Outcome of proximal esophageal cancer after definitive combined chemo-radiation: a Swiss multicenter retrospective study.

To report oncological outcomes and toxicity rates, of definitive platin-based chemoradiadiationtherapy (CRT) in the management of proximal esophageal cancer. We retrospectively reviewed the medical records of patients with cT1-4 cN0-3 cM0 cervical esophageal cancer (CEC) (defined as tumors located below the inferior border of the cricoid cartilage, down to 22 cm from the incisors) treated between 2004 and 2013 with platin-based definitive CRT in four Swiss institutions. Acute and chronic toxicities were retrospectively scored using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE-NCI v.4.0). Primary endpoint was loco-regional control (LRC). We also evaluated overall survival (OS) and disease-free survival (DFS) rates. The influence of patient- and treatment related features have been calculated using the Log-rank test and multivariate Cox proportional hazards model. We enrolled a total of 55 patients. Median time interval from diagnosis to CRT was 78 days (6-178 days). Median radiation dose was 56Gy (28-72Gy). Induction chemotherapy (ICHT) was delivered in 58% of patients. With a median follow up of 34 months (6-110months), actuarial 3-year LRC, DFS and OS were 52% (95% CI: 37-67%), 35% (95% CI: 22-50%) and 52% (95% CI: 37-67%), respectively. Acute toxicities (dysphagia, pain, skin-toxicity) ranged from grade 0 - 4 without significant dose-dependent differences. On univariable analyses, the only significant prognostic factor for LRC was the time interval > 78 days from diagnosis to CRT. On multivariable analysis, total radiation dose >56Gy (p <0.006) and ICHT (p < 0.004) were statistically significant positive predictive factors influencing DFS and OS. Definitive CRT is a reliable therapeutic option for proximal esophageal cancer, with acceptable treatment related toxicities. Higher doses and ICHT may improve OS and DFS and. These findings need to be confirmed in further prospective studies

Liver segmental volume and attenuation ratio (LSVAR) on portal venous CT scans improves the detection of clinically significant liver fibrosis compared to liver segmental volume ratio (LSVR).

BACKGROUND The aim of this proof-of-concept study was to show that the liver segmental volume and attenuation ratio (LSVAR) improves the detection of significant liver fibrosis on portal venous CT scans by adding the liver vein to cava attenuation (LVCA) to the liver segmental volume ratio (LSVR). MATERIAL AND METHODS Patients who underwent portal venous phase abdominal CT scans and MR elastography (reference standard) within 3 months between 02/2016 and 05/2017 were included. The LSVAR was calculated on portal venous CT scans as LSVR*LVCA, while the LSVR represented the volume ratio between Couinaud segments I-III and IV-VIII, and the LVCA represented the density of the liver veins compared to the density in the vena cava. The LSVAR and LSVR were compared between patients with and without significantly elevated liver stiffness (based on a cutoff value of 3.5 kPa) using the Mann-Whitney U test and ROC curve analysis. RESULTS The LSVR and LSVAR allowed significant differentiation between patients with (n = 19) and without (n = 122) significantly elevated liver stiffness (p < 0.001). However, the LSVAR showed a higher area under the curve (AUC = 0.96) than the LSVR (AUC = 0.74). The optimal cutoff value was 0.34 for the LSVR, which detected clinically increased liver stiffness with a sensitivity of 53% and a specificity of 88%. With a cutoff value of 0.67 for the LSVAR, the sensitivity increased to 95% while maintaining a specificity of 89%. CONCLUSION The LSVAR improves the detection of significant liver fibrosis on portal venous CT scans compared to the LSVR

