Biliary tract cancers: French national clinical practice guidelines for diagnosis, treatments and follow-up (TNCD, SNFGE, FFCD, UNICANCER, GERCOR, SFCD, SFED, AFEF, SFRO, SFP, SFR, ACABi, ACHBPT).

INTRODUCTION: This document is a summary of the French intergroup guidelines of the management of biliary tract cancers (BTC) (intrahepatic, perihilar and distal cholangiocarcinomas, and gallbladder carcinomas) published in September 2023, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org). METHODS: This collaborative work was conducted under the auspices of French medical and surgical societies involved in the management of BTC. Recommendations were graded in three categories (A, B and C) according to the level of scientific evidence until August 2023. RESULTS: BTC diagnosis and staging is mainly based on enhanced computed tomography, magnetic resonance imaging and (endoscopic) ultrasound-guided biopsy. Treatment strategy depends on BTC subtype and disease stage. Surgery followed by adjuvant capecitabine is recommended for localised disease. No neoadjuvant treatment is validated to date. Cisplatin-gemcitabine chemotherapy combined to the anti-PD-L1 inhibitor durvalumab is the first-line standard of care for advanced disease. Early systematic tumour molecular profiling is recommended to screen for actionable alterations (IDH1 mutations, FGFR2 rearrangements, HER2 amplification, BRAFV600E mutation, MSI/dMMR status, etc.) and guide subsequent lines of treatment. In the absence of actionable alterations, FOLFOX chemotherapy is the only second-line standard-of-care. No third-line chemotherapy standard is validated to date. CONCLUSION: These guidelines are intended to provide a personalised therapeutic strategy for daily clinical practice. Each individual BTC case should be discussed by a multidisciplinary team.

Splenic vein tumor thrombosis is a major prognostic factor in distal pancreatic adenocarcinoma.

BACKGROUND: The prognostic value of splenic vessel involvement in distal pancreatic adenocarcinoma remains controversial. The aim of the study was to assess its prognostic relevance in a large multicenter cohort. METHODS: Patients who underwent pancreatosplenectomy for distal pancreatic adenocarcinoma were identified from 5 pancreatic surgical centers. A pathology review of the surgical specimens was performed to assess splenic vessel involvement, defined as invasion of the vessel's adventitia or deeper, and confirm the presence of splenic vein tumor thrombosis. Prognostic factors associated with overall and relapse-free survival were evaluated. RESULTS: 149 patients underwent upfront surgery. Splenic vascular involvement was observed in 69 of them (46.3%). A parietal infiltration of the splenic artery or splenic vein was observed in 26 (17.5%) and 49 patients (32.8%), respectively. A pathologic tumor thrombosis of the splenic vein was identified in 22 patients (14.8%) and associated with larger tumors (>20 mm) (P = .023), more perineural (P = .017), and lymphovascular (P = .002) invasion, and more positive lymph node (P = .001). After a median follow-up of 50.8 months (95% confidence interval: 44.3-57.3), the cumulative 5-year overall and relapse-free survival were 46.2% and 33%, respectively. In multivariate analysis, in addition to lymph node metastasis (hazard ratio = 1.8; 95% confidence interval [1.1-3.1]; P = .023) and perineural invasion (hazard ratio = 3.5; 95% confidence interval [1.3-9.7]; P = .016), presence of splenic vein tumor thrombosis was the only splenic vascular involvement that affected independently the overall survival (HR = 2.3; 95% confidence interval [ 1.3-4.3]; P = .006). CONCLUSION: In resectable distal pancreatic adenocarcinoma, a pathologic tumor thrombosis of the splenic vein is an independent prognostic factor of overall survival. To define the perioperative oncological strategy, a preoperative evaluation of splenic vessel involvement and thrombosis is needed.

Predictive nomograms for postoperative 90-day morbidity and mortality in patients undergoing liver resection for various hepatobiliary diseases.

