Prognostic Marker For Clinical Outcome Research Articles

Association of Preoperative Copeptin Levels with Risk of All-Cause Mortality in a Prospective Cohort of Adult Cardiac Surgery Patients.

We aimed to investigate the association of preoperative copeptin, a new cardiovascular biomarker, with short- and long-term mortality in a cohort of adult patients undergoing cardiac surgery, including its potential as a prognostic marker for clinical outcome. Preoperative blood samples of the Bern Perioperative Biobank, a prospective cohort of adults undergoing cardiac surgery during 2019, were analyzed. The primary and secondary outcome measures were 30-day and 1-year all-cause mortality. Optimal copeptin thresholds were calculated with the Youden Index. Associations of copeptin levels with the two outcomes were examined with multivariable logistic regression models; their discriminatory capacity was assessed with the area under the receiver operating characteristic (AUROC). A total of 519 patients (78.4% male, median age 67 y (IQR: 60-73 y)) were included, with a median preoperative copeptin level of 7.6 pmol/L (IQR: 4.7-13.2 pmol/L). We identified an optimal threshold of 15.9 pmol/l (95%-CI: 7.7 to 46.5 pmol/L) for 30-day mortality and 15.9 pmol/L (95%-CI: 9.0 to 21.3 pmol/L) for 1-year all-cause mortality. Regression models featured an AUROC of 0.79 (95%-CI: 0.56 to 0.95) for adjusted log-transformed preoperative copeptin for 30-day mortality and an AUROC of 0.76 (95%-CI: 0.64 to 0.88) for 1-year mortality. In patients undergoing cardiac surgery, the baseline levels of copeptin emerged as a strong marker for 1-year all-cause death. Preoperative copeptin levels might possibly identify patients at risk for a complicated, long-term postoperative course, and therefore requiring a more rigorous postoperative observation and follow-up.

Prognostic value of systemic inflammation score in patients with esophageal cancer.

The systemic inflammatory score (SIS), a new inflammatory marker based on a combination of the lymphocyte-to-monocyte ratio (LMR) and serum albumin concentration, has been reported to be a useful prognostic marker for several malignancies. The authors conducted this retrospective study on data from a cohort of esophageal cancer patients undergoing potentially curative resection to clarify the value of SIS as a prognostic marker for clinical outcome in this population. This retrospective cohort study included 32 patients who underwent thoracoscopic esophagectomy after neoadjuvant chemotherapy for esophageal cancer between January 2016 and December 2019. Blood samples were collected within one week prior to the initiation of preoperative chemotherapy. Three inflammatory and nutritional markers; SIS, the neutrophil-to-lymphocyte ratio (NLR), and prognostic nutrition index (PNI) were examined in this study. Disease-free survival was assessed using the Kaplan-Meier method, and univariable and multivariable Cox models were applied to evaluate the predictive value of SIS, NLR and PNI. NLR and PNI were not associated with recurrence, while SIS scores of 1 and 2 were significantly associated with recurrence. In multivariate analysis, SIS scores of 1 or 2 were found to be independently associated with recurrence, each with a hazard ratio of 1.98. In addition, when examining immunologic and nutritional factors and survival rates, there was no significant difference in the survival rate for NLR and PNI; for SIS, however, the survival rate was significantly worse in patients with SIS scores of 1 or 2. The authors demonstrated that a novel and easily obtained prognostic score, termed SIS, based on pre-treatment serum albumin and LMR, can serve as an independent prognostic factor in postoperative esophageal cancer patients. It could be incorporated into conventional clinical and pathological algorithms to enhance the prognostic accuracy in this population.