DNA methylation dynamics of the human preimplantation embryo

In mammals, cytosine methylation is predominantly restricted to CpG dinucleotides and stably distributed across the genome, with local, cell type-specific regulation directed by DNA binding factors1-3. This comparatively static landscape dramatically contrasts the events of fertilization, where the paternal genome is globally reprogrammed. Paternal genome demethylation includes the majority of CpGs, though methylation is maintained at several notable features4-7. While these dynamics have been extensively characterized in the mouse, only limited observations are available in other mammals, and direct measurements are required to understand the extent to which early embryonic landscapes are conserved8-10. We present genome-scale DNA methylation maps of human preimplantation development and embryonic stem cell (ESC) derivation, confirming a transient state of global hypomethylation that includes most CpGs, while sites of persistent maintenance are primarily restricted to gene bodies. While most features share similar dynamics to mouse, maternally contributed methylation is divergently targeted to species-specific sets of CpG island (CGI) promoters that extend beyond known Imprint Control Regions (ICRs). Retrotransposon regulation is also highly diverse and transitions from maternally to embryonically expressed, species-specific elements. Together, our data confirm that paternal genome demethylation is a general attribute of early mammalian development that is characterized by distinct modes of epigenetic regulation

Loss of DNMT1o Disrupts Imprinted X Chromosome Inactivation and Accentuates Placental Defects in Females

The maintenance of key germline derived DNA methylation patterns during preimplantation development depends on stores of DNA cytosine methyltransferase-1o (DNMT1o) provided by the oocyte. Dnmt1omat-/- mouse embryos born to Dnmt1Δ1o/Δ1o female mice lack DNMT1o protein and have disrupted genomic imprinting and associated phenotypic abnormalities. Here, we describe additional female-specific morphological abnormalities and DNA hypomethylation defects outside imprinted loci, restricted to extraembryonic tissue. Compared to male offspring, the placentae of female offspring of Dnmt1Δ1o/Δ1o mothers displayed a higher incidence of genic and intergenic hypomethylation and more frequent and extreme placental dysmorphology. The majority of the affected loci were concentrated on the X chromosome and associated with aberrant biallelic expression, indicating that imprinted X-inactivation was perturbed. Hypomethylation of a key regulatory region of Xite within the X-inactivation center was present in female blastocysts shortly after the absence of methylation maintenance by DNMT1o at the 8-cell stage. The female preponderance of placental DNA hypomethylation associated with maternal DNMT1o deficiency provides evidence of additional roles beyond the maintenance of genomic imprints for DNA methylation events in the preimplantation embryo, including a role in imprinted X chromosome inactivation. © 2013 McGraw et al

Molecular marks for epigenetic identification of developmental and cancer stem cells

Epigenetic regulations of genes by reversible methylation of DNA (at the carbon-5 of cytosine) and numerous reversible modifications of histones play important roles in normal physiology and development, and epigenetic deregulations are associated with developmental disorders and various disease states, including cancer. Stem cells have the capacity to self-renew indefinitely. Similar to stem cells, some malignant cells have the capacity to divide indefinitely and are referred to as cancer stem cells. In recent times, direct correlation between epigenetic modifications and reprogramming of stem cell and cancer stem cell is emerging. Major discoveries were made with investigations on reprogramming gene products, also known as master regulators of totipotency and inducer of pluoripotency, namely, OCT4, NANOG, cMYC, SOX2, Klf4, and LIN28. The challenge to induce pluripotency is the insertion of four reprogramming genes (Oct4, Sox2, Klf4, and c-Myc) into the genome. There are always risks of silencing of these genes by epigenetic modifications in the host cells, particularly, when introduced through retroviral techniques. In this contribution, we will discuss some of the major discoveries on epigenetic modifications within the chromatin of various genes associated with cancer progression and cancer stem cells in comparison to normal development of stem cell. These modifications may be considered as molecular signatures for predicting disorders of development and for identifying disease states

[Diagnostics and treatment of traumatic aortic injuries].

