Mature Data Research Articles

EX1 How to Select the Appropriate Survival Extrapolation Method? a Proposed Framework

For HTA, apart from standard parametric models (SPMs), other extrapolation approaches are applied such as piecewise, splines, mixture cure and non-mixture cure, parametric-mixture, and fractional polynomial models. The objective is to validate a survival extrapolation decision framework suggesting cure models for curative therapies, parametric-mixture models in case of a subgroup of long-term survivors, piecewise, splines and fractional polynomials in case of fluctuating hazards, and SPMs for other data. All survival extrapolation approaches were fitted on immature data of three trials; in melanoma the framework recommends a cure model as cure seems clinically plausible, in breast cancer (BC) a parametric-mixture as a subgroup of long-term survivors is expected, and in multiple myeloma (MM) an SPM as no cure, long-term survivors or fluctuating hazards are expected. The statistical fit of the models was assessed using LOOIC. The extrapolation on immature data was compared to mature trial data in terms of ΔMean-Absolute-Deviation (ΔMAD) in months for all arms in the trial. Lower LOOIC and ΔMAD imply better predictions. Restricted mean survival time (RMST) of the mature data was determined to assess the relative size of ΔMAD. The best fitting approach on the melanoma dataset (RMST: 67.88 months) was the log-logistic parametric-mixture (LOOIC=2,870, ΔMAD=19.59). The best fitting cure model was the lognormal (LOOIC=3,249, ΔMAD=10.89). On the BC dataset (RMST: 123.42 months), the lognormal parametric-mixture fitted best (LOOIC=1,782, ΔMAD=9.86) and had one of the lowest ΔMAD. On the MM dataset (RMST: 92.55 months), the Weibull parametric-mixture fitted best (LOOIC=1,944, ΔMAD=11.24), and the best fitting SPM was the exponential (LOOIC=1,988, ΔMAD=7.21). This study shows that the model recommended by the framework generally leads to better long-term extrapolations compared to the statistically best fitting model. Therefore, additional to historical data and long-term comparative effectiveness expectations, this framework can be used for model selection.

Assessing the Long-Term Role of Vaccination against HPV after Loop Electrosurgical Excision Procedure (LEEP): A Propensity-Score Matched Comparison.

Background: Primary prevention through vaccination is a prophylactic approach aiming to reduce the risk of developing human papillomavirus (HPV)-related lesions. No mature and long-term data supported the adoption of vaccination in women undergoing conization. Methods: This is a retrospective multi-institutional study. Charts of consecutive patients undergoing conization between 2010 and 2014 were collected. All patients included had at least 5 years of follow-up. We compared outcomes of patients undergoing conization plus vaccination and conization alone. A propensity-score matching algorithm was applied in order to reduce allocation biases. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models. Results: Overall, charts of 1914 women were analyzed. The study group included 116 (6.1%) and 1798 (93.9%) women undergoing conization plus vaccination and conization alone, respectively. Five-year recurrence rate was 1.7% (n = 2) and 5.7% (n = 102) after conization plus vaccination and conization alone, respectively (p = 0.068). After the application of a propensity-score matching, we selected 100 patients undergoing conization plus vaccination and 200 patients undergoing conization alone. The crude number of recurrences was 2 (2%) and 11 (5.5%) for patients undergoing conization plus vaccination and conization alone, respectively (p = 0.231). Vaccination had no impact on persistent lesions (no negative examination between conization and new cervical dysplasia; p = 0.603), but reduced the risk of recurrent disease (patients who had at least one negative examination between conization and the diagnosis of recurrent cervical dysplasia; p = 0.031). Conclusions: Patients having vaccination experience a slightly lower risk of recurrence than women who had not, although not statistically significantly different. Further evidence is needed to assess the cost effectiveness of adopting vaccination in this setting.

