Development and External Validation of the Munich Sorafenib Evaluation Score for Hepatocellular Carcinoma.

INTRODUCTION: In recent years, increasing options for systemic HCC treatment have become available. The development of therapy-specific prognostic scores has been encouraged. Tailoring therapy to individual patients requires prognostic scores for treatment success in addition to the Barcelona-Clinic-Liver-Cancer (BCLC) classification. We have developed and validated a prognostic score for patients treated with sorafenib. METHODS: Prognostic factors identified in a multivariate analysis of 108 sorafenib patients were used to construct the Munich Sorafenib Evaluation (M-SE) score. M-SE and 9 established HCC prognostic systems were ranked according to concordance-index and AIC. External M-SE validation was performed in an independent HCC sorafenib cohort (n = 101) derived from the prospective multicenter randomized controlled SORAMIC trial. RESULTS: Ascites (p < 0.0001; HR 2.923), tumor burden ≥50% of the liver (p = 0.0033; HR 1.946), and GOT (p < 0.0001; HR 1.716) were identified as independent prognostic parameters. All three M-SE stages were characterized by significantly different survival times (p < 0.0001). M-SE stage-A patients had a median OS of 18.7 months (95% CI: 15.6-21.8); patients in stage B and C showed a significantly shorter survival of 5.7 (2.7-8.7) and 2.0 months (1.6-2.4), respectively. M-SE (c-index 0.70; AIC 621) outperformed all other prognostic systems. External validation in a prospective cohort confirmed its superior prognostic performance. CONCLUSION: The M-SE score allows classification of sorafenib patients in three distinct prognostic stages. Provided that M-SE successfully passes prospective validation, it can help to predict the outcome of patients evaluated for sorafenib treatment.

Online medical history taking course: Opportunities and limitations in comparison to traditional bedside teaching.

Objective: Obtaining a systematic medical history (MH) from a patient is a core competency in medical education and plays a vital role in the diagnosis of diseases. At the Faculty of Medicine at LMU Munich, students have their first course in MH taking during their second year. Due to the COVID-19 pandemic, the traditional bedside MH taking course had to be transformed into an online course (OC). Our objectives were to implement an online MH taking course, to evaluate its feasibility and to compare the evaluation results to a historic cohort that had undertaken the traditional bedside teaching course (BTC). Methods: 874 second-year students participated in the OC (BTC=827). After teaching the theoretical background via asynchronous online lectures, students participated in a practical exercise with fellow students using the video communication platform Zoom where they were able to practice taking a MH on the basis of fictitious, text-based patient cases. Students were then asked to evaluate the course through a standardized online survey with 31 questions on teaching quality and self-perceived learning success, which had also been used in previous years. The survey results were compared to the results of the historic cohort using the Mann-Whitney U test. Results: A total of n=162 students (18.5%) evaluated the OC. In the historic cohort, n=252 (30.5%) completed the survey. 85.3% of the OC respondents thought that the atmosphere during the practical exercise was productive and 83.0% greatly appreciated the flexibility in terms of time management. Moreover, they appreciated the online resources as well as having the opportunity to undertake a MH taking course during the COVID-19 pandemic. 27.7% of the respondents thought that traditional BTCs should be supplemented through more online activities in the future. With respect to the ability of independently taking a MH upon completion of the course, the OC was rated significantly lower relative to the BTC (mean OC=2.4, SD=±1.1 vs. mean BTC=1.9, SD=±1.1 (1=strongly agree; 5=strongly disagree); p<0.0001). Conclusion: OCs are a feasible format and seem to convey the theory and practical implementation in a peer-exercise format of MH taking to medical students. The theoretical background can be acquired with great flexibility. Nevertheless, the students' self-appraisal suggested that the traditional teaching format was more effective at teaching MH taking skills. Thus, we propose a blended learning concept, combining elements of both formats. In this context, we suggest prospective, randomized trials to evaluate blended learning approaches.

