasis. The impact of LN ratio (LNR) on survival is unknown in this disease. PATIENTS AND METHODS We analyzed data from Intergroup trial 0089 of adjuvant chemotherapy for stage II and III patients with colon cancer, in which all patients received fluorouracil-based therapy. Survival was similar for all arms of the study, allowing us to evaluate all patients together. End points included overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). Multivariate analyses were performed on all patients and on groups according to LNR quartiles (LNR: < 0.05, 0.05 to 0.19, 0.2 to 0.39, and 0.4 to 1.0). Covariates included in the models were age, sex, tumor stage, grade, histology, number of positive LNs, number of LNs removed, and LNR. RESULTS The median age was 63.7 years, and the median number of LNs removed was 11. In the multivariate analysis, LNR was a significant factor for OS, DFS, and CSS in patients with 10 to 15 LN and more than 15 LN removed but not for patients with less than 10 LN removed. Using quartiles, LNR maintained its significance for all three end points when patients were grouped by node status. CONCLUSION After curative resection for colorectal cancer, the LNR is an important prognostic factor and should be used in stratification schemes for future clinical trials investigating adjuvant treatments.

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma

BACKGROUND Sentinel‐lymph‐node biopsy is associated with increased melanoma‐specific survival (i.e., survival until death from melanoma) among patients with node‐positive intermediate‐thickness melanomas (1.2 to 3.5 mm). The value of completion lymph‐node dissection for patients with sentinel‐node metastases is not clear. METHODS In an international trial, we randomly assigned patients with sentinel‐node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph‐node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma‐specific survival. Secondary end points included disease‐free survival and the cumulative rate of nonsentinel‐node metastasis. RESULTS Immediate completion lymph‐node dissection was not associated with increased melanoma‐specific survival among 1934 patients with data that could be evaluated in an intention‐to‐treat analysis or among 1755 patients in the per‐protocol analysis. In the per‐protocol analysis, the mean (±SE) 3‐year rate of melanoma‐specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log‐rank test) at a median follow‐up of 43 months. The rate of disease‐free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log‐rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log‐rank test); these results must be interpreted with caution. Nonsentinel‐node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS Immediate completion lymph‐node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma‐specific survival among patients with melanoma and sentinel‐node metastases. (Funded by the National Cancer Institute and others; MSLT‐II ClinicalTrials.gov number, NCT00297895.)

Impact of obesity on perioperative morbidity and mortality after pancreaticoduodenectomy.

BACKGROUND Obesity has been implicated as a risk factor for perioperative and postoperative complications. The aim of this study was to determine the impact of obesity on morbidity and mortality in patients undergoing pancreaticoduodenectomy (PD). STUDY DESIGN Between January 2000 and July 2007, 262 patients underwent PD at Thomas Jefferson University Hospital, of whom 240 had complete data, including body mass index (BMI; calculated as kg/m(2)) for analysis. Data on BMI, preoperative parameters, operative details, and postoperative course were collected. Patients were categorized as obese (BMI >or= 30), overweight (BMI >or= 25 and < 30), or normal weight (BMI < 25). Complications were graded according to previously published scales. Other end points included length of postoperative hospital stay, blood loss, and operative duration. Analyses were performed using univariate and multivariable models. RESULTS There were 103 (42.9%) normal-weight, 71 (29.6%) overweight, and 66 (27.5%) obese patients. There were 5 perioperative deaths (2.1%), with no differences across BMI categories. A significant difference in median operative duration and blood loss between obese and normal-weight patients was identified (439 versus 362.5 minutes, p = 0.0004; 650 versus 500 mL, p = 0.0139). In addition, median length of stay was significantly longer for BMI (9.5 versus 8 days, p = 0.095). Although there were no significant differences in superficial wound infections, obese patients did have an increased rate of serious complications compared with normal-weight patients (24.2% versus 13.6%, respectively; p = 0.10). CONCLUSIONS Obese patients undergoing PD have a substantially increased blood loss and longer operative time but do not have a substantially increased length of postoperative hospital stay or rate of serious complications. These findings should be considered when assessing patients for operation and when counseling patients about operative risk, but they do not preclude obese individuals from undergoing definitive pancreatic operations.

Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival.

The mechanism by which malignant melanoma (MM) cells survive in lymph nodes is poorly understood. One possible mechanism by which MM cells can escape immune surveillance is through upregulation of immunomodulatory enzymes such as indoleamine 2,3-dioxygenase (IDO). In this study, 25 cases of MM lymph node metastases from patients with long and short survival were evaluated for expression of IDO and the number of Forkhead box p3 (FOXP3)-expressing regulatory T cells. Moderate to strong cytoplasmic IDO expression was present in all (15/15) MM lymph node metastases in patients with poor survival. Eight of 10 patients with metastatic MM and long survival were negative or only weakly positive for IDO. Upregulation of IDO in metastatic MM cells was associated with an increased number of regulatory T cells (Tregs). There was a statistically significant association between shorter survival and both a stronger IDO expression (p=0.0019) and a higher number of FOXP3 expressing Tregs (p

TWIST1 is an ERK1/2 effector that promotes invasion and regulates MMP-1 expression in human melanoma cells

Tumor cells often use developmental processes to progress toward advanced disease. The E-box transcription factor TWIST1 is essential to epithelial-mesenchymal transition (EMT) and cell migration in the developing neural crest. In melanoma, which derives from the neural crest cell lineage, enhanced TWIST1 expression has been linked to worse clinical prognosis. However, mechanisms underlying TWIST1 expression and whether aberrant TWIST1 levels promote steps in melanoma progression remain unknown. Here, we report that elevated TWIST1 mRNA/protein expression is dependent on extracellular signal-regulated kinase (ERK)1/2 signaling, which is hyperactive in the majority of melanomas. We show that TWIST1 protein levels are especially high in melanoma cell lines generated from invasive, premetastatic stage tumors. Furthermore, TWIST1 expression is required and sufficient to promote invasion through Matrigel and spheroid outgrowth in three-dimensional dermal-mimetic conditions. Alterations to spheroid outgrowth were not as a result of altered cell death, cell-cycle profile, or paradigm EMT protein changes. Importantly, we identify matrix metalloproteinase-1 (MMP-1) as a novel downstream target of TWIST1. We have determined that TWIST1 acts, in a dose-dependent manner, as a mediator between hyperactive ERK1/2 signaling and regulation of MMP-1 transcription. Together, these studies mechanistically show a previously unrecognized interplay between ERK1/2, TWIST1, and MMP-1 that is likely significant in the progression of melanoma toward metastasis.

Oncologic Efficacy Is Not Compromised, and May Be Improved with Minimally Invasive Esophagectomy

BACKGROUND Major morbidity and mortality rates continue to be high in large series of transthoracic esophagectomies. Minimally invasive approaches are being increasingly used. We compare our growing series of minimally invasive (combined thoracoscopic and laparoscopic) esophagectomies (MIEs) with a series of open transthoracic esophagectomies. STUDY DESIGN We identified 65 patients who underwent an MIE with thoracoscopy/laparotomy (n = 11), Ivor Lewis (n = 2), or 3-hole approach (n = 52). These patients were compared with 53 patients who underwent open Ivor-Lewis esophagectomy (n = 15) or 3-hole esophagectomy (n = 38) over the past 10 years. RESULTS The MIE and open groups were similar regarding gender and average age. The majority of patients in the open group underwent neoadjuvant chemoradiation therapy (81%); a significantly smaller (43%) number of patients in the MIE group underwent neoadjuvant therapy (p < 0.0001). Regarding oncologic efficacy, 97% and 94% of patients in both groups underwent R0 resections. Patients undergoing MIE had a significant increase in the number of harvested lymph nodes (median 20 vs 9; p < 0.0001). Length of stay was significantly decreased in patients who underwent MIE (8.5 days vs 16 days; p = 0.002). Finally, there were significantly fewer serious complications (grades 3-5) in the MIE group (19% vs 48%; p = 0.0008). CONCLUSIONS In this initial report of a single-institution series of MIE, we demonstrate that oncologic efficacy is not compromised and may actually be improved with a significantly increased number of harvested LNs. We also demonstrate that this approach is associated with fewer serious complications and a significant decrease in the length of postoperative hospital stay.

