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- Cutaneous Metastasis in Advanced Gastric Cancer.Publication . Silva, André; Monteiro, Nuno; Mateia, Estanislau; Santos, Isa; Correia, Margarida
- A Composite Endpoint of Liver Surgery (CELS): Development and Validation of a Clinically Relevant Endpoint Requiring a Smaller Sample Size.Publication . Kawashima, Jun; Akabane, Miho; Endo, Yutaka; Woldesenbet, Selamawit; Khalil, Mujtaba; Sahara, Kota; Ruzzenente, Andrea; Aldrighetti, Luca; Bauer, Todd W; Pinto Marques, Hugo; Lopes, Rita; Oliveira, Sara; Martel, Guillaume; Popescu, Irinel; Weiss, Mathew J; Kitago, Minoru; Poultsides, George; Sasaki, Kazunari; Maithel, Shishir K; Hugh, Tom; Gleisner, Ana; Aucejo, Federico; Pulitano, Carlo; Shen, Feng; Cauchy, François; Groot Koerkamp, Bas; Endo, Itaru; Pawlik, Timothy MBackground: The feasibility of trials in liver surgery using a single-component clinical endpoint is low because single endpoints require large samples due to their low incidence. The current study sought to develop and validate a novel composite endpoint of liver surgery (CELS) to facilitate the generation of more feasible and robust high-level evidence in the field of liver surgery. Methods: Patients who underwent curative-intent hepatectomy for hepatocellular carcinoma, intrahepatic cholangiocarcinoma, or colorectal liver metastasis were identified using a multi-institutional database. Components of CELS were selected based on perioperative liver surgery-specific complications using univariable logistic regression models. The association of CELS with prolonged length of stay (LOS) and surgery-related death was evaluated and externally validated. Sample sizes were calculated for both individual outcomes and CELS. Results: Among 1958 patients, 377 (19.3%) met CELS criteria based on postoperative bile leak (n = 221, 11.3%), post-hepatectomy liver failure (n = 71, 3.6%), post-hepatectomy hemorrhage (n = 38, 1.9%), or intraoperative blood loss of 2000 ml or greater (n = 101, 5.2%). CELS demonstrated favorable discriminative accuracy of surgery-related death (analytic cohort: area under the curve [AUC], 0.79 vs external validation cohort: AUC, 0.85). In addition LOS was longer among the patients with a positive CELS (analytic cohort: 14 vs. 9 days [p < 0.001] vs. the validation cohort: 10 vs. 6 days [p < 0.001]). Relative to individual endpoints, CELS allowed a 45.8-91.6% reduction in sample size. Conclusion: CELS effectively predicted surgery-related death and can be used as a standardized, clinically relevant endpoint in prospective trials, facilitating smaller sample sizes and enhancing feasibility compared with single quality outcome metrics.
- Predictive Model for Very Early Recurrence of Patients with Perihilar Cholangiocarcinoma: a Machine Learning Approach.Publication . Kawashima, Jun; Endo, Yutaka; Rashid, Zayed; Altaf, Abdullah; Woldesenbet, Selamawit; Tsilimigras, Diamantis I; Guglielmi, Alfredo; Pinto Marques, Hugo; Maithel, Shishir K; Groot Koerkamp, Bas; Pulitano, Carlo; Aucejo, Federico; Endo, Itaru; Pawlik, Timothy MBackground: Although offering the best chance of potential cure for patients with localized perihilar cholangiocarcinoma (pCCA), resection has been associated with high morbidity and sometimes poor long-term outcomes due to recurrence. We sought to develop a predictive model to identify individuals at high risk for very early recurrence (VER) after curative-intent surgery for pCCA. Methods: Patients who underwent curative-intent surgery for pCCA between 2000-2023 were identified from a multi-institutional database. An eXtreme Gradient Boosting (XGBoost) model was developed to estimate the risk of VER, defined as recurrence within 6 months after resection. The relative importance of clinicopathologic factors was determined using SHapley Additive exPlanations (SHAP) values. Results: Among 434 patients undergoing curative-intent resection for pCCA, 65 (15.0%) patients developed VER. Median overall survival (OS) among patients with and without VER was 8.4 [interquartile range (IQR) 6.6-11.3] versus 38.5 (IQR 31.9-45.7) months (P<0.001). An XGBoost model was able to stratify patients relative to the risk of VER [low-risk: 6-month recurrence-free survival (RFS) 94.6% vs. intermediate-risk: 6-month RFS 88.3% vs. high-risk: 6-month RFS 40.0%; P<0.001]. Similarly, 3-year OS incrementally worsened based on VER risk (low-risk: 75.3% vs. intermediate-risk: 19.5% vs. high-risk: 4.6%; P<0.001). The SHAP algorithm identified age, preoperative carbohydrate antigen 19-9 (CA19-9) levels, tumor size and differentiation/grade, as well as lymph node metastasis as the five most important predictors of VER. The predictive accuracy of the model was good in the training [c-index: 0.74, 95% confidence interval (CI): 0.67-0.81] and internal validation (c-index: 0.77, 95% CI: 0.71-0.83) cohorts. An easy-to-use risk calculator for VER was developed and made available online at: https://junkawashima.shinyapps.io/VER_hilar/. Conclusions: A novel, machine learning based model was able to predict accurately the chance of VER after curative-intent resection of pCCA. In turn, the tool may help surgeons in the selection of patients likely to benefit the most from resection, as well as counsel individuals about the anticipated risk of recurrence in the early post-operative period.