BACKGROUND: Postoperative complications affect the long-term survival and quality of life in patients undergoing liver resection. No model has yet been validated to predict 90-day severe morbidity and mortality. METHODS: The prospective recruitment of patients undergoing liver resection for various indications was performed. Preoperative clinical and laboratory data, including liver stiffness, indocyanine green retention, and intraoperative parameters, were analyzed to develop predictive nomograms for postoperative severe morbidity and mortality. Calibration plots were used to perform external validation. RESULTS: The most common indications in 418 liver resections performed were colorectal metastases (N = 149 [35.6%]), hepatocellular carcinoma (N = 106 [25.4%]), and benign liver tumors (N = 60 [14.3%]). Major liver resections were performed in 164 (39.2%) patients. Severe morbidity and mortality were observed in 87 (20.8%) and 9 (2.2%) of patients, respectively, during the 90-day postoperative period. Post-hepatectomy liver failure was observed in 19 (4.5%) patients, resulting in the death of 4. The independent predictors of 90-day severe morbidity were age (odds ratio:1.02, P = .06), liver stiffness (odds ratio: 1.23, P = .04], number of resected segments (odds ratio: 1.28, P = .004), and operative time (odds ratio: 1.01, P = .01). Independent predictors of 90-day mortality were diabetes mellitus (odds ratio: 6.6, P = .04), tumor size >50 mm (odds ratio:4.8, P = .08), liver stiffness ≥22 kPa (odds ratio:7.0, P = .04), and operative time ≥6 hours (odds ratio: 6.1, P = .05). Nomograms were developed using these independent predictors and validated by testing the Goodness of fit in calibration plots (P = .64 for severe morbidity; P = .8 for mortality). CONCLUSION: Proposed nomograms would enable a personalized approach to identifying patients at risk of complications and adapting surgical treatment according to their clinical profile and the center's expertise.

Surgical and Oncological Outcomes After Preoperative FOLFIRINOX Chemotherapy in Resected Pancreatic Cancer: An International Multicenter Cohort Study.

BACKGROUND: Preoperative FOLFIRINOX chemotherapy is increasingly administered to patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) to improve overall survival (OS). Multicenter studies reporting on the impact from the number of preoperative cycles and the use of adjuvant chemotherapy in relation to outcomes in this setting are lacking. This study aimed to assess the outcome of pancreatectomy after preoperative FOLFIRINOX, including predictors of OS. METHODS: This international multicenter retrospective cohort study included patients from 31 centers in 19 European countries and the United States undergoing pancreatectomy after preoperative FOLFIRINOX chemotherapy (2012-2016). The primary end point was OS from diagnosis. Survival was assessed using Kaplan-Meier analysis and Cox regression. RESULTS: The study included 423 patients who underwent pancreatectomy after a median of six (IQR 5-8) preoperative cycles of FOLFIRINOX. Postoperative major morbidity occurred for 88 (20.8%) patients and 90-day mortality for 12 (2.8%) patients. An R0 resection was achieved for 243 (57.4%) patients, and 259 (61.2%) patients received adjuvant chemotherapy. The median OS was 38 months (95% confidence interval [CI] 34-42 months) for BRPC and 33 months (95% CI 27-45 months) for LAPC. Overall survival was significantly associated with R0 resection (hazard ratio [HR] 1.63; 95% CI 1.20-2.20) and tumor differentiation (HR 1.43; 95% CI 1.08-1.91). Neither the number of preoperative chemotherapy cycles nor the use adjuvant chemotherapy was associated with OS. CONCLUSIONS: This international multicenter study found that pancreatectomy after FOLFIRINOX chemotherapy is associated with favorable outcomes for patients with BRPC and those with LAPC. Future studies should confirm that the number of neoadjuvant cycles and the use adjuvant chemotherapy have no relation to OS after resection.

R1 Vascular or Parenchymal Margins: What Is the Impact after Resection of Intrahepatic Cholangiocarcinoma?

Background: to date, long-term outcomes of R1 vascular (R1vasc) and R1 parenchymal (R1par) resections in the setting of intrahepatic cholangiocarcinoma (iCCA) have been examined in only one study which did not find significant difference. Patients and Methods: we analyzed consecutive patients who underwent iCCA resection between 2000 and 2019 in two tertiary French medical centers. We report overall survival (OS) and disease-free-survival (DFS). Univariate and multivariate analyses were performed to determine associated factors. Results: 195 patients were analyzed. The number of R0, R1par and R1vasc patients was 128 (65.7%), 57 (29.2%) and 10 (5.1%), respectively. The 1- and 2-year OS rates in the R0, R1par and R1vasc groups were 83%, 87%, 57% and 69%, 75%, 45%, respectively (p = 0.30). The 1- and 2-year DFS rates in the R0, R1par and R1vasc groups were 58%, 50%, 30% and 43%, 28%, 10%, respectively (p = 0.019). Resection classification (HR 1.56; p = 0.003) was one of the independent predictors of DFS in multivariate analysis. Conclusions: the survival outcomes after R1par resection are intermediate to those after R0 or R1vasc resection. R1vasc resection should be avoided in patients with iCCA as it does not provide satisfactory oncological outcomes.

