Parenchyma-Preserving Hepatectomy in Perihilar Cholangiocarcinoma: A Chance for Critical Patients?

Introduction: Surgery for perihilar cholangiocarcinoma (pCCA) is associated with high rates of postoperative morbidity and mortality. Extended liver resection (EXT) increases R0 resection rate and survival; however, patients with high perioperative risk are not suitable for extended resection. This study aimed to compare overall survival and surgical morbidity in patients with extended liver resection and parenchyma-preserving hepatectomy (PPH). Methods: Between January 2010 and November 2020, 113 consecutive patients with pCCA underwent surgery at our institution. Eighty-two patients were resected in curative intent. Sixty-four patients received extended liver resection, and 18 patients PPH. Outcomes of resections were evaluated. Results: There was no significant difference in overall survival in patients with PPH compared to extended liver resection (log-rank p = 0.286). Patients with PPH experienced lower rates of postoperative morbidity and mortality. There was no case of in-house mortality in PPH-resected patients compared to 10 cases (16%) in patients that received EXT (p = 0.073). Conclusion: PPH shows similar overall survival with lower rates of postoperative morbidity and mortality. Our findings support the role of a PPH, in selected patients with pCCA, that are not suitable for extended resection due to increased perioperative risk.

Liver surgery in the 2020s: ante-situm and in-situ resection are still indicated - A single-center study.

BACKGROUND: Tumor infiltration of the hepatic outflow comprising all three hepatic veins and the inferior vena cava remains a surgical challenge. Liver resection under total vascular exclusion with or without extracorporeal bypass has been described as a therapeutic option for these tumors. Here, we present our experience with these complex surgical methods. METHODS: We searched our database for patients treated with an in-situ or ante-situm liver resection (ISR and ASR, respectively) with extracorporeal bypass. We collected demographic and perioperative data. RESULTS: From January 2010 to December 2021, we performed 2122 liver resections. Nine patients were treated with ASR and five were treated with ISR. Out of these 14 patients, six had colorectal liver metastases, six had cholangiocarcinoma, and two had non-colorectal liver metastases. The median operative time and bypass time in all patients were 536.5 and 150 min, respectively. Compared with ISR, ASR required a longer operative time (ASR 586 min and ISR 495 min) and a longer bypass time (ASR 155 min and ISR 122 min). Morbidity (Clavien-Dindo grade > 3A adverse events) occurred in 78.5% of patients. 90-day postoperative mortality was 7%. Median overall survival was 33 months. Seven patients experienced recurrence. In these patients, median disease-free survival was 9 months. CONCLUSION: Resection of tumors infiltrating the hepatic outflow poses a high risk for patients. However, with rigorous selection and an experienced perioperative team, these patients can be treated surgically with reasonable oncological outcomes.

The rate of cholangiocarcinoma in Caroli Disease A German multicenter study.

BACKGROUND: Caroli Disease (CD) and Caroli Syndrome (CS) are rare disorders presenting with dilation of the intrahepatic bile ducts. CD/CS are associated with cholangiocarcinoma (CCA). However, the true incidence of CCA is still unclear, although it may serve as an indication for surgery. In this paper, we analyzed (I) the incidence of CCA in German centers, (II) reviewed our single center population together with its clinical presentation and (III) performed a thorough literature review. METHODS: 17 large HPB-centers across Germany were contacted and their patients after surgical treatment due to CD/CS with histopathology were included. Medline search for all studies published in English or German literature was performed. Patients who underwent surgery at our department between 2012 and 2020 due to CD or CS were analyzed. RESULTS: In the multicenter study, 79 patients suffered from CD and 119 patients from CS, with a total number of 198 patients. In 14 patients, CCA was found (Overall: 7,1%; CD: 6,3%, CS 7,6%). Between 2012 and 2020, 1661 liver resections were performed at our department. 14 patients underwent surgery due to CD or CS. Histological examination showed synchronous cholangiocarcinoma in one patient. The literature review revealed a CCA-rate of 7,3% in large series, whereas in case reports a rate of 6,8% was found. CONCLUSION: There is risk of malignant transformation and patients with CD might also benefit from resection due to improvement of symptoms. Therefore, resection is strongly advised. As certain patients with CS require transplantation, treatment should not be guided by the relatively low rate of CCA but by the concomitant diseases that come along with hepatic failure.

