Circulating tumor DNA (ctDNA) is assumed to reflect tumor burden and has been suggested as a tool for prognostication and follow‐up in patients with metastatic pancreatic ductal adenocarcinoma ...(mPDAC). However, the prognostic value of ctDNA and its relation with tumor burden has yet to be substantiated, especially in mPDAC. In this retrospective analysis of prospectively collected samples, cell‐free DNA from plasma samples of 58 treatment‐naive mPDAC patients was isolated and sequenced using a custom‐made pancreatobiliary NGS panel. Pathogenic mutations were detected in 26/58 (44.8%) samples. Cross‐check with droplet digital PCR showed good agreement in Bland–Altman analysis (p = 0.217, nonsignificance indicating good agreement). In patients with liver metastases, ctDNA was more frequently detected (24/37, p < 0.001). Tumor volume (3D reconstructions from imaging) and ctDNA variant allele frequency (VAF) were correlated (Spearman's ρ = 0.544, p < 0.001). Median overall survival (OS) was 3.2 (95% confidence interval CI 1.6–4.9) versus 8.4 (95% CI 1.6–15.1) months in patients with detectable versus undetectable ctDNA (p = 0.005). Both ctDNA VAF and tumor volume independently predicted OS after adjustment for carbohydrate antigen 19.9 and treatment regimen (hazard ratio HR 1.05, 95% CI 1.01–1.09, p = 0.005; HR 1.00, 95% CI 1.01–1.05, p = 0.003). In conclusion, our study showed that ctDNA detection rates are higher in patients with larger tumor volume and liver metastases. Nevertheless, measurements may diverge and, thus, can provide complementary information. Both ctDNA VAF and tumor volume were strong predictors of OS.
What's new?
Circulating tumor DNA (ctDNA) attracts much interest as a possible prognostic tool for cancer. Here, the authors showed that the quantity of ctDNA correlated strongly with tumor volume in metastatic pancreatic ductal adenocarcinoma (mPDAC). They conducted a retrospective analysis using samples collected from 58 untreated mPDAC patients. For this study, the authors designed a pancreatobiliary NGS panel, which they used to test the patients’ cell‐free DNA, along with droplet digital PCR. Both ctDNA variant allele frequency and tumor volume predicted overall survival, they found.
Esophageal adenocarcinoma (EAC) has a dismal prognosis, and survival benefits of recent multimodality treatments remain small. Cancer-associated fibroblasts (CAFs) are known to contribute to poor ...outcome by conferring therapy resistance to various cancer types, but this has not been explored in EAC. Importantly, a targeted strategy to circumvent CAF-induced resistance has yet to be identified. By using EAC patient-derived CAFs, organoid cultures, and xenograft models we identified IL-6 as the stromal driver of therapy resistance in EAC. IL-6 activated epithelial-to-mesenchymal transition in cancer cells, which was accompanied by enhanced treatment resistance, migratory capacity, and clonogenicity. Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines. Analysis of patient gene expression profiles identified ADAM12 as a noninflammation-related serum-borne marker for IL-6–producing CAFs, and serum levels of this marker predicted unfavorable responses to neoadjuvant chemoradiation in EAC patients. These results demonstrate a stromal contribution to therapy resistance in EAC. This signaling can be targeted to resensitize EAC to therapy, and its activity can be measured using serum-borne markers.
Background
Noninvasive diagnostic methods are urgently required in disease stratification and monitoring in nonalcoholic fatty liver disease (NAFLD). Multiparametric magnetic resonance imaging (MRI) ...is a promising technique to assess hepatic steatosis, inflammation, and fibrosis, potentially enabling noninvasive identification of individuals with active and advanced stages of NAFLD.
Purpose
To examine the diagnostic performance of multiparametric MRI for the assessment of disease severity along the NAFLD disease spectrum with comparison to histological scores.
Study Type
Prospective, cohort.
Population
Thirty‐seven patients with NAFLD.
Field Strength/Sequence
Multiparametric MRI at 3.0 T consisted of magnetic resonance (MR) spectroscopy (MRS) with multi‐echo stimulated‐echo acquisition mode, magnitude‐based and three‐point Dixon using a two‐dimensional multi‐echo gradient echo, MR elastography (MRE) using a generalized multishot gradient‐recalled echo sequence and intravoxel incoherent motion (IVIM) using a multislice diffusion weighted single‐shot echo‐planar sequence.
Assessment
Histological steatosis grades were compared to proton density fat fraction measured by MRS (PDFFMRS), magnitude‐based MRI (PDFFMRI‐M), and three‐point Dixon (PDFFDixon), as well as FibroScan® controlled attenuation parameter (CAP). Fibrosis and disease activity were compared to IVIM and MRE. FibroScan® liver stiffness measurements were compared to fibrosis levels. Diagnostic performance of all imaging parameters was determined for distinction between simple steatosis and nonalcoholic steatohepatitis (NASH).