The Feasibility of Percutaneous Dilatational Tracheostomy in Immunosuppressed ICU Patients with or without Thrombocytopenia.

Background: Percutaneous dilatational tracheostomy (PDT) has become the preferred method in several intensive care units (ICUs), but data on PDT performed in immunosuppressed and thrombocytopenic patients are scarce. This study aimed to analyze the feasibility of PDT in immunosuppressed and thrombocytopenic patients compared to conventional open surgical tracheostomy (OST). Methods: We retrospectively analyzed the charts of patients who underwent PDT or OST between May 2017 and November 2020. Our outcomes were stoma site infections and bleeding complications. Results: 63 patients underwent PDT, and 21 patients underwent OST. Distribution of gender ratio, age, SAPS II, time of ventilation before tracheostomy, and preexisting hematooncological diseases was comparable between the two groups. After allogeneic stem cell transplantation (alloSCT), patients were more likely to undergo PDT than OST (p=0.033). The PDT cohort suffered from mucositis more frequently (p=0.043). There were no significant differences in leucocyte or platelet count on the tracheostomy day. Patients with coagulation disorders and patients under immunosuppression were distributed equally among both groups. Stoma site infection was documented in five cases in PDT and eight cases in the OST group. Moderate infections were remarkably increased in the OST group. Smears were positive in six cases in the PDT group; none of these patients had local infection signs. In the OST group, smears were positive in four cases; all had signs of a stroma site infection. Postprocedural bleedings occurred in eight cases (9.5%) and were observed significantly more often in the OST group (p=0.001), leading to emergency surgery in one case of the OST group. Conclusion: PDT is a feasible and safe procedure in a predominantly immunosuppressed and thrombocytopenic patient cohort without an increased risk for stoma site infections or bleeding complications.

Advances in Pharmacotherapy of Hepatocellular Carcinoma: A State-of-the-Art Review.

BACKGROUND: Due to the number of emerging new treatment options, the systemic treatment of hepatocellular carcinoma (HCC) is rapidly changing. We provide here an overview of the current landscape of systemic treatment of HCC and discuss its potential future development. SUMMARY: HCC is a leading cause of tumor-related death worldwide. Despite the efforts aimed at reducing the prevalence of HCC through vaccination and antiviral treatment, and the implementation of screening programs for early tumor detection, most patients are diagnosed with or progress to advanced HCC. For approximately 10 years, sorafenib has been the only effective systemic treatment available for these patients. Recently, however, a number of new systemic compounds, comprising several multi-kinase inhibitors and immune-checkpoint inhibitors, have been approved for treatment of HCC. These new agents are opening a plethora of therapeutic options for the future therapy of HCC. KEY MESSAGES: The rapid progress in the treatment of HCC raises the question of the optimal combination and sequence of these agents in the treatment of patients with advanced disease. The substantial improvements in terms of objective response and survival indicate that the use of immune-checkpoint inhibitors-based treatment combinations may be extended to patients with intermediate-stage HCC.

A Simple Prognostic Scoring System for Hepatocellular Carcinoma Treated with Selective Internal Radiation Therapy.