- Lymphocyte-C-Reactive Protein Ratio: Impact on Prognosis of Patients Following Resection of Primary Liver Cancer.Publication . Altaf, Abdullah; Baldo, Andrea; Khalil, Mujtaba; Rashid, Zayed; Akabane, Miho; Zindani, Shahzaib; Sarfraz, Azza; Ruzzenente, Andrea; Aldrighetti, Luca; Bauer, Todd W; Pinto Marques, Hugo; Martel, Guillaume; Popescu, Irinel; Weiss, Mathew J; Kitago, Minoru; Poultsides, George; Maithel, Shishir K; Lam, Vincent; Hugh, Tom; Gleisner, Ana; Shen, Feng; Cauchy, François; Koerkamp, Bas G; Endo, Itaru; Pawlik, Timothy MObjective: We sought to characterize the prognostic value of lymphocyte-C-reactive protein ratio (LCR) among patients undergoing liver resection (LR) for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Methods: Patients who underwent curative-intent LR for HCC and ICC between 2000 and 2023 were identified from a multiinstitutional database. The prognostic value of nine different inflammatory markers were evaluated relative to short- (i.e., postoperative morbidity) and long-term (recurrence-free survival [RFS] and overall survival [OS]) outcomes. Results: Among 715 patients, 499 (69.8%) and 216 (30.2%) individuals were included in the derivation and validation cohorts, respectively. Patients with advanced disease and poor tumor biology had lower median levels of LCR. An optimal LCR cutoff threshold of 6100 was identified in the derivation cohort. LCR demonstrated the highest accuracy to predict RFS and OS, with areas under the ROC curve of 0.724 and 0.716, respectively. After adjusting for relevant clinicodemographic factors, lower LCR remained associated with higher odds of postoperative complications (OR: 1.98 [95% CI: 1.27-3.10] and p = 0.003) and particularly, infectious complications (OR: 2.80 [95% CI: 1.57-5.01] and p < 0.001). A lower LCR was independently associated with worse RFS (HR: 2.43 [95% CI: 1.41-3.83] and p = 0.002) and OS (HR: 2.95 [95% CI: 2.10-4.16] and p < 0.001). The prognostic ability of LCR for short- and long-term outcomes performed well in an independent validation cohort. Conclusion: LCR was strongly associated with risk of postoperative morbidity as well as worse RFS and OS among patients undergoing LR for HCC and ICC. Preoperative LCR assessment can aid surgeons in the preoperative risk-stratification of patients undergoing surgery for primary liver cancer.
