Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The search for predictive biomarkers is often performed on primary tumours ...tissue. In order to assess the effectiveness of tailored treatment in regard to the primary tumour the differences in the genomic profile needs to be clarified.
Fresh-frozen tissue from primary tumours, synchronous liver metastases and adjacent normal liver was collected from 21 patients and analysed by whole-exome sequencing on the Illumina HiSeq 2500 platform. Gene variants designated as 'damaging' or 'potentially damaging' by Ingenuity software were used for the subsequent comparative analysis. BAM files were used as the input for the analysis of CNAs using NEXUS software.
Shared mutations between the primary tumours and the synchronous liver metastases varied from 50 to 96%. Mutations in APC, KRAS, NRAS, TP53 or BRAF were concordant between the primary tumours and the metastases. Among the private mutations were well-known driver genes such as PIK3CA and SMAD4. The number of mutations was significantly higher in patients with right- compared to left-sided tumours (102 vs. 66, p = 0.004). Furthermore, right- compared to left-sided tumours had a significantly higher frequency of private mutations (p = 0.023). Similarly, CNAs differed between the primary tumours and the metastases. The difference was mostly comprised of numerical and segmental aberrations. However, novel CNAs were rarely observed in specific CRC-relevant genes.
The examined primary colorectal tumours and synchronous liver metastases had multiple private mutations, indicating a high degree of inter-tumour heterogeneity in the individual patient. Moreover, the acquirement of novel CNAs from primary tumours to metastases substantiates the need for genomic profiling of metastases in order to tailor metastatic CRC therapies. As for the mutational status of the KRAS, NRAS and BRAF genes, no discordance was observed between the primary tumours and the metastases.
A guide to immunotherapy for COVID-19 van de Veerdonk, Frank L; Giamarellos-Bourboulis, Evangelos; Pickkers, Peter ...
Nature medicine,
01/2022, Letnik:
28, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Immune dysregulation is an important component of the pathophysiology of COVID-19. A large body of literature has reported the effect of immune-based therapies in patients with COVID-19, with some ...remarkable successes such as the use of steroids or anti-cytokine therapies. However, challenges in clinical decision-making arise from the complexity of the disease phenotypes and patient heterogeneity, as well as the variable quality of evidence from immunotherapy studies. This Review aims to support clinical decision-making by providing an overview of the evidence generated by major clinical trials of host-directed therapy. We discuss patient stratification and propose an algorithm to guide the use of immunotherapy strategies in the clinic. This will not only help guide treatment decisions, but may also help to design future trials that investigate immunotherapy in other severe infections.
Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of ...hundreds to thousands of adenomas in the colorectum. Almost all patients will develop CRC if they are not identified and treated at an early stage. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the APC gene. Recently, a second gene has been identified that also gives rise to colonic adenomatous polyposis, although the phenotype is less severe than typical FAP. The gene is the MUTYH gene and the inheritance is autosomal recessive. In April 2006 and February 2007, a workshop was organised in Mallorca by European experts on hereditary gastrointestinal cancer aiming to establish guidelines for the clinical management of FAP and to initiate collaborative studies. Thirty-one experts from nine European countries participated in these workshops. Prior to the meeting, various participants examined the most important management issues according to the latest publications. A systematic literature search using Pubmed and reference lists of retrieved articles, and manual searches of relevant articles, was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described herein may be helpful in the appropriate management of FAP families. In order to improve the care of these families further, prospective controlled studies should be undertaken.
Lynch syndrome (hereditary non-polyposis colorectal cancer) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one ...of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. The discovery of these genes, 15 years ago, has led to the identification of large numbers of affected families. In April 2006, a workshop was organised by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group), aiming to establish guidelines for the clinical management of Lynch syndrome. 21 experts from nine European countries participated in this workshop. Prior to the meeting, various participants prepared the key management issues of debate according to the latest publications. A systematic literature search using Pubmed and the Cochrane Database of Systematic Reviews reference lists of retrieved articles and manual searches of relevant articles was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described in this manuscript may be helpful for the appropriate management of families with Lynch syndrome. Prospective controlled studies should be undertaken to improve further the care of these families.
Aliment Pharmacol Ther 2011; 34: 1225–1234
Summary
Background Uncertainty remains on topography and persistence of histological subgroups of microscopic colitis (MC).
Aim To assess longitudinal ...clinical, endoscopic, histological, and therapeutic description of MC subgroups including patients with incomplete findings of MC (MCi).
Methods Retrospective review of a consecutive cohort with MC and histological reassessment of MCi.
