The 3-Biomarker Classifier-A Novel and Simple Molecular Risk Score Predicting Overall Survival in Patients with Colorectal Cancer.

INTRODUCTION: Several new molecular markers in colorectal carcinomas have been discovered; however, classical histopathological predictors are still being used to predict survival in patients. We present a novel risk score, which uses molecular markers, to predict outcomes in patients with colorectal carcinoma. METHODS: The immunohistochemistry of tissue micro arrays was used to detect and quantify H2BUB1, RBM3 and Ki-67. Different intensities of staining were categorized for these markers and a score was established. A multivariate analysis was performed and survival curves were established. RESULTS: 1791 patients were evaluated, and multivariate analysis revealed that our risk score, the 3-biomarker classifier, is an independent marker to predict survival. We found a high risk-score to be associated with dismal median survival for the patients. CONCLUSIONS: A more personalized score might be able to better discriminate low- and high-risk patients and suggest adjuvant treatment compared to classical pathological staging. Our score can serve as a tool to predict outcomes in patients suffering from colorectal carcinoma.

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.

The effects of physical prehabilitation: Improved liver regeneration and mitochondrial function after ALPPS operation in a rodent model.

BACKGROUND: To identify the role of physical prehabilitation (PP) in liver regeneration, mitochondrial function, biogenesis, and inflammatory response was investigated after associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in a rodent model. METHODS: Male Wistar rats (n = 60) underwent ALPPS. Animals were divided (n = 30) to the physical prehabilitation group (PP) and sedentary group (S). The animals were exsanguinated before (0 hour) and 24, 48, 72, or 168 hours after the operation. Regeneration rate and proliferation index were assessed. Mitochondrial function, biogenesis, and inflammatory response were evaluated. RESULTS: Regeneration rate and Ki67 index were significantly increased in the PP group compared to the S group (P < .001). Due to the changes in oxidative capacity and ATP production rate, the P/O ratio of PP group compared to the S group was significantly increased (P < .05). PP group was characterized by accelerated mitochondrial biogenesis and less intense inflammatory response compared to the S group. CONCLUSIONS: To our knowledge, this is the first demonstration of the beneficial effects of PP on liver regeneration, mitochondrial function, biogenesis, and the inflammatory response after ALPPS.

[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.

Defining Benchmark Outcomes for ALPPS.

OBJECTIVE: The aim of this study was to use the concept of benchmarking to establish robust and standardized outcome references after the procedure ALPPS (Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy). BACKGROUND AND AIMS: The recently developed ALPPS procedure, aiming at removing primarily unresectable liver tumors, has been criticized for safety issues with high variations in the reported morbidity/mortality rates depending on patient, disease, technical characteristics, and center experience. No reference values for relevant outcome parameters are available. METHODS: Among 1036 patients registered in the international ALPPS registry, 120 (12%) were benchmark cases fulfilling 4 criteria: patients ≤67 years of age, with colorectal metastases, without simultaneous abdominal procedures, and centers having performed ≥30 cases. Benchmark values, defined as the 75th percentile of the median outcome parameters of the centers, were established for 10 clinically relevant domains. RESULTS: The benchmark values were completion of stage 2: ≥96%, postoperative liver failure (ISGLS-criteria) after stage 2: ≤5%, ICU stay after ALPPS stages 1 and 2: ≤1 and ≤2 days, respectively, interstage interval: ≤16 days, hospital stay after ALPPS stage 2: ≤10 days, rates of overall morbidity in combining both stage 1 and 2: ≤65% and for major complications (grade ≥3a): ≤38%, 90-day comprehensive complication index was ≤22, the 30-, 90-day, and 6-month mortality was ≤4%, ≤5%, and 6%, respectively, the overall 1-year, recurrence-free, liver-tumor-free, and extrahepatic disease-free survival was ≥86%, ≥50%, ≥57%, and ≥65%, respectively. CONCLUSIONS: This benchmark analysis sets key reference values for ALPPS, indicating similar outcome as other types of major hepatectomies. Benchmark cutoffs offer valid tools not only for comparisons with other procedures, but also to assess higher risk groups of patients or different indications than colorectal metastases.