PCN246 Review of Published Efficiency Opinions of the French Economic and Public Health Assessment Committee (CEESP) in Chronic Lymphocytic Leukaemia (CLL)

Since 2013, manufacturers are required to submit a pharmacoeconomic evaluation to the French HTA for all innovative products claiming an important added clinical benefit with a substantial impact on healthcare expenditures. The objective of this analysis was to review the French HTA decisions and provide a summary of the methodological concerns (MCs) reported in chronic lymphocytic leukaemia (CLL) indications. All available opinions for CLL indications published up to March 2020 were reviewed. Methodological choices, specific indications, nature of the request and MCs were extracted. A total of eight published opinions were identified and reviewed. The cost-effectiveness was not demonstrated in any of them and only two did not raise major concerns. Overall, 49 MCs were identified: 12 major, 13 important, and 24 minor. Almost half (24/49) of MCs were related to modelling and methodological choices with a non-negligible impact on the overall decision: 10 major, 9 important and 5 minor MCs. The ten major MCs were related to uncertainty and limitations pertaining to the efficacy data (data immaturity, etc.), comparators choices (lack of relevant comparators, etc.), studied population (missing subgroups, etc.) and utilities (non-conformity of the estimations method, etc.). The nine important MCs were caused by the modelling assumptions and their poor discussion as well as by the weak external and internal validity of the model. Most of the minor concerns were related to a lack of clarity in the presentation of the results and the methodological choices, miscalculations, or the absence of required scenario analyses. This review highlighted the lack of available and mature clinical data in CLL, inciting manufacturers to consider an important number of modelling assumptions. Considering assumptions should be associated with a robust rationale, sensitivity analyses and discussion to ensure that the French HTA can properly assess results considering the modelling-related uncertainty.

Rancang Bangun Purwarupa Pemilah Nanas Berdasarkan Tingkat Kematangan Menggunakan Mikrokontroler Blue Pill STM32F103C8T6

The research about a design of prototype automatic pineapple sorting has been done with a belt conveyor system using a Blue Pill STM32F103C8T6 microcontroller. This research was conducted to create a prototype that can sort pineapples based on maturity level by classified unripe, ripe, and fully ripe. Sorting pineapple against the pineapple ripeness classification was carried out by a simulation process using serial data of index maturity sent from the PC monitor serial to microcontroller via serial communication. The serial data sent in character format was an integer 1; 2; 3; 4; 5; 6; and 7. The conveyor using a chain with gear transmission system and a DC motor as a drive. The results showed that the instument is capable of carrying a maximum load of pineapple fruit of 1.0 kg with a transport speed of 27,98 cm/s and can perform pineapple ripeness sorting with an accuracy more than 90%.

Synthesis of the European ALARA network 18th workshop ‘ALARA for decommissioning and site remediation’

The European ALARA Network regularly organises workshops on topical issues in radiation protection. The topic of the 18th workshop was ‘ALARA for Decommissioning and Site Remediation’. The workshop was jointly organised with the ISOE Working Group on Decommissioning (ISOE WG-DECOM) and the French Atomic Alternatives Energy and Atomic Energy Commission (CEA). The main objective was to examine the conceptual and practical aspects of the implementation of the optimisation principle (or ALARA principle) in the ‘nuclear’ and ‘non-nuclear’ sectors and also for legacy sites. This memorandum presents a synthesis of the presentations and working groups discussion that took place. It also summaries the conclusions from former EAN workshops on the same topic (1997, 2006) to highlight the commonalities and the new topics.The theoretical scheme for applying the ALARA principle is illustrated by the various presentations of decommissioning and remediation (D&R) projects given at the workshop. The theoretical scheme includes, a starting point, the planning and implementation of the D&R strategy (including ALARA analysis) and the definition of an end-state. To lay down the foundations of ALARA, the initial characterisation should be comprehensive; considering not only radiation protection but other risks and circumstances both on site and off site. Decision-making is not trivial because many factors influence the D&R strategy and they can be addressed together using an holistic approach. A general methodology for such an approach in D&R was drafted by the participants.Techniques are apparently industrially mature and dosimetric data suggest that good control has been achieved, however experience shows that the D&R strategy will go through multiple adaptations along the way. The management of wastes remains a challenge in many cases as well as the decision on the end-state leading to question of what is a ‘sustainable ALARA end-state?’.

