Therapeutic drug monitoring of neoadjuvant mFOLFIRINOX in resected pancreatic ductal adenocarcinoma

Background: Despite a potentially curative treatment, the prognosis after upfront surgery and adjuvant chemotherapy for patients with resectable pancreatic ductal adenocarcinoma (PDAC) is poor. Modified FOLFIRINOX (mFOLFIRINOX) is a cornerstone in the systemic treatment of PDAC, including the neoadjuvant setting. Pharmacokinetic-guided (PKG) dosing has demonstrated beneficial effects in other tumors, but scarce data is available in pancreatic cancer. Methods: Forty-six patients with resected PDAC after mFOLFIRINOX neoadjuvant approach and included in an institutional protocol for anticancer drug monitoring were retrospectively analyzed. 5-Fluorouracil (5-FU) dosage was adjusted throughout neoadjuvant treatment according to pharmacokinetic parameters and Irinotecan (CPT-11) pharmacokinetic variables were retrospectively estimated. Results: By exploratory univariate analyses, a significantly longer progression-free survival was observed for patients with either 5-FU area under the curve (AUC) above 28 mcg$h/mL or CPT-11 AUC values below 10 mcg$h/mL. In the multivariate analyses adjusted by age, gender, performance status and resectability after stratification according to both pharmacokinetic parameters, the risk of progression was significantly reduced in patients with 5-FU AUC 28 mcg$h/mL [HR ¼ 0.251, 95and CPT-11 AUC <10 mcg$h/mL [HR ¼ 0.189, 95% CI 0.073e0.486, p ¼ 0.001]. Conclusions: Pharmacokinetically-guided dose adjustment of standard chemotherapy treatments might improve survival outcomes in patients with pancreatic ductal adenocarcinoma

Patients With Failed Anterior Cruciate Ligament Reconstruction Have an Increased Posterior Lateral Tibial Plateau Slope: A Case-Controlled Study

Purpose: To compare knee anatomical parameters of patients with failed anterior cruciate ligament reconstruction (ACL-R) with those of a control group of sex-matched patients with successful ACL-R. Methods: Forty-three patients (34 male, 9 female) who experienced graft failure after ACL-R were enrolled in the failed group. These patients were matched to a control group of 43 patients who underwent primary ACL-R with a minimum follow-up of 24 months. On magnetic resonance imaging, the following parameters were evaluated: transepicondylar distance, lateral and medial femoral condyle widths, tibial plateau width, notch width index, and the ratio of width and height of the femoral notch, ratio between the height and depth of the lateral and medial femoral condyle, lateral and medial posterior tibial slopes, and anterior subluxation of the lateral and medial tibial plateau. Multivariate regression with backward elimination, including only the previously identified significant variables, defined the independent predictors for revision surgery. Results: The anatomical variables that were significantly different between the 2 study groups were lateral and medial posterior tibial slopes, anterior subluxation of the lateral and medial tibial plateau, medial tibial plateau width, lateral tibial plateau width, medial femoral condyle width, and transepicondylar distance; however, the multivariate regression analysis identified the lateral posterior tibial slope (LTPs), the anterior subluxation of the medial tibial plateau, and the medial femoral condyle width as significant independent predictors (P &lt;.05). The LPTs had the highest coefficient and the highest sensitivity (88%) and specificity (84%) to identify failures when considering the optimal cutoff value of 7.4\ub0. Conclusions: Several anatomical parameters have been identified that differ significantly between patients with failed ACL-R and those without a documented failure. The most accurate predictor of ACL failure was an LTPs &gt;7.4\ub0, with a sensitivity of 88% and specificity of 84%. Surgeons should consider measuring LTPs during preoperative assessment of ACL-injured patients, and patients with values &gt;7.4\ub0 should be considered at high risk of ACL-R failure. Level of Evidence: Level III retrospective prognostic trial

Current use of navigation system in ACL surgery: a historical review

Purpose: The present review aims to analyse the available literature regarding the use of navigation systems in ACL reconstructive surgery underling the evolution during the years. Methods: A research of indexed scientific papers was performed on PubMed and Cochrane Library database. The research was performed in December 2015 with no publication year restriction. Only English-written papers and related to the terms ACL, NAVIGATION, CAOS and CAS were considered. Two reviewers independently selected only those manuscripts that presented at least the application of navigation system for ACL reconstructive surgery. Results: One hundred and forty-six of 394 articles were finally selected. In this analysis, it was possible to review the main uses of navigation system in ACL surgery including tunnel positioning for primary and revision surgery and kinematic assessment of knee laxity before and after different surgical procedures. In the early years, until 2006, navigation system was mainly used to improve tunnel positioning, but since the last decade, this tool has been principally used for kinematics evaluation. Increased accuracy of tunnel placement was observed using navigation surgery, especially, regarding femoral, 42 of 146 articles used navigation to guide tunnel positioning. During the following years, 82 of 146 articles have used navigation system to evaluate intraoperative knee kinematic. In particular, the importance of controlling rotatory laxity to achieve better surgical outcomes has been underlined. Conlusions: Several applications have been described and despite the contribution of navigation systems, its potential uses and theoretical advantages, there are still controversies about its clinical benefit. The present papers summarize the most relevant studies that have used navigation system in ACL reconstruction. In particular, the analysis identified four main applications of the navigation systems during ACL reconstructive surgery have been identified: (1) technical assistance for tunnel placement; (2) improvement in knowledge of the kinematic behaviour of ACL and other structures; (3) comparison of effectiveness of different surgical techniques in controlling laxities; (4) navigation system performance to improve the outcomes of ACL reconstruction and cost-effectiveness. Level of evidence: IV

Therapeutic drug monitoring of neoadjuvant mFOLFIRINOX in resected pancreatic ductal adenocarcinoma

Background: Despite a potentially curative treatment, the prognosis after upfront surgery and adjuvant chemotherapy for patients with resectable pancreatic ductal adenocarcinoma (PDAC) is poor. Modified FOLFIRINOX (mFOLFIRINOX) is a cornerstone in the systemic treatment of PDAC, including the neoadjuvant setting. Pharmacokinetic-guided (PKG) dosing has demonstrated beneficial effects in other tumors, but scarce data is available in pancreatic cancer. Methods: Forty-six patients with resected PDAC after mFOLFIRINOX neoadjuvant approach and included in an institutional protocol for anticancer drug monitoring were retrospectively analyzed. 5-Fluorouracil (5-FU) dosage was adjusted throughout neoadjuvant treatment according to pharmacokinetic parameters and Irinotecan (CPT-11) pharmacokinetic variables were retrospectively estimated. Results: By exploratory univariate analyses, a significantly longer progression-free survival was observed for patients with either 5-FU area under the curve (AUC) above 28 mcg$h/mL or CPT-11 AUC values below 10 mcg$h/mL. In the multivariate analyses adjusted by age, gender, performance status and resectability after stratification according to both pharmacokinetic parameters, the risk of progression was significantly reduced in patients with 5-FU AUC 28 mcg$h/mL [HR ¼ 0.251, 95and CPT-11 AUC <10 mcg$h/mL [HR ¼ 0.189, 95% CI 0.073e0.486, p ¼ 0.001]. Conclusions: Pharmacokinetically-guided dose adjustment of standard chemotherapy treatments might improve survival outcomes in patients with pancreatic ductal adenocarcinoma