The prevalence of TET2 gene mutations in patients with BCR-ABL-negative myeloproliferative neoplasms (MPN):a systematic review and meta-analysis

SIMPLE SUMMARY: Many molecular biology techniques have been widely used to study the pathogenesis of different diseases, particularly haematologic malignancies which are generally caused by abnormalities in the genome. TET2 gene is one of the commonly found mutated genes in BCR-ABL-negative myeloproliferative neoplasms. However, the prevalence of TET2 gene mutations in the disease remains unclear. Therefore, this study aims to estimate the prevalence of TET2 gene mutations in myeloproliferative neoplasms. The findings may be helpful for future research, diagnoses and the identification of better therapeutic strategies to manage the diseases. ABSTRACT: Multiple recurrent somatic mutations have recently been identified in association with myeloproliferative neoplasms (MPN). This meta-analysis aims to assess the pooled prevalence of TET2 gene mutations among patients with MPN. Six databases (PubMed, Scopus, ScienceDirect, Google Scholar, Web of Science and Embase) were searched for relevant studies from inception till September 2020, without language restrictions. The eligibility criteria included BCR-ABL-negative MPN adults with TET2 gene mutations. A random-effects model was used to estimate the pooled prevalence with 95% confidence intervals (CIs). Subgroup analyses explored results among different continents and countries, WHO diagnostic criteria, screening methods and types of MF. Quality assessment was undertaken using the Joanna Briggs Institute critical appraisal tool. The study was registered with PROSPERO (CRD42020212223). Thirty-five studies were included (n = 5121, 47.1% female). Overall, the pooled prevalence of TET2 gene mutations in MPN patients was 15.5% (95% CI: 12.1–19.0%, I(2) = 94%). Regional differences explained a substantial amount of heterogeneity. The prevalence of TET2 gene mutations among the three subtypes PV, ET and MF were 16.8%, 9.8% and 15.7%, respectively. The quality of the included studies was determined to be moderate–high among 83% of the included studies. Among patients with BCR-ABL-negative MPN, the overall prevalence of TET2 gene mutations was 15.5%

Fraction size in radiation treatment for breast conservation in early breast cancer

Backgroun

Fraction size in radiation therapy for breast conservation in early breast cancer (Review)

Background: Shortening the duration of radiation therapy would benefit women with early breast cancer treated with breast conserving surgery. It may also improve access to radiation therapy by improving efficiency in radiation oncology departments globally. This can only happen if the shorter treatment is as effective and safe as conventional radiation therapy. This is an update of a Cochrane Review first published in 2008 and updated in 2009. Objectives: To assess the effect of altered radiation fraction size for women with early breast cancer who have had breast conserving surgery. Search methods: We searched the Cochrane Breast Cancer Specialised Register (23 May 2015), CENTRAL (The Cochrane Library 2015, Issue 4), MEDLINE (Jan 1996 to May 2015), EMBASE (Jan 1980 to May 2015), the WHO International Clinical Trials Registry Platform (ICTRP) search portal (June 2010 to May 2015) and ClinicalTrials.gov (16 April 2015), reference lists of articles and relevant conference proceedings. No language or publication constraints were applied. Selection criteria: Randomised controlled trials of altered fraction size versus conventional fractionation for radiation therapy in women with early breast cancer who had undergone breast conserving surgery. Data collection and analysis: Two authors performed data extraction independently, with disagreements resolved by discussion. We sought missing data from trial authors. Main results: We studied 8228 women in nine studies. Eight out of nine studies were at low or unclear risk of bias. Altered fraction size (delivering radiation therapy in larger amounts each day but over fewer days than with conventional fractionation) did not have a clinically meaningful effect on: local recurrence-free survival (Hazard Ratio (HR) 0.94, 95% CI 0.77 to 1.15, 7095 women, four studies, high-quality evidence), cosmetic outcome (Risk ratio (RR) 0.90, 95% CI 0.81 to 1.01, 2103 women, four studies, high-quality evidence) or overall survival (HR 0.91, 95% CI 0.80 to 1.03, 5685 women, three studies, high-quality evidence). Acute radiation skin toxicity (RR 0.32, 95% CI 0.22 to 0.45, 357 women, two studies) was reduced with altered fraction size. Late radiation subcutaneous toxicity did not differ with altered fraction size (RR 0.93, 95% CI 0.83 to 1.05, 5130 women, four studies, high-quality evidence). Breast cancer-specific survival (HR 0.91, 95% CI 0.78 to 1.06, 5685 women, three studies, high quality evidence) and relapse-free survival (HR 0.93, 95% CI 0.82 to 1.05, 5685 women, three studies, moderate-quality evidence) did not differ with altered fraction size. We found no data for mastectomy rate. Altered fraction size was associated with less patient-reported (P < 0.001) and physician-reported (P = 0.009) fatigue at six months (287 women, one study). We found no difference in the issue of altered fractionation for patient-reported outcomes of: physical well-being (P = 0.46), functional well-being (P = 0.38), emotional well-being (P = 0.58), social well-being (P = 0.32), breast cancer concerns (P = 0.94; 287 women, one study). We found no data with respect to costs. Authors' conclusions: We found that using altered fraction size regimens (greater than 2 Gy per fraction) does not have a clinically meaningful effect on local recurrence, is associated with decreased acute toxicity and does not seem to affect breast appearance, late toxicity or patient-reported quality-of-life measures for selected women treated with breast conserving therapy. These are mostly women with node negative tumours smaller than 3 cm and negative pathological margins

