Neoadjuvant Chemotherapy and Surgery for Esophageal Adenocarcinoma: Prognostic Value of Circumferential Resection Margin and Stratification of N1 Category

Background  In the UK, it is standard practice to treat esophageal adenocarcinoma with neoadjuvant chemotherapy (no radiation) and surgery. We examined the prognostic value of the status of the circumferential resection margin (CRM) and stratification of the N1 category into 1–4 nodes or ≥5 nodes. Methods  Between 2000 and 2006, 105 patients with radiologically staged T3, T4 or N1 esophageal adenocarcinoma had preoperative chemotherapy. One hundred and one patients had an Ivor Lewis operation with two-field lymphadenectomy, three had a transhiatal operation and one had a three-incision operation. CRM was assessed by painting the specimen with India ink and transverse sections at 5–10 mm intervals. The CRM was considered positive (CRM+) if malignant cells were within 1 mm of the inked margin. Results  There were 87 men. The median age was 61 years (range 37–81 years). Median lymph node yield was 28 (4–77); 86 patients (83%) had ≥18 nodes. Seventy-four patients (70%) had N1 disease, with 1–4 involved nodes in 41 patients (39%) and ≥5 nodes in 33 patients (31%). The CRM was positive in 38 patients (36%). On multivariate analysis, nodal metastasis [N0 versus N1; hazard ratio (HR) 3.3, 3-year survival 80% versus 40%; P = 0.004], CRM status (CRM– versus CRM+: HR 2.6, 3-year survival 64% versus 26%; P = 0.002) and vascular invasion (V0 versus V1: HR 2.2, 3-year survival 67% versus 39%; P = 0.014) retained independently significant prognostic value. N1 patients with 1–4 nodes had longer survival than those with ≥5 nodes (56% versus 21%; P < 0.001). Conclusions  CRM involvement and stratification of the N1 category are independent prognostic factors after multimodal therapy for esophageal adenocarcinoma.     

Rethinking TNM: A Breast Cancer Classification to Guide to Treatment and Facilitate Research

Abstract:  The TNM_UICC classification of breast cancer categorizes tumor size, regional lymph node involvement, and distant metastases. Treatment is influenced by these characteristics, but requires knowledge of several other factors. In fact, effective treatment is dependent on disease extent, hormone receptor status, and other biologic characteristics of the cancer. We propose a new classification [tumor node metastasis (TNM)] that not only includes relevant biologic characteristics and can expand to include others as they are validated but also specifies tumor size exactly (T2.3 indicates a cancer of maximum diameter 2.3 cm), provides more information on regional lymph node involvement, and specifies the site(s) of distant metastases. We also propose abolishing the term "carcinoma" for non-invasive neoplastic conditions and the term "infiltrating" for carcinomas. The new classification is sufficiently similar to the TNM_UICC classification to permit valid comparison of patients classified by both systems, but is more logical, provides information useful for guiding therapy, and is flexible enough to satisfy present and future clinical and research needs.     

Effects of Yearly Zoledronic Acid 5 mg on Bone Turnover Markers and Relation of PINP With Fracture Reduction in Postmenopausal Women With Osteoporosis

In patients with osteoporosis treated with antiresorptive agents, reduction in bone turnover explains much of the observed fracture risk reduction. Lower levels of bone turnover markers (BTMs) appear to be associated with a lower risk of fracture in bisphosphonate‐treated patients. BTMs were measured in a subset of subjects in the HORIZON Pivotal Fracture Trial. Annual infusions of zoledronic acid 5 mg significantly reduced BTMs: median decrease of 50% for β‐C‐terminal telopeptides of type 1 collagen (β‐CTX), 30% for bone alkaline phosphatase (ALP), and 56% for procollagen type 1 amino‐terminal propeptide (PINP). The mean level of BTMs decreased in treated patients but remained within the premenopausal range before the next injection. The percentage of zoledronic acid–treated patients with values below the premenopausal reference range at all time points was 1.7%, 17.8%, and 19% for bone ALP, CTX, and PINP, respectively. The third injection of zoledronic acid resulted in 60% reduction of β‐CTX within 9–11 days, followed by a gradual increase, indicating the persistence of osteoclastic bone resorption. The association between changes in BTMs and fracture incidence was assessed in 1132 patients who had PINP measurements at baseline and 1 yr. There was no association between low PINP levels at 1 yr and increased fracture incidence. In summary, (1) annual injections of zoledronic acid reduced BTMs in the premenopausal range, with a significant response persisting after the third infusion; and (2) low levels of PINP were not associated with increased fracture risk.     

