Machine Learning Predictive Model to Guide Treatment Allocation for Recurrent Hepatocellular Carcinoma After Surgery.

Importance: Clear indications on how to select retreatments for recurrent hepatocellular carcinoma (HCC) are still lacking. Objective: To create a machine learning predictive model of survival after HCC recurrence to allocate patients to their best potential treatment. Design, Setting, and Participants: Real-life data were obtained from an Italian registry of hepatocellular carcinoma between January 2008 and December 2019 after a median (IQR) follow-up of 27 (12-51) months. External validation was made on data derived by another Italian cohort and a Japanese cohort. Patients who experienced a recurrent HCC after a first surgical approach were included. Patients were profiled, and factors predicting survival after recurrence under different treatments that acted also as treatment effect modifiers were assessed. The model was then fitted individually to identify the best potential treatment. Analysis took place between January and April 2021. Exposures: Patients were enrolled if treated by reoperative hepatectomy or thermoablation, chemoembolization, or sorafenib. Main Outcomes and Measures: Survival after recurrence was the end point. Results: A total of 701 patients with recurrent HCC were enrolled (mean [SD] age, 71 [9] years; 151 [21.5%] female). Of those, 293 patients (41.8%) received reoperative hepatectomy or thermoablation, 188 (26.8%) received sorafenib, and 220 (31.4%) received chemoembolization. Treatment, age, cirrhosis, number, size, and lobar localization of the recurrent nodules, extrahepatic spread, and time to recurrence were all treatment effect modifiers and survival after recurrence predictors. The area under the receiver operating characteristic curve of the predictive model was 78.5% (95% CI, 71.7%-85.3%) at 5 years after recurrence. According to the model, 611 patients (87.2%) would have benefited from reoperative hepatectomy or thermoablation, 37 (5.2%) from sorafenib, and 53 (7.6%) from chemoembolization in terms of potential survival after recurrence. Compared with patients for which the best potential treatment was reoperative hepatectomy or thermoablation, sorafenib and chemoembolization would be the best potential treatment for older patients (median [IQR] age, 78.5 [75.2-83.4] years, 77.02 [73.89-80.46] years, and 71.59 [64.76-76.06] years for sorafenib, chemoembolization, and reoperative hepatectomy or thermoablation, respectively), with a lower median (IQR) number of multiple recurrent nodules (1.00 [1.00-2.00] for sorafenib, 1.00 [1.00-2.00] for chemoembolization, and 2.00 [1.00-3.00] for reoperative hepatectomy or thermoablation). Extrahepatic recurrence was observed in 43.2% (n = 16) for sorafenib as the best potential treatment vs 14.6% (n = 89) for reoperative hepatectomy or thermoablation as the best potential treatment and 0% for chemoembolization as the best potential treatment. Those profiles were used to constitute a patient-tailored algorithm for the best potential treatment allocation. Conclusions and Relevance: The herein presented algorithm should help in allocating patients with recurrent HCC to the best potential treatment according to their specific characteristics in a treatment hierarchy fashion.

Impact of COVID-19 on the oncological outcomes of colorectal cancer surgery in northern Italy in 2019 and 2020: multicentre comparative cohort study.

BACKGROUND: This study compared patients undergoing colorectal cancer surgery in 20 hospitals of northern Italy in 2019 versus 2020, in order to evaluate whether COVID-19-related delays of colorectal cancer screening resulted in more advanced cancers at diagnosis and worse clinical outcomes. METHOD: This was a retrospective multicentre cohort analysis of patients undergoing colorectal cancer surgery in March to December 2019 versus March to December 2020. Independent predictors of disease stage (oncological stage, associated symptoms, clinical T4 stage, metastasis) and outcome (surgical complications, palliative surgery, 30-day death) were evaluated using logistic regression. RESULTS: The sample consisted of 1755 patients operated in 2019, and 1481 in 2020 (both mean age 69.6 years). The proportion of cancers with symptoms, clinical T4 stage, liver and lung metastases in 2019 and 2020 were respectively: 80.8 versus 84.5 per cent; 6.2 versus 8.7 per cent; 10.2 versus 10.3 per cent; and 3.0 versus 4.4 per cent. The proportions of surgical complications, palliative surgery and death in 2019 and 2020 were, respectively: 34.4 versus 31.9 per cent; 5.0 versus 7.5 per cent; and 1.7 versus 2.4 per cent. Cancers in 2020 (versus 2019) were more likely to be symptomatic (odds ratio 1.36 (95 per cent c.i. 1.09 to 1.69)), clinical T4 stage (odds ratio 1.38 (95 per cent c.i. 1.03 to 1.85)) and have multiple liver metastases (odds ratio 2.21 (95 per cent c.i. 1.24 to 3.94)), but were not more likely to be associated with surgical complications (odds ratio 0.79 (95 per cent c.i. 0.68 to 0.93)). CONCLUSION: Colorectal cancer patients who had surgery between March and December 2020 had an increased risk of advanced disease in terms of associated symptoms, cancer location, clinical T4 stage and number of liver metastases.

