Quantifying the Efficacy of Magnetic Nanoparticles for MRI and Hyperthermia Applications via Machine Learning Methods.

Magnetic nanoparticles are a prospective class of materials for use in biomedicine as agents for magnetic resonance imagining (MRI) and hyperthermia treatment. However, synthesis of nanoparticles with high efficacy is resource-intensive experimental work. In turn, the use of machine learning (ML) methods is becoming useful in materials design and serves as a great approach to designing nanomagnets for biomedicine. In this work, for the first time, an ML-based approach is developed for the prediction of main parameters of material efficacy, i.e., specific absorption rate (SAR) for hyperthermia and r1 /r2 relaxivities in MRI, with parameters of nanoparticles as well as experimental conditions as descriptors. For that, a unique database with more than 980 magnetic nanoparticles collected from scientific articles is assembled. Using this data, several tree-based ensemble models are trained to predict SAR, r1 and r2 relaxivity. After hyperparameter optimization, models reach performances of R2 = 0.86, R2 = 0.78, and R2 = 0.75, respectively. Testing the models on samples unseen during the training shows no performance drops. Finally, DiMag, an open access resource created to guide synthesis of novel nanosized magnets for MRI and hyperthermia treatment with machine learning and boost development of new biomedical agents, is developed.

Perioperative omega-3 fatty acids fail to confer protection in liver surgery: Results of a multicentric, double-blind, randomized controlled trial.

BACKGROUND & AIMS: In a variety of animal models, omega-3 polyunsaturated fatty acids (Ω3-FAs) conferred strong protective effects, alleviating hepatic ischemia/reperfusion injury and steatosis, as well as enhancing regeneration after major tissue loss. Given these benefits along with its safety profile, we hypothesized that perioperative administration of Ω3-FAs in patients undergoing liver surgery may ameliorate the postoperative course. The aim of this study was to investigate the perioperative use of Ω3-FAs to reduce postoperative complications after liver surgery. METHODS: Between July 2013 and July 2018, we carried out a multicentric, double-blind, randomized, placebo-controlled trial designed to test whether 2 single intravenous infusions of Omegaven® (Ω3-FAs) vs. placebo may decrease morbidity. The primary endpoints were postoperative complications by severity (Clavien-Dindo classification) integrated within the comprehensive complication index (CCI). RESULTS: A total of 261 patients (132 in the Omegaven and 129 in the placebo groups) from 3 centers were included in the trial. Most cases (87%, n = 227) underwent open liver surgery and 56% (n = 105) were major resections (≥3 segments). In an intention-to-treat analysis including the dropout cases, the mortality rate was 4% and 2% in the Omegaven and placebo groups (odds ratio0.40;95% CI 0.04-2.51; p = 0.447), respectively. Any complications and major complications (Clavien-Dindo ≥ 3b) occurred in 46% vs. 43% (p = 0.709) and 12% vs. 10% (p = 0.69) in the Omegaven and placebo groups, respectively. The mean CCI was 17 (±23) vs.14 (±20) (p = 0.417). An analysis excluding the dropouts provided similar results. CONCLUSIONS: The routine perioperative use of 2 single doses of intravenous Ω3-FAs (100 ml Omegaven) cannot be recommended in patients undergoing liver surgery (Grade A recommendation). LAY SUMMARY: Despite strong evidence of omega-3 fatty acids having liver-directed, anti-inflammatory and pro-regenerative action in various rodent models, 2 single omega-3 fatty acid infusions given to patients before and during liver surgery failed to reduce complications. Because single omega-3 fatty acid infusions failed to confer liver protection in this trial, they cannot currently be recommended. TRIAL REGISTRATION: ClinicalTrial.gov: ID: NCT01884948; Institution Ethical Board Approval: KEK-ZH-Nr. 2010-0038; Swissmedic Notification: 2012DR3215.

Comparative analysis of learning curve in complex robot-assisted and laparoscopic liver resection.

