Characterization of Overlap in Observational Studies

Overlap between treatment groups is required for non-parametric estimation of causal effects. If a subgroup of subjects always receives the same intervention, we cannot estimate the effect of intervention changes on that subgroup without further assumptions. When overlap does not hold globally, characterizing local regions of overlap can inform the relevance of causal conclusions for new subjects, and can help guide additional data collection. To have impact, these descriptions must be interpretable for downstream users who are not machine learning experts, such as policy makers. We formalize overlap estimation as a problem of finding minimum volume sets subject to coverage constraints and reduce this problem to binary classification with Boolean rule classifiers. We then generalize this method to estimate overlap in off-policy policy evaluation. In several real-world applications, we demonstrate that these rules have comparable accuracy to black-box estimators and provide intuitive and informative explanations that can inform policy making.Comment: To appear at AISTATS 202

Importance of inspection of the oil-oil shell and tube heat exchanger for needs of sustainable development and environmental protection

Postrojenja za stabilizaciju nafte omogućavaju rekuperaciju i komercijalnu eksploataciju nafte koja se izdvaja iz gasa dopremljenog iz bušotine. Kondenzovani topli tečni ugljovodonici koji su prečišćeni iz prirodnog gasa mogu se koristiti za zagrevanje fluida koji dolazi u proces u kome se vrši njegovo razdvajanje na lakše i tečne komponente. U radu je prikazan pregled razmenjivača toplote nafta-nafta i objašnjen značaj inspekcije u pogledu održivog razvoja i zaštite životne sredine. Debljina materijala merena je ultrazvučnom tehnikom. Određivanje stepena korozije i preostalog radnog veka razmenjivača toplote izvršeni su prema API 510 i API 572 standardu. Vizuelni test je otkrio određena mehanička oštećenja i površinsku koroziju, metoda inspekcije penetrantskim metodama nije detektovala prsline u zavarenim spojevima u vreme pregleda.Plant for oil stabilisation is enable to recovery and commercial exploitation of oil which is rectified from excavated raw gas. Condensed hot liquid hydrocarbons that are separated from natural gas can be used to heat the fluid that enters the process in which it is separated into liquid and lighter components. This paper presents the inspection of an oil heat exchanger and explains the importance of inspection regarding sustainable development and environmental protection. The thickness of the material was measured by ultrasonic technique. Determination of corrosion rate and remaining life of oil-oil shell and tube heat exchanger is performed according to the API 510 and API 572 standards. The visual test revealed some mechanical damages and surface corrosion; a liquid penetrant inspection method showed no cracks at the time of inspection.Mesto i datum održavanja konferencije: Privredna komora Srbije, Beograd, 17. i 18. oktobar 2022. Place and date conference: Chamber of Commerce and Industry of Serbia, Belgrade, October 17. and 18., 202

The impact of histopathology and NAB2-STAT6 fusion subtype in classification and grading of meningeal solitary fibrous tumor/hemangiopericytoma.

Meningeal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) is a rare tumor with propensity for recurrence and metastasis. Although multiple classification schemes have been proposed, optimal risk stratification remains unclear, and the prognostic impact of fusion status is uncertain. We compared the 2016 WHO CNS tumor grading scheme (CNS-G), a three-tier system based on histopathologic phenotype and mitotic count, to the 2013 WHO soft-tissue counterpart (ST-G), a two-tier system based on mitotic count alone, in a cohort of 133 patients [59 female, 74 male; mean age 54 years (range 20-87)] with meningeal SFT/HPC. Tumors were pathologically confirmed through review of the first tumor resection (n = 97), local recurrence (n = 35), or distant metastasis (n = 1). A STAT6 immunostain showed nuclear expression in 132 cases. NAB2-STAT6 fusion was detected in 99 of 111 successfully tested tumors (89%) including the single STAT6 immunonegative tumor. Tumors were classified by CNS-G as grade 1 (n = 43), 2 (n = 41), or 3 (n = 49), and by ST-G as SFT (n = 84) or malignant SFT (n = 49). Necrosis was present in 16 cases (12%). On follow-up, 42 patients had at least one subsequent recurrence or metastasis (7 metastasis only, 33 recurrence only, 2 patients had both). Twenty-nine patients died. On univariate analysis, necrosis (p = 0.002), CNS-G (p = 0.01), and ST-G (p = 0.004) were associated with recurrence-free (RFS) but not overall survival (OS). NAB2-STAT6 fusion type was not significantly associated with RFS or OS, but was associated with phenotype. A modified ST-G incorporating necrosis showed higher correlation with RFS (p = 0.0006) and remained significant (p = 0.02) when considering only the primary tumors. From our data, mitotic rate and necrosis appear to stratify this family of tumors most accurately and could be incorporated in a future grading scheme

