Predictive preoperative clinical score for patients with liver-only oligometastatic colorectal cancer.

BACKGROUND: Resection of liver metastases from colorectal cancer (CRC) in the oligometastatic stage improves survival and is a potentially curative treatment. Thus, predictive scores that reliably identify those patients who especially benefit from surgery are essential. PATIENTS AND METHODS: In this multicenter analysis, 512 patients had undergone surgery for liver metastases from CRC. We investigated distinct cancer-specific risk factors that are routinely available in clinical practice and developed a predictive preoperative score using a training cohort (TC), which was thereafter tested in a validation cohort (VC). RESULTS: Inflammatory response to the tumor, a right-sided primary tumor, multiple liver metastases, and node-positive primary tumor were significant adverse variables for overall survival (OS). Patients were stratified in five groups according to the cumulative score given by the presence of these risk factors. Median OS for patients without risk factors was 133.8 months [95% confidence interval (CI) 81.2-not reached (nr)] in the TC and was not reached in the VC. OS decreased significantly for each subsequent group with increasing number of risk factors. Median OS was significantly shorter (P < 0.0001) for patients presenting all four risk factors: 14.3 months (95% CI 10.5 months-nr) in the TC and 16.6 months (95% CI 14.6 months-nr) in the VC. CONCLUSIONS: Including easily obtainable variables, this preoperative score identifies oligometastatic CRC patients with prolonged survival rates that may be cured, and harbors potential to be implemented in daily clinical practice.

Reversal of end-ileostomy in patients with Crohn's disease.

PURPOSE: End-ileostomy after two-staged ileocolic resection is frequently performed in Crohn's disease patients at high risk for postoperative complications. However, there is paucity on data regarding the morbidity after the stoma reversal. METHODS: One hundred thirty patients undergoing closure of end-ileostomy between 1994 and 2016 were included. Data collection was retrospective in 11 first, and it was prospective in 119 last patients. Anastomotic complications were defined as anastomotic leak, perianastomotic abscess, and perianastomotic peritonitis. RESULTS: The median interval between ileostomy construction and reversal was 4.0 months. Ninety-seven of 121 patients with available data (80%) gained weight between both surgeries. Hemoglobin level increased between surgeries in 107 patients (85%). Fifteen patients (11.5%) received parenteral fluid substitution or parenteral nutrition between both surgeries. There were 37 hospital readmissions during the time between stoma construction and reversal (29%). After ileostomy reversal, 14 patients developed anastomotic complications (11%). By multivariate regression analysis, preoperative steroid intake (hazard ratio 4.5, 95% CI: 1.11-18.0, p = 0.035) and hospital readmission for infectious complications (HR 4.5, 95% CI: 1.11-18.0, p = 0.035) were statistically significantly associated with an increased risk to develop postoperative anastomotic complications. There were no postoperative deaths. CONCLUSION: Closure of end-ileostomy could be complicated by some serious morbidity. These risks should be taken into consideration weighing carefully between the one- and two-stage ileocolic resection in Crohn's disease patients.

[Intraoperative ultrasound in visceral surgery]. / Intraoperativer Ultraschall in der Viszeralchirurgie.

BACKGROUND: Intraoperative ultrasound is a routine procedure in abdominal surgery. Not only detection of focal lesions but also perfusion and elasticity analyses using color-coded Doppler sonography, contrast-enhanced ultrasound and elastography enable highly sensitive and highly specific diagnostics, especially in oncological surgery. OBJECTIVE: This article provides an overview on current techniques of intraoperative ultrasound and gives an outlook on future possibilities and applications. MATERIAL AND METHODS: Literature-based presentation of evidence-based intraoperative ultrasound, discussion of current basic research and expert recommendations. RESULTS: Modern intraoperative ultrasound is a highly efficient technique for detection and characterization of focal space-occupying lesions in surgery of benign and malignant diseases. CONCLUSION: Intraoperative ultrasound is a highly sensitive and specific diagnostic tool, providing real-time diagnostics with a manageable amount of technical equipment. Thus, preoperative diagnostics can be refined, partly resulting in a modification of intraoperative treatment management. Future developments in the fields of digital image fusion with preoperative sectional imaging, optical guidance of surgical instruments and molecular targeted tumor therapy will increase the importance of intraoperative sonography even more.

[Surgical innovations in treatment of metastatic colorectal cancer : Complexity of metastatic surgery as example for personalized medicine]. / Chirurgische Innovationen in der Therapie des metastasierten kolorektalen Karzinoms : Die Komplexität der Metastasenchirurgie als Beispiel für personalisierte Medizin.