Learning curve of three European centers in laparoscopic, hybrid laparoscopic, and robotic pancreatoduodenectomy.

INTRODUCTION: There are limited numbers of high-volume centers performing minimally invasive pancreatoduodenectomy (MIPD) routinely. Several approaches to MIPD have been described. Aim of this analysis was to show the learning curve of three different approaches to MIPD. Focus was on determining the number of cases necessary to obtain proficient level in MIPD. PATIENTS AND METHODS: Retrospective study wherein outcomes of 300 consecutive patients at three centers-at each center the initial 100 consecutive patients undergoing MIPD for malignant and benign tumors of the head of the pancreas and perimpullary area, performed by three experienced surgeons were collected and analyzed. RESULTS: Overall, 300 patients after MIPD were included: the three different cohorts (laparoscopic n = 100, hybrid n = 100, robotic n = 100). CUSUM analysis of operating time in each center demonstrated that the plateau for laparoscopic PD was n = 61, for hybrid PDes was n = 32 and for robotic PD was n = 68. Median operative time for laparoscopic, hybrid, and robotic approaches was 395 min, 404 min, 510 min, respectively. Intraoperative blood loss for laparoscopic PD, hybrid PD, and robotic PD was 250 ml, 250 ml, and 413 ml, respectively. Delayed gastric emptying occurred 12% in laparoscopic cohort, 10% in hybrid, and 53% in robotic cohort. Major complications (Clavien-Dindo III/IV) rate for laparoscopic PD, hybrid PD, and robotic PD was 32%, 37%, and 22% with 5% death in each cohorts, respectively. CONCLUSION: This analysis of the learning curve of three European centers found a shorter learning curve with hybrid PD as compared to laparoscopic and robotic PD. In implementation of a MIPD program, a stepwise approach might be beneficial.

Implementation and outcome of minor and major minimally invasive liver surgery in the Netherlands.

BACKGROUND: While most of the evidence on minimally invasive liver surgery (MILS) is derived from expert centers, nationwide outcomes remain underreported. This study aimed to evaluate the implementation and outcome of MILS on a nationwide scale. METHODS: Electronic patient files were reviewed in all Dutch liver surgery centers and all patients undergoing MILS between 2011 and 2016 were selected. Operative outcomes were stratified based on extent of the resection and annual MILS volume. RESULTS: Overall, 6951 liver resections were included, with a median annual volume of 50 resections per center. The overall use of MILS was 13% (n = 916), which varied from 3% to 36% (P < 0.001) between centers. The nationwide use of MILS increased from 6% in 2011 to 23% in 2016 (P < 0.001). Outcomes of minor MILS were comparable with international studies (conversion 0-13%, mortality <1%). In centers which performed ≥20 MILS annually, major MILS was associated with less conversions (14 (11%) versus 41 (30%), P < 0.001), shorter operating time (184 (117-239) versus 200 (139-308) minutes, P = 0.010), and less overall complications (37 (30%) versus 58 (42%), P = 0.040). CONCLUSION: The nationwide use of MILS is increasing, although large variation remains between centers. Outcomes of major MILS are better in centers with higher volumes.

Minimally Invasive Versus Open Distal Pancreatectomy (LEOPARD): A Multicenter Patient-blinded Randomized Controlled Trial.

