KRAS early testing. Consensus initiative and cost-effectiveness evaluation for metastatic colorectal patients in an italian setting

KRAS testing is relevant for the choice of the most appropriate first-line therapy of metastatic colorectal cancer (CRC). Strategies for preventing unequal access to the test should be implemented, but their relevance in the practice is related to economic sustainability. The study adopted the Delphi technique to reach a consensus on several topics. Issues related to execution of KRAS testing were identified by an expert's board and proposed to 108 Italian oncologists and pathologists through two subsequent questionnaires. The emerging proposal was evaluated by decision analyses models employed by technology assessment agencies in order to assess cost-effectiveness. Alternative therapeutic strategies included most commonly used chemotherapy regimens alone or in combination with cetuximab or bevacizumab. The survey indicated that time interval for obtaining KRAS test should not exceed 15 days, 10 days being an optimal interval. To assure the access to proper treatment, a useful strategy should be to anticipate the test after radical resection in patients at high risk of relapse. Early KRAS testing in high risk CRC patients generates incremental cost-effectiveness ratios between 6,000 and 13,000 Euro per quality adjusted life year (QALY) gained. In extensive sensitivity analyses ICER's were always below 15,000 Euro per QALY gained, far within the threshold of 60,000 Euro/QALY gained accepted by regulatory institutions in Italy. In metastatic CRC a time interval higher than 15 days for result of KRAS testing limits access to therapeutic choices. Anticipating KRAS testing before the onset of metastatic disease in patients at high risk does not affect the sustainability and cost-effectiveness profile of cetuximab in first-line mCRC. Early KRAS testing may prevent this inequality in high-risk patients, whether they develop metastases, and is a cost-effective strategy. Based on these results, present joined recommendations of Italian societies of Oncology and Pathology should be updated including early KRAS testing

KRAS Early Testing: Consensus Iniziative and Cost-Effectiveness Evaluation for metastatic colerectal patiens in an Italian Setting

Abstract KRAS testing is relevant for the choice of the most appropriate first-line therapy of metastatic colorectal cancer (CRC). Strategies for preventing unequal access to the test should be implemented, but their relevance in the practice is related to economic sustainability. The study adopted the Delphi technique to reach a consensus on several topics. Issues related to execution of KRAS testing were identified by an expert\u2019s board and proposed to 108 Italian oncologists and pathologists through two subsequent questionnaires. The emerging proposal was evaluated by decision analyses models employed by technology assessment agencies in order to assess cost-effectiveness. Alternative therapeutic strategies included most commonly used chemotherapy regimens alone or in combination with cetuximab or bevacizumab. The survey indicated that time interval for obtaining KRAS test should not exceed 15 days, 10 days being an optimal interval. To assure the access to proper treatment, a useful strategy should be to anticipate the test after radical resection in patients at high risk of relapse. Early KRAS testing in high risk CRC patients generates incremental cost-effectiveness ratios between 6,000 and 13,000 Euro per quality adjusted life year (QALY) gained. In extensive sensitivity analyses ICER\u2019s were always below 15,000 Euro per QALY gained, far within the threshold of 60,000 Euro/QALY gained accepted by regulatory institutions in Italy. In metastatic CRC a time interval higher than 15 days for result of KRAS testing limits access to therapeutic choices. Anticipating KRAS testing before the onset of metastatic disease in patients at high risk does not affect the sustainability and cost-effectiveness profile of cetuximab in first-line mCRC. Early KRAS testing may prevent this inequality in high-risk patients, whether they develop metastases, and is a cost-effective strategy. Based on these results, present joined recommendations of Italian societies of Oncology and Pathology should be updated including early KRAS testing

Surgical Approach for Long-term Survival of Patients With Intrahepatic Cholangiocarcinoma: A Multi-institutional Analysis of 434 Patients.

OBJECTIVES To examine the outcomes of a hepatectomy for intrahepatic cholangiocarcinoma (IHC) and to clarify the prognostic impact of a lymphadenectomy and the surgical margin. Large series of patients who were surgically treated for IHC are scarce. Thus, prognostic factors and long-term survival after resection of IHC remain uncertain. DESIGN Prospective study of patients who were surgically treated for IHC. Clinicopathologic, operative, and long-term survival data were analyzed. SETTING Prospectively collected data of all consecutive patients with pathologically confirmed IHC who had undergone liver resection with a curative intent at 1 of 16 tertiary referral centers were entered into a multi-institutional registry. PATIENTS All consecutive patients who underwent a hepatectomy with a curative intent for IHC (1990-2008) were identified from a multi-institutional registry. RESULTS A total of 434 patients were included in the analysis. Most patients underwent a major or extended hepatectomy (70.0%) and a systematic lymphadenectomy (62.2%). The incidence of lymph node metastases (overall, 36.9%) increased with increased tumor size, with 24.4% of patients with a small IHC (diameter 643 cm) having N1 disease. Almost one-third of patients required an additional major procedure to obtain a R0 resection in 84.6% of the cases. In these patients, the median time of survival was 39 months, and the 5-year survival rate was 39.8%. Lymph node metastases (hazard ratio, 2.21; P < .001), multiple tumors (hazard ratio, 1.50; P = .009), and an elevated preoperative cancer antigen 19.9 level (hazard ratio, 1.62; P = .006) independently predicted an adverse prognosis. Conversely, survival was not influenced by the width of a negative resection margin (P = .61). The potential survival benefit of a lymphadenectomy was assessed with the therapeutic value index, which was calculated to be 5.9 points. CONCLUSIONS Survival rates after a hepatectomy with a curative intent for IHC at tertiary referral centers exceed the survival rates reported in most study series in single institutions, which strengthens the value of an aggressive approach to radical resection. Lymph node metastases and multiple tumors are associated with decreased survival rates, but they should not be considered selection criteria that prevent other patients from undergoing a potentially curative resection. Lymphadenectomy should be considered for all patients