Regional hydrocarbon potential of the northeastern Caribbean based on integration of sediment thickness and source rock maturity data

AbstractOver 72 exploration wells have been drilled on the Caribbean islands of Hispaniola and Puerto Rico over the past century, but with no commercial success. A question is whether these Caribbean oceanic islands have experienced sufficient subsidence and burial for any potential source rocks to reach maturity and produce commercial hydrocarbons. Subsurface data from previous studies were compiled into a regional depth to basement and sediment thickness map for Hispaniola, Puerto Rico and their offshore areas. The thickest basins include the Enriquillo/Cul-de-Sac basin (6.3 km), San Juan/Plateau Central basin (5 km), Azua basin (2.8 km), Cibao basin (5 km), North Coast basin (2.5 km), South Coast basin (1.3 km), Haiti sub-basin (3.7 km), Hispaniola basin (3.5 km) and San Pedro basin (3 km). One-dimensional modelling for six onland basins shows that only the Azua basin of the south-central Dominican Republic has reached sufficient maturity to place potential source rocks into the oil window. Our study shows that commercial hydrocarbons are possible in the deeper basins – Azua basin, San Juan–Plateau Central basin and Cibao basin of Hispaniola – but unlikely in the shallower basins that lack sufficient overburden for organic maturity.

DDRE-20. GENERATION OF A HIGH-AFFINITY EGFR/EGFRvIII-TARGETED D2C7 CAR-T CELL

Abstract BACKGROUND The intent of this investigation is to validate a novel, high-affinity epidermal growth factor receptor (EGFR) chimeric antigen receptor (CAR) T-cell product for adoptive immunotherapy of EGFR-expressing malignancies of the central nervous system (CNS). Wild type EGFR is ubiquitously expressed on glial tumors in both children and adults, and the majority of solid tumors that metastasize to the CNS but is not expressed on healthy CNS tissues. EGFR and its isoform mutant, EGFRvIII, are hyperactivated or overexpressed receptor tyrosine kinases described in many human cancers. D2C7 is a recombinant monoclonal antibody short chain variable fragment (scFv) that binds to both wild type EGFR and EGFRvIII. We hypothesize that D2C7 adapted as a CAR on primary human T cells will generate potent, cytotoxic activity against EGFR-expressing tumors in vivo. METHODS In vitro interferon gamma release assays comparing the D2C7 CAR to the EGFRvIII CAR have proven that D2C7 CAR-T cells have high specificity and potent cytotoxicity against established murine glioblastoma (GBM) tumor cell lines, expressing both EGFR and EGFRvIII. Next steps include pre-clinical in vivo testing of the D2C7 CAR-T cells in murine models of CNS tumors expressing EGFR/EGFRvIII such as GBM, non-small cell lung carcinoma (NSCLC), breast carcinoma, and melanoma. CONCLUSIONS To improve and validate the effectiveness of CAR T-cell therapy for EGFR-expressing CNS tumors, our team has designed a high-affinity CAR-T cell that targets both EGFRvIII and wild-type EGFR, known as a D2C7 CAR-T cell. This investigation has established pre-clinical anti-tumor activity of D2C7-CAR T cells in vitro and we plan to present more mature data regarding efficacy in orthotopic murine models of GBM, NSCLC, breast carcinoma, and melanoma at the meeting this Fall.

Polatuzumab Vedotin Plus Bendamustine and Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Updated Results of a Phase Ib/II Randomized Study and Preliminary Results of a Single-Arm Extension

Polatuzumab Vedotin Plus Bendamustine and Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Updated Results of a Phase Ib/II Randomized Study and Preliminary Results of a Single-Arm Extension

Impact of Mutated Genes By Next Generation Sequencing on Overall Survival in a Cohort of Peruvian Patients with AML/MDS