Early Peripheral Blood Blast Clearance As a Prognostic Marker for Early Treatment Response in Pediatric Acute Myeloid Leukemia

Background and Significance The cure rate of pediatric acute myeloid leukemia (AML) has improved significantly; however, relapses still occur in up to 30% of the total patient population in high-income countries (HICs), and in an even higher percentage of patients in low- and middle-income countries (LMICs). Early treatment response, cytogenetics and minimal residual disease (MRD) are well-known prognostic factors for treatment outcome; however, sophisticated techniques for identifying prognostic factors are often lacking in LMICs, and are sometimes unsuccessful in HICs. Early treatment response assessed by a bone marrow (BM) aspirate on day 15 or day 22 (D22) (depending on the applicable protocol) after initiation of chemotherapy is a known prognostic factor for outcome in patients with pediatric AML, but does not allow modifications of the first induction chemotherapy course (Creutzig 2014, Abrahamsson 2011, Kern 2003). In both pediatric acute lymphoid leukemia (ALL) and adult AML, early peripheral blood blast clearance (PBBC) is a known early indicator of treatment response (Manabe 2008, Arellano 2012), whereas to the best of our knowledge, this has not yet been reported in pediatric AML. In this study, we evaluated the significance of time to complete PBBC, and rate of PBBC after initiation of chemotherapy, in relation to disease status in BM D22, as measure of early treatment response that has prognostic significance. Study Design and Methods Pediatric patients with AML, aged 0-18 years, that were treated according to the NOPHO-DBH AML-2012 protocol were included. The first 5 days of induction therapy consisted of etoposide, followed by 7 days of low-dose cytarabine and mitoxantrone or liposomal daunorubicin. Peripheral blood (PB) was assessed by morphology at the time of diagnosis, daily in the first week, and thrice weekly until D22 or until occurrence of complete clearance of blasts. BM D22 was assessed by morphology and flow cytometry. A receiver operating characteristic (ROC) analysis was performed to evaluate the predictive power of days from starting chemotherapy to complete PBBC. The correlation between time to complete PBBC and BM D22 results was analyzed using a logistic regression model. Multivariable logistic regression models were applied for the association after adjusting for effects of other covariates. Rate of PBBC was defined as the percentage of the absolute PB blast count on the day of diagnosis that cleared with each day of therapy, on average, until D22 or the day of complete PBBC. Results In total, 319 patients were included, out of whom 241 were eligible for analysis, and 78 not eligible due to missing or incomplete data. Day 9 after initiation of chemotherapy was identified as the most discriminating cut-off point for predicting BM D22 response. Patients were categorized into early PBBC (≤9 days; n=159) and delayed PBBC (>9 days; n=82) groups. Early PBBC was associated with having <5% AML cells in BM D22 as assessed by both morphology (OR 3.11; P=0.005) and flow cytometry (OR 2.73; P=0.041). Early PBBC also showed a much lower likelihood of having >15% AML cells in BM D22 by morphology (OR 0.08; P=0.002). None of the early PBBC patients had >15% AML cells in BM D22 by flow cytometry. For 217 patients (selection due to missing data [n=24]), the rate of PBBC could be calculated, and a discriminative cut-off value of 11% was identified. Patients were categorized into high rate of PBBC (>11%; n=132) and low rate of PBBC (≤11%; n=85). High rate of PBBC was associated with having <5% AML cells in BM D22 by flow cytometry (OR 4.30; P=0.007) and negative MRD status (OR 2.02; P=0.004), while also showing a strong association with a lower likelihood of >15% AML cells in BM D22 (OR 0.11; P=0.007) by morphology. None of the high rate PBBC patients had >15% AML cells in BM D22 by flow cytometry. Conclusion Both early complete PBBC and rate of PBBC after initiation of chemotherapy holds promise as prognostic marker for clinical outcome in pediatric AML, as it correlates significantly with BM D22 response. These findings may offer an early and easily accessible prognostic factor, particularly beneficial for LMICs, as well as for patients with unsuccessful MRD analyses.

Coronary calcifications as a new prognostic marker in COVID-19 patients: role of CT.