Statistical Tests
Spearman's rank test, Kruskal–Wallis test, Dunn's post‐hoc test with Holm‐Bonferroni P‐value adjustment, receiver operating characteristic curve analysis. A P‐value <0.05 was considered statistically significant.
Results
Histological steatosis grade correlated significantly with PDFFMRS (rs = 0.66, P < 0.001), PDFFMRI‐M (rs = 0.68, P < 0.001), and PDFFDixon (rs = 0.67, P < 0.001), whereas no correlation was found with CAP. MRE and IVIM diffusion and perfusion significantly correlated with disease activity (rs = 0.55, P < 0.001, rs = −0.40, P = 0.016, rs = −0.37, P = 0.027, respectively) and fibrosis (rs = 0.55, P < 0.001, rs = −0.46, P = 0.0051; rs = −0.53, P < 0.001, respectively). MRE and IVIM diffusion had the highest area‐under‐the‐curve for distinction between simple steatosis and NASH (0.79 and 0.73, respectively).
Data Conclusion
Multiparametric MRI is a promising method for noninvasive, accurate, and sensitive distinction between simple hepatic steatosis and NASH, as well as for the assessment of steatosis and fibrosis severity.
Level of Evidence
2
Technical Efficacy
2
OBJECTIVE:Assessment of long-term comprehensive outcome of multimodality treatment of bile duct injury (BDI) in terms of morbidity, mortality, quality of life (QoL), survival, and work related ...limitations.
BACKGROUND:The impact of BDI on work ability is scarcely investigated.
METHODS:BDI patients referred to a tertiary center after BDI were included (n = 800). QoL and work related limitations (HLQ) were compared with 175 control patients after uncomplicated laparoscopic cholecystectomy.
RESULTS:The mean survival after BDI was 17.6 years (95% confidence interval, CI, 17.2–18.0 years). BDI related mortality was 3.5% (28/800). Corrected for sex, ASA classification, treatment and type of injury, survival is worse in male patients (hazard ratio, HR 1.50, 95% CI 1.01–2.33) and progressively worse with higher ASA classification (ASA25.25 (2.94–9.37), ASA318.1 (9.79–33.3). Patients treated surgically had a significantly better survival (HR0.45 (95% CI0.25–0.80). BDI patients reported a significantly worse physical QoL compared with the control group and worse disease specific QoL. Loss of productivity of work was significantly higher among BDI patients. There also was a significant hindrance in unpaid work. A higher number of bile duct injury patients were receiving disability benefits after long-term follow-up (34.9% vs 19.6%, P = 0.004).
CONCLUSIONS:Reconstructive surgery in BDI patients is associated with improved survival. Although the clinical outcome of multidisciplinary treatment of bile duct injury is good, it is associated with a significant decrease in QoL, loss of productivity in both paid and unpaid work and high rates of disability benefits use.
Percutaneous biliary drainage and stenting (PTBD) for palliation of malignant obstructive jaundice has evolved to a safe and effective technique. PTBD is equally effective for treatment of distal and ...proximal bile obstruction. Metal self-expandable stents have proved superior to plastic stents and should therefore be used. Technical success is >90% en clinical success is >75% in all major series. There are a considerable number of complications, but most can be treated conservatively and procedure-related mortality is <2% in most series. Thirty-day mortality after PTBD is >10% in many series, but this is largely due to the underlying disease. About 10–30% of patients will have recurrent jaundice at some point in their disease after PTBD and require re-intervention.
Background and Aims
The heterogeneity of intermediate‐stage hepatocellular carcinoma (HCC) and the widespread use of transarterial chemoembolization (TACE) outside recommended guidelines have ...encouraged the development of scoring systems that predict patient survival. The aim of this study was to build and validate statistical models that offer individualized patient survival prediction using response to TACE as a variable.
Approach and Results
Clinically relevant baseline parameters were collected for 4,621 patients with HCC treated with TACE at 19 centers in 11 countries. In some of the centers, radiological responses (as assessed by modified Response Evaluation Criteria in Solid Tumors mRECIST) were also accrued. The data set was divided into a training set, an internal validation set, and two external validation sets. A pre‐TACE model (“Pre‐TACE‐Predict”) and a post‐TACE model (“Post‐TACE‐Predict”) that included response were built. The performance of the models in predicting overall survival (OS) was compared with existing ones. The median OS was 19.9 months. The factors influencing survival were tumor number and size, alpha‐fetoprotein, albumin, bilirubin, vascular invasion, cause, and response as assessed by mRECIST. The proposed models showed superior predictive accuracy compared with existing models (the hepatoma arterial embolization prognostic score and its various modifications) and allowed for patient stratification into four distinct risk categories whose median OS ranged from 7 months to more than 4 years.
Conclusions
A TACE‐specific and extensively validated model based on routinely available clinical features and response after first TACE permitted patient‐level prognostication.
