Ivan Cecconello

SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas

Lineage-survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development. Here we show that a peak of genomic amplification on chromosome 3q26.33 found in squamous cell carcinomas (SCCs) of the lung and esophagus contains the transcription factor gene SOX2, which is mutated in hereditary human esophageal malformations, is necessary for normal esophageal squamous development, promotes differentiation and proliferation of basal tracheal cells and cooperates in induction of pluripotent stem cells. SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 here cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors show expression of markers of both squamous differentiation and pluripotency. These characteristics identify SOX2 as a lineage-survival oncogene in lung and esophageal SCC.

Bacterial translocation: Overview of mechanisms and clinical impact

Bacterial translocation (BT) is a phenomenon in which live bacteria or its products cross the intestinal barrier. Gut translocation of bacteria has been shown in both animal and human studies. BT and its complications have been shown clearly to occur in animal models, but its existence and importance in humans has been difficult to ascertain. We review the mechanisms of BT and its clinical impact based on the current literature.

Interval Between Surgery and Neoadjuvant Chemoradiation Therapy for Distal Rectal Cancer: Does Delayed Surgery Have an Impact on Outcome?

BACKGROUND The optimal interval between neoadjuvant chemoradiation therapy (CRT) and surgery in the treatment of patients with distal rectal cancer is controversial. The purpose of this study is to evaluate whether this interval has an impact on survival. METHODS AND MATERIALS Patients who underwent surgery after CRT were retrospectively reviewed. Patients with a sustained complete clinical response (cCR) 1 year after CRT were excluded from this study. Clinical and pathologic characteristics and overall and disease-free survival were compared between patients undergoing surgery 12 weeks or less from CRT and patients undergoing surgery longer than 12 weeks from CRT completion and between patients with a surgery delay caused by a suspected cCR and those with a delay for other reasons. RESULTS Two hundred fifty patients underwent surgery, and 48.4% had CRT-to-surgery intervals of 12 weeks or less. There were no statistical differences in overall survival (86% vs. 81.6%) or disease-free survival rates (56.5% and 58.9%) between patients according to interval (< or =12 vs. >12 weeks). Patients with intervals of 12 weeks or less had significantly higher rates of Stage III disease (34% vs. 20%; p = 0.009). The delay in surgery was caused by a suspected cCR in 23 patients (interval, 48 +/- 10.3 weeks). Five-year overall and disease-free survival rates for this subset were 84.9% and 51.6%, not significantly different compared with the remaining group (84%; p = 0.96 and 57.8%; p = 0.76, respectively). CONCLUSIONS Delay in surgery for the evaluation of tumor response after neoadjuvant CRT is safe and does not negatively affect survival. These results support the hypothesis that shorter intervals may interrupt ongoing tumor necrosis.

International consensus on standardization of data collection for complications associated with esophagectomy: Esophagectomy Complications Consensus Group (ECCG)

INTRODUCTION Perioperative complications influence long- and short-term outcomes after esophagectomy. The absence of a standardized system for defining and recording complications and quality measures after esophageal resection has meant that there is wide variation in evaluating their impact on these outcomes. METHODS The Esophageal Complications Consensus Group comprised 21 high-volume esophageal surgeons from 14 countries, supported by all the major thoracic and upper gastrointestinal professional societies. Delphi surveys and group meetings were used to achieve a consensus on standardized methods for defining complications and quality measures that could be collected in institutional databases and national audits. RESULTS A standardized list of complications was created to provide a template for recording individual complications associated with esophagectomy. Where possible, these were linked to preexisting international definitions. A Delphi survey facilitated production of specific definitions for anastomotic leak, conduit necrosis, chyle leak, and recurrent nerve palsy. An additional Delphi survey documented consensus regarding critical quality parameters recommended for routine inclusion in databases. These quality parameters were documentation on mortality, comorbidities, completeness of data collection, blood transfusion, grading of complication severity, changes in level of care, discharge location, and readmission rates. CONCLUSIONS The proposed system for defining and recording perioperative complications associated with esophagectomy provides an infrastructure to standardize international data collection and facilitate future comparative studies and quality improvement projects.

