Resectability,conversion, metastasectomy and outcome according to RAS and BRAF status for metastatic colorectal cancer in the prospective RAXO study

Background Outcomes after metastasectomy for metastatic colorectal cancer (mCRC) vary with RAS and BRAF mutational status, but their effects on resectability and conversion rates have not been extensively studied.Methods This substudy of the prospective RAXO trial included 906 patients recruited between 2011 and 2018. We evaluated repeated centralised resectability assessment, conversion/resection rates and overall survival (OS), according to RAS and BRAF status.Results Patients included 289 with RAS and BRAF wild-type (RAS and BRAFwt), 529 with RAS mutated (RASmt) and 88 with BRAF mutated (BRAFmt) mCRC. Metastatic prevalence varied between the RAS and BRAFwt/RASmt/BRAFmt groups, for liver (78%/74%/61%), lung (24%/35%/28%) and peritoneal (15%/15%/32%) metastases, respectively. Upfront resectability (32%/29%/15%), conversion (16%/13%/7%) and resection/local ablative therapy (LAT) rates (45%/37%/17%) varied for RASa and BRAFwt/RASmt/BRAFmt, respectively. Median OS for patients treated with resection/LAT (n = 342) was 83/69/30 months, with 5-year OS-rates of 67%/60%/24%, while systemic therapy-only patients (n = 564) had OS of 29/21/15 months with 5-year OS-rates of 11%/6%/2% in RAS and BRAFwt/RASmt/BRAFmt, respectively. Resection/LAT was associated with improved OS in all subgroups.Conclusions There were significant differences in resectability, conversion and resection/LAT rates according to RAS and BRAF status. OS was also significantly longer for RAS and BRAFwt versus either mutant. Patients only receiving systemic therapy had poorer long-term survival, with variation according to molecular status.Clinical trial registration {"type":"clinical-trial","attrs":{"text":"NCT01531621","term_id":"NCT01531621"}}NCT01531621/EudraCT2011-003158-24Subject terms: Metastasis, Colorectal cancer, Surgical oncology, Prognostic markers     

Efficacy of sequential use of superparamagnetic iron oxide and gadolinium in liver MR imaging

Purpose: To evaluate the efficacy of combined (double contrast) use of superparamagnetic iron particles (SPIOs) and gadolinium (Gd) in liver MR imaging.Material and Methods: Unenhanced, Gd-enhanced, SPIO-enhanced, and both SPIO- and Gd-enhanced images were acquired at 1.5 T. Twenty patients with previously detected liver lesions were included. Fast SE-STIR, and breath-hold true FISP, fat-suppressed T1- and T2-weighted sequences were obtained with all techniques. Lesion count was assessed by consensus reading.Results: Collective evaluation of all MR sequences revealed 61 lesions in 16 patients; SPIO-enhanced MR detected lesions with a sensitivity of 95% (n=58). The sensitivity of unenhanced MR imaging was 90% (n=55). There was no statistical difference between SPIO-enhanced and unenhanced MR images. From single sequences, the greatest number of lesions was detected with the SPIO-enhanced fast SE-STIR sequence (n=56, sensitivity 92%). By using the fat-suppressed T1-weighted sequence, Gd-enhanced and both SPIO- and Gd-enhanced MR images demonstrated sensitivities of 77% (n=47) and 80% (n=49), respectively. Despite the combined use of both contrast media, this sequence was significantly less sensitive in lesion detection when compared to SPIO-enhanced imaging.Conclusion: SPIO-enhanced MR imaging was the most sensitive method in lesion detection. The benefit of the combined use of SPIO and Gd was negligible.     