- The Influence of Tumor Burden Score and Lymph Node Metastasis on the Survival Benefit of Adjuvant Chemotherapy in Intrahepatic Cholangiocarcinoma.Publication . Kawashima, Jun; Endo, Yutaka; Woldesenbet, Selamawit; Khalil, Mujtaba; Akabane, Miho; Cauchy, François; Shen, Feng; Maithel, Shishir; Popescu, Irinel; Kitago, Minoru; Weiss, Matthew J; Martel, Guillaume; Pulitano, Carlo; Aldrighetti, Luca; Poultsides, George; Ruzzente, Andrea; Bauer, Todd W; Gleisner, Ana; Pinto Marques, Hugo; Groot Koerkamp, Bas; Endo, Itaru; Pawlik, Timothy MIntroduction: While postoperative adjuvant chemotherapy (AC) is generally recommended for intrahepatic cholangiocarcinoma (ICC), its benefit remains debated. This study aimed to identify patients that may benefit from AC following liver resection of ICC. Methods: Patients who underwent liver resection for ICC between 2000 and 2023 were identified from an international multi-institutional database. Individual multivariable Cox models were used to evaluate the interaction between each prognostic factor and the effect of AC on survival. Results: Among 1412 patients, 431 (30.5%) received AC. Both higher tumor burden score (TBS; hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.91-1.00; p = 0.033) and metastatic lymph node status (HR 0.58, 95% CI 0.38-0.89; p = 0.014) demonstrated interactions with the survival benefit from receipt of AC. Interaction plots highlighted how AC was associated with improved survival beyond a TBS of approximately 6. Notably, among 555 (39.3%) patients with TBS <6 and N0 or Nx status, 5-year overall survival (OS) was no different between patients who received AC versus individuals who did not (55.1% [95% CI 48.9-62.1] vs. 58.7% [95% CI 49.8-69.2]; p = 0.900). In contrast, among 857 (60.7%) patients with TBS ≥6 or N1 status, AC was associated with improved 5-year OS (30.7% [95% CI 26.2-36.0] vs. 33.0% [95% CI 26.9-40.5]; p = 0.018). Conclusions: TBS and lymph node status may be useful in a multidisciplinary setting to inform decisions about AC planning for ICC patients following curative-intent resection.
- Enhancing Recurrence-Free Survival Prediction in Hepatocellular Carcinoma: A Time-Updated Model Incorporating Tumor Burden and AFP Dynamics.Publication . Akabane, Miho; Kawashima, Jun; Altaf, Abdullah; Woldesenbet, Selamawit; Cauchy, François; Aucejo, Federico; Popescu, Irinel; Kitago, Minoru; Martel, Guillaume; Ratti, Francesca; Aldrighetti, Luca; Poultsides, George A; Imaoka, Yuki; Ruzzenente, Andrea; Endo, Itaru; Gleisner, Ana; Pinto Marques, Hugo; Oliveira, Sara; Balaia, Jorge; Lam, Vincent; Hugh, Tom; Bhimani, Nazim; Shen, Feng; Pawlik, Timothy MBackground: Existing models to predict recurrence-free survival (RFS) after hepatectomy for hepatocellular carcinoma (HCC) rely on static preoperative factors such as alpha-fetoprotein (AFP) and tumor burden score (TBS). These models overlook dynamic postoperative AFP changes, which may reflect evolving recurrence risk. We sought to develop a dynamic, real-time model integrating time-updated AFP values with TBS for improved recurrence prediction. Patients and methods: Patients undergoing curative-intent hepatectomy for HCC (2000-2023) were identified from an international, multi-institutional database with RFS as the primary outcome. AFP trajectory was monitored from preoperative to 6- and 12-month postoperative values, using time-varying Cox regression with AFP as a time-dependent covariate. The predictive accuracy of this time-updated model was compared with a static preoperative Cox model excluding postoperative AFP. Results: Among 1911 patients, AFP trajectories differed between recurrent and nonrecurrent cases. While preoperative AFP values were similar, recurrent cases exhibited higher AFP at 6 and 12 months. Multivariable analysis identified TBS (hazard ratio (HR):1.043 [95% confidence interval (CI): 1.002-1.086]; p = 0.039) and postoperative log AFP dynamics (HR:1.216 [CI 1.132-1.305]; p < 0.001) as predictors. Contour plots depicted TBS's influence decreasing over time, while postoperative AFP became more predictive. The time-varying Cox model was created to update RFS predictions continuously on the basis of the latest AFP values. The preoperative Cox model, developed with age, AFP, TBS, and albumin-bilirubin score, had a baseline C-index of 0.61 [0.59-0.63]. At 6 months, the time-varying model's C-index was 0.70 [0.67-0.73] versus 0.59 [0.56-0.61] for the static model; at 12 months, it was 0.70 [0.66-0.73] versus 0.56 [0.53-0.59]. The model was made available online ( https://nm49jf-miho-akabane.shinyapps.io/AFPHCC/ ). Conclusions: Incorporating postoperative AFP dynamics into RFS prediction after HCC resection enhanced prediction accuracy over time, as TBS's influence decreased. This adaptive, time-varying model provides refined RFS predictions throughout follow-up.