Perihilar Cholangiocarcinoma - Novel Benchmark Values for Surgical and Oncological Outcomes From 24 Expert Centers.

OBJECTIVE: The aim of this study was to define robust benchmark values for the surgical treatment of perihilar cholangiocarcinomas (PHC) to enable unbiased comparisons. BACKGROUND: Despite ongoing efforts, postoperative mortality and morbidity remains high after complex liver surgery for PHC. Benchmark data of best achievable results in surgical PHC treatment are however still lacking. METHODS: This study analyzed consecutive patients undergoing major liver surgery for PHC in 24 high-volume centers in 3 continents over the recent 5-year period (2014-2018) with a minimum follow-up of 1 year in each patient. Benchmark patients were those operated at high-volume centers (≥50 cases during the study period) without the need for vascular reconstruction due to tumor invasion, or the presence of significant co-morbidities such as severe obesity (body mass index ≥35), diabetes, or cardiovascular diseases. Benchmark cutoff values were derived from the 75th or 25th percentile of the median values of all benchmark centers. RESULTS: Seven hundred eight (39%) of a total of 1829 consecutive patients qualified as benchmark cases. Benchmark cut-offs included: R0 resection ≥57%, postoperative liver failure (International Study Group of Liver Surgery): ≤35%; in-hospital and 3-month mortality rates ≤8% and ≤13%, respectively; 3-month grade 3 complications and the CCI: ≤70% and ≤30.5, respectively; bile leak-rate: ≤47% and 5-year overall survival of ≥39.7%. Centers operating mostly on complex cases disclosed better outcome including lower post-operative liver failure rates (4% vs 13%; P = 0.002). Centers from Asia disclosed better outcomes. CONCLUSION: Surgery for PHC remains associated with high morbidity and mortality with now the availability of benchmark values covering 21 outcome parameters, which may serve as key references for comparison in any future analyses of individuals, group of patients or centers.

Intraoperative (Contrast-Enhanced) Ultrasound Has the Highest Diagnostic Accuracy of Any Imaging Modality in Resection of Colorectal Liver Metastases.

AIM: Defining sensitivity, specificity, diagnostic accuracy for detection of colorectal liver metastases in imaging compared to intraoperative assessment. Defining a cutoff, where accuracy of detection is impaired. METHODS: Prospective single-institution clinical trial (clinicaltrials.gov: NCT01522209). Patients underwent CEUS, MDCT, and 3 Tesla EOB-MRI within 2 weeks preoperatively. Intraoperative palpation, IOUS, and CEIOUS were performed. A patient and lesion-based database was analyzed for accuracy of detection of CEUS, CT, MRI, and Palp/IOUS/CEIOUS combined read. Histology was standard of reference. RESULTS: Forty-seven high tumor load (mean 5, 4 lesions) patients were analyzed. Histopathology confirmed 264 lesions (245 malignant: 19 benign). Accuracy for detection of all lesions: CEUS 63%, CT 71%, MRI 92%, and PALP/IOUS/CEIOUS 98%. ROC analysis for lesion size showed severe impairment of accuracy in lesion detection smaller than 5mm. Intraoperative imaging was not impaired by lesion size. Patient-based analysis revealed a change of resection plan after IOUS/CEIOUS in 35% of patients. CONCLUSION: At 5-mm lesion size, preoperative imaging shows a drop in accuracy of detection. In patients with multiple lesions, addition of MRI to MDCT seems useful. Accuracy of intraoperative ultrasound is not impacted by lesion size and should be mandatory. CEIOUS can improve intraoperative decision-making. TRIAL REGISTRATION: Study registered with clinicaltrials.gov : NCT01522209.

