Dragon 1 Protocol Manuscript: Training, Accreditation, Implementation and Safety Evaluation of Portal and Hepatic Vein Embolization (PVE/HVE) to Accelerate Future Liver Remnant (FLR) Hypertrophy.

STUDY PURPOSE: The DRAGON 1 trial aims to assess training, implementation, safety and feasibility of combined portal- and hepatic-vein embolization (PVE/HVE) to accelerate future liver remnant (FLR) hypertrophy in patients with borderline resectable colorectal cancer liver metastases. METHODS: The DRAGON 1 trial is a worldwide multicenter prospective single arm trial. The primary endpoint is a composite of the safety of PVE/HVE, 90-day mortality, and one year accrual monitoring of each participating center. Secondary endpoints include: feasibility of resection, the used PVE and HVE techniques, FLR-hypertrophy, liver function (subset of centers), overall survival, and disease-free survival. All complications after the PVE/HVE procedure are documented. Liver volumes will be measured at week 1 and if applicable at week 3 and 6 after PVE/HVE and follow-up visits will be held at 1, 3, 6, and 12 months after the resection. RESULTS: Not applicable. CONCLUSION: DRAGON 1 is a prospective trial to assess the safety and feasibility of PVE/HVE. Participating study centers will be trained, and procedures standardized using Work Instructions (WI) to prepare for the DRAGON 2 randomized controlled trial. Outcomes should reveal the accrual potential of centers, safety profile of combined PVE/HVE and the effect of FLR-hypertrophy induction by PVE/HVE in patients with CRLM and a small FLR. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04272931 (February 17, 2020). Toestingonline.nl: NL71535.068.19 (September 20, 2019).

Preoperative portal vein or portal and hepatic vein embolization: DRAGON collaborative group analysis.

BACKGROUND: The extent of liver resection for tumours is limited by the expected functional reserve of the future liver remnant (FRL), so hypertrophy may be induced by portal vein embolization (PVE), taking 6 weeks or longer for growth. This study assessed the hypothesis that simultaneous embolization of portal and hepatic veins (PVE/HVE) accelerates hypertrophy and improves resectability. METHODS: All centres of the international DRAGON trials study collaborative were asked to provide data on patients who had PVE/HVE or PVE on 2016-2019 (more than 5 PVE/HVE procedures was a requirement). Liver volumetry was performed using OsiriX MD software. Multivariable analysis was performed for the endpoints of resectability rate, FLR hypertrophy and major complications using receiver operating characteristic (ROC) statistics, regression, and Kaplan-Meier analysis. RESULTS: In total, 39 patients had undergone PVE/HVE and 160 had PVE alone. The PVE/HVE group had better hypertrophy than the PVE group (59 versus 48 per cent respectively; P = 0.020) and resectability (90 versus 68 per cent; P = 0.007). Major complications (26 versus 34 per cent; P = 0.550) and 90-day mortality (3 versus 16 per cent respectively, P = 0.065) were comparable. Multivariable analysis confirmed that these effects were independent of confounders. CONCLUSION: PVE/HVE achieved better FLR hypertrophy and resectability than PVE in this collaborative experience.

MR imaging features for improved diagnosis of hepatocellular carcinoma in the non-cirrhotic liver: Multi-center evaluation.

PURPOSE: To determine MR-imaging features for the differentiation between hepatocellular carcinoma (HCC) and benign hepatocellular tumors in the non-cirrhotic liver. MATERIAL AND METHODS: 107 consecutive patients without liver cirrhosis (46 male; 45 ± 14 years) who underwent liver resection due to suspicion of HCC were included in this multi-center study. The following imaging features were assessed: lesion diameter and demarcation, satellite-lesions, central-scar, capsule, fat-content, hemorrhage, vein-infiltration and signal-intensity (SI) on native T1-, T2- and dynamic-enhanced T1-weighted images (center versus periphery). In addition, contrast-media (CM) uptake in the liver specific phase was analyzed in a sub-group of 42 patients. RESULTS: Significant differences between HCC (n=55) and benign lesions (n=52) were shown for native T1-, T2- and dynamic-enhanced T1-SI, fat-content, and satellite-lesions (all, P<.05). Independent predictors for HCC were T1-hypointensity (odds-ratio, 4.81), T2-hypo-/hyperintensity (5.07), lack of central tumor-enhancement (3.36), and satellite-lesions (5.78; all P<0.05). Sensitivity and specificity of HCC was 91% and 75% respectively for two out-of four independent predictors, whereas specificity reached 98% for all four predictors. Sub-analysis, showed significant differences in liver specific CM uptake between HCC (n=18) and benign lesions (n=24; P<0.001) and revealed lack of liver specific CM uptake (odds-ratio, 2.7) as additional independent feature for diagnosis of HCC. CONCLUSION: Independent MRI features indicating HCC are T1-hypointensity, T2-hypo- or hyperintensity, lack of central tumor-enhancement, presence of satellite-lesions and lack of liver specific CM-uptake. These features may have the potential to improve the diagnosis of HCC in the non-cirrhotic liver.