- Impact of Anatomical Resection on Non-transplantable Recurrence Among Patients with Hepatocellular Carcinoma: An International Multicenter Inverse Probability of Treatment Weighting Analysis.Publication . Kawashima, Jun; Endo, Yutaka; Khalil, Mujtaba; Woldesenbet, Selamawit; Akabane, Miho; Ruzzenente, Andrea; Ratti, Francesca; Marques, Hugo; Oliveira, Sara; Balaia, Jorge; Cauchy, François; Lam, Vincent; Poultsides, George; Kitago, Minoru; Popescu, Irinel; Martel, Guillaume; Gleisner, Ana; Hugh, Thomas J; Aldrighetti, Luca; Endo, Itaru; Pawlik, Timothy MBackground: Among patients with hepatocellular carcinoma (HCC), the impact of anatomic resection (AR) versus non-anatomic resection (NAR) on non-transplantable recurrence (NTR) remains poorly defined. We sought to compare the risk of NTR among patients treated with AR versus NAR as the primary surgical strategy for HCC. Patients and methods: Patients with HCC within Milan criteria who underwent curative-intent resection between 2000 and 2020 were identified from an international multi-institutional database. The inverse probability of treatment weighting (IPTW) method was utilized to compare short- and long-term outcomes among patients undergoing AR versus NAR. Results: Among 1038 patients, 747 (72.0%) patients underwent AR, while 291 (28.0%) patients underwent NAR. After IPTW adjustment, patients who underwent AR had better 5-year recurrence-free survival than individuals treated with NAR (63.9 vs. 52.0%; hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.62-0.99); however, there was no difference in 5-year overall survival (80.2 vs. 75.6%; HR 0.76; 95% CI 0.55-1.05). Notably, individuals who underwent AR were less likely to have a NTR versus individuals treated with NAR (3-year NTR 9.8 vs. 14.4%; HR 0.62; 95% CI 0.40-0.96). In particular, AR was associated with a lower risk of NTR among patients with a medium tumor burden score (TBS) (HR 0.53; 95% CI 0.28-0.99), while the benefit among patients with a low TBS was less pronounced (HR 0.73; 95% CI 0.40-1.32). Conclusions: AR was associated with a lower risk of NTR and improved recurrence-free survival (RFS) among patients with HCC, especially individuals with higher TBS. An anatomically defined surgical approach should be strongly considered in patients with a higher HCC tumor burden.
- A Comprehensive Preoperative Predictive Score for Post-Hepatectomy Liver Failure After Hepatocellular Carcinoma Resection Based on Patient Comorbidities, Tumor Burden, and Liver Function: the CTF Score.Publication . Alaimo, Laura; Endo, Yutaka; Lima, Henrique A; Moazzam, Zorays; Shaikh, Chanza Fahim; Ruzzenente, Andrea; Guglielmi, Alfredo; Ratti, Francesca; Aldrighetti, Luca; Pinto Marques, Hugo; Cauchy, François; Lam, Vincent; Poultsides, George A; Popescu, Irinel; Alexandrescu, Sorin; Martel, Guillaume; Hugh, Tom; Endo, Itaru; Pawlik, Timothy MBackground: Post-hepatectomy liver failure (PHLF) is a dreaded complication following liver resection for hepatocellular carcinoma (HCC) with a high mortality rate. We sought to develop a score based on preoperative factors to predict PHLF. Methods: Patients who underwent resection for HCC between 2000 and 2020 were identified from an international multi-institutional database. Factors associated with PHLF were identified and used to develop a preoperative comorbidity-tumor burden-liver function (CTF) predictive score. Results: Among 1785 patients, 106 (5.9%) experienced PHLF. On multivariate analysis, several factors were associated with PHLF including high Charlson comorbidity index (CCI ≥ 5) (OR 2.80, 95%CI, 1.08-7.26), albumin-bilirubin (ALBI) (OR 1.99, 95%CI, 1.10-3.56), and tumor burden score (TBS) (OR 1.06, 95%CI, 1.02-1.11) (all p < 0.05). Using the beta-coefficients of these variables, a weighted predictive score was developed and made available online ( https://alaimolaura.shinyapps.io/PHLFriskCalculator/ ). The CTF score (c-index = 0.67) performed better than Child-Pugh score (CPS) (c-index = 0.53) or Barcelona clinic liver cancer system (BCLC) (c-index = 0.57) to predict PHLF. A high CTF score was also an independent adverse prognostic factor for survival (HR 1.61, 95%CI, 1.12-2.30) and recurrence (HR 1.36, 95%CI, 1.08-1.71) (both p = 0.01). Conclusion: Roughly 1 in 20 patients experienced PHLF following resection of HCC. Patient (i.e., CCI), tumor (i.e., TBS), and liver function (i.e., ALBI) factors were associated with risk of PHLF. These preoperative factors were incorporated into a novel CTF tool that was made available online, which outperformed other previously proposed tools.