The inflammatory response in transgastric surgery: gastric content leak leads to localized inflammatory response and higher adhesive disease

Risk of gastric spillage during transgastric surgery is a potential complication of NOTES procedures. The aim of this study was to determine risk outcomes from gastric spillage in a rat survival model by measuring local and systemic inflammatory markers, adhesive disease, and morbidity. We performed a minilaparotomy with needle aspiration of 2 ml of gastric contents mixed with 2 ml of sterile saline (study group, SG) or 4 ml of sterile saline (control group, CG) injected into the peritoneal cavity of 60 male rats. Inflammatory markers (TNFα, IL-6, and IL-10) were analyzed at 1, 3, 6, and 24 h postoperatively by obtaining plasma levels and peritoneal washings. At necropsy, the peritoneal cavity was examined grossly for adhesions. Adhesions were seen more frequently in the SG versus the CG (100% vs. 33.3%, p < 0.014). There was a significant difference in the peritoneal TNFα levels in the SG compared with the CG, which peaked 1 h after surgery (p < 0.02). Both peritoneal IL-6 and IL-10 levels were higher in the SG versus the CG, which peaked 3 h after surgery (p < 0.005 and p < 0.001, respectively). All peritoneal inflammatory markers returned to undetectable levels at 24 h for both groups. Plasma cytokines were undetectable at all time intervals. The inflammatory response was found to be a localized and not systemic event, with plasma cytokine levels remaining normal while peritoneal washings revealed a brisk, short-lived localized inflammatory response. There was a significantly higher rate of adhesive disease in the SG compared with the CG; this, however did not translate into a difference in apparent clinical outcome. We conclude that gastric leakage in this NOTES rodent model induces a localized inflammatory response, followed by mild to moderate adhesive disease. This may be important in human NOTES

A complex of α(6) integrin and E-cadherin drives liver metastasis of colorectal cancer cells through hepatic angiopoietin-like 6.

Homing of colorectal cancer (CRC) cells to the liver is a non-random process driven by a crosstalk between tumour cells and components of the host tissue. Here we report the isolation of a liver metastasis-specific peptide ligand (CGIYRLRSC) that binds a complex of E-cadherin and α(6) integrin on the surface of CRC cells. We identify angiopoietin-like 6 protein as a peptide-mimicked natural ligand enriched in hepatic blood vessels of CRC patients. We demonstrate that an interaction between hepatic angiopoietin-like 6 and tumoural α(6) integrin/E-cadherin drives liver homing and colonization by CRC cells, and that CGIYRLRSC inhibits liver metastasis through interference with this ligand/receptor system. Our results indicate a mechanism for metastasis whereby a soluble factor accumulated in normal vessels functions as a specific ligand for circulating cancer cells. Consistently, we show that high amounts of coexpressed α(6) integrin and E-cadherin in primary tumours represent a poor prognostic factor for patients with advanced CRC

A complex of α6 integrin and E-cadherin drives the liver metastasis of colorectal cancer cells by a physical and functional interaction with hepatic angiopoietin-like 6

Homing of colorectal cancer (CRC) cells to the liver is a non-random process driven by a crosstalk between tumour cells and components of the host tissue. Here we report the isolation of a liver metastasis-specific peptide ligand (CGIYRLRSC) that binds a complex of E-cadherin and α(6) integrin on the surface of CRC cells. We identify angiopoietin-like 6 protein as a peptide-mimicked natural ligand enriched in hepatic blood vessels of CRC patients. We demonstrate that an interaction between hepatic angiopoietin-like 6 and tumoural α(6) integrin/E-cadherin drives liver homing and colonization by CRC cells, and that CGIYRLRSC inhibits liver metastasis through interference with this ligand/receptor system. Our results indicate a mechanism for metastasis whereby a soluble factor accumulated in normal vessels functions as a specific ligand for circulating cancer cells. Consistently, we show that high amounts of coexpressed α(6) integrin and E-cadherin in primary tumours represent a poor prognostic factor for patients with advanced CRC