BACKGROUND Traumatic aortic injuries (TAI) are rare injuries in blunt thoracic trauma, which have a high morbidity and mortality. Rapid and accurate diagnosis as well as the correct choice of treatment are elementary for patient survival. OBJECTIVE Determination of the current standards for diagnostics of TAI in the acute trauma setting and evaluation of the current guidelines for treatment. MATERIAL AND METHODS A literature search was carried out for articles describing diagnostics of TAI. Furthermore, the guidelines for treatment and follow-up of TAI were summarized. RESULTS Despite the low specificity conventional chest X‑ray is still named in the literature as initial diagnostic procedure. Primarily, computed tomography (CT) should follow as the method of choice for diagnostics and treatment stratification due to the high sensitivity and specificity. Thoracic endovascular aortic repair (TEVAR) is recommended by all guidelines as first line treatment of higher grades of TAI (grades II-IV) and has replaced open surgery in most cases. CONCLUSION After rapid diagnosis and classification of TAI with CT, in most cases TEVAR has become the preferred treatment over open surgery

Value of MRI/CT Image Fusion for Targeting "invisible" Lesions in Stereotactic Microwave Ablation (SMWA) of Malignant Liver Lesions: A Retrospective Analysis.

PURPOSE To assess the technical feasibility of MRI/CT image fusion and completeness of ablation treatment for primary or metastatic liver lesions invisible on contrast-enhanced CT planning scans and outcome in patients treated with stereotactic microwave ablation (SMWA). MATERIALS AND METHODS The study was approved by the local ethics committee. Patients who underwent SMWA between January 2015 and December 2018 were retrospectively analyzed. All liver lesions for which MRI/CT fusion was performed due to invisibility on pre-interventional CT planning scans were included and reassessed. The outcome measurement was successful ablation of the lesion at first follow-up imaging. RESULTS During the study period, 236 patients underwent 312 SMWAs with ablation of 496 lesions. Twenty-four lesions in 15 patients (mean age, 62 years; range, 43-80 years) were included. Following MRI/CT image fusion, all 24 lesions could be sufficiently localized to perform SMWA. The first follow-up imaging showed complete ablation of 22 lesions. Two initially incompletely ablated lesions were hepatocellular carcinomas and were successfully re-ablated afterwards. CONCLUSION SMWA with MRI/CT image fusion is an accurate and safe treatment option for patients with liver lesions not detectable on contrast-enhanced CT planning scans. MRI/CT image fusion may allow more patients with malignant liver lesions to benefit from local ablation treatment even if their lesions are not visible on CT planning examinations

Distinct Roles of DMAP1 in Mouse Development ▿

DMAP1 (DNMT1-associated protein 1) is a member of the TIP60-p400 complex that maintains embryonic stem (ES) cell pluripotency and a complex containing the somatic form of DNA methyltransferase 1 (DNMT1s). DMAP1 interacts with DNMT1s through a domain that is absent in Dnmt1V/V mice expressing just the oocyte form (DNMT1o). A Dmap1-null allele was generated to study the role of DMAP1 in development. Consistent with the phenotypes of loss of other members of the TIP60-p400 complex, Dmap1−/− mice died during preimplantation in both Dnmt1+/+ and Dnmt1V/V backgrounds. Unexpectedly, in the Dnmt1V/V background, Dmap1+/− parents produced mainly Dmap1+/− mice. Most Dmap1+/+ progeny died during midgestation, with loss of DNA methylation on imprinted genes, suggesting that DMAP1 influences maintenance methylation mediated by DNMT1o. In this regard, a DMAP1-DNMT1o complex was detected in ES cells when DNMT1o was stably expressed but not when transiently expressed, indicating a novel interaction between DMAP1 and DNMT1o. These results suggest that DMAP1-DNMT1s and DMAP1-DNMT1o interactions are essential for normal development and that DMAP1-DNMT1o complexes are not readily formed in the embryo. Therefore, DMAP1 mediates distinct preimplantation epigenetic reprogramming processes: TIP60-p400 nucleosome remodeling and DNMT1 maintenance methylation