INTRODUCTION: Selective internal radiation therapy (SIRT) is a local treatment option for patients with hepatocellular carcinoma (HCC). Its exact role next to other HCC therapies has yet to be defined. In order to identify patients most suitable for SIRT, a SIRT-specific prognostic score should be developed. METHODS: A cohort of 72 SIRT patients treated at the University Hospital of Munich was retrospectively analyzed. The prognostic performance of 12 HCC staging systems and prognostic scores was assessed. Cox-regression analysis was used to identify independent prognostic factors, which formed the basis of the Munich-SIRT score (M-SIRT). All scores were ranked by calculating the c-Index and Akaike information criterion (AIC). External validation was performed in a cohort of 128 SIRT patients treated at the University Hospital of Pamplona, Spain. RESULTS: median overall survival was 13 months (95% confidence interval 9.9-21.9). AFP (p = 0.005; hazard ratio [HR] 2.38), albumin (p < 0.001; HR 5.87), and alkaline phosphatase (p < 0.001; HR 8.38) were identified as independent prognostic factors. M-SIRT comprises 3 prognostic groups with a median survival of 38.9, 14.6, and 7.7 months, respectively (I vs. II: p = 0.003, II vs. III: p < 0.001). AIC (318) and concordance index (0.711) ranked M-SIRT superior to the established HCC staging systems, and the score successfully passed external validation in an independent SIRT cohort (I vs. II: p = 0.03; II vs. III: p = 0.007). CONCLUSION: Therapy-specific prognostic scores can facilitate treatment decisions and prognostication for HCC patients. Considering its performance in 200 SIRT patients, M-SIRT is a promising prognostic tool for HCC patients evaluated for SIRT.

Biliary Cannulation in Endoscopic Retrograde Cholangiography: How to Tackle the Difficult Papilla.

BACKGROUND: In the setting of a naïve papilla, biliary cannulation is a key step in successfully performing endoscopic retrograde cholangiography. Difficult biliary cannulation (DBC) is associated with an increased risk of post-ERCP pancreatitis and failure of the whole procedure. SUMMARY: Recommendations for biliary cannulation can be divided into (a) measures to reduce the likelihood of a difficult papilla situation a priori and (b) rescue techniques in case the endoscopist is actually facing DBC. (a) Careful inspection of the papillary anatomy and optimizing its accessibility by scope positioning is fundamental. A sphincterotome in combination with a soft-tip hydrophilic guidewire rather than a standard catheter with a standard guidewire should be used in most situations. (b) The most important rescue techniques are needle-knife precut, double-guidewire technique, and transpancreatic sphincterotomy. In few cases, anterograde cannulation techniques are needed. To this regard, the EUS-guided biliary drainage followed by rendezvous is increasingly used as an alternative to percutaneous transhepatic biliary drainage. Key Messages: Biliary cannulation can be accomplished with alternative retrograde or less frequently by salvage anterograde techniques, once conventional direct cannulation attempts have failed. Considering recent favorable data for the early use of transpancreatic sphincterotomy, an adopted version of the 2016 European Society for Gastrointestinal Endoscopy (ESGE) algorithm on biliary cannulation is proposed.

Combination of Sorafenib and Transarterial Chemoembolization in Selected Patients with Advanced-Stage Hepatocellular Carcinoma: A Retrospective Cohort Study at Three German Liver Centers.

BACKGROUND AND AIMS: Systemic treatment with sorafenib has been the standard of care (SOC) in patients with advanced Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) for more than a decade. TACE has been reported to allow better local tumor control in selected patients with BCLC stage C HCC. METHODS: A retrospective analysis of patients with BCLC stage C HCC that were treated with sorafenib and TACE was conducted; they were compared to BCLC stage C patients treated either with TACE or sorafenib in the same period of time outside a clinical trial. RESULTS: A total of 201 patients with BCLC stage C were identified, who were treated with either sorafenib and TACE (group A; n = 54), sorafenib (group B; n = 82) or TACE (group C; n = 65). No significant difference in baseline characteristics was observed. Time to progression was 7.0 months (95% CI: 4.3-9.7), 4.1 months (95% CI: 3.6-4.7) and 5.0 months (95% CI: 2.9-7.1) in groups A, B and C, respectively, and overall survival was 16.5 months (95% CI: 15.0-18.1), 8.4 months (95% CI: 6.0-10.8) and 10.5 months (95% CI: 7.5-13.6), respectively (group A vs. group B: p < 0.001; group A vs. group C: p = 0.0023). Adverse events of grade 3/4 occurred in 34% of patients in group A. CONCLUSIONS: Although sorafenib is a SOC in patients with BCLC stage C HCC, TACE is frequently used as an additional locoregional treatment in selected patients. This combined approach resulted in a significant overall survival benefit in selected patients, although randomized trials have not yet proven this benefit.