Background Acute myeloid leukemia and myelodysplastic syndrome (AML/MDS) represents a broad and complex group of diseases characterized by involvement of the myeloid lineage on hematopoiesis with remarkable variability on clinical presentation, genes mutations, karyotype and molecular abnormalities. Precise characterization on AML/MDS biology is important and the identification of the pathogenic mutated genes is relevant for risk stratification and therapy strategy, mainly for those patients in which targeted therapies is a must. Among pathogenic mutated genes in AML/MDS; TP53 is associated with lower response and high mortality rates. The cumulated number of mutated genes is associated with bad clinical outcomes as well. Aims To explore the frequency and impact of mutated genes on clinical outcomes in a cohort of Peruvian patients diagnosed with AML/MDS studied at diagnosis. Methods In this report we showed 31 consecutive AML/MDS cases treated at three medical centers in Lima (Clínica Delgado, Clínica Anglo Americana and INEN) from January 2016 until July 2020. Information available at diagnosis was: clinical, karyotype, molecular PCR panel, Illumina TruSight Myeloid Sequencing (TSM) panel which include 53 genes involved on oncogenesis, therapy regimen, response to treatment and overall survival (OS). Results A total of 31 cases were studied. F/M ratio 0.55 (11/20), median age 62 years (range 16-87), number of cases by disease were AML=23 and MDS=8. Among the 26 available karyotypes, the abnormal vs diploid karyotype ratio was 0.18 (4/22). Ad hoc PCR panel were positive in just 5 cases among 30 studies available, for FLT3-ITD(n=2), CBFB-MYH11(n=1), NPM1(n=1) and AML-ETO (n=1). In the TSM analysis, median number of pathogenic mutated genes was 3 (range 0-15). Most common (≥18%) pathogenic mutated genes wereBCOR (n=11; 35,5%), CUX1 (n=7; 22,6%) , DNMT3 (n=7; 22,6%), RAD21(n=6; 19,4%), and STAG2 (n=6; 19,4%)with different rates compare with other series (figure 1). Response rate were as follow: 58,1% complete (18/31), 9,7% partial (3/31), 19,3% non-response (6/31) and 12,9% non-evaluable (4/31). The estimated median OS was 36,67 months for the entire cohort, the 1 and 3-years OS rates were 69,9% and 62,2% respectively. For AML and MDS cases median OS was not reached, 1-year OS rates were 68,6% and 72,9% respectively, 3-years OS rates were 54,9% and 72,9% respectively (Log Rank 0,071 p=0,79). MutatedTP53was detected in 5 cases (MDS=3 and AML=2) with no therapy response in 4 and all of them had already dead; median OS for mutatedTP53cases was 3,53±0,43 months; 1-year OS rates for non-mutated vs mutatedTP53cases were 80,2% and 20% respectively, 3-year OS rates for cases with non-mutated vs mutatedTP53were 70,2% and 20% respectively (Log Rank 14,6 p<0,0001) (figure 2). The median OS for mutatedBCORwas not reached; 1-year OS rates for non-mutated vs mutatedBCORwere 77,4% and 52,6% respectively; 3-year OS rates for non-mutated vs mutatedBCORwere 64,5% and 52,6% respectively (Log Rank 0,09 p=0,76). The medians OS were not reached for <3 and ≥3 pathogenic mutated genes cases, 1-year OS rates were 92,3% and 53,5% respectively and 3-years OS rates were 73,8% and 53,5% respectively (Log Rank 1,98 p=0,159). The median OS for ≥4 pathogenic mutated genes cases was 11,93±2,5 months, 1-year OS for <4 and ≥4 were 88,9% and 42,4% respectively and 3-years OS for <4 and ≥4 were 71,1% and 42,4% respectively (Log Rank 3,293 p=0,07). Ad-hoc composite analysis for cases of <4 vs ≥4±mutated-TP53showed medians OS not reached and 9,87±2,9 months respectively; 1-year OS rates were 100% and 40,8% and 3-years OS were 75,0% and 40,8% respectively (Log Rank 9,10 p=0,003)(figure 3). Conclusion NGS for LMA/MDS is an important tool for diagnosis, assessment and risk stratification in our serie of cases. Only 5 over 53 genes were detected in ≥ 18% of casesBCOR, CUX1, DNMT3, RAD, and STAG. TP53 was related with a high therapy failure response and short OS. Number of pathogenic mutated genes ≥3 or ≥4 by TSM showed tendencies for shorter OS. A composite analysis for patients with 4 mutated genes with or without mutated-TP53showed significant shorter OS. Further studies with mature data and more cases are warrant to propose genetics characterization and risk stratification by NGS in Peruvian AML/MDS cases. Disclosures No relevant conflicts of interest to declare.