COVID-19 pneumonia, caused by the virus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), was declared a pandemic by the WHO on 11th March 2020. While Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) represents the diagnostic gold standard of infection, computed tomography (CT) has been shown to have an important role in supporting the diagnosis, quantifying the severity, and assessing the efficacy of treatment and its response. Coronary artery calcification (CAC) is a CT finding that estimates atherosclerosis and can be quantified using the coronary artery calcium score (CACS). The purpose of this study is to demonstrate the correlation between coronary artery calcification and mortality rate in COVID-19 patients. Three hundred seventeen (317) hospitalized patients with SARS-CoV-2 infection were ruled in this retrospective study. All patients underwent a non-ECG-gated chest CT to evaluate lung parenchymal involvement. In the same cohort, we observed the two main coronary arteries (common trunk, circumflex, anterior interventricular and right coronary heart) using a visual score, so patients were divided into four groups based on Ordinal CAC Score (OCS) levels. The multivariate analysis proved that the OCS value was statistically correlated with the mortality rate (p < 0.001). In fact, in the group of patients with an OCS value of 0, the mortality rate was 10.1% (10/99 patients), in the group with OCS between 1 and 4 was 18.9% (21/111), in the OCS group of patients ranged from 5 to 8 was 30.4% (24/79) and in the OCS group between 9 and 12 was 46.4% (13/28). We suggest that calcific atheromasia of the coronary arteries in patients with COVID-19 can be considered a prognostic marker of clinical outcome.

Assessment of cerebral vasomotor reactivity in patients with acute stroke and transient ischemic attack (TIA) with different etiopathogenesis: Preliminary results

An impaired vasomotor reactivity (VMR) represents a negative prognostic factor for vascular and degenerative cognitive deterioration. Only few studies have addressed VMR in acute phase of stroke. We aim to investigate if VMR, calculated through the breath holding index (BHI), is a prognostic marker of clinical outcome in stroke/TIA patients.

Adverse remodeling of the subpulmonary left ventricle in patient with systemic right ventricle is associated with clinical outcome

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): This research received project funding by KU Leuven Background – Early recognition of adverse remodeling is important since outcome is unfavorable once patients with a systemic right ventricle (sRV) become symptomatic. We aimed assessing prognostic markers linked to short-term clinical evolution in this population. Purpose - We aimed assessing short-term clinical evolution and early prognostic markers of cardiac complications in adults with sRV (atrial switch repair for D-transposition of the great arteries (D-TGA) and congenitally corrected transposition of the great arteries (ccTGA)) based on detailed phenotyping. Methods– Thirty-three patients with sRV underwent detailed phenotyping including exercise CMR. Adverse outcome was a composite of heart failure episode and tachyarrhythmia. Descriptive statistics and univariate cox regression analyses were performed. Results - Thirty-three patients (76% male) with sRV were followed over mean follow-up time of 3 years. Mean age was 40 ± 8 (range 26-57) years at latest follow-up. When compared to baseline, (I) most patients remained in NYHA functional class I (76%), (II) the degree of severity of the SAVV regurgitation rose and (III) more electrical instability was documented at latest follow-up. Six (18%) of a total of nine events were counted as first cardiovascular events (9% heart failure, 9% arrhythmia). NTproBNP (HR 11.02 (95%CI 1.296-93.662), p= 0.028), oxygen pulse (HR 1.202 (95% CI 1.012-1.428), p = 0.037), left ventricle end diastolic volume index (LVEDVi) in rest (HR 1.046 (95% CI 1.002-1.092), p = 0.041) and during exercise (HR 1.035 (95% CI 1.002-1.069), p = 0.038), stroke volume index (SVi) of the subpulmonary left ventricle (LV) in rest (HR 1.154 (95% CI 1.005-1.322), p = 0.038) and at peak exercise (HR 1.065 (95% CI 1.007-1.125), p = 0.026) were significantly associated with the first cardiovascular event (Figure 1A and B). Conclusion – NTproBNP was by far the best prognostic marker for clinical outcome. Adverse remodelling with increase of LVEDVi and SVi of the subpulmonary LV at rest and during exercise were associated with worse clinical outcome. We theorize that remodeling of the subpulmonary ventricle might be an early sign of a failing sRV circulation (Figure 2).

Adverse functional remodelling of the subpulmonary left ventricle in patients with a systemic right ventricle is associated with clinical outcome.