SEPT6 drives hepatocellular carcinoma cell proliferation, migration and invasion via the Hippo/YAP signaling pathway.

Septin 6 (SEPT6) is a member of the GTP­binding protein family that is highly conserved in eukaryotes and regulates various biological functions, including filament dynamics, cytokinesis and cell migration. However, the functional importance of SEPT6 in hepatocellular carcinoma (HCC) is not completely understood. The present study aimed to investigate the expression levels and roles of SEPT6 in HCC, as well as the underlying mechanisms. The reverse transcription quantitative PCR, western blotting and immunohistochemistry staining results demonstrated that SEPT6 expression was significantly elevated in HCC tissues compared with corresponding adjacent non­tumor tissues, which indicated that SEPT6 expression may serve as a marker of poor prognosis for HCC. By performing plasmid transfection and G418 treatment, stable SEPT6­knockdown and SEPT6­overexpression cell lines were established. The Cell Counting Kit­8, flow cytometry and Transwell assay results demonstrated that SEPT6 overexpression significantly increased HCC cell proliferation, cell cycle transition, migration and invasion compared with the Vector group, whereas SEPT6 knockdown displayed significant suppressive effects on HCC cell lines in vitro compared with the control group. Mechanistically, SEPT6 might facilitate F­actin formation, which induced large tumor suppressor kinase 1 dephosphorylation, inhibited Hippo signaling, upregulated yes­associated protein (YAP) expression and nuclear translocation, and upregulated cyclin D1 and matrix metallopeptidase 2 (MMP2) expression. Furthermore, YAP overexpression significantly reversed SEPT6 knockdown­induced inhibitory effects on HCC, whereas YAP knockdown significantly inhibited the oncogenic effect of SEPT6 overexpression on HCC. Collectively, the present study demonstrated that SEPT6 may promote HCC progression by enhancing YAP activation, suggesting that targeting SEPT6 may serve as a novel therapeutic strategy for HCC.

Development of amoebic liver abscess in early pregnancy years after initial amoebic exposure: a case report.

BACKGROUND: Infection with Entamoeba histolytica and associated complications are relatively rare in developed countries. The overall low prevalence in the Western world as well as the possibly prolonged latency period between infection with the causing pathogen and onset of clinical symptoms may delay diagnosis of and adequate treatment for amoebiasis. Amoebic liver abscess (ALA) is the most common extraintestinal manifestation of invasive amoebiasis. Pregnancy has been described as a risk factor for development of invasive amoebiasis and management of these patients is especially complex. CASE PRESENTATION: A 30-year-old Caucasian woman in early pregnancy presented to our emergency department with abdominal pain alongside elevated inflammatory markers and liver function tests. Travel history revealed multiple journeys to tropic and subtropic regions during the past decade and a prolonged episode of intermittently bloody diarrhea during a five month stay in Indonesia seven years prior to admission. Sonographic and magnetic resonance imaging revealed a 5 × 4 cm hepatic abscess. After ultrasound-guided transcutaneous liver drainage, both abscess fluids and blood cultures showed neither bacterial growth nor microscopic signs of parasitic disease. Serological testing confirmed an infection with Entamoeba histolytica, which was treated with metronidazole, followed by eradication therapy with paromomycin. Subsequent clinical, laboratory and imaging follow-up exams showed regression of the ALA. In addition, the pregnancy completed without complications and a healthy baby boy was born 7 months after termination of treatment. CONCLUSIONS: This case of invasive amoebiasis in early pregnancy outside of endemic regions and several years after exposure demonstrates the importance of broad differential diagnostics in the context of liver abscesses. The complex interdisciplinary decisions regarding the choice of imaging techniques as well as interventional and antibiotic therapy in the context of pregnancy are discussed. Furthermore, we present possible explanations for pregnancy as a risk factor for an invasive course of amoebiasis.