Role of FOLFIRINOX and chemoradiotherapy in locally advanced and borderline resectable pancreatic adenocarcinoma: update of the AGEO cohort.

BACKGROUND: FOLFIRINOX has shown promising results in locally advanced (LAPA) or borderline resectable (BRPA) pancreatic adenocarcinoma. We report here a cohort of patients treated with this regimen from the AGEO group. METHODS: This is a retrospective multicentre study. We included all consecutive patients with non-pre-treated LAPA or BRPA treated with FOLFIRINOX. RESULTS: We included 330 patients (57.9% male, 65.4% <65 years, 96.4% PS <2). Disease was classified as BRPA in 31.1% or LAPA in 68.9%. Objective response rate with FOLFIRINOX was 29.5% and stable disease 51%. Subsequent CRT was performed in 46.4% of patients and 23.9% had curative intent surgery. Resection rates were 42.1% for BRPA and 15.5% for LAPA. Main G3/4 toxicities were fatigue (15%), neutropenia (12%) and neuropathy (G2/3 35%). After a median follow-up of 26.7 months, median OS (mOS) and PFS were 21.4 and 12.4 months, respectively. For patients treated by FOLFIRINOX alone, or FOLFIRINOX followed by CRT, or FOLFIRINOX + /- CRT + surgery, mOS was 16.8 months, 21.8 months and not reached, respectively (p < 0.0001). CONCLUSIONS: FOLFIRINOX for LAPA and BRPA seems to be effective with a manageable toxicity profile. These promising results in "real-life" patients now have to be confirmed in a Phase 3 randomised trial.

Does Fungal Biliary Contamination after Preoperative Biliary Drainage Increase Postoperative Complications after Pancreaticoduodenectomy?

(1) Background: preoperative biliary drainage before pancreaticoduodenectomy (PD) is associated with bacterial biliary contamination (>85%) and a significant increase in global and infectious complications. In view of the lack of published data, the aim of our study was to investigate the impact of fungal biliary contamination after biliary drainage on the complication rate after PD. (2) Methods: a multicentric retrospective study that included 224 patients who underwent PD after biliary drainage with intraoperative biliary culture. (3) Results: the global rate of positive intraoperative biliary sample was 92%. Respectively, the global rate of biliary bacterial contamination and the rate of fungal contamination were 75% and 25%, making it possible to identify two subgroups: bacterial contamination only (B+, n = 154), and bacterial and fungal contamination (BF+, n = 52). An extended duration of preoperative drainage (62 vs. 49 days; p = 0.08) increased the risk of fungal contamination. The overall and infectious complication rates were not different between the two groups. In the event of postoperative infectious or surgical complications, the infectious samples taken did not reveal more fungal infections in the BF+ group. (4) Conclusions: fungal biliary contamination, although frequent, does not seem to increase the rate of global and infectious complications after PD, preceded by preoperative biliary drainage.

Correction to: Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy - a multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study).

Following publication of the original article [1], the authors reported an error in the "Samples size calculation and statistical considerations" section.

Spleen volumetry and liver transient elastography: Predictors of persistent posthepatectomy decompensation in patients with hepatocellular carcinoma.