Early recognition of adverse remodelling is important since outcome is unfavorable once patients with a systemic right ventricle (sRV) become symptomatic. We aimed assessing prognostic markers linked to short-term clinical evolution in this population. Thirty-three patients (76% male) with sRV (atrial switch repair for D-transposition of the great arteries and congenitally corrected transposition of the great arteries) underwent detailed phenotyping including exercise cardiac magnetic resonance and were followed over mean follow-up time of 3 years. Mean age was 40 ± 8 (range 26-57) years at latest follow-up. Adverse outcome was a composite of heart failure (HF) and tachyarrhythmia. Descriptive statistics and univariate cox regression analyses were performed. When compared with baseline: (i) most patients remained in New York Heart Association functional class I (76%), (ii) the degree of severity of the systemic atrioventricular valve regurgitation rose, and (iii) more electrical instability was documented at latest follow-up. Six (18%) of a total of 9 events were counted as first cardiovascular events (9% HF and 9% arrhythmia). NT-proBNP, oxygen pulse, left ventricle end-diastolic volume index (LVEDVi), and stroke volume index (SVi) of the subpulmonary left ventricle (LV) both in rest and at peak exercise were significantly associated with the first cardiovascular event. NT-proBNP was by far the best prognostic marker for clinical outcome. Adverse remodelling with increase of LVEDVi and SVi of the subpulmonary LV at rest and during exercise were associated with worse clinical outcome. We theorize that remodelling of the subpulmonary ventricle might be an early sign of a failing sRV circulation.

PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma

BRAF inhibitors (BRAFi) selectively target oncogenic BRAFV600E/K and are effective in 80% of advanced cutaneous malignant melanoma cases carrying the V600 mutation. However, the development of drug resistance limits their clinical efficacy. Better characterization of the underlying molecular processes is needed to further improve treatments. We previously demonstrated that transcription of PTEN is negatively regulated by the PTEN pseudogene antisense RNA, PTENP1-AS, and here we investigated the impact of this transcript on clinical outcome and BRAFi resistance in melanoma. We observed that increased expression levels of PTENP1-AS in BRAFi resistant cells associated with enrichment of EZH2 and H3K27me3 at the PTEN promoter, consequently reducing the expression levels of PTEN. Further, we showed that targeting of the PTENP1-AS transcript sensitized resistant cells to BRAFi treatment and that high expression of PTENP1-AS in stage III melanoma correlated with poor survival. Collectively, the data presented here show that PTENP1-AS is a promising target for re-sensitizing cells to BRAFi and also a possible prognostic marker for clinical outcome in stage III melanoma.

BNIP3L Is a New Autophagy Related Prognostic Biomarker for Melanoma Patients Treated With AGI-101H.

Skin melanoma belongs to the most invasive malignancies with no cure for a progressing disease. Personalized therapy would allow for the selection of patients that will benefit from treatment. For this purpose, proper predictive biomarkers must be defined. Allogeneic whole-cell gene-modified therapeutic melanoma vaccine (AGI-101H) was applied in advanced melanoma patients. Humoral responses were analyzed using SEREX, and in silico gene expression analysis in TCGA melanoma patients was performed. A specific antibody response was raised against an antigen identified as BNIP3L, which correlated with a good prognosis. Moreover, AGI-101H directs an immune response against autophagy, as BNIP3L is a marker of this process. Medium and high expression of BNIP3L was also linked with longer overall survival. BNIP3L is a candidate prognostic marker of clinical outcome of melanoma patients treated with AGI-101H, and may be considered as a prediction marker for patient survival.

Effects of the Tumor Environment on Ion Channels: Implication for Breast Cancer Progression.

In recent years, it has been shown that breast cancer consists not only of neoplastic cells, but also of significant alterations in the surrounding stroma or tumor microenvironment. These alterations are now recognized as a critical element for breast cancer development and progression, as well as potential therapeutic targets. Furthermore, there is no doubt that ion channels are deregulated in breast cancer and some of which are prognostic markers of clinical outcome. Their dysregulation is also associated with aberrant signaling pathways. The number of published data on ion channels modifications by the microenvironment has significantly increased last years. Here, we summarize the state of the art on the cross talk between the tumor microenvironment and ion channels, in particular collagen 1, EGF, TGF-β, ATP, hypoxia, and pH, on the development and progression of breast cancer.