Endothelial monocyte-activating polypeptide II, a tumor-derived cytokine that plays an important role in inflammation, apoptosis, and angiogenesis.

The interactions between a tumor and its surrounding environment are complex and characterized by a variety of factors. Tumors produce a number of proteins that enable them to recruit a vascular supply, invade into surrounding tissues, and metastasize to distant sites. The host, in turn, responds to these signals by producing its own repertoire of molecules that may either assist or prevent the actions of the tumor. A thorough understanding of this relationship is critical to the development of novel anti-cancer therapies. The tumor-derived cytokine endothelial monocyte-activating polypeptide II (EMAP-II) has profound effects on the tumor as well as on host response. These effects target the inflammatory cascade as well as the processes involved in angiogenesis. In this review the authors describe the current understanding of the role of EMAP-II in inflammation, apoptosis, and angiogenesis and use this molecule to illustrate the complex interactions that occur in the tumor microenvironment.

The Influence of Total Nodes Examined, Number of Positive Nodes, and Lymph Node Ratio on Survival After Surgical Resection and Adjuvant Chemoradiation for Pancreatic Cancer: A Secondary Analysis of RTOG 9704

PURPOSE Lymph node status is an important predictor of survival in pancreatic cancer. We performed a secondary analysis of Radiation Therapy Oncology Group (RTOG) 9704, an adjuvant chemotherapy and chemoradiation trial, to determine the influence of lymph node factors--number of positive nodes (NPN), total nodes examined (TNE), and lymph node ratio (LNR ratio of NPN to TNE)--on OS and disease-free survival (DFS). PATIENT AND METHODS Eligible patients from RTOG 9704 form the basis of this secondary analysis of lymph node parameters. Actuarial estimates for OS and DFS were calculated using Kaplan-Meier methods. Cox proportional hazards models were performed to evaluate associations of NPN, TNE, and LNR with OS and DFS. Multivariate Cox proportional hazards models were also performed. RESULTS There were 538 patients enrolled in the RTOG 9704 trial. Of these, 445 patients were eligible with lymph nodes removed. Overall median NPN was 1 (min-max, 0-18). Increased NPN was associated with worse OS (HR=1.06, p=0.001) and DFS (HR=1.05, p=0.01). In multivariate analyses, both NPN and TNE were associated with OS and DFS. TNE>12, and >15 were associated with increased OS for all patients, but not for node-negative patients (n=142). Increased LNR was associated with worse OS (HR=1.01, p<0.0001) and DFS (HR=1.006, p=0.002). CONCLUSION In patients who undergo surgical resection followed by adjuvant chemoradiation, TNE, NPN, and LNR are associated with OS and DFS. This secondary analysis of a prospective, cooperative group trial supports the influence of these lymph node parameters on outcomes after surgery and adjuvant therapy using contemporary techniques.

Selectively starving cancer cells through dietary manipulation: methods and clinical implications

As the link between obesity and metabolic syndrome and cancer becomes clearer, the need to determine the optimal way to incorporate dietary manipulation in the treatment of cancer patients becomes increasingly important. Metabolic-based therapies, such as caloric restriction, intermittent fasting and a ketogenic diet, have the ability to decrease the incidence of spontaneous tumors and slow the growth of primary tumors, and may have an effect on distant metastases in animal models. Despite the abundance of preclinical data demonstrating the benefit of dietary modification for cancer, to date there are few clinical trials targeting diet as an intervention for cancer patients. We hypothesize that this may be due, in part, to the fact that several different types of diet modification exist with no clear recommendations regarding the optimal method. This article will delineate three commonly used methods of dietary manipulation to assess the potential of each as a regimen for cancer therapy.

Extra–Gastrointestinal Stromal Tumor of the Pancreas: Case Report and a Review of the Literature

Gastrointestinal (GI) stromal tumors are mesenchymal tumors that arise from the GI tract. In rare cases, these tumors are found in intra-abdominal sites unrelated to the GI tract and are immunohistochemically similar to their GI tract counterparts. Primary pancreatic GI stromal tumors are very rare, with only 4 previous cases reported.