BACKGROUND: There is no comparative analysis of the learning curves for robot-assisted and laparoscopic liver resection. We aimed to compare learning curves in complex robotic and conventional laparoscopic liver resections with regards to estimation of the difficulty index score. METHODS: The results of 131 consecutive liver resections were analyzed retrospectively (40 robot-assisted and 91 laparoscopic). The learning curve evaluation was based on calculation of procedures number before significant change of the difficulty index for minimally invasive liver resection or the rate of posterosuperior segments resection. Groups of early and late experience were compared in every type of approach (robot-assisted and laparoscopic). RESULTS: Significant increase of difficulty index (from 5.0 [3.0-7.7] to 7.3 [4.3-10.2]) of robotic procedures required 16 procedures. It was necessary to perform 29 laparoscopic resections in order to significantly increase the rate of laparoscopic posterosuperior segments resection but without significant increase of difficulty index. The implementation of minimally invasive liver resection started with the robotic approach. CONCLUSION: The learning curve for robot-assisted liver resections is shorter in comparison with laparoscopic resections. The inclusion of robot-assisted resections in a minimally invasive liver surgery program may be useful to rapidly increase the complexity of laparoscopic liver resections.

"A randomized, double-blind study of the effects of omega-3 fatty acids (Omegaven) on outcome after major liver resection".

BACKGROUND: The body is dependent on the exogenous supply of omega-3 polyunsaturated fatty acids (n3-PUFA). These essential fatty acids are key players in regulating metabolic signaling but also exert anti-inflammatory and anti-carcinogenic properties. The liver is a major metabolic organ involved in fatty acid metabolism. Under experimental conditions, n3-PUFA exert beneficial effect on hepatic steatosis, regeneration and inflammatory insults such as ischemic injury after surgery. Some of these effects have also been observed in human subjects. However, it is unclear whether perioperative administration of n3-PUFA is sufficient to protect the liver from ischemic injury. Therefore, we designed a randomized controlled trial (RCT) assessing n3-PUFA (pre-) conditioning strategies in patients scheduled for liver surgery. METHODS/DESIGN: The Omegaven trial is a multi-centric, double-blind, randomized, placebo- controlled trial applying two single doses of Omegaven or placebo on 258 patients undergoing major liver resection. Primary endpoints are morbidity and mortality one month after hospital discharge, defined by the Clavien- Dindo classification of surgical complications (Ann Surg 240(2):205-13, 2004) as well as the Comprehensive Complication Index (CCI) (Ann Surg 258(1):1-7, 2013). Secondary outcome variables include length of Intensive Care Unit (ICU) and hospital stay, postoperative liver function tests, fatty acid and eicosanoid concentration, inflammatory markers in serum and in liver tissue. An interim analysis is scheduled after the first 30 patients per randomization group. DISCUSSION: Long-term administration of n3-PUFA have a beneficial effect on metabolism and hepatic injury. Patients often require surgery without much delay, thus long-term n3-PUFA uptake is not possible. Also, lack of compliance may lead to incomplete n3-PUFA substitution. Hence, perioperative Omegaven™ may provide an easy and controllable way to ensure hepaative application of tic protection. TRIAL REGISTRATION: ClinicalTrial.gov: ID: NCT01884948 , registered June 14, 2013; Institution Ethical Board Approval: KEK-ZH-Nr. 2010-0038; Swissmedic Notification: 2012DR3215.

Cell-Free Tumor DNA Detection-Based Liquid Biopsy of Plasma and Bile in Patients with Various Pancreatic Neoplasms.

The key challenge of cell-free tumor DNA (cftDNA) analysis in pancreatic ductal adenocarcinoma (PDAC) is overcoming its low detection rate, which is mainly explained by the overall scarcity of this biomarker in plasma. Obstructive jaundice is a frequent event in PDAC, which enables bile collection as a part of routine treatment. The aim of this study was to evaluate the performance of KRAS-mutated cftDNA detection-based liquid biopsy of plasma and bile in patients with pancreatic neoplasms using digital droplet PCR. The study included healthy volunteers (n = 38), patients with PDAC (n = 95, of which 20 had obstructive jaundice) and other pancreatic neoplasms (OPN) (n = 18). The sensitivity and specificity compared to the control group were 61% and 100% (AUC-ROC-0.805), and compared to the OPN group, they were 61% and 94% (AUC-ROC-0.794), respectively. Bile exhibited higher cftDNA levels than plasma (248.6 [6.743; 1068] vs. 3.26 [0; 19.225] copies/mL) and a two-fold higher detection rate (p < 0.01). Plasma cftDNA levels were associated with distant metastases, tumor size, and CA 19-9 (p < 0.05). The probability of survival was worse in patients with higher levels of cftDNA in plasma (hazard ratio-2.4; 95% CI: 1.3-4.6; p = 0.005) but not in bile (p > 0.05). Bile is a promising alternative to plasma in patients with obstructive jaundice, at least for the diagnostic purposes of liquid biopsy.