The Munich-Transarterial Chemoembolisation Score Holds Superior Prognostic Capacities Compared to TACE-Tailored Modifications of 9 Established Staging Systems for Hepatocellular Carcinoma.

BACKGROUND/AIMS: The recently proposed Munich-transarterial chemoembolisation-score (M-TACE) was tailored to suit hepatocellular Carcinoma (HCC) patients evaluated for TACE. M-TACE outperformed the established HCC-staging-systems and successfully passed external validation. Modifications of staging-systems through the rearrangement of stages or by adding prognostic factors are methods of improving prognostic power. M-TACEs performance compared to scores modified this way should be tested. METHODS: Seven well-known HCC staging-systems (including Cancer of the Liver Italian Program-score [CLIP] and Barcelona Clinic liver cancer [BCLC]) and 2 TACE-specific scores (Selection for Transarterial Chemoembolisation Treatment [STATE] and Hepatoma Arterial embolisation Prognostic [HAP]) were rearranged in a cohort of 186 TACE-patients through score-point-analysis and subsequent linking of non-significant adjacent score-points. Additionally, a new score was constructed by combining the top established staging-system in TACE patients (CLIP-TACE) and the prognostic parameter with the highest hazard ratio for death in the TACE-cohort [C-reactive protein (CRP)]. Additionally, the TACE-tailored-scores were applied to an external TACE-cohort (n = 71). -Results: Rearrangement resulted in optimal stratification and monotonicity. CLIP-TACE demonstrated the best prognostic capability of all rearranged scores (c-index 0.668, AIC 1294) and the addition of CRP yielded further prognostic improvement (c-index 0.680, AIC 1289). However, superiority over M-TACE could not be achieved by any of the new scores in the internal and external cohort. CONCLUSION: M-TACE outperforms TACE-tailored modifications of all relevant HCC-staging-systems. Prospective validation of M-TACE to promote its role as the preferred staging-system for TACE-patients is therefore justified.

Impaired Consciousness in the Emergency Department.

BACKGROUND: The approach to unconscious patients in the emergency department (ED) is difficult, often depends on local resources and interests, and workup strategies often lack standardization. One reason for this is that data on causes, management, and outcome of patients who present to the ED with sudden onset unconsciousness of unknown cause is limited. OBJECTIVES: This study was performed to analyze the causes of acute impaired consciousness in patients in an interdisciplinary ED. METHODS: Here, we analyzed all patients who were admitted to the ED of a tertiary care hospital with the dominating symptom of "sudden onset unconsciousness" within 1 year (September 2014 until August 2015). Patients with a clear diagnosis at arrival that explained the altered state of consciousness or other dominating symptoms at the time of arrival were not included. RESULTS: A total of 212 patients were analyzed. In 88% of the patients, a final diagnosis could be established in the ED. Most common causes for unconsciousness were cerebrovascular diseases (24%), infections (14%), epileptic seizures (12%), psychiatric diseases (8%), metabolic causes (7%), intoxications (7%), transient global amnesia (5%), and cardiovascular causes (4%). The diagnoses were predominantly established by physical examination in combination with computed tomography (23%) and by the results of laboratory testing (25%). In-hospital mortality was 11%, and 59% of all patients were discharged with a Glasgow Outcome Score of 2-4. CONCLUSIONS: This analysis demonstrates a large variety of etiologies in patients with unknown unconsciousness of acute onset who are admitted to an ED. As neurological diagnoses are among the most common etiologies, neurological qualification is required in the ED, and availability of diagnostics such as cerebral imaging is indispensable and recommended as an early step in a standardized clinical approach.

Extracorporeal Membrane Oxygenation in Predominantly Leuco- and Thrombocytopenic Haematologic/Oncologic Patients with Acute Respiratory Distress Syndrome - a Single-Centre Experience.