Long-Amplicon Sequencing of Rearranged IGH Chains Enables Simultaneous Measurement of Somatic Hypermutation and Isotype in Chronic Lymphocytic Leukemia

Background Chronic lymphocytic leukemia (CLL) is a common form of leukemia characterized by clonal expansion of neoplastic mature B cells and a heterogenous disease course ranging from aggressive clonal expansion requiring early intervention to indolent disease that does not require treatment. Accumulating evidence suggests that the somatic hypermutation (SHM) status of the IGHV gene of the malignant clone may serve as a prognostic marker of clinical outcome, where a SHM frequency of &gt;2% indicates a favorable outcome (SHM-M) while &lt; 2% SHM (SHM-U) indicates comparatively poor prognosis. Current next-generation sequencing (NGS) approaches for analyzing SHM commonly rely on multiplex primers targeting the framework 1 (FR1) or leader region of the IGH variable gene in combination with joining gene primers to amplify rearranged IGH chains from gDNA template. Limitations include the potential for joining gene mutations to interfere with primer binding and an inability to evaluate isotype, which could potentially serve as an additional prognostic marker given the mechanistic link between somatic hypermutation and class-switch recombination. Here we present a novel method for translational research investigations of IGH chain SHM employing multiplex FR1 and isotype (constant gene) specific primers to amplify IGH chains from RNA template. We demonstrate performance of the assay via sequencing of synthesized CLL IGH chains derived from literature. Methods Multiplex PCR primers were designed to target all IGH variable genes and constant genes and alleles in the IMGT database (Oncomine IGH-LR assay). Primers were used to amplify IGH chains in samples consisting of 25ng healthy donor peripheral blood leukocyte (PBL) total RNA spiked with one of 7 synthesized monoclonal CLL rearrangements including three germline rearrangements (0% SHM), and four mutated rearrangements (SHM ranging from 3-9%), each expressed with a different isotype. Resultant libraries were sequenced on the Gene Studio S5 and analyzed via Ion Reporter to identify clonotypes, quantify SHM, and identify B cell clonal lineages. Automated downsampling analysis was used to confirm that libraries had been sequenced to an appropriate depth. Results 7 of 7 synthesized rearrangements were correctly classified as SHM-M or SHM-U, and in each instance the isotype was correctly identified by the software. Clonal lineage analysis indicated that each spike in rearrangement was monoclonal, consistent with expectation. In silico analysis revealed a high correlation between SHM estimates obtained using the entire v-gene sequence and those obtained from FR1-targeting primers (Pearson's correlation &gt;.99). Conclusions These results support the robustness and reliability of multiplex FR1 and constant gene based IGH chain amplification, combined with clonotyping and lineage analysis, for the translational research characterization of somatic hypermutation in CLL and other B cell neoplasms, including efforts to understand the potential prognostic value of isotype. Disclosures Looney: Thermo Fisher Scientific: Employment. Lowman:Thermo Fisher Scientific: Employment. Pickle:Thermo Fisher Scientific: Employment. Chang:Thermo Fisher Scientific: Employment. Topacio-Hall:Thermo Fisher Scientific: Employment. Toro:Thermo Fisher Scientific: Employment. Hyland:Thermo Fisher Scientific: Employment.

P6472Novel cardiac imaging prognostic markers of clinical outcome in patients with bicuspid aortic valve and chronic aortic regurgitation