Pancreatectomy with En Bloc Superior Mesenteric Vein and All Its Tributaries Resection without PV/SMV Reconstruction for "Low" Locally Advanced Pancreatic Head Cancer.

The "vein definition" for locally advanced pancreatic ductal adenocarcinoma (LA PDAC) assumes portal-to-superior mesenteric vein (PV/SMV) unreconstructability due to tumor involvement or occlusion. Radical pancreatectomies with SMV resection without PV/SMV reconstruction are scarcely discussed in the literature. Retrospective analysis of 19 radical pancreatectomies for "low" LA PDAC with SMV and all its tributaries resection without PV/SMV reconstruction has shown zero mortality; overall morbidity-56%; Dindo-Clavien-3-10.5%; R0-rate-82%; mean operative procedure time-355 ± 154 min; mean blood loss-330 ± 170 mL; delayed gastric emptying-25%; and clinically relevant postoperative pancreatic fistula-8%. In three cases, surgery was associated with superior mesenteric (n2) and common hepatic artery (n1) resection. Surgery was completed without vein reconstruction (n13) and with inferior mesenteric-to-splenic anastomosis (n6). There were no cases of liver, gastric, or intestinal ischemia. A specific complication of the SMV resection without reconstruction was 2-3 days-long intestinal edema (48%). Median overall survival was 25 months, and median progression-free survival was 18 months. All the relapses, except two, were distant. The possibility of successful SMV resection without PV/SMV reconstruction can be predicted before surgery by CT-based reconstructions. The mandatory anatomical conditions for the procedure were as follows: (1) preserved SMV-SV confluence; (2) occluded SMV for any reason (tumor or thrombus); (3) well-developed inferior mesenteric vein collaterals with dilated intestinal veins; (4) no right-sided vein collaterals; and (5) no varices in the upper abdomen. Conclusion: "Low" LA PDACs involving SMV with all its tributaries can be radically and safely resected in highly and specifically selected cases without PV/SMV reconstruction with an acceptable survival rate.

Hemodynamic, Surgical and Oncological Outcomes of 40 Distal Pancreatectomies with Celiac and Left Gastric Arteries Resection (DP CAR) without Arterial Reconstructions and Preoperative Embolization.

DPCAR's short- and long-term outcomes are highly diverse, while the causes and prevention of ischemic complications are unclear. To assess oncological, surgical, and hemodynamic outcomes of 40 consecutive DPCARs for pancreatic (n37) and gastric tumors (n3) (2009−2021), retrospective analyses of mortality, morbidity, survival, and hemodynamic consequences after DPCAR were undertaken using case history data, IOUS, and pre- and postoperative CT measurements. In postoperative complications (42.5%), the pancreatic fistula was the most frequent event (27%), 90-day mortality was 7.5. With 27 months median follow-up, median overall (OS) and progression-free survival (PFS) for PDAC were 29 and 18 months, respectively; with 1-, 3-, and 5-years, the OS were 90, 60, and 28%, with an R0-resection rate of 92.5%. Liver and gastric ischemia developed in 0 and 5 (12.5%) cases. Comparison of clinical and vascular geometry data revealed fast adaptation of collateral circulation, insignificant changes in proper hepatic artery diameter, and high risk of ischemic gastropathy if the preoperative diameter of pancreaticoduodenal artery was <2 mm. DP CAR can be performed with acceptable morbidity and survival. OS and RFS in this super-selective cohort were compared to those for resectable cancer. The changes in the postoperative arterial geometry could explain the causes of ischemic complications and determine directions for their prevention.