[Clinical nutrition in surgery. Guidelines of the German Society for Nutritional Medicine]. / Klinische Ernährung in der Chirurgie. S3-Leitlinie der Deutschen Gesellschaft für Ernährungsmedizin e. V.

BACKGROUND: While enhanced recovery after surgery (ERAS) programs are the standard for perioperative management, special nutritional care has to be administered to malnourished patients and those at metabolic risk with special regard to patients with postoperative complications. METHODS: Existing guidelines of the German and European societies of nutritional medicine (DGEM and ESPEN) on enteral and parenteral nutrition in surgery were merged and in accordance with the principles of the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF, German Association of the Scientific Medical Societies) and Ärztliches Zentrum für Qualität in der Medizin (AeZQ, German Agency for Quality in Medicine) revised and extended. RESULTS AND DISCUSSION: The working group developed 41 consensus-based recommendations for perioperative nutrition. The recommendation strength is: 9x A (recommendation based on significant good quality literature containing at least one randomized controlled trial), 12x B (recommendation based on well-designed trial without randomization), 13x C (recommendation based on expert opinions and/or clinical experience of respected authorities) and 7x CCP (clinical consensus point). CONCLUSION: Even in patients without obvious malnutrition perioperative nutritional support is indicated when oral food intake is not feasible or inadequate for a longer period of time.

Histopathological evidence of invasive gastric mucormycosis after transarterial chemoembolization and liver transplantation.

We describe a case of a 62-year-old diabetic woman with hepatocellular carcinoma due to chronic hepatitis B virus infection. Two weeks after orthotopic liver transplantation, endoscopy for massive upper gastrointestinal bleeding revealed a large necrotic area in the gastric fundus. The patient underwent emergency resection. Histopathologically, angioinvasive mold infection compatible with mucormycosis was diagnosed in a large area of necrosis, mimicking an atypically localized gastric ulcer. Foreign bodies originating from transarterial chemoembolization (TACE) performed 7 and 8 months earlier and 40 days before transplantation were identified in the submucosal tissue. The patient was treated with liposomal amphotericin B (LAB) for 5 weeks, followed by 7 weeks of posaconazole. Follow-up biopsies after 1 and 5 months confirmed successful treatment. Review of the radiological images of the TACE procedure showed that some of the TACE material had been diverted to the stomach via an accessory gastric branch originating from the left hepatic artery. TACE agents may be associated with chronic, refractory gastroduodenal ulcers. We hypothesize that the ischemic lesion was first colonized with presumed Mucorales mold and invasive growth was promoted by the posttransplantation immunosuppression. Careful exploration of extrahepatic collaterals during TACE may prevent this complication.

Giant mesenteric cystic lymphangioma of mesocolic origin in an asymptomatic adult patient.

A 34-year-old patient was scheduled for valve replacement to treat a symptomatic mitral regurgitation. The preoperative work-up incidentally discovered an intra-abdominal cystic tumour extending from the epigastrium to the pelvic region on a computed tomography scan. The patient had no abdominal symptoms by the giant cyst from unkown origin. An open "en bloc" resection disclosed a large cyst in the mesocolon. Pathological examination, including immunohistochemistry, enabled the diagnosis of a mesenteric cystic lymphangioma. Long-term follow-up of 12 months shows no recurrence. Mesenteric cystic lymphangioma, which is extremely rare in adults, is a challenge to diagnose and needs complete resection to ensure dignity and to avoid recurrence.