BACKGROUND: Posthepatectomy decompensation remains a frequent and poor outcome after hepatectomy, but its prediction is still inaccurate. Liver stiffness measurement can predict posthepatectomy decompensation, but there is a so-called "gray zone" that requires another predictor. Because splenomegaly is an objective sign of portal hypertension, we hypothesized that spleen volumetry could improve the identification of patients at risk. METHODS: Patients with hepatocellular carcinoma who underwent hepatectomy in our tertiary center between August 2014 and December 2017 were reviewed. The primary endpoint was to determine if the spleen volumetry and liver stiffness measurement were independent predictors of posthepatectomy decompensation, and secondarily, to determine if they were synergistic through a theoretic predictive model. RESULTS: One hundred and seven patients were included. The median follow-up time was 3 months (3-5). Postoperative 90-day mortality was 4.7%. By multivariate analysis, liver stiffness measurement and spleen volumetry predicted posthepatectomy decompensation. The liver stiffness measurement had a cutoff point of 11.6 kPa (area under receiver operating curve = 0.71 confidence interval 95% 0.71-0.88, sensitivity: 89%, specificity: 47%). The spleen volumetry cutoff point was 381.1 cm3 (area under receiver operating curve = 0.78, 95% confidence interval 0.77-0.93, sensitivity: 55%, specificity: 91%). The spleen volumetry improved prediction of posthepatectomy decompensation, because use of the spleen volumetry increased sensitivity (from 62% to 97%) and the negative predictive value (from 96% to 100%) along with a negligible decrease in specificity (from 96.7 to 93.4) and positive predictive value (from 64% to 59%) (P = .003). CONCLUSION: Spleen volumetry (>380 cm3) and liver stiffness measurement (>12 kPa) are non-invasive, independent, and synergistic tools that appear to be able to predict posthepatectomy decompensation. The importance of this finding is that these measurements may help to anticipate posthepatectomy decompensation and may possibly be used to direct alternative treatments to resection.

Ischemic Cholangiopathy Following Transcatheter Arterial Chemoembolization for Recurrent Hepatocellular Carcinoma After Hepatectomy: an Underestimated and Devastating Complication.

BACKGROUND: Ischemic cholangiopathy (IC) has a known poor prognosis. However, the risks and outcomes of this complication after transcatheter arterial chemoembolization (TACE) in hepatectomized patients are poorly documented. This study aimed to evaluate the incidence of and to identify the predictive factors for IC following TACE for recurrent hepatocellular carcinoma (HCC) after hepatectomy. METHOD: From a cohort with a total of 486 patients who underwent resection for HCC, we included all consecutive patients who were treated with TACE for recurrent HCC after hepatectomy between 2000 and 2017. IC was defined by the coexistence of biological cholestasis and morphological lesions. RESULTS: A total of 156 patients underwent TACE for the treatment of HCC recurrence after hepatectomy. Of them, eight (5.1%) developed IC. Their prognosis was poor compared with patients without IC (3-year survival 23.4% vs 76.2%; P = 0.008). Two factors, namely, time between hepatectomy and TACE (4.8 months vs. 16.0 months, P = 0.001) and TACE for a remnant liver mobilized during hepatectomy (P = 0.001), were associated with IC. Receiver operating characteristic (ROC) curve analysis showed that 7 months was the more discriminant cutoff for the time period. IC occurred in 33.3% of the patients with the two factors, in 5.0% of those with one factor, and 0% in the absence of any factors. CONCLUSION: TACE for treating HCC recurrence carries a high risk of IC when performed early after hepatectomy in a previously mobilized liver. Our results might aid in identifying candidates for TACE for recurrent HCC, considering the major effect on patient outcomes.

Characteristic and outcomes of patients with pathologic complete response after preoperative treatment in borderline and locally advanced pancreatic adenocarcinoma: An AGEO multicentric retrospective cohort.