OBJECTIVE: This trial followed a structured nationwide training program in minimally invasive distal pancreatectomy (MIDP), according to the IDEAL framework for surgical innovation, and aimed to compare time to functional recovery after minimally invasive and open distal pancreatectomy (ODP). BACKGROUND: MIDP is increasingly used and may enhance postoperative recovery as compared with ODP, but randomized studies are lacking. METHODS: A multicenter patient-blinded randomized controlled superiority trial was performed in 14 centers between April 2015 and March 2017. Adult patients with left-sided pancreatic tumors confined to the pancreas without vascular involvement were randomly assigned (1:1) to undergo MIDP or ODP. Patients were blinded for type of surgery using a large abdominal dressing. The primary endpoint was time to functional recovery. Analysis was by intention to treat. This trial was registered with the Netherlands Trial Register (NTR5689). RESULTS: Time to functional recovery was 4 days [interquartile range (IQR) 3-6) in 51 patients after MIDP versus 6 days (IQR 5-8) in 57 patients after ODP (P < 0.001). The conversion rate of MIDP was 8%. Operative blood loss was less after MIDP (150 vs 400 mL; P < 0.001), whereas operative time was longer (217 vs 179 minutes; P = 0.005). The Clavien-Dindo grade ≥III complication rate was 25% versus 38% (P = 0.21). Delayed gastric emptying grade B/C was seen less often after MIDP (6% vs 20%; P = 0.04). Postoperative pancreatic fistulas grade B/C were seen in 39% after MIDP versus 23% after ODP (P = 0.07), without difference in percutaneous catheter drainage (22% vs 20%; P = 0.77). Quality of life (day 3-30) was better after MIDP as compared with ODP, and overall costs were non-significantly less after MIDP. No 90-day mortality was seen after MIDP versus 2% (n = 1) after ODP. CONCLUSIONS: In patients with left-sided pancreatic tumors confined to the pancreas, MIDP reduces time to functional recovery compared with ODP. Although the overall rate of complications was not reduced, MIDP was associated with less delayed gastric emptying and better quality of life without increasing costs.

Minimally invasive versus open distal pancreatectomy (LEOPARD): study protocol for a randomized controlled trial.

BACKGROUND: Observational cohort studies have suggested that minimally invasive distal pancreatectomy (MIDP) is associated with better short-term outcomes compared with open distal pancreatectomy (ODP), such as less intraoperative blood loss, lower morbidity, shorter length of hospital stay, and reduced total costs. Confounding by indication has probably influenced these findings, given that case-matched studies failed to confirm the superiority of MIDP. This accentuates the need for multicenter randomized controlled trials, which are currently lacking. We hypothesize that time to functional recovery is shorter after MIDP compared with ODP even in an enhanced recovery setting. METHODS: LEOPARD is a randomized controlled, parallel-group, patient-blinded, multicenter, superiority trial in all 17 centers of the Dutch Pancreatic Cancer Group. A total of 102 patients with symptomatic benign, premalignant or malignant disease will be randomly allocated to undergo MIDP or ODP in an enhanced recovery setting. The primary outcome is time (days) to functional recovery, defined as all of the following: independently mobile at the preoperative level, sufficient pain control with oral medication alone, ability to maintain sufficient (i.e. >50%) daily required caloric intake, no intravenous fluid administration and no signs of infection. Secondary outcomes are operative and postoperative outcomes, including clinically relevant complications, mortality, quality of life and costs. DISCUSSION: The LEOPARD trial is designed to investigate whether MIDP reduces the time to functional recovery compared with ODP in an enhanced recovery setting. TRIAL REGISTRATION: Dutch Trial Register, NTR5188 . Registered on 9 April 2015.

Carboxypeptidase-B activation peptide, a marker of pancreatic acinar injury, but not L-selectin, a marker of neutrophil activation, predicts severity of acute pancreatitis.