A Multicenter Real-Life Study of Polatuzumab Vedotin Combined with Immunochemotherapy in Patients with R/R DLBCL: Preliminary Data on Efficacy and Safety in Chinese Cohort

Background For patients with relapse/refractory(R/R) Diffuse Large B Cell Lymphoma (DLBCL), intensive therapy (such as R-ICE, R-DHAP) followed by autologous stem cell transplant (ASCT) can provide potential cure. However, not all patients would be eligible for such aggressive therapy. The ASCT ineligible or patients have very low survival rates and no curative options. Polatuzumab vedotin (Pola) is a conjugated antibody that delivers the microtubule inhibitor MMAE to CD79b-expressing cells. Pola administered in combination with Bendamustine-Rituximab (P-BR) has been approved for R/R DLBCL patients in USA and Europe consecutively. But real-life data of Pola on efficacy and safety in this setting especially in Chinese patients remain very limited. Aim This study aims to investigate the efficacy and tolerability of Pola with BR or R in R/R patients with DLBCL treated through a Compassionate Use Program (CUP) after failing ≥2 prior regimens. Methods We collected and analyzed the data of all patients enrolled in Pola CUP in four Chinese centers. Patients with R/R DLBCL who have exhausted all therapeutic options after at least 2 prior treatments could be enrolled in this program. Pola was administered at a dose of 1.8 mg/kg/cycle iv in combination with rituximab±bendamustine for a total of up to 6 cycles. Response was assessed after every 2 cycles and at end of treatment. Results From Dec 12 2019 to Jul 30 2020, 27 patients were treated in the CUP of Pola and there are 20 patients whose diseases had already been assessed at least once for the response evaluation. Baseline characteristics of the 20 patients are shown in Table1. Nine patients received Pola-BR combination and 3 of them received the bendamustine combined regimen after the 3rd or 4th cycle in order to improve the efficacy. For the other 11 patients only Pola-R was administered. All patients received rituximab in front lines and 80.0%(16/20) of them are refractory to the prior therapy (no response or relapsed≤6 mon). 70.0% (14/20) patients had a high-intermediate or high risk disease (IPI score≥3); 10.0% (2/20) had ECOG performance status (PS) 3-4. 25.0% (5/20) patients had already received prior Car-T and 5.0% (1/20) had prior ASCT therapy. At time of analysis, six patients finished all 6 cycles of treatment and 3 discontinued therapy due to personal reason or disease progression. The remaining patients are still in the process of treatment. The achieved overall response was Complete Response (CR) in 1 patients (5.0%) and Partial Response (PR) in 15 patients (75.0%). One patient progressed after 2 cycles of Pola-R therapy, but achieved PR after receiving Bendamustine combined therapy from the 3rd cycle. The overall response rate and treatment duration is shown in table 2 and Figure 1. The median follow-up is 48 days and the progression free survival (PFS) of the two progressed patients is 29 and 148 days. (Table 3 & Figure 2). The main toxicity was hematological. Four patients developed grade 3-4 neutropenia (20.0%) and 2 patient (10.0%) had grade 3-4 thrombocytopenia. Febrile neutropenia was reported in 2 patients. One patient had pneumonia but recovered after anti-infection therapy. The adverse event of peripheral neuropathy was not observed. Conclusion For this R/R DLBCL cohort with heavily treated, high risk and refractory diseases, the Pola-(B)R regimen still achieved promising efficacy. However considering the limited sample size and short follow-up, more mature data and long-term survival outcomes is warrant. Key words Relapse/refractory; DLBCL; Polatuzumab Vedotin; Compassionate Use Disclosures No relevant conflicts of interest to declare.

Real-World Conditional Survival Analysis of Patients with Relapsed/Refractory Classical Hodgkin's Lymphoma in the US