INTRODUCTION: Following publication of improved patients' outcome using first line FOLFIRINOX for metastatic pancreatic adenocarcinoma, many physicians now prescribe it as neo-adjuvant or induction treatment for borderline and locally advanced pancreatic cancer. A pathologic complete response, rarely seen with previous preoperative regimens, is sometimes observed in these patients. The aim of this study was to assess long-term outcomes of patients presenting pathologic complete response after preoperative FOLFIRINOX usually followed by chemo-radiation therapy for non-metastatic pancreatic adenocarcinoma. MATERIAL AND METHODS: We retrospectively identified all resected patients with pancreatic cancer presenting pathologic complete response after FOLFIRINOX in 9 French centers from the AGEO group between November 2010 and May 2017. RESULTS: 29 patients were enrolled, 14 had borderline, 14 locally advanced and 1 oligo-metastatic pancreatic cancer. M/F ratio was 1.2 and the mean age was 57 years. All patients were treated with FOLFIRINOX (n = 29), de-escalated to gemcitabine (n = 1) and FOLFIRI (n = 2), and 24 (83 %) received radiation therapy after chemotherapy. Objective response rate to preoperative chemotherapy was 66% (RECIST V1.1). Only 8 patients received postoperative chemotherapy. After a median follow-up of 34 months from surgery, the median overall survival was not reached and the median disease free survival was 48 months. The 1-year and 2-year survival rates were 100% for OS and 96% and 72 % for DFS from surgery, 8 of the 9 observed recurrences were distant metastases. CONCLUSIONS: The promising 1 and 2-year overall survival and disease free survival rates suggest that pathologic complete response is a major prognostic factor in resected pancreatic cancer following preoperative chemo-radiotherapy. A longer follow-up and prospective series are now necessary to confirm these encouraging results and to potentially validate pathologic complete response as a relevant surrogate marker of preoperative treatment efficacy.

Impact of Surgical Treatment for Recurrence After 2-Stage Hepatectomy for Colorectal Liver Metastases, on Patient Outcome.

OBJECTIVE: To evaluate the impact of repeat surgery for recurrence on the long-term survival after 2-stage hepatectomy (TSH) for extensive colorectal liver metastases (CRLM). BACKGROUND: Although TSH is now deemed effective for selected patients with extensive bilobar CRLM, disease recurrence after TSH is very frequent because of the extensive tumor load. METHODS: Among a total cohort of 1235 patients who underwent hepatectomy for CRLM between 1992 and 2012, 139 with extensive bilobar CRLM were scheduled for TSH. Of these, 93 patients had completion of TSH and were enrolled in this study. RESULTS: The 5-year overall survival (OS) rate after TSH was 41.3%. Twenty-two patients (23.7%) had a concomitant extrahepatic disease (EHD), and curative resection of concomitant EHD was achieved in 13 patients. Among the 81 patients who achieved complete tumor removal for primary, CRLM, and concomitant EHD, 62 (76.5%) had recurrence. Repeat surgery was performed in 38 patients; 35 for recurrence after curative surgery and 3 for liver recurrence with unresected concomitant EHD or primary tumor. Of these 38 patients, 31 were salvaged. The patients who underwent repeat surgery had a significantly longer OS than those who did not (45.8% vs 26.3%; P = 0.0041). A multivariate analysis revealed that repeat surgery was an independent prognostic factor of the OS after TSH (hazard ratio 0.31, P = 0.0012). CONCLUSIONS: Repeat surgery for recurrence after TSH may be crucial for the long-term survival in patients with extensive bilobar CRLM. Intensive oncosurgical surveillance is essential to avoid missing the chance for repeat surgery after TSH.

Left-liver Adult-to-Adult Living Donor Liver Transplantation: Can It Be Improved? A Retrospective Multicenter European Study.

OBJECTIVE: To evaluate the European experience after Adult-to-adult living donor liver transplantation using the left liver (LL-aLDLT). SUMMARY BACKGROUND DATA: LL-aLDLT decreases donor risk but provides a smaller graft that increases recipient risk as compared with right liver (RL-aLDLT). However, there is little knowledge of results obtained after LL-aLDLT in Europe. METHODS: This is a European multicenter retrospective study which aims to analyze donor and recipient outcomes after 46 LL-aLDLT. RESULTS: Seventy-six percent of the grafts were harvested by minimally invasive approach. Mean donor hospital stay was 7.5 ±â€Š3.5 days. Donor liver function was minimally impaired, with 36 donors (78.3%) without any 90-day complication, and 4 (8.7%) presenting major complications. One, 3, and 5-year recipient survival was 90.9%, 82.7%, and 82.7%, respectively. However, graft survival was of 59.4%, 56.9%, and 56.9% at 1, 3, and 5 years respectively, due to a 26.1% urgent liver retransplantation (ReLT) rate, mainly due to SFSS (n = 5) and hepatic artery thrombosis (HAT, n = 5). Risk factor analysis for ReLT and HAT showed an association with a graft to body weight ratio (GBWR) <0.6% (P = 0.01 and P = 0.024, respectively) while SFSS was associated with a recipient MELD ≥14 (P = 0.019). A combination of donor age <45 years, MELD <14 and actual GBWR >0.6% was associated with a lower ReLT rate (0% vs. 33%, P = 0.044). CONCLUSIONS: Our analysis showed low donor morbidity and preserved liver function. Recipient outcomes, however, were hampered by a high ReLT rate. A strict selection of both donor and recipients is the key to minimize graft loss.

Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy - a multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study).

BACKGROUND: At time of diagnosis, less than 10% of patients with pancreatic adenocarcinomas (PDAC) are considered to be immediately operable (i.e. resectable). Considering their poor overall survival (OS), only tumours without vascular invasion (NCCN 2017) should be considered for resection, i.e. those for which resection with disease-free margins (R0) is theoretically possible in absence of presurgery treatment. With regard to high R1 rates and undetectable locoregional and/or metastatic spreading prior to surgery explain (at least in part) the observed 1-year relapse and mortality rates of 50 and 25%, respectively. Today, upfront surgery followed by adjuvant chemotherapy is the reference treatment in Europe. The main limitation of the adjuvant approach is the low rate of completion of the full therapeutic sequence. Indeed, only 47 to 60% patients received any adjuvant therapy after resection compared to more than 75% for neoadjuvant therapy. No previous prospective study has compared this approach to a neoadjuvant FOLFIRINOX or FOLFOX chemotherapy for resectable PDAC. METHODS: PANACHE01-PRODIGE48 is a prospective multicentre controlled randomized non comparative Phase II trial, evaluating the safety and efficacy of two regimens of neo-adjuvant chemotherapy (4 cycles of mFOLFIRINOX or FOLFOX) relative to the current reference treatment (surgery and then adjuvant chemotherapy) in patients with resectable PDAC. The main co-primary endpoints are OS rate at 12 months and the rate of patients undergoing the full therapeutic sequence. DISCUSSION: The "ideal" cancer treatment for resectable PDAC would have the following characteristics: administration to the highest possible proportion of patients, ability to identify fast-progressing patients (i.e. poor candidates for surgery), a low rate of R1 resections (through optimisation of local disease control), and an acceptable toxicity profile. The neoadjuvant approach may meet all these criteria. With respect to published data on the efficacy of FOLFOX and mFOLFIRINOX, these two regimens are potential candidates for neoadjuvant use in the aim to optimising oncological outcomes in resectable PDAC. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02959879 . Trial registration date: November 9, 2016.

Rare genetic heterogeneity within single tumor discovered for the first time in colorectal liver metastases after liver resection.

Effective individualized treatment of patients with colorectal liver metastases (CLM) requires tumor genotyping, usually based on the analysis of one single sample per patient. Therapy failure may partially be explained by sampling errors and/or intratumoral genetic heterogeneity. We aimed to demonstrate intratumoral genetic heterogeneity in CLM and enable pathologists to select tumor tissue for genotyping. All the tumors of 86 patients who underwent liver resection for a single CLM were reviewed. Of the 86 patients, 66 patients received chemotherapy and 20 patients did not receive chemotherapy before liver resection. All the tumor areas sampled were analyzed for KRAS, BRAF, PIK3CA, and NRAS mutations. The mutational status was tested in 74 cases, 7 cases had no tumoral cells due to complete responses and 5 blocks were unavailable. Of the 59/74 CLM with > 1 sample, 56 showed the same mutational status between the samples. The remaining 3 cases (5% of all cases) showed genetic heterogeneity for KRAS in 2 and BRAF in 1 patient. Genetic heterogeneity correlated with lower rate of viable tumor cells (p=0.009) and higher rate of mucin pools (p=0.013). We demonstrate for the first time the existence of genetic intratumoral heterogeneity in 5% of CLM. In routine practice, this low incidence does not require the genotyping of additional tumor samples. The correlation between the genetic heterogeneity and some histological components of the CLM should be verified by further in situ mutation assay.

Effectiveness of Cetuximab as First-Line Therapy for Patients With Wild-Type KRAS and Unresectable Metastatic Colorectal Cancer in Real-Life Practice: Results of the EREBUS Cohort.