Background
Transarterial (chemo-)embolization/lipiodolization (TAE/TAL) might be an attractive minimally invasive alternative to surgery in the treatment of symptomatic hepatic haemangioma. This ...review assesses the efficacy and safety of TAE/TAL as primary treatment for symptomatic hepatic haemangioma.
Methods
A systematic search of the literature was performed by two reviewers following the PRISMA guidelines. Cohort studies and case reports were identified; outcomes of cohort studies were reported. The primary efficacy outcome was tumour size before and after TAE/TAL. Improvement of symptoms and quality of life (QoL) were secondary outcomes; the primary safety outcome was complications. The Downs and Black statement was used for quality assessment.
Results
Eighteen cohort studies were identified, including 1284 patients. TAE/TAL led to a decrease in tumour size in 1100/1223 (89.9%) patients and to improvement or disappearance of symptoms in 1080/1096 (98.5%) patients. A significant decrease in tumour size from 9.79 ± 0.79 cm to 4.00 ± 1.36 cm (
p
< 0.001) was shown. Grade 3 complications occurred in 37/1284 (2.9%) patients. Surgical treatment was necessary in 35/1284 (2.7%) of patients.
Conclusion
TAE/TAL appears to be a promising and safe treatment to decrease tumour size of hepatic haemangioma. The technique might also provide partial relief of symptoms, although no randomized clinical trials or prospective studies using validated QoL questionnaires are available. TAE/TAL may be considered as a viable alternative to resection.
Background High dose unilobar radioembolization (also termed 'radiation lobectomy')--the transarterial unilobar infusion of radioactive microspheres as a means of controlling tumour growth while ...concomitantly inducing future liver remnant hypertrophy--has recently gained interest as induction strategy for surgical resection. Prospective studies on the safety and efficacy of the unilobar radioembolization-surgery treatment algorithm are lacking. The RALLY study aims to assess the safety and toxicity profile of holmium-166 unilobar radioembolization in patients with hepatocellular carcinoma ineligible for surgery due to insufficiency of the future liver remnant. Methods The RALLY study is a multicenter, interventional, non-randomized, open-label, non-comparative safety study. Patients with hepatocellular carcinoma who are considered ineligible for surgery due to insufficiency of the future liver remnant (< 2.7%/min/m.sup.2 on hepatobiliary iminodiacetic acid scan will be included. A classical 3 + 3 dose escalation model will be used, enrolling three to six patients in each cohort. The primary objective is to determine the maximum tolerated treated non-tumourous liver-absorbed dose (cohorts of 50, 60, 70 and 80 Gy). Secondary objectives are to evaluate dose-response relationships, to establish the safety and feasibility of surgical resection following unilobar radioembolization, to assess quality of life, and to generate a biobank. Discussion This will be the first clinical study to assess the unilobar radioembolization-surgery treatment algorithm and may serve as a stepping stone towards its implementation in routine clinical practice. Trial registration Netherlands Trial Register NL8902, registered on 2020-09-15. Keywords: Radiation lobectomy, Radioembolization, Holmium-166, .sup.166Ho, Hepatocellular carcinoma, Unilobar radioembolization
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Multimodality treatment has advanced the outcome of esophageal adenocarcinoma (EAC), but overall survival remains poor. Therapeutic pressure activates effective resistance mechanisms and we ...characterized these mechanisms in response to the currently used neoadjuvant treatment against EAC: carboplatin, paclitaxel and radiotherapy. We developed an in vitro approximation of this regimen and applied it to primary patient‐derived cultures. We observed a heterogeneous epithelial‐to‐mesenchymal (EMT) response to the high therapeutic pressure exerted by chemoradiation. We found EMT to be initiated by the autocrine production and response to transforming growth factor beta (TGF‐β) of EAC cells. Inhibition of TGF‐β ligands effectively abolished chemoradiation‐induced EMT. Assessment of TGF‐β serum levels in EAC patients revealed that high levels after neoadjuvant treatment predicted the presence of fluorodeoxyglucose uptake in lymph nodes on the post‐chemoradiation positron emission tomography‐scan. Our study shows that chemoradiation contributes to resistant metastatic disease in EAC patients by inducing EMT via autocrine TGF‐β production. Monitoring TGF‐β serum levels during treatment could identify those patients at risk of developing metastatic disease, and who would likely benefit from TGF‐β targeting therapy.
What's new?
Therapeutic resistance and disease recurrence are major setbacks affecting the survival of patients with esophageal adenocarcinoma (EAC). Resistance mechanisms in EAC, however, await elucidation. Here, epithelial‐to‐mesenchymal transition (EMT), a hallmark of invasive tumor phenotype, was investigated as a possible mechanism driving chemoradiation resistance in EAC. In EAC cells, chemoradiation was found to induce EMT, a process mediated via autocrine TGF‐β production. Inhibition of TGF‐β counteracted this process. In patients, elevated circulating TGF‐β levels post‐chemoradiation were associated with progressive disease. Together, these data suggest that TGF‐β is a useful marker for identifying patients who might benefit from TGF‐β inhibition during chemoradiation.
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