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.

Did the International ALPPS Meeting 2015 Have an Impact on Daily Practice? The Hamburg Barmbek Experience of 58 Cases.

BACKGROUND: ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) was introduced only 10 years ago and has gained wide acceptance as a variation of staged procedures in liver surgery. It has been criticized for its high morbidity and mortality, which all centers reported in their initial series. METHODS: After a world expert meeting in Hamburg in 2015 where all experts in the field met to discuss this method, caveats were extracted and formulated. We researched our complete prospective ALPPS database to see if the recommendations had any impact on outcome. RESULTS: In total, we performed 58 ALPPS procedures in our center. 33 patients were operated on before, 25 after the meeting. Results in terms of morbidity and mortality were significantly better after the meeting, as were patient selection and strategy. CONCLUSION: In our own center's experience, the implementation of the meetings' recommendations and the information gathered through this valuable exchange had a dramatic impact on results. Having performed 58 ALPPS procedures in total, we can now conclude that ALPPS has become much safer in our hands since the 2015 meeting and that morbidity and mortality are no longer the issue to be discussed. Future research must focus on oncologic outcomes in these patients.

ALPPS and simultaneous right hemicolectomy - step one and resection of the primary colon cancer.

BACKGROUND: Resection of the liver is often limited due to the volume of the parenchyma. To address this problem, several approaches to induce hypertrophy were developed. Recently, the 'associating liver partition and portal vein ligation for staged hepatectomy' (ALPPS) procedure was introduced and led to rapid hypertrophy in a short interval. Additionally to the portal vein occlusion, the parenchyma is transected, which disrupts the inter-parenchymal vascular connections. Since the first description of the ALPPS procedure, various reports around the world were published. In some cases, due to the high morbidity and mortality, a decent oncologic algorithm is not deliverable in a timely manner. If a patient is to be treated with a liver-first approach, the resection of the primary could sometimes be severely protracted. To overcome the problem, a simultaneous resection of the primary tumor and step one of ALPPS were performed. CASE PRESENTATION: A 73-year-old male patient underwent portal vein embolization (PVE) after suffering from a synchronous hepatic metastasized carcinoma of the right colic flexure in order to perform a right trisectionectomy. Sufficient hypertrophy could not be obtained by PVE. Thus a 'Rescue-ALPPS' was undertaken. During step one of ALPPS, we simultaneously performed a right hemicolectomy. The postoperative course after the first step was uneventful, and sufficient hypertrophy was achieved. CONCLUSION: In order to achieve a macroscopic disease-free state and lead the patient as soon as possible to the oncologic path (with, for example, chemotherapy), sometimes a simultaneous resection of the primary with step one of the ALPPS procedure seems justified. A resection of the primary with step two is not advisable, due to the high morbidity and mortality after this step. This case shows that a simultaneous resection is feasible and safe. Whether other locations of the primary should be treated this way must be part of further investigations.

Traumatic ceramic femoral head fracture: an initial misdiagnosis.

BACKGROUND AND PURPOSE: Ceramic heads are widely used in modern total hip arthroplasty (THA). Although a rare complication, fractures of ceramic heads are described in the literature, evoking uncertainties regarding the in vivo stability of this material, especially when impaction of a fractured ceramic head can lead to disastrous results. METHODS: In this case report, we present a fracture of a ceramic head after trauma. A misinterpretation of the initial radiographs led to severe fragmentation of the ceramic head two weeks after the incident, later resulting in complete destruction of the arthroplasty. RESULTS AND INTERPRETATION: Remarkably, radiographs obtained more than one year after the trauma led to this delayed diagnosis. A single radiographic evaluation, especially in patients with persistent pain after major trauma, with a ceramic head in a THA, seems to be insufficient.