Introduction:While the majority of patients (pts) with newly diagnosed classical Hodgkin's lymphoma (cHL) achieve remission following first-line therapy, approximately 30-40% will relapse or become refractory (R/R). Despite R/R status, the 5-year relative survival rate in this population is high (ranging from 78% to 92%) (American Cancer Society 2020). While overall survival (OS) is an unambiguous measure of efficacy in clinical trials, using it as a primary end point requires a long duration of follow-up and may prolong the process of identifying novel and potentially beneficial therapy. Surrogate outcomes, such as progression-free survival (PFS) and time to progression (TTP) are sometimes regarded as valid alternatives when assessing efficacy of a treatment in the absence of mature OS data. The objectives of this study were to assess the conditional survival (CS) given prior PFS among R/R cHL pts treated in the real-world setting. Methods:This retrospective cohort study used electronic medical record (EMR) data of US pts from a network of oncology practices, including practices affiliated with CancerLinQ, maintained in the Definitive Oncology Dataset. Eligible adult (≥18 years) pts who had a confirmed diagnosis of cHL and ≥1 R/R event that occurred between 2000 to 2019 were included. Refractory disease was defined as not achieving a complete or partial response (CR or PR) during a line of therapy. Relapsed disease was defined as the reappearance of cHL at any time after the end of treatment after having achieved a CR or PR. PFS and OS were measured from the start of second-line [2L] therapy to the earlier or disease progression or death; pts without evidence of disease progression or death were censored at the last observed visit. The association between PFS and OS was quantified through the nonparametric Kendall tau rank correlation for bivariate censored data. CS was defined as the Kaplan-Meier probability of surviving an additionalymonths (from the start of 2L), given no OS or PFS event in the previousx(< y) months. Results:A total of 286 R/R cHL pts were included. Most pts were Caucasian (77.3%, n=221) with a median age of 35 years (range: 19-86) at the first R/R event. Median length of follow-up was 12 months from the first R/R event. The most common B symptoms reported were night sweats (38.8%, n=111), weight loss (36.4%, n=104), and fatigue (27.3%, n=78). More than half of pts (54.9%, n=157) received autologous stem-cell transplant (SCT) and 6.6% (n=19) received allogenic SCT. Two-hundred twenty-six pts (79.0%) had documented 2L therapy (first R/R event). From the first R/R event, among these 226 pts, median PFS was 21.0 months (95% confidence interval [CI]: 15.1, 52.5) and median OS was 146.7 months (95% CI: 119.9, not achieved [NA]). CS rates among pts alive without disease progression increased with time: 1-year and 6-year survival rates were 95.7% (95% CI: 91.5, 97.8) and 79.3% (95% CI: 70.5, 85.7), respectively, in pts alive without progression at 3 months, but increased to 100.0% (95% CI: 100, 100) and 94.6% (95% CI: 79.9, 98.6) in pts alive without progression at 3-years (Table). The calculated Kendall tau correlation was 0.42 (p<0.0001), which suggested a statistically significant dependence between PFS and OS. Conclusion:In the real-world setting, R/R cHL pts with longer time without disease progression had lower rates of death and better prognosis. Results from this study support a relationship between PFS and OS; however, further validation and acceptance of PFS as a surrogate endpoint in cHL is required. Establishing these relationships may inform future clinical trial design and interpretation of interim trial data. Disclosures Desai: Merck & Co., Inc:Current Employment, Current equity holder in publicly-traded company.Yang:Merck & Co, Inc.:Current Employment.Gilligan:ConcertAI:Current Employment;Merck & Co., Inc.:Research Funding.Li:Merck & Co., Inc.:Current Employment, Current equity holder in publicly-traded company.Raut:Merck & Co., Inc.:Current Employment.Nahar:Merck Sharp & Dohme, Corp., a subsididary of Merck & Co., Inc., Kenlworth, NJ, USA:Current Employment.

A New Risk Stratification Model (R2-ISS) in Newly Diagnosed Multiple Myeloma: Analysis of Mature Data from 7077 Patients Collected By European Myeloma Network within Harmony Big Data Platform

A New Risk Stratification Model (R2-ISS) in Newly Diagnosed Multiple Myeloma: Analysis of Mature Data from 7077 Patients Collected By European Myeloma Network within Harmony Big Data Platform

Excess Neuronal Branching Allows for Local Innervation of Specific Dendritic Compartments in Mature Cortex.

The connectivity of cortical microcircuits is a major determinant of brain function; defining how activity propagates between different cell types is key to scaling our understanding of individual neuronal behavior to encompass functional networks. Furthermore, the integration of synaptic currents within a dendrite depends on the spatial organization of inputs, both excitatory and inhibitory. We identify a simple equation to estimate the number of potential anatomical contacts between neurons; finding a linear increase in potential connectivity with cable length and maximum spine length, and a decrease with overlapping volume. This enables us to predict the mean number of candidate synapses for reconstructed cells, including those realistically arranged. We identify an excess of potential local connections in mature cortical data, with densities of neurite higher than is necessary to reliably ensure the possible implementation of any given axo-dendritic connection. We show that the number of local potential contacts allows specific innervation of distinct dendritic compartments.