Clinical Laboratory Testing Practices in Diffuse Gliomas Prior to Publication of 2021 World Health Organization Classification of Central Nervous System Tumors

CONTEXT.—: Integration of molecular data into glioma classification supports diagnostic, prognostic, and therapeutic decision-making; however, testing practices for these informative biomarkers in clinical laboratories remain unclear. OBJECTIVE.—: To examine the prevalence of molecular testing for clinically relevant biomarkers in adult and pediatric gliomas through review of a College of American Pathologists proficiency testing survey prior to the release of the 2021 World Health Organization Classification of Central Nervous System Tumors. DESIGN.—: College of American Pathologists proficiency testing 2020 survey results from 96 laboratories performing molecular testing for diffuse gliomas were used to determine the use of testing for molecular biomarkers in gliomas. RESULTS.—: The data provide perspective into the testing practices for diffuse gliomas from a broad group of clinical laboratories in 2020. More than 98% of participating laboratories perform testing for glioma biomarkers recognized as diagnostic for specific subtypes, including IDH. More than 60% of laboratories also use molecular markers to differentiate between astrocytic and oligodendroglial lineage tumors, with some laboratories providing more comprehensive analyses, including prognostic biomarkers, such as CDKN2A/B homozygous deletions. Almost all laboratories test for MGMT promoter methylation to identify patients with an increased likelihood of responding to temozolomide. CONCLUSIONS.—: These findings highlight the state of molecular testing in 2020 for the diagnosis and classification of diffuse gliomas at large academic medical centers. The findings show that comprehensive molecular testing is not universal across clinical laboratories and highlight the gaps between laboratory practices in 2020 and the recommendations in the 2021 World Health Organization Classification of Central Nervous System Tumors

Molecular Analysis of Precursor Lesions in Familial Pancreatic Cancer

PMCID: PMC3553106This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE) : a double-blind phase III study of haemostatic therapy

Background: Single-dose human fibrinogen concentrate (FCH) might have haemostatic benefits in complex cardiovascular surgery. Methods: Patients undergoing elective aortic surgery requiring cardiopulmonary bypass were randomly assigned to receive FCH or placebo. Study medication was administered to patients with a 5 min bleeding mass of 60-250 g after separation from bypass and surgical haemostasis. A standardized algorithm for allogeneic blood product transfusion was followed if bleeding continued after study medication. Results: 519 patients from 34 centres were randomized, of whom 152 (29%) met inclusion criteria for study medication. Median (IQR) pretreatment 5 min bleeding mass was 107 (76-138) and 91 (71-112) g in the FCH and placebo groups, respectively (P=0.13). More allogeneic blood product units were administered during the first 24 h after FCH, 5.0 (2.0-11.0), when compared with placebo, 3.0 (0.0-7.0), P=0.026. Fewer patients avoided transfusion in the FCH group (15.4%) compared with placebo (28.4%), P=0.047. The FCH immediately increased plasma fibrinogen concentration and fibrin-based clot strength. Adverse event rates were comparable in each group. Conclusions: Human fibrinogen concentrate was associated with increased allogeneic blood product transfusion, an unexpected finding contrary to previous studies. Human fibrinogen concentrate may not be effective in this setting when administered according to 5-minute bleeding mass. Low bleeding rates and normal-range plasma fibrinogen concentrations before study medication, and variability in adherence to the complex transfusion algorithm, may have contributed to these results.Peer reviewe

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Improved discrimination of melanotic schwannoma from melanocytic lesions by combined morphological and GNAQ mutational analysis