BACKGROUND: Extensive, bilobular and multifocal colorectal liver metastases (CLM) or metastases that are critically situated require an experienced surgeon and advanced surgical techniques to enable curative resection. OBJECTIVE: This article describes the toolbox of hepato-oncologic surgery including functional augmentation of liver segments by portal vein embolization/ligation, combinations of ablation and resection, two-stage resections and in situ split liver resection, also known as associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Furthermore, the curative resection of extrahepatic, oligometastatic disease are briefly discussed. MATERIAL AND METHODS: Review of current literature as well as discussion of the ALPPS procedure, which was developed at our institute. RESULTS: In recent years, oncologic resections for CLM have been significantly refined, leading to a constant increase of curative resection rates. CONCLUSION: In a multimodality treatment setting, surgical resection of CLM remains the gold standard curative approach and even in the event of presumed hopeless cases with extensive metastasis, experienced hepatobiliary surgeons must evaluate the resectability of colorectal metastases.

Communicative reprogramming non-curative hepatocellular carcinoma with low-dose metronomic chemotherapy, COX-2 inhibitor and PPAR-gamma agonist: a phase II trial.

Systemic therapy for advanced hepatocellular carcinoma (HCC) is still challenging. A biomodulatory therapy approach targeting the communicative infrastructure of HCC, including metronomic low-dose chemotherapy with capecitabine, pioglitazone and rofecoxib, has been evaluated in patients with non-curative HCC. Altogether 38 patients were evaluable in this one-arm, multicenter phase II trial. The primary endpoint, median progression-free survival was 2.7 months (95% CI: 1.6-3.79) for all evaluable patients and 8.4 months (95% CI: 0-18.13) for patients ≥ 6 weeks on protocol. Median overall survival (OS) was 6.7 months (95% CI: 4.08-9.31) and 9.4 months (95% CI: 4.82-13.97), respectively. Most common adverse events were edemas grade 3, which were commonly related to the advanced stage, with 66% of the patients suffering from liver cirrhosis. Exploratory data analyses showed significant impact of ECOG performance status grade 0 versus 1 and CLIP score 0/1 versus > 1 on OS, 9.8 months (95% CI: 4.24-15.35) versus 2.7 months (95% CI: 1.03-4.36; P = 0.002), and 9.8 months (95% CI: 3.23-16.37) versus 4.4 months (95% CI: 3.14-5.66; P = 0.009), respectively. Preceding tumor surgery had significant beneficial impact on survival, as well as maximal tumor diameter of < 5 cm. The correlation of C-reactive protein decrease with significantly improved OS underlines the close link between inflammation and tumor control. Biomodulatory therapy in advanced HCC may be a low toxic, efficacious treatment and principally demonstrates that such approaches should be followed further for treatment of advanced HCC.

Efficiency of contrast enhanced ultrasound for immediate assessment of ablation status after intraoperative radiofrequency ablation of hepatic malignancies.

AIM: To evaluate the efficiency of intraoperative contrast enhanced ultrasound (Io-CEUS) for assessment of radiofrequency ablation (RFA) during liver tumor surgery. MATERIAL AND METHODS: Retrospective analysis was performed on a total number of 18 patients out of over 500 patients who underwent combined liver tumor surgery and RFA of 27 hepatic tumors between 02/2011 and 12/2016. Io-CEUS was performed by bolus injections of up to 10 ml sulphur hexaflourid microbubbles for diagnostic purposes. To guide the RFA up to 20 ml microbubbles were applied to monitor the procedure and assess the ablation status finally. A fully avascular area or absence of any residual vascularization intratumorally was considered technical success. These findings were correlated to findings of follow-up imaging results (CEUS, MRI, CT) at least 1 up to 40 months (mean 11 months) after surgery. RESULTS: 13 male and 5 female patients aged between 45-77 years (mean 59.2±17.1 years) with 26 malignant and one most probable benign hepatic lesion were treated with intraoperative RFA. Io-CEUS detected 23 preoperatively unknown liver lesions leading to a change in therapy in 13/18 cases (72,2%). All 27 treated lesions showed an avascular area immediately after RFA. According to follow-up imaging results (1 month - 3 years after surgery, mean follow-up time 11 months), 2/18 patients had local recurrences, 8 patients had distant intrahepatic recurrences or extrahepatic recurrence, 8 patients remained tumor-free. Thereby, a success rate of CEUS guided RFA of 89% could be obtained concerning the targeted liver lesions. CONCLUSION: Modern intraoperative ultrasound using B-mode and Io-CEUS is a valuable tool for optimization of diagnostic and therapeutic intraoperative liver procedures and ablative therapies.