AIMS: The acute respiratory distress syndrome (ARDS) is a frequent condition following pneumonia in immunocompromised cancer patients. Extracorporeal membrane oxygenation (ECMO) may serve as a rescue therapy in refractory ARDS but has still not been studied in predominantly leuco- and thrombocytopenic cancer patients. PATIENTS AND METHODS: In this monocentric, retrospective, observational study, we assessed all cancer patients treated with ECMO for ARDS between 2013 and 2017. RESULTS: 25 patients, 11 of whom underwent haematopoietic stem cell transplantation (SCT), were analysed. The main reason for ARDS was pneumonia in 72%. All patients were under invasive ventilation at ECMO. All but 9/3 patients suffered from leuco-/thrombocytopenia due to anti-cancer treatment or underlying disease. Overall, 17 patients (68%) died on ECMO, whereas 5 patients survived to hospital discharge (20%). All patients after recent allogeneic (allo-)SCT have died. 4 patients experienced severe bleeding events. CONCLUSIONS: Discouraging survival rates in patients treated after allo-SCT do not support the use of ECMO for ARDS in this patient subgroup. On the contrary, cancer patients in at least stable disease otherwise eligible for full-code intensive care unit management, even those with severe thrombocytopenia, may be potential candidates for ECMO in case of severe ARDS failing conventional measures.

Transarterial chemoembolization for hepatocellular carcinoma: development and external validation of the Munich-TACE score.

BACKGROUND: Allocation of patients with hepatocellular carcinoma (HCC) to the adequate therapy is determined by both tumor burden and liver function. The Barcelona Clinic Liver Cancer (BCLC) staging system and therapeutic algorithm recommends transarterial chemoembolization (TACE) based on the best evidence available to patients with intermediate-stage HCC (BCLC-B). However, many centers also treat subgroups of patients outside these recommendations and with more advanced disease by TACE. The purpose of this study was to identify prognostic factors in a TACE cohort, including BCLC-B patients, as well as patients treated outside of BCLC-B, to test the prognostic capabilities of published staging systems and to optimize prognostication for TACE patients. PATIENTS AND METHODS: A cohort of 186 first-line TACE patients was analyzed. Independent prognostic factors were identified and used to construct the Munich-TACE score (M-TACE). M-TACE was tested against established staging systems (including BCLC and two recently published TACE-specific scores) and a ranking using concordance index and Akaike Information Criterion was performed. Finally, an external validation in an independent TACE cohort (n=71) was conducted. RESULTS: Bilirubin, Quick/international normalized ratio, C-reactive protein, creatinine, α-feto protein, and tumor extension were identified as independent prognostic factors and used to construct M-TACE. M-TACE identifies three distinct subgroups (P<0.0001) with median survival times of 35.2, 16.9, and 8.6 months, respectively. Compared with established staging systems, M-TACE showed the best prognostic capabilities in both cohorts of patients (cohort 1: c-index, 0.71; Akaike Information Criterion: 1276; cohort 2: c-index, 0.754). CONCLUSION: We identified independent risk factors for patients treated with TACE. The newly constructed M-TACE score is superior to established staging systems and might prove helpful to identify patients who are most suitable for TACE.

Differential significance of early surgical complications for acute and long-term recurrence-free survival following surgical resection of hepatocellular carcinoma: do comorbidities play a role?