The histological differential diagnosis between melanotic schwannoma, primary leptomeningeal melanocytic lesions and cellular blue nevus can be challenging. Correct diagnosis of melanotic schwannoma is important to select patients who need clinical evaluation for possible association with Carney complex. Recently, we described the presence of activating codon 209 mutations in the GNAQ gene in primary leptomeningeal melanocytic lesions. Identical codon 209 mutations have been described in blue nevi. The aims of the present study were to (1) perform a histological review of a series of lesions (initially) diagnosed as melanotic schwannoma and analyze them for GNAQ mutations, and (2) test the diagnostic value of GNAQ mutational analysis in the differential diagnosis with leptomeningeal melanocytic lesions. We retrieved 25 cases that were initially diagnosed as melanotic schwannoma. All cases were reviewed using established criteria and analyzed for GNAQ codon 209 mutations. After review, nine cases were classified as melanotic schwannoma. GNAQ mutations were absent in these nine cases. The remaining cases were reclassified as conventional schwannoma (n = 9), melanocytoma (n = 4), blue nevus (n = 1) and lesions that could not be classified with certainty as melanotic schwannoma or melanocytoma (n = 2). GNAQ codon 209 mutations were present in 3/4 melanocytomas and the blue nevus. Including results from our previous study in leptomeningeal melanocytic lesions, GNAQ mutations were highly specific (100%) for leptomeningeal melanocytic lesions compared to melanotic schwannoma (sensitivity 43%). We conclude that a detailed analysis of morphology combined with GNAQ mutational analysis can aid in the differential diagnosis of melanotic schwannoma with leptomeningeal melanocytic lesions

Proceedings of the Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) Oligodendroglioma Workshop.

Background: Oligodendroglioma is a rare primary central nervous system (CNS) tumor with highly variable outcome and for which therapy is usually not curative. At present, little is known regarding the pathways involved with progression of oligodendrogliomas or optimal biomarkers for stratifying risk. Developing new therapies for this rare cancer is especially challenging. To overcome these challenges, the neuro-oncology community must be particularly innovative, seeking multi-institutional and international collaborations, and establishing partnerships with patients and advocacy groups thereby ensuring that each patient enrolled in a study is as informative as possible. Methods: The mission of the National Cancer Institute\u27s NCI-CONNECT program is to address the challenges and unmet needs in rare CNS cancer research and treatment by connecting patients, health care providers, researchers, and advocacy organizations to work in partnership. On November 19, 2018, the program convened a workshop on oligodendroglioma, one of the 12 rare CNS cancers included in its initial portfolio. The purpose of this workshop was to discuss scientific progress and regulatory challenges in oligodendroglioma research and develop a call to action to advance research and treatment for this cancer. Results: The recommendations of the workshop include a multifaceted and interrelated approach covering: biology and preclinical models, data sharing and advanced molecular diagnosis and imaging; clinical trial design; and patient outreach and engagement. Conclusions: The NCI-CONNECT program is well positioned to address challenges in oligodendroglioma care and research in collaboration with other stakeholders and is developing a list of action items for future initiatives

Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system

Primary melanocytic neoplasms of the central nervous system (CNS) are uncommon neoplasms derived from melanocytes that normally can be found in the leptomeninges. They cover a spectrum of malignancy grades ranging from low-grade melanocytomas to lesions of intermediate malignancy and overtly malignant melanomas. Characteristic genetic alterations in this group of neoplasms have not yet been identified. Using direct sequencing, we investigated 19 primary melanocytic lesions of the CNS (12 melanocytomas, 3 intermediate-grade melanocytomas, and 4 melanomas) for hotspot oncogenic mutations commonly found in melanocytic tumors of the skin (BRAF, NRAS, and HRAS genes) and uvea (GNAQ gene). Somatic mutations in the GNAQ gene at codon 209, resulting in constitutive activation of GNAQ, were detected in 7/19 (37%) tumors, including 6/12 melanocytomas, 0/3 intermediate-grade melanocytomas, and 1/4 melanomas. These GNAQ-mutated tumors were predominantly located around the spinal cord (6/7). One melanoma carried a BRAF point mutation that is frequently found in cutaneous melanomas (c.1799 T>A, p.V600E), raising the question whether this is a metastatic rather than a primary tumor. No HRAS or NRAS mutations were detected. We conclude that somatic mutations in the GNAQ gene at codon 209 are a frequent event in primary melanocytic neoplasms of the CNS. This finding provides new insight in the pathogenesis of these lesions and suggests that GNAQ-dependent mitogen-activated kinase signaling is a promising therapeutic target in these tumors. The prognostic and predictive value of GNAQ mutations in primary melanocytic lesions of the CNS needs to be determined in future studies