Comparison of nutritional risk screening tools for predicting clinical outcomes in hospitalized patients

OBJECTIVE International nutritional screening tools are recommended for screening hospitalized patients for nutritional risk, but no tool has been specifically evaluated in the Brazilian population. The aim of this study was to identify the most appropriate nutritional screening tool for predicting unfavorable clinical outcomes in patients admitted to a Brazilian public university hospital. METHODS The Nutritional Risk Screening 2002 (NRS 2002), Mini-Nutritional Assessment-Short Form (MNA-SF), and Malnutrition Universal Screening Tool (MUST) were administered to 705 patients within 48 h of hospital admission. Tool performance in predicting complications, very long length of hospital stay (LOS), and death was analyzed using receiver operating characteristic curves. RESULTS NRS 2002, MUST, and MNA-SF identified nutritional risk in 27.9%, 39.6%, and 73.2% of the patients, respectively. NRS 2002 (complications: 0.6531; very long LOS: 0.6508; death: 0.7948) and MNA-SF (complications: 0.6495; very long LOS: 0.6197; death: 0.7583) had largest areas under the ROC curve compared to MUST (complications: 0.6036; very long LOS: 0.6109; death: 0.6363). For elderly patients, NRS 2002 was not significantly different than MNA-SF (P>0.05) for predicting outcomes. CONCLUSION Considering current criteria for nutritional risk, NRS 2002 and MNA-SF have similar performance to predict outcomes but NRS 2002 seems to provide a best yield.

Metabolic Improvements in Obese Type 2 Diabetes Subjects Implanted for 1 Year with an Endoscopically Deployed Duodenal–Jejunal Bypass Liner

BACKGROUND The purpose of this study was to evaluate the effect of the duodenal-jejunal bypass liner (DJBL), a 60-cm, impermeable fluoropolymer liner anchored in the duodenum to create a duodenal-jejunal bypass, on metabolic parameters in obese subjects with type 2 diabetes. METHODS Twenty-two subjects (mean age, 46.2±10.5 years) with type 2 diabetes and a body mass index between 40 and 60 kg/m(2) (mean body mass index, 44.8±7.4 kg/m(2)) were enrolled in this 52-week, prospective, open-label clinical trial. Endoscopic device implantation was performed with the patient under general anesthesia, and the subjects were examined periodically during the next 52 weeks. Primary end points included changes in fasting blood glucose and insulin levels and changes in hemoglobin A1c (HbA1c). The DJBL was removed endoscopically at the end of the study. RESULTS Thirteen subjects completed the 52-week study, and the mean duration of the implant period for all subjects was 41.9±3.2 weeks. Reasons for early removal of the device included device migration (n=3), gastrointestinal bleeding (n=1), abdominal pain (n=2), principal investigator request (n=2), and discovery of an unrelated malignancy (n=1). Using last observation carried forward, statistically significant reductions in fasting blood glucose (-30.3±10.2 mg/dL), fasting insulin (-7.3±2.6 μU/mL), and HbA1c (-2.1±0.3%) were observed. At the end of the study, 16 of the 22 subjects had an HbA1c<7% compared with only one of 22 at baseline. Upper abdominal pain (n=11), back pain (n=5), nausea (n=7), and vomiting (n=7) were the most common device-related adverse events. CONCLUSIONS The DJBL improves glycemic status in obese subjects with diabetes and therefore represents a nonsurgical, reversible alternative to bariatric surgery.

Absence of Lymph Nodes in the Resected Specimen After Radical Surgery for Distal Rectal Cancer and Neoadjuvant Chemoradiation Therapy: What does it Mean?

PurposeThe number of retrieved lymph nodes during radical surgery has been considered of great importance to ensure adequate staging and radical resection. However, this finding may not be applicable after neoadjuvant therapy in which, not only is there a decrease in lymph nodes recovered, but also a subgroup of patients with absence of lymph nodes in the resected specimen.MethodsPatients with absence of lymph nodes were compared with patients with ypN0 disease and patients with ypN+ disease.ResultsThirty-two patients (11 percent) had absence of lymph nodes, 171 patients (61 percent) had ypN0 disease, and 78 patients (28 percent) had ypN+ disease. Patients with absence of lymph nodes had significantly lower ypT status (ypT0-1, 40 vs. 13 percent; P < 0.001) and decreased risk of perineural invasion (6 vs. 21 percent; P = 0.04) compared with ypN0 patients. Five-year disease-free survival (74 percent) was similar to patients with ypN0 (59 percent; P = 0.2), and both were significantly better than patients with ypN+ disease (30 percent; P < 0.001).ConclusionsAbsence of lymph nodes retrieved from the resected specimen is associated with favorable pathologic features (ypT and perineural invasion status) and good disease-free survival rates. In this setting, absence of retrieved lymph nodes may reflect improved response to neoadjuvant chemoradiation therapy rather than inappropriate or suboptimal oncologic radicality.