BACKGROUND: Postoperative complications of Clavien-Dindo grade 3 or more are of prognostic significance in patients who undergo liver resection for hepatocellular carcinoma (HCC). However, perioperative mortality and patient comorbidities represent relevant factors that interfere with postoperative long-term survival. To clarify this, a retrospective single-center study was carried out. PATIENTS AND METHODS: Patient data were prospectively collected in a continuously updated liver resection database. Overall, 184 consecutive patients who underwent liver resection for HCC with a curative intent between March 2003 and December 2013 were selected for the study. The patients were assigned to two groups according to the presence or absence of postoperative complications. Pre-existing comorbidities, perioperative mortality, surgical outcome, and long-term survival data were analyzed. RESULTS: Postoperative complications requiring revision surgery were identified in 17.4% of the patients. The in-house mortality rate was 4.8%. Compared with patients without complications, patients with complications were older and had significantly more pre-existing comorbidities, more advanced tumors, more intrahepatic metastasis, longer operation times, greater blood loss, and more extensive resections. The overall 5-year survival rates were 40.1 and 52.5% in patients with or without postoperative complications, respectively. The corresponding 5-year recurrence-free survival rates were 46.3 and 46.7% (perioperative mortality excluded). Multivariate analysis showed that elevation of the Charlson Comorbidity Index was associated independently with decreased overall and recurrence-free survival. CONCLUSION: In patients with HCC, posthepatectomy complications are confirmed to have predictive value. However, closer analysis and exclusion of perioperative mortality effects show an independent impact of pre-existing comorbidities on long-term overall und recurrence-free survival.

Methylated free-circulating HPP1 DNA is an early response marker in patients with metastatic colorectal cancer.

Detection of methylated free-circulating DNA (mfcDNA) for hyperplastic polyposis 1 (HPP1) in blood is correlated with a poor prognosis for patients with metastatic colorectal cancers (mCRC). Here, we analyzed the plasma levels of HPP1 mfcDNA in mCRC patients treated with a combination therapy containing a fluoropyrimidine, oxaliplatin and bevacizumab to test whether HPP1 mfcDNA is a suitable prognostic and response biomarker. From 467 patients of the prospective clinical study AIO-KRK-0207, mfcDNA was isolated from plasma samples at different time points and bisulfite-treated mfcDNA was quantified using methylation specific PCR. About 337 of 467 patients had detectable levels for HPP1 mfcDNA before start of treatment. The detection was significantly correlated with poorer overall survival (OS) (HR = 1.86; 95%CI 1.37-2.53). About 2-3 weeks after the first administration of combination chemotherapy, HPP1 mfcDNA was reduced to non-detectable levels in 167 of 337 patients. These patients showed a better OS compared with patients with continued detection of HPP1 mfcDNA (HR HPP1(sample 1: pos/ sample 2: neg) vs. HPP1(neg/neg) = 1.41; 95%CI 1.00-2.01, HPP1(neg,pos/pos) vs. HPP1(neg/neg) = 2.60; 95%CI 1.86-3.64). Receiver operating characteristic analysis demonstrated that HPP1 mfcDNA discriminates well between patients who do (not) respond to therapy according to the radiological staging after 12 or 24 weeks (AUC = 0.77 or 0.71, respectively). Detection of HPP1 mfcDNA can be used as a prognostic marker and an early marker for response (as early as 3-4 weeks after start of treatment compared with radiological staging after 12 or 24 weeks) to identify patients who will likely benefit from a combination chemotherapy with bevacizumab.

CyberKnife Radiosurgery - Value as an Adjunct to Surgical Treatment of HCC?

INTRODUCTION: CyberKnife radiosurgery (CK) is an effective tool for the treatment of malignancies. Its greatest potential is in high-dose radiosurgery delivered to targets in organs that move with respiration, e.g., liver tumors. For hepatocellular carcinoma (HCC), however, surgical treatment (resection, transplantation) is most likely to produce long-term survival; for non-resectable tumors, therapies other than radiosurgery are typically recommended. This study evaluated the long-lasting anti-tumor effects of CK combined with surgery in patients with HCC. MATERIALS AND METHODS : Eighteen patients (three women, 15 men) were included in this prospective observational study. They received 21 single-fraction CK treatments (26 Gy). Patient characteristics, treatment effects, tumor response (according to the Response Evaluation Criteria In Solid Tumors (RECIST) grading) and survival were measured for a median period of 29 months. RESULTS: Local tumor control was achieved in 15 patients, with complete and partial remission observed in 10 and five patients, respectively. One patient was treated for two separate lesions in one session, and one received three treatments each separated by two-year intervals; both patients are tumor-free. Two patients showed minimal response, and in one patient local tumor viability could not be excluded by MRI. Nine patients had HCC recurrence, all distant to the treated site. Nine patients died during follow-up, including two with clear relation to tumor progress. Tumor-free survival was 79.4% after one year and 29.8% after three years, and the corresponding overall survival was 84.8% and 66%. CONCLUSION : This study shows the high effectiveness of single-session frameless CyberKnife radiosurgery for treatment of hepatocellular carcinoma and reconfirms previous results of fractioned radiotherapy of HCC. It also demonstrates the potential of radiosurgery to be combined with surgical concepts.