Abstract Background Patients with chronic aortic regurgitation (AR) can have a substantial myocardial damage despite being asymptomatic. Early surgical strategy might be beneficial. Bicuspid aortic valve (BAV) is a congenital heart disease present in almost 30% of these patients. Purpose Identify novel imaging predictors of early disease progression. Methods Prospective three-centre study of patients with chronic AR of at least moderate to severe (3+) grade and BAV morphology. Patients without currently recognised indication for surgical treatment were enrolled. Baseline examination included echocardiography (ECHO) with 3-dimensional (3D) vena contracta area and magnetic resonance (MR) with regurgitant fraction measured from flow sequence. All imaging studies were analysed in CoreLab. The primary endpoint was defined as a combination of cardiovascular death, surgical treatment or hospitalization for heart failure. Results A total of 83 patients with BAV and at least 3+ AR were enrolled during 2015–2018. Median follow-up was 759±455 days, primary composite endpoint occurred in 13 patients who met criteria for surgical treatment, no patient died or was hospitalized for heart failure. Baseline parameters were compared between two groups: patients with and without endpoint. Clinical and laboratory data did not differ between the two groups. Left ventricular (LV) ejection fraction was normal in all patients. LV diameters and volumes were significantly larger in patients with primary endpoint. This was most pronounced in MR measured indexed volumes in end-diastole and end-systole, P=0.003 and P=0.003. Non-invasive markers of diffuse myocardial fibrosis (native T1 relaxation time and global longitudinal strain, P=0.614 and P=0.137 respectively) were not different. Novel markers of AR severity were significantly increased in surgically treated patients: 3D vena contracta 0.26±0.10 cm2 versus 0.38±0.11 cm2 (P&lt;0.001), MR regurgitant fraction 33.9±15.4 versus 50.2±12.2% (P=0.001). Both 3D vena contracta with cutoff value ≥0.4 cm2 (sensitivity=85%, specificity=84%, area under the curve=0.85) and MR regurgitant fraction with cutoff value ≥34% (sensitivity=94%, specificity=58%, area under the curve=0.76) showed high accuracy to identify patients who require early surgical intervention. Adding 3D vena contracta and MR regurgitant fraction to indexed LV end-systolic volumetric parameters significantly increases the predictive value for early disease progression with p=0.001 and p=0.006 (Likelihood-ratio test). 3D vena contracta predictive value Conclusions Novel imaging parameters of AR severity such as 3D vena contracta and MR derived regurgitant fraction predict early disease progression in patients with BAV and at least 3+ chronic AR. These values significantly increase the predictive value of traditional parameters based on LV size measures.

The prognostic role of lymphovascular invasion and lymph node metastasis in perihilar and intrahepatic cholangiocarcinoma

IntroductionCholangiocellular carcinoma (CCA) is an aggressive malignancy with a dismal prognosis. Among curative treatment options for CCA, radical surgical resection with extrahepatic bile duct resection, hepatectomy and en-bloc lymphadenectomy are considered the mainstay of curative therapy. Here, we aimed to identify prognostic markers of clinical outcome in CCA-patients who underwent surgical resection in curative intent. Material and methodsBetween 2011 and 2016, 162 patients with CCA (perihilar CCA (pCCA): n = 91, intrahepatic CCA (iCCA): n = 71) underwent surgery in curative intent at our institution. Preoperative characteristics, perioperative data and oncological follow-up were obtained from a prospectively managed institutional database. The associations of overall- (OS) and disease-free-survival (DFS) with clinico-pathological characteristics were assessed using univariate and multivariable cox regression analyses. ResultsThe median OS and DFS were 38 and 36 months for pCCA and 25 and 13 months for iCCA, respectively. Lymphovascular invasion (LVI) and lymph node metastasis as well as surgical complications as assessed by the comprehensive complication index (CCI) and tumor grading were independently associated with OS for the pCCA (LVI; RR = 2.36, p = 0.028; CCI; RR = 1.04, p < 0.001) and iCCA cohorts (N-category; RR = 3.21, p = 0.040; tumor grading; RR = 3.75, p = 0.013; CCI, RR = 4.49, p = 0.010), respectively. No other clinical variable including R0-status and Bismuth classification was associated with OS. ConclusionMajor liver resections for CCA are feasible and safe in experienced high-volume centers. Lymph node metastasis and LVI are associated with adverse clinical outcome, supporting the role of systematic lymphadenectomy. The assessment of LVI may be useful in identifying high-risk patients for adjuvant treatment strategies.

CINSARC signature as a prognostic marker for clinical outcome in sarcomas and beyond.

Prognostication is a key issue for sarcoma patients' care as it triggers the therapeutic approach including chemotherapy, which is still not standard for localized patients. Current prognostic evaluation, based on the FNCLCC grading system, has recently been improved by the CINSARC signature outperforming histology-based grading system by identifying high-risk patients in every grade, even in those considered as low. CINSARC is an expression-based signature related to mitosis and chromosome integrity with prognostic value in a wide range of cancers additional to sarcoma. First developed with frozen material, CINSARC is now coupled with NanoString technology allowing evaluation from FFPE blocks used in clinical practice. Consequently, CINSARC is currently evaluated in clinical trials with a dual objective of demonstrating the benefit of chemotherapy in sarcoma patients and testing its response prediction. Considering its overarching value in oncology, its development is welcome in any cancers where the prognostication needs to be improved.