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Follow-up strategies for patients treated for non-metastatic colorectal cancer (Review)

Background: It is common clinical practice to follow patients with colorectal cancer (CRC) for several years following their curative surgery or adjuvant therapy, or both. Despite this widespread practice, there is considerable controversy about how often patients should be seen, what tests should be performed, and whether these varying strategies have any significant impact on patient outcomes. This is the second update of a Cochrane Review first published in 2002 and first updated in 2007. Objectives: To assess the effects of intensive follow-up for patients with non-metastatic colorectal cancer treated with curative intent. Search methods: For this update, we searched CENTRAL (2016, Issue 3), MEDLINE (1950 to May 20th, 2016), Embase (1974 to May 20th, 2016), CINAHL (1981 to May 20th, 2016), and Science Citation Index (1900 to May 20th, 2016). We also searched reference lists of articles, and handsearched the Proceedings of the American Society for Radiation Oncology (2011 to 2014). In addition, we searched the following trials registries (May 20th, 2016): ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. We further contacted study authors. No language or publication restrictions were applied to the search strategies. Selection criteria: We included only randomised controlled trials comparing different follow-up strategies for participants with non-metastatic CRC treated with curative intent. Data collection and analysis: Two authors independently determined trial eligibility, performed data extraction, and assessed methodological quality. Main results: We studied 5403 participants enrolled in 15 studies. (We included two new studies in this second update.) Although the studies varied in setting (general practitioner (GP)-led, nurse-led, or surgeon-led) and "intensity" of follow-up, there was very little inconsistency in the results. Overall survival: we found no evidence of a statistical effect with intensive follow-up (hazard ratio (HR) 0.90, 95% confidence interval (CI) 0.78 to 1.02; I2 = 4%; P = 0.41; high-quality evidence). There were 1098 deaths among 4786 participants enrolled in 12 studies. Colorectal cancer-specific survival: this did not differ with intensive follow-up (HR 0.93, 95% CI 0.78 to 1.12; I2 = 0%; P = 0.45; moderate-quality evidence). There were 432 colorectal cancer deaths among 3769 participants enrolled in seven studies. Relapse-free survival: we found no statistical evidence of effect with intensive follow-up (HR 1.03, 95% CI 0.90 to 1.18; I2 = 5%; P = 0.39; moderate-quality evidence). There were 1416 relapses among 5253 participants enrolled in 14 studies. Salvage surgery with curative intent: this was more frequent with intensive follow-up (risk ratio (RR) 1.98, 95% CI 1.53 to 2.56; I2 = 31%; P = 0.14; high-quality evidence). There were 457 episodes of salvage surgery in 5157 participants enrolled in 13 studies. Interval (symptomatic) recurrences: these were less frequent with intensive follow-up (RR 0.59, 95% CI 0.41 to 0.86; I2 = 66%; P = 0.007; moderate-quality evidence). Three hundred and seventy-six interval recurrences were reported in 3933 participants enrolled in seven studies. Intensive follow-up did not appear to affect quality of life, anxiety, nor depression (reported in three studies). Harms from colonoscopies did not differ with intensive follow-up (RR 2.08, 95% CI 0.11 to 40.17; moderate-quality evidence). In two studies, there were seven colonoscopic complications in 2112 colonoscopies. Authors' conclusions: The results of our review suggest that there is no overall survival benefit for intensifying the follow-up of patients after curative surgery for colorectal cancer. Although more participants were treated with salvage surgery with curative intent in the intensive follow-up group, this was not associated with improved survival. Harms related to intensive follow-up and salvage therapy were not well reported