Reduced Periprocedural Analgesia After Replacement of Water for Injection with Glucose 5% Solution as the Infusion Medium for 90Y-Resin Microspheres.

The primary aim of our study was to compare the need for periinterventional on-demand analgesia when water for injection (WFI) was replaced with glucose 5% (G5) for 90Y-resin microsphere administration. METHODS: Forty-one patients who received 77 radioembolization procedures with G5 (2014-2015) were retrospectively matched with 41 patients (77 radioembolization procedures) who received radioembolization with WFI (2011-2014) at our center. The need for on-demand pain medication was chosen as an objective and accessible measure of periprocedural pain experienced by patients. RESULTS: Patients were well matched according to sex, age, tumor type and involvement, and prior antiangiogenic therapies. Periinterventional analgesic requirements were significantly lower for radioembolization procedures performed with G5 than WFI: 5 of 77 (6.5%) versus 29 of 77 (37.7%), P ≤ 0,001, respectively. Early stasis (defined as slowed antegrade flow, before total vascular stasis) occurred in 12 of 154 (7.8%) radioembolization procedures overall and was not different (P ≤ 0.229) between the 2 groups (4/77 [5.2%] vs. 8/77 [10.4%]). CONCLUSION: Slow pulsatile administration of 90Y-resin microspheres with WFI is associated with a low rate of stasis. Replacement of WFI with G5 significantly reduces the need for periprocedural analgesia. These data favor the use G5 for 90Y-resin microsphere implantation in daily practice.

Miliary pattern of brain metastases - a case report of a hyperacute onset in a patient with malignant melanoma documented by magnetic resonance imaging.

BACKGROUND: Miliary brain metastases are a rare condition but associated with an exceedingly poor prognosis. We present the case of a patient suffering from malignant melanoma with an acute progressively worsening of neurological symptoms up to the loss of consciousness. The magnetic resonance imaging (MRI) demonstrated a new onset of disseminated, miliary spread of central nervous system metastases from a malignant melanoma within 4 days. CASE PRESENTATION: We report on a 57-year-old woman suffering from metastatic malignant melanoma positive for BRAF-V600E mutation who developed an acute onset of neurological symptoms. The patient received vemurafenib and dacarbacin as chemotherapeutic regime for treatment of malignant melanoma. After admission to our hospital due to progressive disturbance of memory and speech difficulty a magnetic resonance tomography (MRI) was performed. This showed no evidence of cerebral tumour manifestation. The symptoms progressed until a loss of consciousness occurred on day five after admission and the patient was admitted to our intensive care unit for orotracheal intubation. No evidence for infectious, metabolic or autoimmune cerebral disorders was found. Due to the inexplicable acute worsening of the neurological symptoms a second MRI was performed on day five. This revealed a new onset of innumerable contrast-enhancing miliary lesions, especially in the grey matter which was proven as metastases from malignant melanoma on histopathology. CONCLUSION: This case describes an unique hyperacute onset of tumour progression correlating with an acute deterioration of neurological symptoms in a patient suffering from miliary brain metastasis from BRAF positive malignant melanoma.