INTRODUCTION: Few real-life data are available on cetuximab benefit. The EREBUS cohort was performed to assess metastases resection rate, use, safety, and survival outcomes in wild-type KRAS (Kirsten rat sarcoma viral oncogene) patients with initially unresectable metastatic colorectal cancer (mCRC) treated by cetuximab in real practice. PATIENTS AND METHODS: The study cohort comprised patients initiating cetuximab between January 2009 and December 2010 in 65 French centers, with initially unresectable mCRC and wild-type KRAS. Kaplan-Meier analysis estimated 24-month probability of metastases resection and progression-free survival, and 36-month overall survival (OS). Cox proportional hazards models investigated factors associated with survival outcomes. RESULTS: Among the 389 patients included, median age was 64 years, 67.4% were male, 77.9% had Eastern Cooperative Oncology Group performance status ≤ 1, and hepatic metastases were most frequent at baseline (n = 146 exclusively, n = 149 not exclusively, n = 94 nonliver only). Median duration of cetuximab use was 4.8 months. Metastases resection was performed in 106 patients (27.2%) (n = 60 liver exclusively, n = 33 not exclusively, n = 13 nonliver only). The 24-month probability (95% confidence interval) of metastases resection occurrence was 33.6% (28.5-39.3). Median progression-free survival was 9.2 (8.5-9.8) months for the total cohort and 13.0 (11.6-15.1) for those resected; median OS was 23.0 (20.6-26.3) months for the total cohort and was not reached after 36 months for those who were resected. The strongest factor associated with higher OS was metastases resection with complete remission (hazard ratio, 0.41; 95% confidence interval, 0.19-0.88). CONCLUSION: This cohort study highlights in French real-life practice the benefit of cetuximab in first-line mCRC therapy, notably in case of metastases resection with complete remission.

Long-term survival and cure model following liver resection for breast cancer metastases.

INTRODUCTION: Long-term survival is still rarely achieved with current systemic treatment in patients with breast cancer liver metastases (BCLM). Extended survival after hepatectomy was examined in a select group of BCLM patients. PATIENTS AND METHODS: Hepatectomy for BCLM was performed in 139 consecutive patients between 1985 and 2012. Patients who survived < 5 years were compared to those who survived ≥ 5 years from first diagnosis of hepatic metastases. Predictive factors for survival were analyzed. Statistically cured, defined as those patients who their hazard rate returned to that of the general population, was analyzed. RESULTS: Of the 139, 43 patients survived ≥ 5 years. Significant differences between patient groups (< 5 vs. ≥ 5 years) were mean time interval between primary tumor and hepatic metastases diagnosis (50 vs. 43 months), mean number of resected tumors (3 vs. 2), positive estrogen receptors (54% vs. 79%), microscopic lymphatic invasion (65% vs. 34%), vascular invasion (63% vs. 37%), hormonal therapy after resection (34% vs. 74%), number of recurrence (40% vs. 65%) and repeat hepatectomy (1% vs. 42%), respectively. The probability of statistical cure was 14% (95% CI 1.4-26.7%) in these patients. CONCLUSIONS: Hepatectomy combined with systemic treatment can provide a chance of long-term survival and even cure in selected patients with BCLM. Microscopic vascular/lymphatic invasion appears to be a novel predictor for long-term survival after hepatectomy for BCLM and should be part of the review when discussing multidisciplinary treatment strategies.

Impact of laparoscopy in patients aged over 70 years requiring distal pancreatectomy: a French multicentric comparative study.