Complex Liver Resections for Intrahepatic Cholangiocarcinoma.

The only curative treatment option for intrahepatic cholangiocarcinoma (iCCA) is liver resection. Due to central tumor localization and vascular invasion, complex liver resections play an important role in curative treatment. However, the long-term outcomes after complex liver resection are not known. Methods: A retrospective cohort study was conducted for all patients undergoing liver surgery for iCCA. Complex liver resections included ante situm resections, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) and major liver resection with vascular reconstructions. Results: Forty-nine patients (34%) received complex liver resection, 66 patients (46%) received conventional liver resection and 28 patients (20%) were not resectable during exploration. Preoperative characteristics were not different between the groups, except for Union for International Cancer Control (UICC) stages. The postoperative course for complex liver resections was associated with more complications and perioperative mortality. However, long-term survival was not different between complex and conventional resections. Independent risk factors for survival were R0 resections and UICC stage. Four patients underwent ante situm resection without any mortality. Conclusions: Complex liver resections are justified in selected patients and survival is comparable with conventional liver resections. Survival in iCCA is affected by UICC stage or resections margins and not by the complexity of the case.

The clinical relevance of the Hippo pathway in pancreatic ductal adenocarcinoma.

PURPOSE: The Hippo pathway has broadened in cancer research in the past decade and revealed itself to be an important driver for tumorigenesis and metastatic spread. In this study, we investigated the clinical relevance of the Hippo pathway with regard to metastatic invasion, patients' outcome and histopathological features. METHODS: Protein expression of components of the Hippo pathway were analyzed by immunohistochemistry (IHC) using paraffin-embedded tissue from 103 patients who had been diagnosed with pancreatic ductal adenocarcinoma and had undergone surgery. Results were correlated with clinicopathological data, disease-free and overall survival. RESULTS: Immunohistochemistry studies in pancreatic tumour tissues revealed a significant upregulation of MST1, MST2, pLATS, pYAP and 14-3-3, representing the active Hippo pathway, in non-metastasized patients (p < 0.01). In turn, the pathway is more inactive in metastasized patients and relating liver metastases as LATS1, LATS2, YAP, transcriptional factors TEAD2 and TEAD3 were upregulated in these patients (p < 0.01). A higher pYAP expression was associated with a favorable OS and DFS. CONCLUSION: The Hippo pathway is inactive in metastasized patients releasing the pro-metastatic and proliferative potential of the pathway. Furthermore, our study underlines the prognostic relevance of the Hippo pathway as a shift in the balance towards the inactive pathway predicts an unfavorable OS and DFS.

Impact of acute kidney injury after extended liver resections.

BACKGROUND: Complex liver resection is a risk factor for the development of AKI, which is associated with increased morbidity and mortality. Aim of this study was to assess risk factors for acute kidney injury (AKI) and its impact on outcome for patients undergoing complex liver surgery. METHODS: AKI was defined according to the KDIGO criteria. Primary endpoint was the occurrence of AKI after liver resection. Secondary endpoints were complications and mortality. RESULTS: Overall, 146 patients undergoing extended liver resection were included in the study. The incidence of AKI was 21%. The incidence of chronic kidney disease (CKD) and hepatocellular carcinoma were significantly higher in patients with AKI. In the AKI group, the proportion of extended right hepatectomies was the highest (53%), followed by ALPPS (43%). Increased intraoperative blood loss, increased postoperative complications and perioperative mortality was associated with AKI. Besides age and CKD, ALPPS was an independent risk factor for postoperative AKI. A small future liver remnant seemed to increase the risk of AKI in patients undergoing ALPPS. CONCLUSION: Following extended liver resection, AKI is associated with an increased morbidity and mortality. ALPPS is a major independent risk factor for the development of AKI and a sufficient future liver remnant could avoid postoperative AKI.

Association of subcellular localization of TEAD transcription factors with outcome and progression in pancreatic ductal adenocarcinoma.