Cytokine profiles in acute liver failure treated with albumin dialysis

Abstract:  Cytokines are released within the liver in response to hepatic injury, and acute liver failure (ALF) triggers systemic inflammation. Pro-inflammatory (tumor necrosis factor-alpha [TNF-α] and interleukin-8 [IL-8]) and anti-inflammatory (interleukin-10 [IL-10] and interleukin-6 [IL-6]) cytokines and the lymphocyte activation marker (interleukin-2-soluble receptor alpha chain [IL-2sRα]) were monitored in 49 ALF patients considered for liver transplantation and treated with albumin dialysis (molecular adsorbent recirculating system [MARS]). Twenty-six patients were categorized by clinical outcome as "good" (native liver recovered) and 23 as "poor" (patient bridged to liver transplantation or deceased). MARS did not clearly affect cytokine profiles during treatment; only IL-10 levels decreased in the whole patient population and mostly in patients with the worst prognosis. In the good outcome group, IL-8 and IL-6 levels decreased during treatment; on the contrary, in poor outcome patients IL-6 levels even increased. Initial IL-2sRα levels were higher in poor outcome patients relative to the good outcome subset. Cytokine profiles seem to differ in ALF according to patient outcome. A deeper understanding of cytokine patterns during pathogenesis could reveal prognostic markers and aid the development of immunomodulating ALF therapies.     

Prevalence and incidence of primary biliary cirrhosis are increasing in Finland

OBJECTIVE: To examine the epidemiology of primary biliary cirrhosis (PBC) in Finland and to evaluate whether the possible increase in prevalence was attributable to the increasing incidence, better survival, or both. MATERIAL AND METHODS: The Hospital Discharge Register, pathology registers, and death certificates for the years 1988 99 were scrutinized, and the patients identified were followed-up for survival until 31 October 2004. The study area covered four university hospital districts: a total of 25 hospitals. The diagnosis of PBC was regarded as definite (or probable) if three (or two) of the following criteria were fulfilled: positive antimitochondrial antibodies, constantly elevated alkaline phosphatase, and compatible liver histology. RESULTS: In the total population of the study areas, the age-standardized prevalence of PBC increased during the study period from 103 (95% CI: 97-110) to 180 (172-189) per million inhabitants. Incidence increased from 12 (10-14) to 17 (15-20) per million inhabitants per year. The annual average increase in prevalence was 5.1% (4.2-5.9%, p <0.0001) and in incidence 3.5% (0.9%-6.0%, p =0.008). In gender-specific analyses among women, the prevalence of PBC increased from 161 (151-171) to 292 (277-207) per million during the study period and the incidence from 20 (16-24) to 27 (23-32) per million per year. The death rate was 4% per year and half the deaths were from liver-related causes. Survival after diagnosis during the study period lengthened. CONCLUSIONS: The prevalence of PBC increased in Finland during 1988-99, owing to both the increased incidence and the prolonged survival.     

Infectious Complications More Than 1 Year after Liver Transplantation: A 3‐Decade Nationwide Experience

Because few reports have addressed infections late (≥1 year) after liver transplantation (LT), we evaluated the incidence, risk factors and pathogens involved. Infection data were from the Finnish LT registry, with starting date, type and relevant pathogens for 501 Finnish adult LT patients surviving ≥1 year post‐transplant. Follow‐up end points were end of study, death or retransplantation. Logistic regression to assess risk factors was adjusted for age, gender and follow‐up time. With 3923 person‐years of follow‐up, overall infection incidence was 66/1000 person‐years; 155 (31%) suffered 259 infections, and two‐thirds experienced only one infection. Cholangitis (20%), pneumonia (19%) and sepsis (14%) were most common. The most frequent bacteria were Enterococcus spp. and Escherichia coli, and the most frequent viruses cytomegalovirus and varicella zoster virus. Fungal infections were rare (n = 7). With 13 fatal infections, 17% of all late deaths involved infection. Primary sclerosing cholangitis (PSC) and Roux‐en‐Y‐type biliary anastomosis were associated with cholangitis; 18% of PSC patients suffered late cholangitis. Late acute rejection was associated with sepsis. Age, gender or cytomegalovirus did not significantly influence late infections. In conclusion, although infection risk under maintenance immunosuppression therapy is relatively low, particular vigilance regarding cholangitis, pneumonia and sepsis seems appropriate.     