- Roux-en-Y Gastric Bypass, Sleeve Gastrectomy, or One Anastomosis Gastric Bypass As Rescue Therapy After Failed Adjustable Gastric Banding: a Multicenter Comparative Study.Publication . Pujol Rafols, Juan; Al Abbas, Amr I; Devriendt, Stefanie; Guerra, Anabela; Herrera, Miguel F; Himpens, Jacques; Pardina, Eva; Peinado-Onsurbe, Julia; Ramos, Almino; Ribeiro, Rui José da Silva; Safadi, Bassem; Sanchez-Aguilar, Hugo; de Vries, Claire; Van Wagensveld, BartBackground: To date, laparoscopic adjustable gastric banding remains the third most commonly performed surgical procedure for weight loss. Some patients fail to get acceptable outcomes and undergo revisional surgery at rates ranging from 7% to 60%. Roux-en-Y gastric bypass (RYGB), one anastomosis gastric bypass (OAGB), and sleeve gastrectomy (SG) are among the most common salvage options for failed laparoscopic adjustable gastric banding. Objective: To compare the outcomes of converting failed laparoscopic adjustable gastric banding to RYGB, OAGB, or SG. Methods: Data collected from 7 experienced bariatric centers around the world were retrospectively collected, reviewed, and analyzed. Final body mass index (BMI), change in BMI, percentage excess BMI loss, and major complications with particular attention to leaks, hemorrhage, and mortality were reported. Results: Of 1219 patients analyzed, 74% underwent RYGB, 16% underwent OAGB, and 10% underwent SG after banding failure. The mean age was 38 years (±10 yr), and 82% of patients were women. The mean follow-up was 33 months. The follow-up rate was 100%, 87%, and 52% at 1, 3, and 5 years, respectively. At the latest follow-up, percentage excess BMI loss >50% was achieved by 75% of RYGB, 85% of OAGB, and 67% of SG patients. Postoperative complications occurred in 13% of patients after RYGB, 5% after OAGB, and 15% after SG. Conclusion: Our data show that it is possible to achieve or maintain significant weight loss with an acceptable complication rate with all 3 surgical options.
- Should Utilization of Lymphadenectomy Vary According to Morphologic Subtype of Intrahepatic Cholangiocarcinoma?Publication . Zhang, Xu-Feng; Lv, Yi; Weiss, Matthew; Popescu, Irinel; Pinto Marques, Hugo; Aldrighetti, Luca; Maithel, Shishir K; Pulitano, Carlo; Bauer, Todd W; Shen, Feng; Poultsides, George A; Soubrane, Oliver; Martel, Guillaume; Koerkamp, B Groot; Itaru, Endo; Pawlik, Timothy MObjective: We sought to evaluate the utilization of lymphadenectomy (LND) and the incidence of lymph node metastasis (LNM) among different morphologic types of intrahepatic cholangiocarcinoma (ICC). Methods: Clinical data of patients undergoing curative-intent resection for ICC between 1990 and 2017 were collected and analyzed. The preoperative nodal status was evaluated by imaging studies, and the morphologic and lymph node (LN) status was collected on final pathology report. Results: Overall, 1032 patients had a mass-forming (MF) or intraductal growth (IG) ICC subtype, whereas 150 patients had a periductal infiltrating (PI) or MF + PI subtype. Among the 924 patients with MF/IG ICC subtype who had nodal assessment on preoperative imaging, 747 (80.8%) were node-negative, whereas 177 (19.2%) patients were suspicious for metastatic nodal disease. On final pathological analysis, 71 of 282 (25.2%) patients who had preoperative node-negative disease ultimately had LNM. In contrast, 79 of 135 (58.5%) patients with preoperative suspicious/metastatic LNs had pathologically confirmed LNM (odds ratio [OR] 4.2, p < 0.001). Among the 129 patients with PI/MF + PI ICC subtype and preoperative nodal information, 72 (55.8%) were node-negative on preoperative imaging. In contrast, 57 (44.2%) patients had suspicious/metastatic LNs. On final pathologic examination, 45.3% (n = 24) of patients believed to be node-negative on preoperative imaging had LNM; 68.0% (n = 34) of patients who had suspicious/positive nodal disease on imaging ultimately had LNM (OR 2.6, p = 0.009). Conclusion: Given the low accuracy of preoperative imaging evaluation of nodal status, routine LND should be performed at the time of resection for both MF/IG and PI/MF + PI ICC subtypes.