BACKGROUND: Transcriptional enhanced associated domain (TEAD) transcription factors are nuclear effectors of several oncogenic signalling pathways including Hippo, WNT, TGF-ß and EGFR pathways that interact with various cancer genes. The subcellular localization of TEAD regulates the functional output of these pathways affecting tumour progression and patient outcome. However, the impact of the TEAD family on pancreatic ductal adenocarcinoma (PDAC) and its clinical progression remain elusive. METHODS: A cohort of 81 PDAC patients who had undergone surgery was established. Cytoplasmic and nuclear localization of TEAD1, TEAD2, TEAD3 and TEAD4 was evaluated with the immunoreactive score (IRS) by immunohistochemistry (IHC) using paraffin-embedded tissue. Results were correlated with clinicopathological data, disease-free and overall survival. RESULTS: Nuclear staining of all four TEADs was increased in pancreatic cancer tissue. Patients suffering from metastatic disease at time of surgery showed a strong nuclear staining of TEAD2 and TEAD3 (p < 0.05). Furthermore, a nuclear > cytoplasmic ratio of TEAD2 and TEAD3 was associated with a shorter overall survival and TEAD2 emerged as an independent prognostic factor for disease-free survival. CONCLUSION: Our study underlines the importance of TEAD transcription factors in PDAC as a nuclear localization was found to be associated with metastatic disease and an unfavourable prognosis after surgical resection.

Extended liver resection including hypertrophy concept with portal venous embolisation for giant haemangioma. Too much surgery?

Haemangiomas of the liver are benign tumours, which are often diagnosed randomly. With an increase in size haemangiomas could become symptomatic. In this case therapeutic options, surgical or interventional, have to be weighted to a conservative approach. We present a case of a 36-year old woman with a symptomatic giant haemangioma of the right liver lobe. Because of the size of the tumor and the small future liver remnant we decided to perform a major liver resection after hypertrophy induction with a preoperative portal vein embolization; an option mainly used for major hepatectomies in malignant tumors of the liver. But however, this case shows, that using a hypertrophy concept also for benign liver tumours is the safer approach, if an extended resection is necessary and the future liver remnant is critical.

Adenosquamous Carcinoma of the Pancreas Comprise a Heterogeneous Group of Tumors With the Worst Outcome: A Clinicopathological Analysis of 25 Cases Identified in 562 Pancreatic Carcinomas Resected With Curative Intent.

OBJECTIVES: Information of the clinicopathological characteristics and outcome data of patients with adenosquamous carcinoma of the pancreas (ASCAP) remains limited. This study's aim is to describe the clinical, pathological, and molecular characteristics of 25 resected ASCAPs. METHODS: Of all 25 cases, patient characteristics, follow-up data, and pathological/immunohistological features were reviewed and analyzed. RESULTS: In this 3-institutional retrospective analysis of 562 pancreatic cancer patients, we identified 25 cases with histologically confirmed ASCAP (4.4%). Follow-up was available in 21 ASCAP and 50 pancreatic ductal adenocarcinoma control patients with a median overall survival of 8.2 and 21 months, respectively. Age, tumor size, localization in the tail, lymph node status, and resection margin seem to be the most significant factors of survival in our ASCAP cohort. In contrast to pancreatic ductal adenocarcinoma, positive expression of p63, keratins K5/14, and the epidermal growth factor receptor are a robust marker profile of these tumors. CONCLUSIONS: Adenosquamous carcinoma of the pancreas comprises a group of neoplasms in which stage and adverse morphological features contribute to its bad prognosis. Further work must be pursued to improve detection and treatment options to reduce mortality. Specifically, differences in biology might become a target for the development of possible therapies.

Significance of unphosphorylated and phosphorylated heat shock protein 27 as a prognostic biomarker in pancreatic ductal adenocarcinoma.

