Value of routine intraoperative frozen sections of proximal bile duct margins in perihilar cholangiocarcinoma, a retrospective multicenter and matched case-control study.

BACKGROUND: Currently, the potential benefits of additional resection after positive proximal intraoperative frozen sections (IFS) in perihilar cholangiocarcinoma (pCCA) on residual disease and oncological outcome remain uncertain. Therefore, the aim of this study is to investigate the number of R0 resections after additional resection of a positive proximal IFS and the influence of additional resections on overall survival (OS) in patients with pCCA. MATERIALS AND METHODS: A retrospective, multicenter, matched case-control study was performed, including patients undergoing resection for pCCA between 2000 and 2019 at three tertiary centers. Primary outcome was the number of achieved 'additional' R0 resections. Secondary outcomes were OS, recurrence, severe morbidity and mortality. RESULTS: Forty-four out of 328 patients undergoing resection for pCCA had a positive proximal IFS. An additional resection was performed in 35 out of 44 (79.5%) patients, which was negative in 24 (68.6%) patients. Nevertheless, seven out of these 24 patients were eventually classified as R1 resection due to other positive resection margins. Therefore, 17 (48.6%) patients could be classified as "true" R0 resection after additional resection. Ninety-day mortality after R1 resections was high (25%) and strongly influenced OS. After correction for 90-day mortality, median OS after negative additional resection was 33 months (95%CI:29.5-36.5) compared to 30 months (95%CI:24.4-35.6) after initial R1 (P = 0.875) and 46 months (95%CI:32.7-59.3) after initial R0 (P = 0.348). CONCLUSION: There were only 17 patients (out of a total of 328 patients) that potentially benefitted from routine IFS. Additional resection for a positive IFS leading to R0 resection was not associated with improved long-term survival.

Expression of integrin ανß6 differentiates perihilar cholangiocarcinoma (PHC) from benign disease mimicking PHC.

BACKGROUND: Approximately 15% of patients undergoing resection for presumed perihilar cholangiocarcinoma (PHC) have benign disease at final pathological assessment. Molecular imaging targeting tumor-specific biomarkers could serve as a novel diagnostic tool to reduce these futile surgeries. Imaging agents have been developed, selectively binding integrin ανß6, a cell receptor upregulated in pancreatobiliary malignancies, for both (preoperative) PET and (intraoperative) fluorescent imaging. Here, expression of integrin ανß6 is evaluated in PHC, intrahepatic cholangiocarcinoma (ICC), hepatocellular carcinoma (HCC) and benign disease mimicking PHC using immunohistochemistry. MATERIALS & METHODS: Three tissue microarrays (TMA) including 103 PHC tumor cores and sixty tissue samples were selected from resection specimens of pathologically proven PHC (n = 20), ICC (n = 10), HCC (n = 10), metastatic PHC lymph nodes (n = 10) and benign disease (presumed PHC with benign disease at pathological assessment, n = 10). These samples were stained for integrin ανß6 and quantified using the H-score. RESULTS: Immunohistochemical staining for integrin ανß6 showed membranous expression in all twenty PHC whole mount slides (100%) and 93 out of 103 (92%) PHC tumor cores. Mean H-score of PHC samples was 195 ± 71, compared to a mean H-score of 126 ± 57 in benign samples (p = 0.013). In both benign and PHC samples, inflammatory infiltrates and pre-existent peribiliary glands showed integrin ανß6 expression. The mean H-score across ten ICC was 33 ± 53, which was significantly lower compared to PHC (p < 0.001) but too weak to consistently discriminate ICC from HCC (H-score 0)(p = 0.062). CONCLUSION: Integrin ανß6 is abundantly expressed in PHC and associated metastatic lymph nodes. Expression is significantly higher in PHC as compared to benign disease mimicking PHC, ICC and HCC, emphasizing its potential as a target for tumor-specific molecular imaging.

Molecular targets for diagnostic and intraoperative imaging of pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX treatment.

Neoadjuvant systemic treatment is increasingly being integrated in the standard treatment of pancreatic ductal adenocarcinoma (PDAC) patients to improve oncological outcomes. Current available imaging techniques remain unreliable in assessing response to therapies, as they cannot distinguish between (vital) tumor tissue and therapy induced fibrosis (TIF). Consequently, resections with tumor positive margins and subsequent early post-operative recurrences occur and patients eligible for potential radical resection could be missed. To optimize patient selection and monitor results of neoadjuvant treatment, PDAC-specific diagnostic and intraoperative molecular imaging methods are required. This study aims to evaluate molecular imaging targets for PDAC after neoadjuvant FOLFIRINOX treatment. Expression of integrin αvß6, carcinoembryonic antigen cell adhesion molecule 5 (CEACAM5), mesothelin, prostate-specific membrane antigen (PSMA), urokinase-type plasminogen activator receptor, fibroblast activating receptor, integrin α5 subunit and epidermal growth factor receptor was evaluated using immunohistochemistry. Immunoreactivity was determined using the semiquantitative H-score. Resection specimens from patients after neoadjuvant FOLFIRINOX treatment containing PDAC (n = 32), tumor associated pancreatitis (TAP) and TIF (n = 15), normal pancreas parenchyma (NPP) (n = 32) and tumor positive (n = 24) and negative (n = 56) lymph nodes were included. Integrin αvß6, CEACAM5, mesothelin and PSMA stainings showed significantly higher expression in PDAC compared to TAP and NPP. No expression of αvß6, CEACAM5 and mesothelin was observed in TIF. Integrin αvß6 and CEACAM5 allow for accurate metastatic lymph node detection. Targeting integrin αvß6, CEA, mesothelin and PSMA has the potential to distinguish vital PDAC from fibrotic tissue after neoadjuvant FOLFIRINOX treatment. Integrin αvß6 and CEACAM5 detect primary tumors and tumor positive lymph nodes.