Selective intra-arterial chemotherapy with floxuridine as second- or third-line approach in patients with unresectable colorectal liver metastases.

BACKGROUND: An outcome assessment was performed of patients with unresectable colorectal liver metastases (CRLM) treated in second or third line with floxuridine (FUDR)-based hepatic artery infusion (HAI). METHODS: Twenty-three patients who were pretreated with systemic (immuno)chemotherapy received FUDR-HAI alone or combined with systemic chemotherapy. We reviewed patient charts and our prospective patient database for survival and associated risk factors. RESULTS: Patients received FUDR-HAI for unresectable CRLM from January 2000 to September 2010. Twelve patients (52%) received concurrent systemic chemotherapy. Median overall survival (OS), progression-free survival (PFS), and hepatic PFS were 15.6 months (range, 2.5-55.7 months), 3.9 months (range, 0.7-55.7 months), and 5.5 months (range, 1.6-55.7 months), respectively. The liver resection rate after HAI was 35%. PFS was better in patients undergoing secondary resection than in patients without resection (hazard ratio [HR] 0.21; 95% confidence interval [95% CI] 0.07-0.66; P = 0.0034), while OS showed a trend toward improvement (HR 0.4; 95% CI 0.13-1.2; P = 0.09). No differences were observed in OS (P = 0.69) or PFS (P = 0.086) in patients who received FUDR-HAI alone compared with patients treated with combined regional and systemic chemotherapy. No statistically significant differences were seen in patients previously treated with one chemotherapy line compared with patients treated with two lines. Presence of extrahepatic disease was a negative risk factor for PFS (liver-only disease: HR 0.03; 95% CI 0.0032-0.28; P < 0.0001). Toxicities were manageable with dose modifications and supportive measures. CONCLUSIONS: FUDR-HAI improves PFS and results in a trend toward improved OS in selected patients able to undergo liver resection after tumor is downsized.

CT- and MRI-based volumetry of resected liver specimen: comparison to intraoperative volume and weight measurements and calculation of conversion factors.

OBJECTIVE: To compare virtual volume to intraoperative volume and weight measurements of resected liver specimen and calculate appropriate conversion factors to reach better correlation. METHODS: Preoperative (CT-group, n=30; MRI-group, n=30) and postoperative MRI (n=60) imaging was performed in 60 patients undergoing partial liver resection. Intraoperative volume and weight of the resected liver specimen was measured. Virtual volume measurements were performed by two readers (R1,R2) using dedicated software. Conversion factors were calculated. RESULTS: Mean intraoperative resection weight/volume: CT: 855 g/852 mL; MRI: 872 g/860 mL. Virtual resection volume: CT: 960 mL(R1), 982 mL(R2); MRI: 1112 mL(R1), 1115 mL(R2). Strong positive correlation for both readers between intraoperative and virtual measurements, mean of both readers: CT: R=0.88(volume), R=0.89(weight); MRI: R=0.95(volume), R=0.92(weight). Conversion factors: 0.85(CT), 0.78(MRI). CONCLUSION: CT- or MRI-based volumetry of resected liver specimen is accurate and recommended for preoperative planning. A conversion of the result is necessary to improve intraoperative and virtual measurement correlation. We found 0.85 for CT- and 0.78 for MRI-based volumetry the most appropriate conversion factors.

Systematic review and meta-analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis.

BACKGROUND: A combined antiviral and tumoricidal effect of interferon (IFN) is assumed to occur after resection or ablation of hepatocellular carcinoma (HCC). METHODS: An electronic search of the Medline, Embase and Central databases from January 1998 to October 2007 was conducted to identify randomized controlled trials evaluating adjuvant effects of IFN after curative treatment of HCC. A meta-analysis was performed to estimate the effects of IFN on 2-year outcome. RESULTS: Seven trials enrolling a total of 620 patients were included in the meta-analysis. Adjuvant treatment with IFN significantly reduced the 2-year mortality rate after curative treatment of HCC, with a pooled risk ratio of 0.65 (95 per cent confidence interval 0.52 to 0.80); P < 0.001) in absence of any significant heterogeneity (I(2) = 0 per cent, P = 0.823 for chi(2)). The effect on reduction of tumour recurrence was less pronounced but still significant (pooled risk ratio 0.86 (95 per cent c.i. 0.76 to 0.97); P = 0.013). IFN had to be discontinued in 8-20 per cent of patients. CONCLUSION: IFN has a significant beneficial effect after curative treatment of HCC in terms of both survival and tumour recurrence.