Results Clinical characteristics of 168 patients with lymphocytic colitis (LC), 270 with collagenous colitis (CC) and 101 with MCi were similar. At colonoscopy 95% (95% CI: 91–98%) of CC and 98% (93–100%) of LC cases had diagnostic histopathology of MC in both left and right colon. Eight and three patients had characteristics of MC only in the left and right colon, respectively. Histology findings resembling coexistence of the other MC subtype was present in 48% (40–55%) with CC and 24% (18–31%) with LC. A first diagnosis of MC was made in 49 (30%) of 164 patients only at repeat endoscopy. Another 34 of 115 (30%) with MC in the first endoscopy did not fulfil the MC criteria at repeat endoscopy. Only seven cases had a primary endoscopy without histopathological abnormalities. Fifteen percentage of MCi were reclassified as MC. Ileal inflammation was present in 33 of 81 patients. Budesonide was efficacious in all MC subgroups irrespective of bile acid malabsorption.
Conclusions Clinical characteristics of microscopic colitis subgroups are indistinguishable. Biopsies from the left colon suffice to exclude microscopic colitis, and the histological diagnosis of microscopic colitis is inconsistent over time. Ileal inflammation is common. The term microscopic colitis should perhaps be considered one clinical entity and include lymphocytic colitis, collagenous colitis, and incomplete findings of microscopic colitis.
Ischaemic heart disease (IHD) remains the leading cause of death and disability worldwide. As a result, novel therapies are still needed to protect the heart from the detrimental effects of acute ...ischaemia-reperfusion injury, in order to improve clinical outcomes in IHD patients. In this regard, although a large number of novel cardioprotective therapies discovered in the research laboratory have been investigated in the clinical setting, only a few of these have been demonstrated to improve clinical outcomes. One potential reason for this lack of success may have been the failure to thoroughly assess the cardioprotective efficacy of these novel therapies in suitably designed preclinical experimental animal models. Therefore, the aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to provide recommendations for improving the preclinical assessment of novel cardioprotective therapies discovered in the research laboratory, with the aim of increasing the likelihood of success in translating these new treatments into improved clinical outcomes.
We present the first far infrared (FIR) dust emission polarization map covering the full extent of Milky Way’s central molecular zone (CMZ). The data, obtained with the PILOT balloon-borne ...experiment, covers the Galactic center region − 2° < ℓ < 2°, − 4° < b < 3° at a wavelength of 240 μm and an angular resolution of 2.2′. From our measured dust polarization angles, we infer a magnetic field orientation projected onto the plane of the sky (POS) that is remarkably ordered over the full extent of the CMZ, with an average tilt angle of ≃22° clockwise with respect to the Galactic plane. Our results confirm previous claims that the field traced by dust polarized emission is oriented nearly orthogonally to the field traced by GHz radio synchrotron emission in the Galactic center region. The observed field structure is globally compatible with the latest Planck polarization data at 353 and 217 GHz. Upon subtraction of the extended emission in our data, the mean field orientation that we obtain shows good agreement with the mean field orientation measured at higher angular resolution by the JCMT within the 20 and 50 km s−1 molecular clouds. We find no evidence that the magnetic field orientation is related to the 100 pc twisted ring structure within the CMZ. The low polarization fraction in the Galactic center region measured with Planck at 353 GHz combined with a highly ordered projected field orientation is unusual. This feature actually extends to the whole inner Galactic plane. We propose that it could be caused by the increased number of turbulent cells for the long lines of sight towards the inner Galactic plane or to dust properties specific to the inner regions of the Galaxy. Assuming equipartition between magnetic pressure and ram pressure, we obtain magnetic field strength estimates of the order of 1 mG for several CMZ molecular clouds.
Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, ...MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.
Objective
The aim of this Meta‐analysis is to evaluate the impact of different treatment strategies for early postoperative hypoparathyroidism on hypocalcemia‐related complications and long‐term ...hypoparathyroidism.
Data Sources
Embase.com, MEDLINE, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and the top 100 references of Google Scholar were searched to September 20, 2022.
Review Methods
Articles reporting on adult patients who underwent total thyroidectomy which specified a treatment strategy for postthyroidectomy hypoparathyroidism were included. Random effect models were applied to obtain pooled proportions and 95% confidence intervals. Primary outcome was the occurrence of major hypocalcemia‐related complications. Secondary outcome was long‐term hypoparathyroidism.
Results
Sixty‐six studies comprising 67 treatment protocols and 51,096 patients were included in this Meta‐analysis. In 8 protocols (3806 patients), routine calcium and/or active vitamin D medication was given to all patients directly after thyroidectomy. In 49 protocols (44,012 patients), calcium and/or active vitamin D medication was only given to patients with biochemically proven postthyroidectomy hypoparathyroidism. In 10 protocols (3278 patients), calcium and/or active vitamin D supplementation was only initiated in case of clinical symptoms of hypocalcemia. No patient had a major complication due to postoperative hypocalcemia. The pooled proportion of long‐term hypoparathyroidism was 2.4% (95% confidence interval, 1.9‐3.0). There was no significant difference in the incidence of long‐term hypoparathyroidism between the 3 supplementation groups.
Conclusions
All treatment strategies for postoperative hypocalcemia prevent major complications of hypocalcemia. The early postoperative treatment protocol for postthyroidectomy hypoparathyroidism does not seem to influence recovery of parathyroid function in the long term.
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