PURPOSE: Few studies reported about the potential of unphosphorylated heat shock protein 27 (HSP27) and phosphorylated heat shock protein 27 (pHSP27) as a predictor for survival and gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC). In this study, we analysed the expression patterns of pHSP27 and HSP27 in a patient population after surgery and correlated the immunohistochemical results with clinicopathological data and long-term outcome of the patients. METHODS: HSP27 and pHSP27 (Ser-15, Ser-78 and Ser-82) protein expression were analysed by immunohistochemistry using the immunoreactive score (IRS) from paraffin-embedded tissue of 106 patients with PDAC who underwent surgery. Immunohistochemical results were correlated with clinicopathological data, disease-free (DFS) and overall survival (OS). RESULTS: HSP27 expression was significantly lower in patients with a shorter OS (p = 0.006) and DFS (p < 0.0001). A higher HSP27 expression was associated with a better response to gemcitabine in the resected, non-metastasised patients group (p = 0.001). Furthermore, HSP27 was downregulated in patients suffering from metastases at time of surgery (p < 0.001) and in undifferentiated tumours (p = 0.007). In contrast, pHSP27-Ser15, -Ser78 and -Ser82 were not associated with any survival data of the study population. CONCLUSION: HSP27 seems to be a strong indicator for the prediction of OS and DFS. Moreover, HSP27 could play a role in the formation and migration of liver metastases of PDAC.

[Diagnostic and prognostic significance of α-fetoprotein in hepatocellular carcinoma]. / Diagnostische und prognostische Bedeutung des α-Feto-Proteins beim hepatozellulären Karzinom.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive tumor with a growing socioeconomic burden. International guidelines do not predominantly recommend the pretherapeutic determination of the alpha-fetoprotein (AFP) concentration. Regarding the prognostic value of AFP, the European study data are not sufficiently meaningful. OBJECTIVE: This study aimed to demonstrate possible aspects of the AFP level and to investigate the prognostic value of AFP levels as well as to provide impetus for future prospective studies. MATERIAL AND METHODS: At the time of data retrieval the prospective liver databank showed 1382 entries. All patients with a histologically confirmed HCC were included resulting in 92 final entries. For these patients, information on T, N, M and G stages, R status as well as sex, age and etiology of the HCC were available. For data analysis the patient population was divided into six groups based on three cut-off values. Furthermore, a survival analysis was performed using Kaplan-Meier and a multifactorial analysis of the influencing factors regarding outcome. RESULTS: The AFP serum level showed a statistically significant correlation with the tumor diameter (T1/T2 vs. T3/T4) and grading (G1/G2 vs. G3/G4). The survival prognosis was significantly lower in patients with higher AFP values (p < 0.05). The median survival time for patients with AFP levels >8 µg/l was 35 months, with AFP levels >200 µg/l or >400 µg/l showed a reduced median survival of 15 months and 11 months, respectively. High AFP levels were a significant influencing factor for the outcome independent of the T stage, age and R status of patients in comparison to low AFP levels. CONCLUSION: Taking the present results into consideration, the AFP level can have a therapeutic usefulness. Therapeutic consequences could be derived from the height of the measured AFP concentration, with respect to the treatment strategy. Therefore, preoperative and postoperative determination of the AFP serum level is recommended in all HCC patients.

Renal Impairment Is Associated with Reduced Outcome After Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy.

BACKGROUND: Impaired postoperative renal function is associated with increased morbidity and mortality after liver resection. The role of impaired renal function in the two-stage hepatectomy setting of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is unknown. METHODS: An international multicenter cohort of ALPPS patients captured in the ALPPS Registry was analyzed. Particular attention was drawn to the renal function in the interstage interval to determine outcome after stage 2 surgery. Interstage renal impairment (RI) was defined as an increase of serum creatinine of ≥ 0.3 mg/dl referring to a preoperative value or an increase of serum creatinine of ≥ 1.5× of the preoperative value on the fifth postoperative day after stage 1. RESULTS: A total of 705 patients were identified of which 7.5% had an interstage RI. Patients developing an interstage RI were significantly older. During stage 1, a longer operation time, higher rate of intraoperative transfusions, and additional procedures were observed in patients that developed interstage RI. After stage 1, interstage RI patients had more major complications and higher interstage mortality (1% vs. 8%, p < 0.001). Furthermore, these patients developed more and severe complications after completion of stage 2. Mortality of patients with interstage RI was 38% vs. 8% without interstage RI. In 41% of patients with interstage RI, the renal function recovered before stage 2; however, the mortality after stage 2 remained 28% in those patients. Risk factors for the development of an interstage RI were age over 67 years, prolonged operative time, and additional procedure during stage 1. CONCLUSION: This study shows that interstage RI is a predictor for interstage and post-stage 2 morbidity and perioperative mortality. The causality of impaired renal function on outcome, however, remains unknown. Interstage RI may directly cause adverse outcome but may also be a surrogate marker for major complications.