Preoperative assessment of focal liver lesions: multidetector computed tomography challenges magnetic resonance imaging

PURPOSE: To investigate prospectively multidetector computed tomography (CT) (MDCT) and magnetic resonance (MR) imaging (MRI) in the preoperative assessment of focal liver lesions. MATERIAL AND METHODS: Multiphasic MDCT and conventional gadolinium-enhanced MRI were performed on 31 consecutive patients prior to hepatic surgery. All images were blindly analyzed as consensus reading. Lesion counts and their relation to vascular structures and possible extrahepatic disease were determined. The data from the MDCT and MRI were compared with the results obtained by intraoperative ultrasound (IOUS) and palpation. Histopathologic verification was available. RESULTS: At surgery, IOUS and palpation revealed 45 solid liver lesions. From these, preoperative MDCT detected 43 (96%) and MRI 35 (78%) deposits. MDCT performed statistically better than MRI in lesion detection (P=0.008). Assessment of lesion vascular proximity was correctly determined by MDCT in 98% of patients and by MRI in 87%. Statistical difference was found (P=0.002). IOUS and palpation changed the preoperative surgical plan as a result of extrahepatic disease in 8/31 (26%) cases. In MDCT as well in MRI extrahepatic involvement was suspected in two cases. CONCLUSION: MDCT was superior to MRI and nearly equal to IOUS in liver lesion detection and in the determination of lesion vascular proximity. However, both techniques fail to reliably detect extrahepatic disease.     

Delayed Introduction of Reduced-Dose Tacrolimus, and Renal Function in Liver Transplantation: The 'ReSpECT' Study

We report a multicenter, prospective, randomized, open-label trial investigating the effect of lower levels and delayed introduction of tacrolimus on renal function in liver transplant recipients. Adult patients with good renal function undergoing primary liver transplant were randomized to either: group A (standard-dose tacrolimus [target trough levels >10 ng/mL] and corticosteroids; n = 183); group B (mycophenolate mofetil [MMF] 2g/day, reduced-dose tacrolimus [target trough levels ≤8 ng/mL], and corticosteroids; n = 170); group C (daclizumab induction, MMF, reduced-dose tacrolimus delayed until the fifth day posttransplant and corticosteroids, n = 172). The primary endpoint was change from baseline in estimated glomerular filtration rate (eGFR) at 52 weeks. The eGFR decreased by 23.61, 21.22 and 13.63 mL/min in groups A, B and C, respectively (A vs C, p = 0.012; A vs B, p = 0.199). Renal dialysis was required less frequently in group C versus group A (4.2% vs. 9.9%; p = 0.037). Biopsy-proven acute rejection rates were 27.6%, 29.2% and 19.0%, respectively. Patient and graft survival was similar. In conclusion, daclizumab induction, MMF, corticosteroids and delayed reduced-dose tacrolimus was associated with less nephrotoxicity than therapy with standard-dose tacrolimus and corticosteroids without compromising efficacy or tolerability.     

Infectivity-enhanced adenoviruses deliver efficacy in clinical samples and orthotopic models of disseminated gastric cancer.

PURPOSE: Metastatic gastric cancer remains a common and devastating disease without curative treatment. Recent proof-of-concept clinical trials have validated gene therapy with adenoviruses as an effective and safe modality for the treatment of cancer. However, expression of the primary coxsackie-adenovirus receptor is variable in advanced cancers, and therefore, the use of heterologous receptors could be advantageous. EXPERIMENTAL DESIGN: Here, we used capsid-modified adenoviruses for increasing the transduction and subsequent antitumor efficacy. 5/3 chimeric viruses have a serotype 3 knob which allows binding to a receptor distinct from coxsackie-adenovirus receptor. The fiber of Ad5lucRGD is modified with an integrin-targeted motif. Polylysine motifs, pK7 and pK21, bind to heparan sulfates. Oncolytic adenoviruses replicate in and kill tumor cells selectively. Gastric cancer cell lines and fresh clinical samples from patients were infected with transductionally targeted viruses. Capsid-modified oncolytic adenoviruses were used in cell killing experiments. To test viral transduction and therapeutic efficacy in vivo, we developed orthotopic mouse models featuring i.p. disseminated human gastric cancer, which allowed the evaluation of biodistribution and antitumor efficacy in a system similar to humans. RESULTS: Capsid modifications benefited gene transfer efficiency and cell killing in gastric cancer cell lines and clinical samples in vitro and in vivo. Modified oncolytic adenoviruses significantly increased the survival of mice with orthotopic gastric cancer. CONCLUSIONS: These preclinical data set the stage for the clinical evaluation of safety and efficacy in patients with disease refractory to current modalities.