Estimated need for surgery worldwide based on prevalence of diseases : a modelling strategy for the WHO global health estimate

Background: Surgery is a foundational component of health-care systems. However, previous efforts to integrate surgical services into global health initiatives do not reflect the scope of surgical need and many health systems do not provide essential interventions. We estimate the minimum global volume of surgical need to address prevalent diseases in 21 epidemiological regions from the Global Burden of Disease Study 2010 (GBD). Methods: Prevalence data were obtained from GBD 2010 and organised into 119 disease states according to the WHO's Global Health Estimate (GHE). These data, representing 187 countries, were then apportioned into the 21 GBD epidemiological regions. Using previously defined values for the incident need for surgery for each of the 119 GHE disease states, we calculate minimum global need for surgery based on the prevalence of each condition in each region. Findings: We estimate that at least 321·5 million surgical procedures would be needed to address the burden of disease for a global population of 6·9 billion in 2010. Minimum rates of surgical need vary across regions, ranging from 3383 operations per 100 000 in central Latin America to 6495 operations per 100 000 in western sub-Saharan Africa. Global surgical need also varied across subcategories of disease, ranging from 131 412 procedures for nutritional deficiencies to 45·8 million procedures for unintentional injuries. Interpretation: The estimated need for surgical procedures worldwide is large and addresses a broad spectrum of disease states. Surgical need varies between regions of the world according to disease prevalence and many countries do not meet the basic needs of their populations. These estimates could be useful for policy makers, funders, and ministries of health as they consider how to incorporate surgical capacity into health systems.Published versio

IMECCHI-DATANETWORK : empowering knowledge generation through international data network

ABSTRACT Objectives The International Methodology Consortium for Coded Health Information (IMECCHI), an international collaboration of health services researchers, launched the IMECCHI-DATANETWORK initiative in October 2015. Its main objective is to enable replication of observational studies across countries through a distributed data infrastructure. Approach In a distributed data infrastructure, individual raw data are not shared. Instead, data are converted locally using a common data model (CDM) and loaded into a common software for data processing and analysis. Whenever a study protocol is agreed upon and ethically approved, an ad hoc procedure is programmed - using that software - including the data processing steps needed to create the analytical dataset from the CDM: record linkage, case selection, sampling, matching, etc. The procedure is then shared and locally run by each partner to generate an analytical dataset of integrated data. Analytical datasets may then be shared and pooled for statistical analyses. Results Six partners of the IMECCHI collaboration, located in countries across 4 continents (Canada, Denmark, Italy, New Zealand, South Korea, and Switzerland), currently participate in the initiative. They first conducted a survey to describe the origin, content, completeness and main attributes of each table in their original databases. Based on the results of the survey, a CDM was created, encompassing 4 tables of coded or structured data to be linked at the individual level using a common personal identifier: (1) characteristics of the subjects with dates of birth and death; (2) hospital discharge summaries with diagnosis and procedure codes, and admission, discharge and procedure dates; (3) drug dispensing information with date of dispensing, drug name, duration of the amount of active principle according to the Defined Daily Dose of the World Health Organization; (4) causes of death. In each table, additional attributes describe the coding systems in which the other attributes are coded. Using such specific attributes facilitates interoperability across multiple coding systems. The open source Java-based software, TheMatrix, which operates on flat csv files using a domain-specific programming language, was chosen to embed the ad hoc procedure. Conclusion Within the IMECCHI-DATANETWORK initiative, databases from various countries will be locally converted in a CDM which will facilitate study replication in a distributed fashion while granting interoperability across coding systems. Through such international data networks, data are empowered for creating results which are generalizable to multiple countries. Cross-border data sharing and international comparisons are also facilitated