Effect of structured use of preoperative portal vein embolization on outcomes after liver resection of perihilar cholangiocarcinoma.

BACKGROUND: Portal vein embolization (PVE) is performed to reduce the risk of liver failure and subsequent mortality after major liver resection. Although a cut-off value of 2·7 per cent per min per m2 has been used with hepatobiliary scintigraphy (HBS) for future remnant liver function (FRLF), patients with perihilar cholangiocarcinoma (PHC) potentially benefit from an additional cut-off of 8·5 per cent/min (not corrected for body surface area). Since January 2016 a more liberal approach to PVE has been adopted, including this additional cut-off for HBS of 8·5 per cent/min. The aim of this study was to assess the effect of this approach on liver failure and mortality. METHODS: This was a single-centre retrospective study in which consecutive patients undergoing liver resection under suspicion of PHC in 2000-2015 were compared with patients treated in 2016-2019, after implementation of the more liberal approach. Primary outcomes were postoperative liver failure (International Study Group of Liver Surgery grade B/C) and 90-day mortality. RESULTS: Some 191 patients with PHC underwent liver resection. PVE was performed in 6·4 per cent (9 of 141) of the patients treated in 2000-2015 and in 32 per cent (16 of 50) of those treated in 2016-2019. The 90-day mortality rate decreased from 16·3 per cent (23 of 141) to 2 per cent (1 of 50) (P = 0·009), together with a decrease in the rate of liver failure from 19·9 per cent (28 of 141) to 4 per cent (2 of 50) (P = 0·008). In 2016-2019, 24 patients had a FRLF greater than 8·5 per cent/min and no liver failure or death occurred, suggesting that 8·5 per cent/min is a reliable cut-off for patients with suspected PHC. CONCLUSION: The major decrease in liver failure and mortality rates in recent years and the simultaneous increased use of PVE suggests an important role for PVE in reducing adverse outcomes after surgery for PHC.

ANTECEDENTES: La embolización de la vena porta (portal vein embolization, PVE) se realiza para reducir el riesgo de insuficiencia hepática y de mortalidad asociada después de una resección hepática mayor. Aunque con la gammagrafía hepato-biliar (hepato-biliary scintigraphy, HBS) se ha utilizado un punto de corte de 2,7%/min/m2 para la función hepática remanente futura (future remnant liver function, FRLF), los pacientes con colangiocarcinoma perihilar (perihilar cholangiocarcinoma, PHC) se beneficiarían potencialmente de un punto de corte adicional de 8,5%/min (no corregido para el área de superficie corporal). Desde enero de 2016, se adoptó un enfoque más liberal para la PVE, incluyendo este punto de corte adicional para la HBS de 8,5%/min. El objetivo de este estudio fue evaluar el efecto de este enfoque sobre la insuficiencia hepática y la mortalidad. MÉTODOS: Se trata de un estudio retrospectivo de un solo centro, en el que los pacientes consecutivos sometidos a resección hepática por sospecha de PHC entre 2000-2016 se compararon con los pacientes tratados entre 2016-2019, después de la implementación de un enfoque más liberal. Los objetivos primarios fueron la insuficiencia hepática postoperatoria (ISGLS grado B/C) y la mortalidad a los 90 días. RESULTADOS: Un total de 191 pacientes con PHC se sometieron a resección hepática. Se realizó PVE en el 6% (9/141) de los pacientes antes de 2016 y en el 32% (16/50) de los pacientes después de 2016. La mortalidad disminuyó del 16% (23/141) al 2% (1/50) (P = 0,009), junto con una disminución de la insuficiencia hepática del 20% (28/141) al 4% (2/50) (P = 0,008). Después de 2016, 20 pacientes tuvieron un FRLF > 8,5%/min y no se produjo insuficiencia hepática o mortalidad, lo que sugiere que el 8,5%/min es un punto de corte fiable para los pacientes con sospecha de PHC. CONCLUSIÓN: La disminución marcada de la insuficiencia hepática y de la mortalidad en los últimos años y el aumento simultáneo del uso de la PVE, sugiere que la PVE ha jugado un importante papel en el descenso de los resultados adversos después de la cirugía para el PHC.

Minimally invasive surgery for perihilar cholangiocarcinoma: a systematic review.

Minimally invasive surgery (MIS) is quickly becoming mainstream in hepato-pancreato-biliary surgery because of presumed advantages. Surgery for perihilar cholangiocarcinoma (PHC) is highly demanding which may hamper the feasibility and safety of MIS in this setting. This study aimed to systematically review the existing literature on MIS for PHC. A systematic literature review was performed according to the PRISMA statement. The PubMed and EMBASE databases were searched and all studies describing MIS in patients with PHC were included. Data extraction and risk of bias were assessed by two independent researchers. Overall, 21 studies reporting on a total of 142 MIS procedures for PHC were included. These included 82 laparoscopic, 59 robot-assisted and 1 hybrid procedure(s). Risk of bias was deemed substantial. Pooled conversion rate was 7/142 (4.9%), pooled morbidity 30/126 (23.8%), and pooled mortality rate 4/126 (3.2%). The only comparative study, comparing 10 robot-assisted procedures to 32 open procedures, reported a significant increased operative time and higher morbidity rate with MIS. The available evidence on MIS for PHC is limited and generally of poor quality. This systematic review shows that the implementation of MIS for patients with PHC is still in its infancy.