Lymphovascular invasion and surgical complications predict clinical outcome in patients with perihilar and intrahepatic cholangiocarcinoma

Background: Cholangiocarcinoma (CCC) is a relatively rare malignancy that is typically diagnosed at an advanced disease stage. Major liver resection with portal vein reconstruction has evolved as the mainstay of treatment for patients with perihilar (PHCC) and intrahepatic cholangiocarcinoma (IHCC). Despite recent advancements, the overall- (OS) and recurrence-free survival (RFS) in CCC remains lower than for most other solid tumors. Here we aimed to identify prognostic markers of clinical outcome in CCC-patients that underwent surgical resection in curative intent. Methods: Between 2010 and 2016, 162 patients with CCC (PHCC: n=91, IHCC; n=71) underwent surgery in curative intent at our institution. Preoperative characteristics, perioperative data and oncological follow-up were obtained from a prospectively managed institutional database. The associations of RFS and OS with clinico-pathological characteristics were assessed using univariate and multivariate survival analyses. Results: The median OS and RFS were 38 and 36 months for PHCC and 25 and 13 months for IHCC, respectively. Lymphovascular invasion (LVI) as well as surgical complications as assessed by the comprehensive complication index were independently associated with OS for the PHCC (LVI; Exp(B)=2.28, p=0.042; CCI; Exp(B)=1.04, p< 0.001) and IHCC cohorts (LVI, Exp(B)=5.08, p=0.028; CCI, Exp(B)=1.04, p=0.002), respectively. No other clinical variable including R0-status and Bismuth classification was associated with OS. Conclusions: Surgical resections for CCC are safe in experienced high-volume liver centers. Tumor and patient characteristics were not associated with clinical outcome. In patients with PHCC and IHCC, LVI and CCI are associated with OS, suggesting a similar tumor biology.

Genetic alterations analysis in prognostic stratified groups identified TP53 and ARID1A as poor clinical performance markers in intrahepatic cholangiocarcinoma

The incidence and mortality rates of intrahepatic cholangiocarcinoma have been rising worldwide. Few patients present an early-stage disease that is amenable to curative surgery and after resection, high recurrence rates persist. To identify new independent marker related to aggressive behaviour, two prognostic groups of patient were selected and divided according to prognostic performance. All patients alive at 36 months were included in good prognostic performers, while all patients died due to disease within 36 months in poor prognostic performers. Using high-coverage target sequencing we analysed principal genetic alterations in two groups and compared results to clinical data. In the 33 cases included in poor prognosis group, TP53 was most mutated gene (p = 0.011) and exclusively present in these cases. Similarly, ARID1A was exclusive of this group (p = 0.024). TP53 and ARID1A are mutually exclusive in this study. Statistical analysis showed mutations in TP53 and ARID1A genes and amplification of MET gene as independent predictors of poor prognosis (TP53, p = 0.0031, ARID1A, p = 0.0007, MET, p = 0.0003 in Cox analysis). LOH in PTEN was also identified as marker of disease recurrence (p = 0.04) in univariate analysis. This work improves our understanding of aggressiveness related to this tumour type and has identified novel prognostic markers of clinical outcome.

Neonatal screening parameters in infants with congenital Cytomegalovirus infection

Congenital Cytomegalovirus infection (cCMV) is the most common cause of congenital infections worldwide that can cause long-term impairment (LTI). The metabolic alterations due to cCMV are largely unknown. This study aims to assess the metabolites included in the neonatal screening in relation to cCMV and cCMV outcome, allowing the identification of prognostic markers for clinical outcome. Essential amino acids, hormones, carnitines and enzymes from Dried Blood Spots (DBS) were analyzed of 102 children with cCMV and 179 children without cCMV, and they were related to symptoms at birth and LTI at 6years of age. In this cohort, the neonatal screening parameters did not change in relation to cCMV, nor to symptoms at birth or LTI. However, metabolic changes were observed in children born preterm, with lower concentrations of essential amino acids in premature infants with cCMV compared to premature controls. Finally, a higher concentration of palmytoilcarnitine (C16) in the group with higher viral load was observed. Though these data demonstrate limitations in the use of neonatal screening data as predictors for long-term cCMV outcome, the metabolism of preterm neonates with cCMV merits further evaluation.