BACKGROUND: Severity prediction is difficult early in the course of acute pancreatitis. Markers of pancreatic injury, or inflammatory activation are candidate markers of severity. The aim of the present study was to assess predictive abilities of carboxypeptidase-B activation peptide (CAPAP-B) and soluble L-selectin (sL-selectin) using samples collected on admission to hospital. METHODS: Patients with acute pancreatitis and disease (acute abdomen) and normal controls were studied. Samples were collected at admission and daily for 5 days. There were significant differences between mild and severe pancreatitis in urinary and plasma CAPAP-B on admission, C-reactive protein on day 3 and acute physiology and chronic health evaluation (APACHE)-II scores. Prediction of severity with CAPAP-B on admission was as good as with APACHE-II score after 48 h. Carboxypeptidase-B activation peptide was not raised in disease controls. By contrast, sL-selectin was lowered in all cases of acute pancreatitis, and in disease controls. There was no difference between mild and severe pancreatitis. CONCLUSION: Urinary CAPAP-B, a marker of acinar injury, can be used to predict severity of acute pancreatitis at the time of admission to hospital, but sL-selectin has no value in this regard. The extent of acinar injury may be a more important early marker of severity than markers of inflammatory activation.

Surgical treatment for liver metastases from colorectal carcinoma: results of 228 patients.

BACKGROUND/AIMS: Liver metastases are a very common event. Multiple choices of therapies can be used. The aim of this paper is to analyze results and methods of a single institution series of 228 consecutive patients with colorectal liver metastases. METHODOLOGY: 228 consecutive patients underwent hepatic resection for colorectal liver metastases. From different periods intraoperative ultrasound, intraoperative histological examination, locoregional intra-arterial chemotherapy, and radiofrequency thermal ablation were introduced. RESULTS: Operative mortality was 0.9%. Mean follow-up was 29.5 months. Overall survival was 16% and 9% at 5 and 10 years. 5-year survival was 23% and 6% for patients with single and multiple metastases respectively. For patients with extrahepatic metastatic single lesion 5-year survival was 15%. From the start of intraoperative ultrasound use, 5-year survival was 9% and 27% for patients with multiple and single metastases. Five-year survival for re-resected patients was 13%. Overall survival at 1 and 3 years was 90% and 58% in patients treated with HAI and systemic chemotherapy (disease-free 70% and 47%) and 94% and 12% in patients treated with systemic chemotherapy alone after radical resection (disease-free 53% and 0%). CONCLUSIONS: Aggressive approach, re-resections, intraoperative ultrasound staging, intra-arterial chemotherapy and radiofrequency thermal ablation are justified in multimodal therapeutic strategy of colorectal metastases and seem to improve patients' survival.

A case of rapid intrahepatic dissemination of hepatocellular carcinoma after radiofrequency thermal ablation.

BACKGROUND: Radiofrequency ablation (RFA) is a novel technique for the treatment of liver malignancies that is becoming increasingly more popular because of its feasibility, effectivity, repeatability, and safety. However, an increased number of complications after RFA has been reported in literature. The aim of this paper is to discuss the possible role of RFA in rapid intrahepatic spreading of hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We treated a 66-year-old woman who had a 3.5-cm HCC with two courses of percutaneous RFA using a modified needle with seven hooks. The effectiveness of the treatment was assessed 1 month later by enhanced computed tomography. RESULTS: Two courses of treatment were needed owing to the nodule position (close to the inferior vena cava). Computed tomography scan performed 1 month after the second RFA showed an intrahepatic arteriovenous fistula. Angiography performed after 1 month showed a rapid intrahepatic spreading of HCC. CONCLUSIONS: Radiofrequency ablation can create an arteriovenous fistula that can facilitate migration of tumoral cells from the nodule to the hepatic portal system and rapid intrahepatic dissemination of HCC.

Prophylactic pylorus-preserving gastric transposition in unresectable carcinoma of the pancreatic head.

Patients with unresectable carcinoma of the pancreas head often present with intestinal obstruction during their disease, but the efficacy of a prophylactic gastrointestinal anastomosis is still under debate. Some investigators consider the population of patients who eventually develop this complication too small to justify the prophylactic use of this procedure. When done prophylactically, the gastrointestinal anastomosis tends not to function and close. Other surgeons have proposed supplementing the gastric bypass using technique alternatives. To demonstrate the low morbidity, the feasibility, and the advantages and disadvantages of this procedure, we report our personal experience with transection of the duodenum and re-establishment of the continuity of the alimentary tract with a duodenojejunal anastomosis performed in 34 patients.