[Intraoperative fluorescence angiography and cholangiography with indocyanine green in hepatobiliary surgery]. / Intraoperative Fluoreszenzangio- und cholangiographie mit Indocyaningrün bei hepatobiliären Eingriffen.

Intraoperative fluorescence angiography and cholangiography with indocyanine green (ICG) are increasingly used in routine hepatobiliary surgery. Its usage is manifold. It improves and facilitates navigation especially in minimal invasive and robotic surgery and therefore increases the safety of the surgical intervention. In laparoscopic cholecystectomy for example, the bileduct anatomy can be easily visualized, even in complicated cholecystitis or anatomical variants without being too time consuming. ICG fluorescence also enables the visualization of vascular structures and perfusion. Anatomical liver resections, for example in hepatocellular carcinoma (HCC), can be performed easily as liver segments and territories can be identified. Anatomical resection is becoming more important, e.g. in the treatment of HCC. Another useful application is the intraoperative detection of bile leakages after liver resection. In particular, the intraoperative control of a biliodigestive anastomosis is possible with ICG fluorescence cholangiography and therefore reduces morbidity. Even primary and secondary liver tumors can be detected with ICG fluorescence. Whereas well-differentiated HCCs homogeneously take up ICG, poorly differentiated HCCs and metastases do not: however, in these cases the adjacent liver parenchyma stores ICG more intensively than healthy liver tissue, which creates a ring-like fluorescence pattern. To conclude, the use of ICG fluorescence in hepatobiliary surgery is diverse but in Germany it is still at the beginning compared to other countries.

Liver Resection with In Situ Hypothermic Perfusion: An Old but Effective Method.

BACKGROUND: More than 40 years ago, patients with tumors infiltrating the confluence of the hepatic veins were deemed unresectable; however, in situ hypothermic perfusion, first described by Fortner et al. (Ann Surg 180(4):644-652, 1974), allowed resection of these tumors. In order to prevent liver ischemia after total vascular exclusion, the liver was flushed with a cooled organ preservation solution. The surgeon was able to resect the tumor and reconstruct the hepatic veins with occlusion of the hepatic inflow and outflow. METHODS: A 55-year-old female suffering from a leiomyosarcoma of the inferior vena cava (IVC) presented to our clinic. Three years ago, the IVC was replaced with a synthetic graft. During the patient's follow-up, a computed tomography (CT) scan revealed three hepatic metastases of the sarcoma. A central metastasis in Segment 8 infiltrated the right hepatic vein (RHV), and two additional metastases were located in the left lateral segments. We used Fortner's technique to resect these tumors. RESULTS: The postoperative course of the patient was prolonged due to a hematoma that partially compressed the new RHV graft. A re-laparotomy was performed and drains were placed. On the 15th postoperative day, the patient was discharged in good health. CONCLUSIONS: Although nowadays patients with these unfortunate tumor locations can, to some extent, be managed non-operatively, surgery remains an option with a chance of cure. Azoulay et al. (Ann Surg 262(1):93-104, 2015) were able to show satisfactory 5-year-survival in 77 patients (30.4%), however 90-day mortality was high (19.5%). Therefore, patients need to be selected carefully. In the era of minimally invasive liver surgery, these old techniques should not vanish from the armamentarium of liver surgeons.