The CINSARC signature as a prognostic marker for clinical outcome in multiple neoplasms

We previously reported the CINSARC signature as a prognostic marker for metastatic events in soft tissue sarcomas, breast carcinomas and lymphomas through genomic instability, acting as a major factor for tumor aggressiveness. In this study, we used a published resource to investigate CINSARC enrichment in poor outcome-associated genes at pan-cancer level and in 39 cancer types. CINSARC outperformed more than 15,000 defined signatures (including cancer-related), being enriched in top-ranked poor outcome-associated genes of 21 cancer types, widest coverage reached among all tested signatures. Independently, this signature demonstrated significant survival differences between risk-groups in 33 published studies, representing 17 tumor types. As a consequence, we propose the CINSARC prognostication as a general marker for tumor aggressiveness to optimize the clinical managements of patients.

Volumetric and morphological characteristics of the hippocampus are associated with progression to schizophrenia in patients with first-episode psychosis

BackgroundAbnormalities in the hippocampus have been implicated in the pathophysiology of psychosis. However, it is still unclear whether certain abnormalities are a pre-existing vulnerability factor, a sign of disease progression or a consequence of environmental factors. We hypothesized that first-episode psychosis patients who progress to schizophrenia after one year of follow up will display greater volumetric and morphological changes from the very beginning of the disorder. MethodsWe studied the hippocampus of 41 patients with a first-episode psychosis and 41 matched healthy controls. MRI was performed at the time of the inclusion in the study. After one year, the whole sample was reevaluated and divided in two groups depending on the diagnoses (schizophrenia vs. non-schizophrenia). ResultsPatients who progressed to schizophrenia showed a significantly smaller left hippocampus volume than control group and no-schizophrenia group (F=3.54; df=2, 77; P=0.03). We also found significant differences in the morphology of the anterior hippocampus (CA1) of patients with first-episode psychosis who developed schizophrenia compared with patients who did not. ConclusionsThese results are consistent with the assumption of hyperfunctioning dopaminergic cortico-subcortical circuits in schizophrenia, which might be related with an alteration of subcortical structures, such as the hippocampus, along the course of the disease. According with these results, hippocampus abnormalities may serve as a prognostic marker of clinical outcome in patients with a first-episode psychosis.

Significance of endothelial progenitor cells (EPC) for tumorigenesis of head and neck squamous cell carcinoma (HNSCC): possible marker of tumor progression and neovascularization?

Angiogenesis and neovascularisation plays a crucial role for tumorigenesis and tumor progression in head and neck squamous cell carcinoma (HNSCC). The aim of our study was to investigate the neovascularization capacity by endothelial progenitor cells (EPC) in tumor patient as a possible predictor for tumor progression and tumor stage. Therefore, we investigated the cell number and biologic activity by cell migration and colony-forming ability of EPC. Cells were isolated from the peripheral venous blood of 79 patients who suffer HNSCC in different stages of disease. Thirty-three healthy individuals served as the control group. Significantly increased biological activities were reflected by expression of the migration rate (1027±1510) in comparison to the control group (632±269) and the clonal potency measured by colony-forming unit (CFU) (tumor patients (19.7±12.3) vs. control group (10.84±4.8)). To determine whether or not EPC number can be used as a valid prognostic marker for clinical outcome of tumor patients, we furthermore compared a "high EPC-number-subgroup" (HI) with a "low EPC-number-subgroup" (LO) in a Kaplan-Meier survival curve. The HI-subgroup shows herein clearly a worse outcome. Our findings indicate a possible pathway for EPC to play a critical role in the vasculogenesis and consequently in the progression of HNSCC. Our findings could serve as possible predictors for the neovascularisation potential in HNSCC tumor patients.