BACKGROUND: Few data are available concerning short-term results of minimally invasive surgery in patients > 70 years old requiring distal pancreatectomy. The aim of this study was to compare short-term results after laparoscopic (LDP) versus open distal pancreatectomy (ODP) in this subgroup of patients. METHODS: All patients > 70 years who underwent distal pancreatectomy in 3 expert centers between 1995 and 2017 were included and data were retrospectively analyzed. Demographic, intraoperative data and postoperative outcomes in LDP and ODP groups were compared. RESULTS: A distal pancreatectomy was performed in 109 elderly patients; LDP group included 53 patients while ODP group included 56. There were 55 (50.5%) males and 54 (49.5%) women with a median age of 75 years (range 70-87). Fifty (45.9%) patients were 70-74, 40 (36.7%) patients were 75-79, and 19 (17.4%) patients were over 80 years. Nine (8.2%) patients required conversion to open surgery. The median operative time was not different between LDP and ODP (204 vs. 220 min, p = 0.62). The intraoperative blood loss was significantly lower in the LDP group (238 ± 312 vs. 425 ± 582 ml, p = 0.009) with no difference regarding the intraoperative transfusion rate. 90-day mortality (0 vs. 5%, p = 0.42), overall complication (45.4 vs. 51.8%, p = 0.53), major complication (18.2 vs. 12.5%, p = 0.43), grade B/C pancreatic fistula (6.8 vs. 7.1%, p = 0.71), were comparable in the 2 groups. Only postoperative confusion rate was significantly lower in the LDP group (4.5 vs. 25%, p = 0.01). Median length of stay was significantly lower in the LDP group (14 ± 10 vs. 16 ± 11 days, p = 0.04). R0 resection was performed in 94% of LDP patients and 89% in ODP patients without significant difference (p = 0.73). CONCLUSIONS: The laparoscopic approach seems to reduce blood loss, postoperative confusion, and length of stay in elderly patients requiring distal pancreatectomy.

Margin Status is Still an Important Prognostic Factor in Hepatectomies for Colorectal Liver Metastases: A Propensity Score Matching Analysis.

OBJECTIVE: The width of resection margin is still a matter of debate in case of colorectal liver metastasis resection. The aim of this study was to determine the risk factors for R1 resection. Once risk factors had been identified, patients were matched according to Fong's prognostic criteria, in order to evaluate whether R1 resection still remained a negative prognostic factor impacting overall and disease-free survival. METHODS: A total of 1784 hepatectomies were analyzed from a multicentric retrospective cohort of hepatectomies. Patients were compared before and after a 1:1 propensity score analysis in order to compare R0 versus R1 resections according to Fong criteria. RESULTS: Primary tumor nodes found positive after colorectal resection (RR = 1.20, p = 0.02), operative time (> 240 min) (RR = 1.26, p = 0.05), synchronous liver metastasis (RR = 1.27, p = 0.02), pedicle clamping (> 40 min) (RR = 1.52, p = 0.001), lesion size larger than 50 mm (RR = 1.54, p = 0.001), rehepatectomy (RR = 1.68, p = 0.001), more than 3 lesions (RR = 1.69, p = 0.0001), and bilateral lesions (RR = 1.74, p = 0.0001) were identified as risk factors in multivariate analysis. After a 1:1 PSM according to Fong criteria, R1 resection still remained a negative prognostic factor impacting overall and disease-free survival, with 1-, 3-, 5-year OS at 94, 81, and 70% in R0 and 92, 75, and 58% in R1, respectively, (p = 0.008), and disease-free survival (DFS) with 1-, 3-, 5-year survival at 64, 41, and 28% in R0 versus 51, 28, and 18% in R1 (p = 0.0002), respectively. CONCLUSION: Even after using PSM as an oncological prognostic criterion, R1 resection still impacts overall and disease-free survival negatively.

Prediction of the Total Liver Weight using anthropological clinical parameters: does complexity result in better accuracy?

BACKGROUND: The performance of linear models predicting Total Liver Weight (TLW) remains moderate. The use of more complex models such as Artificial Neural Network (ANN) and Generalized Additive Model (GAM) or including the variable "steatosis" may improve TLW prediction. This study aimed to assess the value of ANN and GAM and the influence of steatosis for predicting TLW. METHODS: Basic clinical and morphological variables of 1560 cadaveric donors for liver transplantation were randomly split into a training (2/3) and validation set (1/3). Linear models, ANN and GAM were built by using the training cohort and evaluated with the validation cohort. RESULTS: The TLW is subject to major variations among donors with similar morphological parameters. The performance of ANN and GAM were moderate and similar to that of linear models (concordance coefficient from 0.36 to 0.44). In 28-30% of cases, TLW cannot be predicted with a margin of error ≤20%. The addition of the variable "steatosis" to each model did not improve their performance. CONCLUSION: TLW prediction based on anthropological parameters carry a significant risk of error despite the use of more complex models. Others determinants of TLW need to be identified and imaging-based volumetric measurements should be preferred when feasible.