Positron emission tomography (PET) for cholangiocarcinoma.

The combination of positron emission tomography (PET) with computed tomography (PET-CT) provides simultaneous metabolic and anatomic information on tumors in the same imaging session. Sensitivity of PET/PET-CT is higher for intrahepatic (>90%) than for extrahepatic cholangiocarcinoma (CCA) (about 60%). The detection rate of distant metastasis is 100%. PET, and particularly PET-CT, improves the results and impacts on the oncological management in CCA compared with other imaging modalities. Therefore, PET-CT is recommended in the preoperative staging of intrahepatic (strength of recommendation: moderate) and extrahepatic (strength of recommendation: low) CCA.

Systematic evaluation of surgical strategies for acute malignant left-sided colonic obstruction.

BACKGROUND: Surgical strategy for acute colorectal obstruction due to colorectal cancer remains controversial. One-, two- and three-stage surgical procedures, and preoperative stenting of the stenosis as a bridge to surgery, are available. METHODS: A systematic review was conducted, searching MEDLINE, EMBASE and CENTRAL, as well as bibliographies of included studies, to identify randomized and non-randomized controlled trials that compared two or more surgical procedures in acute colonic obstruction. RESULTS: After screening 1748 titles and abstracts, 209 were selected for full text assessment; 29 studies with 2286 patients were finally included. In general, the quality of the studies was limited, with only three randomized trials. Eight non-randomized studies comparing one-stage with two- or three-stage surgery consistently favoured a one-stage procedure in terms of mortality (relative risk difference from - 2 to - 27 per cent), but reported morbidity rates were not different. Trials of different one-stage procedures (segmental and total/subtotal colectomy) showed none to be clearly superior. Stenting procedures were superior to non-stenting treatments. CONCLUSION: One-stage surgery appears to be superior to two- or three-stage procedures. Stenting is a promising option, allowing the resection to be carried out in an elective setting.

Incarcerated vermiform appendix in a left-sided inguinal hernia.

We report here of a patient with an incarcerated vermiform appendix occurring in a left-sided indirect inguinal hernia. Occasionally, appendices are found in a hernial sac; however, the finding of an incarcerated vermiform appendix in an inguinal hernia on the left side is very unusual and has only been previously described once. The patient suffering this rare entity underwent appendectomy and repair of the hernia and experienced an uneventful postoperative recovery. The possibility of the presence of a situs inversus, or malrotation, as an underlying cause for the observed pathology was excluded by x-ray examination.

DNA concentrations in BAL fluid of cystic fibrosis patients with early lung disease: influence of treatment with dornase alpha.

Recombinant DNase (dornase alpha) was shown to improve lung function and reduce pulmonary exacerbations in cystic fibrosis (CF) patients, but its effects on DNA concentrations in the lower airways remain unclear at the present time. As part of the Bronchoalveolar Lavage in the Evaluation of Anti-Inflammatory Treatment (BEAT) Study, a multicenter open study to evaluate the evolution of inflammation in CF patients with early lung disease and its modulation by dornase alpha treatment, we studied DNA concentrations in the bronchoalveolar lavage (BAL) fluid of 48 CF patients with mild lung disease. After the initial BAL, 29 patients received daily treatment with 2.5 mg of dornase alpha; 19 patients served as controls. BAL was repeated after 18 months in all patients. Mean BAL fluid DNA concentrations were not different between groups at baseline (mean +/- SD, 14.1 +/- 6.9 microg/ml for controls, and 17.6 +/- 11.2 microg/ml for the dornase alpha group), but higher than previously reported for infants with CF. A weak but positive correlation (P <0.01) was observed between the percentage of neutrophils in BAL fluid and DNA levels. On reassessment after 18 months, the percentage of neutrophils was not different between the two groups, but DNA had increased in controls, whereas decreased levels were observed in treated patients (P <0.03, t-test). DNA concentrations increased by more than 10 microg/ml in 7 of 19 controls compared to 2 of 29 CF patients treated with rhDNase (P=0.01, Fisher's test). Therefore, treatment with dornase alpha over 18 months reduces DNA load in BAL fluid, which may have a positive effect on the clearance of lower airway secretions.