IMP3 is a novel biomarker for triple negative invasive mammary carcinoma associated with a more aggressive phenotype

IMP3, an oncofetal protein, is a member of the insulin-like growth factor-II (IGF-II) mRNA-binding protein family. Its relevance as a novel biomarker in lung, pancreatic, renal, and cervical adenocarcinoma was recently revealed. However, its role in breast carcinogenesis and tumor progression is not yet established. Basal-like carcinoma was initially identified by gene expression profiling. It accounts for 15% to 30% of all breast cancers. These tumors express basal epithelial markers including cytokeratin 5 but lack expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), therefore, are often referred to as triple negative breast cancer. They have been found to be associated with a worse overall and disease-free survival. In this retrospective study, we examined the IMP3 expression in invasive ductal carcinoma of the breast and correlated its expression with morphological and biologic prognostic factors. The study group comprised 138 cases of invasive ductal carcinoma retrieved from the surgical pathologic files for a 10-year period from 1997 to 2006. Survival data and clinical stage were available on all 138 patients. Tumor characteristics including size, grade, lymphovascular invasion, necrosis, lymph node metastasis, estrogen receptor, progesterone receptor, and HER2 status were obtained from pathologic reports. Immunohistochemistry was performed on formalin-fixed paraffin-embedded tissue using mouse monoclonal antibody against IMP3 and CK5/6. Of the 138 breast cancer cases, IMP3 expression was seen in 45 (33%). Twenty-five of the IMP3+ cases were triple negative. We found significant correlation between IMP3 expression and higher grade (P = .001), necrosis (P< .0001) triple negative, and CK5/6 expression (P < .0001 for each). Cox multivariate analysis showed a hazard ratio of IMP3 expression at 3.14 (P = .05). IMP3 is a novel biomarker for triple negative (basal-like) invasive mammary carcinoma, and its expression is associated with a more aggressive phenotype and decreased overall survival.     

Preoperative Resolution of Jaundice Following Biliary Stenting Predicts More Favourable Early Survival in Resected Pancreatic Ductal Adenocarcinoma

Introduction  Despite the widespread use of endoscopic biliary stenting in patients presenting with potentially resectable pancreatic cancer, there is no general consensus regarding whether this represents a superior management approach over expeditious surgical intervention. The objective of this study was to investigate the influence of preoperative biliary stenting and resolution of jaundice on subsequent postoperative survival following resection for pancreatic cancer. Methods  155 patients undergoing partial pancreatoduodenectomy for pancreatic ductal adenocarcinoma between January 1997 and August 2007 were identified from a prospectively maintained database. Results  There was no survival difference when comparing patients undergoing preoperative biliary drainage (n = 130) with those who did not (n = 25) (log rank, P = 0.981). When analysing individual prognostic factors as continuous variables in univariate Cox analysis, lower albumin levels (P = 0.016), elevated alkaline phosphatase levels (P = 0.011) and elevated CRP levels (P = 0.021) were associated with poorer overall survival. Multivariable Cox regression demonstrated that both albumin (P = 0.008) and CRP (P = 0.038) remained significant independent predictors of overall survival alongside lymph node ratio (P = 0.018). Although preoperative bilirubin levels were not associated with overall survival when analysed as a continuous variable (Cox, P = 0.786), the presence of jaundice (i.e., bilirubin >35 μmol/l) at the time of surgery was a significant adverse predictor of early survival in patients undergoing preoperative biliary drainage (Breslow–Gehan–Wilcoxon, P = 0.013) and remained a significant predictor of early survival when included in a further Cox analysis with censoring of cases who survived beyond 6 months (Cox, P = 0.017). Conclusion  These results suggest that the presence of jaundice at the time of resection has an adverse impact on early, but not overall, postoperative survival in pancreatic cancer patients undergoing preoperative biliary drainage.     

Extensive Pathological Analysis of Selected Melanoma Sentinel Lymph Nodes: High Metastasis Detection Rates at Reduced Workload

Background Extensive pathological workup of sentinel lymph nodes (SLNs) in melanoma detects more patients with metastasis-positive SLNs than do routine protocols, but at the cost of high laboratory workloads. We aimed to design a protocol that reduced this workload without compromising metastasis detection. Methods We analyzed 920 SLNs from 321 consecutive patients with melanoma by complete step sectioning and immunohistochemistry. We designed different models to theoretically reduce the number of histological sections examined and compared the results from these simulations with results obtained with our extended protocol, with the restricted national Danish protocol, and with the protocol recommended by the European Organization for Research and Treatment of Cancer (EORTC). Results The extended protocol increased the metastasis detection rate by 22% (95% confidence interval, 11–34; 30.8% vs. 25.2%, P < .0001) compared with the national Danish protocol, and it had a similar rate to that reported by the EORTC (30.8% vs. 29.4%, P = .6229). The workload associated with complete step sectioning could be reduced by 40% by focusing step sectioning on the SLNs with the highest gamma counts, while examining SLNs with lower gamma counts with one to three central sections. The false-negative rate for detecting metastases with this reduced protocol was 6% compared with complete step sectioning. Conclusions Combining complete step sectioning of SLNs with immunohistochemistry ensures high metastasis detection rates. Workloads can be markedly reduced with only a slight increase in the false-negative rate by focusing analysis on the SLNs most likely to contain metastases, i.e., those with the highest gamma counts.