Improved Detection of preclinical Colorectal Liver Metastases by High Resolution Ultrasound including Molecular Ultrasound Imaging using the targeted Contrast Agent BR55.

PURPOSE: Aim of the present study was to investigate the sensitivity of high resolution ultrasound (HRU), standard contrast-enhanced ultrasound (CEUS) and CEUS using a novel vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast agent for the detection of hepatic metastases in a mouse model of colorectal cancer using clinical standard technology. MATERIALS AND METHODS: The human colon cancer cell line HT29, transfected with luciferase cDNA for in vivo bioluminescence monitoring, was injected intrasplenically into CB17.SCID mice. Mice were monitored weekly by bioluminescence and after 2 and 4.5 weeks by HRU and CEUS. Contrast media (untargeted BR1, targeted BR55) was applied and digital cine loops from the arterial phase (15 - 45 sec), portal venous phase (50 - 120 s) and late phases (3 - 5 min, 1hour) of the whole liver were analyzed. Data were correlated with postmortem histopathology. RESULTS: Without contrast enhancement, lesions > 4 mm were reliably detected. After use of untargeted CEUS, lesions > 2 mm were reliably detected and enhanced rim vascularization and late-phase wash-out was shown. With BR55, lesions > 0.8 mm were reliably detected with excellent documentation of vascularization. A persistent contrast enhancement was seen > 30 min after injection. Contrast-enhancement patterns with BR55 significantly correlated with CD31 (R2 = 0.74) and VEGFR2-immunohistochemistry (R2 = 0.66). CONCLUSION: Detection of metastases by HRU and CEUS was earlier and more accurate than monitoring via bioluminescence. In vivo monitoring of hepatic micrometastases can thus be performed without prior modification of cancer cells using standard technology.

[Surgical technique for laparoscopic kidney donation]. / Die chirurgische Technik der laparoskopischen Nierenlebendspende.

OBJECTIVE: Dialysis cannot fully replace kidney function in patients diagnosed with end-stage renal disease. Patients undergoing dialysis therapy show a significantly reduced quality of life, morbidity and mortality compared to healthy individuals. Every patient diagnosed with end-stage renal disease should be evaluated for a potential kidney transplant, potentially by means of living-donor kidney donation. INDICATIONS: Via living-donor kidney donation, patients diagnosed with end-stage renal disease can receive a kidney transplant already before dialysis therapy needs to be initiated. Those patients show a significantly improved long-term graft and patient survival in comparison to patients transplanted after cadaveric organ donation. PROCEDURE: We here describe the evaluation process of living-donor kidney donation and the procedure of transperitoneal laparoscopic donor-nephrectomy. CONCLUSION: Although technically demanding, laparoscopic donor nephrectomy after careful donor evaluation is a safe procedure. An interdisciplinary medical-surgical management is important for both careful patient selection and life-long aftercare.

NGR-TNF, a novel vascular-targeting agent, does not induce cytokine recruitment of proangiogenic bone marrow-derived cells.

BACKGROUND: Administration of certain chemotherapy drugs at the maximum tolerated dose, vascular-disrupting agents (VDAs) and irradiation can induce mobilisation and tumour homing of proangiogenic bone marrow-derived cells (BMDCs). Increases in cytokines and chemokines contribute to such mobilisation that eventually promotes tumour (re)growth. NGR-TNF is a vascular-targeting agent in advanced clinical development, coupling the CNGRCG angiogenic vessel-homing peptide with tumour necrosis factor-alpha (TNF). We investigated whether NGR-TNF mobilises host BMDCs and growth factors. METHODS: Blood was obtained from Lewis lung carcinoma and 4T1 tumour-bearing mice at different time points following NGR-TNF, VDA or anti-VEGFR2/flk-1 antibody treatment. Levels of circulating growth factors were assessed by ELISAs. BMDCs were characterised by FACS. Circulating endothelial progenitor cells were defined as CD45(-)/CD13(+)/flk-1(+)/CD117(+)/7AAD(-), Tie2-expressing monocytes as CD45(+)/CD11b(+)/Tie2(+) and myeloid-derived suppressor cells as CD45(+)/CD11b(+)/Gr1(+) cells. RESULTS: NGR-TNF decreases tumour blood vessel density-inducing apoptosis of tumour and tumour endothelial cells. Unlike VDAs, or high-dose NGR-TNF, lower doses of NGR-TNF, comparable to those used in clinical trials, neither mobilise nor recruit to the tumour site proangiogenic BMDCs or induce host growth factors. CONCLUSION: Low-dose NGR-TNF exerts antitumour activity without inducing proangiogenic host responses, conceivably important for preventing/overcoming resistance and designing combination therapeutic strategies.