Direct sputum analysis of Pseudomonas aeruginosa macrorestriction fragment genotypes in patients with cystic fibrosis.

The distribution of bacterial populations in the airways of 13 patients with cystic fibrosis who were colonized for 6-23 years with Pseudomonas aeruginosa was investigated by genotyping of bacterial chromosomes directly isolated from 21 sputa. After removal of host material from sputum by hypotonic cell lysis and repetitive washing and centrifugation steps, agarose-embedded bacterial cells were lysed, residual eukaryotic DNA separated by field inversion gel electrophoresis, and the purified bacterial chromosomes subjected to macrorestriction fragment pattern and Southern analyses. Bacterial populations consisted of a single P. aeruginosa clone in 17 sputa, of which more than one clonal variant was apparent in two SpeI fragment fingerprints. Two clones of P. aeruginosa and another species co-existed in four samples. Genomically homogeneous populations of P. aeruginosa are characteristic for chronically colonized lungs in most cases of cystic fibrosis.

Infections with Pseudomonas aeruginosa in patients with cystic fibrosis.

The lung infection with Pseudomonas aeruginosa is regarded as one of the major causes of health decline in patients with cystic fibrosis (CF). The CF host response to the persistent bacterial antigen load in the endobronchiolar lumen is characterized by a pronounced humoral response, local production of cytokines, influx of neutrophils into the lung and a protease-protease inhibitor imbalance predominantly sustained by released neutrophil elastase. CF is an autosomal recessive disease, and we could demonstrate for our local patient population that the age-dependent risk to become chronically colonized with P. aeruginosa can be differentiated by the disease-causing CFTR mutation genotype. The age-specific colonisation rates were significantly lower in pancreas sufficient than in pancreas insufficient patients. P. aeruginosa is occasionally detected in throat swabs already in infancy or early childhood in most patients although there is a lapse of several years amenable to preventive measures such as vaccination until onset of persistent colonization. The epidemiology of the infection with P. aeruginosa was investigated by quantitative macrorestriction fragment pattern analysis. The distribution and frequency of clones found in CF patients match that found in other clinical and environmental aquatic habitats, but the over-representation of specific clones at a CF clinic indicates a significant impact of nosocomial transmission for the prevalence of P. aeruginosa-positive patients at a particular center. Most patients remain colonized with the initially acquired P. aeruginosa clone. According to direct sputum analysis the majority of patients is carrying a single clonal variant at a concentration of 10(7)-10(9) CFU. Co-colonization with other species or other clones is infrequent. Independent of the underlying genotype, the CF lung habitat triggers a uniform, genetically fixed conversion of bacterial phenotype. Most CFP, aeruginosa strains become non-motile, mucoid, LPS-, pyocin- and phage-deficient, secrete less virulence determinants and shift the production of cytokines evoked in neutrophils. On the other hand, other properties such as antimicrobial susceptibility or adherence to bronchial mucins remain highly variable reflecting the capacity of P. aeruginosa to adapt to ongoing changes in the CF lung habitat.

DNA concentration and length in sputum of patients with cystic fibrosis during inhalation with recombinant human DNase.

BACKGROUND: The clinical benefit of the administration of aerosolised recombinant human DNase (rhDNase) on pulmonary function in patients with cystic fibrosis has already been demonstrated but the biochemical action of rhDNase on DNA in bronchial secretions in vivo has not yet been investigated. METHODS: Sputum was collected from 135 patients with cystic fibrosis before and during treatment with aerosolised rhDNase and examined to ascertain DNA concentration and length by colorimetric assay and densitometry of gel separated DNA. RESULTS: Treatment with rhDNase reduced the concentration and the size of extracellular DNA in the sputum. The median interquartile range of DNA length decreased from 0.5-2.6 kbp before treatment to 0.3-1.0 kbp during treatment. CONCLUSIONS: rhDNase was delivered to the secretions and was enzymatically active in vivo.