The role of carcinoembriogenic antigen in predicting response and survival to neoadjuvant chemoradiotherapy for distal rectal cancer.

PURPOSE: Carcinoembriogenic antigen (CEA) is the most frequently used tumor marker in rectal cancer. A decrease in carcinoembriogenic antigen after radical surgery is associated with survival in these patients. Neoadjuvant chemoradiotherapy may lead to significant primary tumor downstaging, including complete tumor regression in selected patients. Therefore, we hypothesized that a decrease in CEA after neoadjuvant chemoradiotherapy could reflect tumor response to chemoradiotherapy, affecting final disease stage and ultimately survival. METHODS: Patients with distal rectal cancer managed by neoadjuvant chemoradiotherapy and available pretreatment and postchemoradiotherapy levels of CEA were eligible for the study. Outcomes studied included final disease stage, relapse, and survival, and these were compared according to initial CEA level, post-chemoradiotherapy CEA level, and the reduction in CEA. RESULTS: Overall 170 patients were included. Post-chemoradiotherapy CEA levels <5 ng/ml were associated with increased rates of complete clinical response and pathologic response. Additionally, postchemoradiotherapy CEA levels <5 ng/ml were associated with increased overall and disease-free survival (P = 0.01 and P = 0.03). There was no correlation between initial CEA level or reduction in CEA and complete response or survival. CONCLUSION: A postchemoradiotherapy CEA level <5 ng/ml is a favorable prognostic factor for rectal cancer and is associated with increased rates of earlier disease staging and complete tumor regression. Postchemoradiotherapy CEA levels may be useful in decision making for patients who may be candidates for alterative treatment strategies.

The prognostic value of CD147/EMMPRIN is associated with monocarboxylate transporter 1 co-expression in gastric cancer

The aim of the present work was to assess the role of monocarboxylate transporters (MCTs), namely MCT1 and MCT4 as well as MCT/CD147 co-expression in gastric tissues and evaluate their clinico-pathological significance in gastric carcinoma. For that, we analysed the immunohistochemical expression of MCT1, MCT4 and CD147, in a large series of gastric samples, including non-neoplastic, tumour and metastatic tissues. A significant decrease in MCT4 plasma membrane expression was observed from non-neoplastic to gastric primary malignant tissues and to lymph-node metastasis and both MCT1 and MCT4 correlated with CD147. Importantly, both MCT4 and CD147 were more frequently expressed in Laurens intestinal-type tumours and MCT1/CD147 co-expression was associated with advanced gastric carcinoma, Laurens intestinal type, TNM staging and lymph-node metastasis. Our results showed that the prognostic value of CD147 was associated with MCT1 co-expression in gastric cancer cells, supporting the view that CD147 plasma membrane activity is dependent on MCT co-expression.

Molecular aspects of esophageal squamous cell carcinoma carcinogenesis

BACKGROUND The development of human esophageal cancer is a multistep, progressive process. An early indicator of this process is an increased proliferation of esophageal epithelial cells morphologically including basal cell hyperplasia, dysplasia, carcinoma in situ and advanced esophageal squamous cell carcinoma. The process of tumorigenesis at cellular level is related to disorders of the control of cell proliferation and differentiation and controlled cell death (apoptosis). Most of cancer cells contain genetic alterations related to the control of these processes, including transcription factors and apoptosis related proteins. AIM In this review, the current knowledge of the genetic profile of this subtype of esophageal tumor is discussed, focusing on the potential of the development of novel tools for clinical management of esophageal squamous cell carcinoma. CONCLUSIONS The advances in the field of molecular biology have let us to deeper our knowledge of the process of carcinogenesis of esophagus. Ideally, this knowledge should be translated in benefits for patients suffering from cancer. Thus, better understanding of molecular alterations during carcinogenesis is expected to improve tumor control and prevention and also may lead to better disease management.