On the trail of anti-CDE to unexpected highlights of the RHD*weak 4.3 allele in the Upper Austrian population.

BACKGROUND AND OBJECTIVES: The application of a commercial available microcolumn system for ABO/RH determination lead to irregular results in CDE typing of seemingly D- blood samples. In this study, we introduce a comprehensive serological and molecular work-up of a novel haplotype carrying the RHD*weak 4.3 in combination with an aberrant RHCE*ce. MATERIALS AND METHODS: The molecular background was characterized by RHD and RHCE-specific DNA sequencing, RHD cDNA sequencing and RHD zygosity testing. Haplotype-specific extraction and inheritance analysis were initiated to determine the linkage of the polymorphisms. The genetic admixture was studied by whole genome SNP array analysis. Serology was done using commercial available standard techniques and by in-house sera likewise. RESULTS: All samples (n = 29) were shown to harbour an altered RHD(T201R, F223V, P291R) allele known as RHD*weak 4.3 associated with a RHCE*ce(W16C, A36T, L245V) gene formation, expressing C(X) and VS. Both anti-C(X) and anti-V/VS were detected as contaminating antibodies in a commercial available microcolumn system for ABO/RH determination accounting for the positive results in CDE typing. Compared with other population data, the samples were clearly identified as Caucasian. CONCLUSION: The RHD*weak 4.3 allele with markedly reduced antigen D expression was shown to be associated with an altered RHCE gene formation leading to the expression of C(X) and VS. Its frequency was estimated 1 in 854 among apparently D- Upper Austrian blood donors.

Overcoming methodical limits of standard RHD genotyping by next-generation sequencing.

BACKGROUND AND OBJECTIVES: Molecular variations of the RHD gene may result in the reduced expression of the D antigen and altered Rh phenotypes. In many occasions, they cannot be typed reliably by standard serological methods. Sequence-based typing is the gold standard to determine rare and unknown RHD genotypes. For this pilot study, sequence-based typing by standard Sanger sequencing was compared to a newly established next-generation sequencing approach based on pyrosequencing. MATERIALS AND METHODS: Twenty-six DNA samples were selected after primary serological testing exhibiting a weak reaction in Rh phenotype. Parallel sequence analysis of the complete coding sequence including adjacent intronic sequences allowed a comparison of the methodical potency in mutation detection of Sanger with next-generation sequencing. RESULTS: Sanger sequencing revealed 39 RHD polymorphisms in 21 of 26 samples in the RHD coding region, while pyrosequencing detected all but two alterations resulting in a concordance rate of 94·9% and clearly revealed a heterozygous compound mutation in one sample with RHDψ and Weak D type 4 alleles. The resolution of cis/trans linkage of polymorphisms and exact characterization of a 37 bp duplication was achieved by next-generation sequencing. CONCLUSION: Our data suggest that next-generation sequencing offers a new development for high-throughput and clonal sequencing for molecular RHD genotyping. However, further attempts in the methodical set-up have to be undertaken prior to validation and introduction as a routine service.

Preliminary experiments for the analysis of tetrahydrotetrols of benz[a]anthracene and benzo[a]pyrene derived from their hemoglobin adducts using a coupled-column high-performance liquid chromatographic system.

Improved technologies for the detection of polycyclic aromatic hydrocarbon adducts are required for human biomonitoring. Therefore, a coupled-column high-performance liquid chromatographic method, with system-integrated sample processing, has been developed and its applicability for determination of tetrahydrotetrols of polycyclic aromatic hydrocarbons in acid hydrolysates of human hemoglobin has been investigated. A novel column-switching technique applying "thermotransfer' is used to separate tetrahydrotetrols of benzo[a]pyrene and benz[a]anthracene more efficiently. Derivatives of polycyclic aromatic hydrocarbons from blood hydrolysates are concentrated on a pre-column and then transferred to the analytical column by applying an electrical current to heat the solvent eluting the pre-column. This method allows for rapid and quantitative transfer of the analytes from the pre-column to the analytical column, after HPLC-integrated sample processing.