Comparing natural and artificial thermal maturation of a Type II-S source rock, Late Cretaceous, Israel

Marine source rocks that are sulfur-rich (i.e., Type II-S kerogen) start to mature earlier than their sulfur-lean equivalents (Type II). This affects the amount of petroleum generated with the increase in thermal maturation. However, the evolution of HI with Tmax upon thermal maturation is not described quantitatively (or semi-quantitatively) for Type II-S kerogen. Here we explore the natural thermal maturation of the Ein Zeitim/Ghareb Formation (Late Cretaceous) type II-S source rock in the Golan Basin, north Israel. This is done by comparing geochemical data on cuttings from the section in the Golan Basin with an artificial maturation experiment conducted on an immature analog core taken from the Shfela Basin, central Israel. Using bulk Rock-Eval analyses of unextracted and extracted samples, the natural and artificial maturation paths are found to be comparable and show sub-parallel trends for the relative decrease in hydrogen index (HI) and the increase in the normalized bitumen content (mgBitumen/gTOC) with increasing thermal maturation (measured as Tmax). This comparison suggests that maturation in the Golan Basin increases with depth across the ~350 m thick section from an early maturation state to the peak of bitumen generation. While the original HI (HIo) is estimated from the field data, the original S2 prior to maturation (S2o) is estimated based on the empirical relationship derived from the artificial maturation data trend in order to estimate hydrocarbon generation. Second-order differences between the artificial and natural maturation trends may be due to small differences in the sulfur content of the immature kerogens from the two basins (0.5–1 wt% from the kerogen), leading to an offset in the Tmax maturation scale. Thus, a lower-case scenario is considered to estimate lower values for S2o and the hydrocarbons generated across the source rock section. As sulfur in the immature kerogen has a substantial effect on the onset of maturation, we postulate that the maturation path presented here is more representative for sulfur-rich kerogens then that of the sulfur-lean Type II kerogens. However, variability in the sulfur content within sulfur-rich kerogens, will probably change the specific maturation path of a given kerogen.

Multi-institutional Analysis of Prognostic Factors and Outcomes After Hypofractionated Stereotactic Radiotherapy to the Resection Cavity in Patients With Brain Metastases

For brain metastases, the combination of neurosurgical resection and postoperative hypofractionated stereotactic radiotherapy (HSRT) is an emerging therapeutic approach preferred to the prior practice of postoperative whole-brain radiotherapy. However, mature large-scale outcome data are lacking. To evaluate outcomes and prognostic factors after HSRT to the resection cavity in patients with brain metastases. An international, multi-institutional cohort study was performed in 558 patients with resected brain metastases and postoperative HSRT treated between December 1, 2003, and October 31, 2019, in 1 of 6 participating centers. Exclusion criteria were prior cranial radiotherapy (including whole-brain radiotherapy) and early termination of treatment. A median total dose of 30 Gy (range, 18-35 Gy) and a dose per fraction of 6 Gy (range, 5-10.7 Gy) were applied. The primary end points were overall survival, local control (LC), and the analysis of prognostic factors associated with overall survival and LC. Secondary end points included distant intracranial failure, distant progression, and the incidence of neurologic toxicity. A total of 558 patients (mean [SD] age, 61 [0.50] years; 301 [53.9%] female) with 581 resected cavities were analyzed. The median follow-up was 12.3 months (interquartile range, 5.0-25.3 months). Overall survival was 65% at 1 year, 46% at 2 years, and 33% at 3 years, whereas LC was 84% at 1 year, 75% at 2 years, and 71% at 3 years. Radiation necrosis was present in 48 patients (8.6%) and leptomeningeal disease in 73 patients (13.1%). Neurologic toxic events according to the Common Terminology Criteria for Adverse Events grade 3 or higher occurred in 16 patients (2.8%) less than 6 months and 24 patients (4.1%) greater than 6 months after treatment. Multivariate analysis identified a Karnofsky Performance Status score of 80% or greater (hazard ratio [HR], 0.61; 95% CI, 0.46-0.82; P < .001), 22 to 33 days between resection and radiotherapy (HR, 1.50; 95% CI, 1.07-2.10; P = .02), and a controlled primary tumor (HR, 0.69; 95% CI, 0.52-0.90; P = .007) as prognostic factors associated with overall survival. For LC, a single brain metastasis (HR, 0.57; 95% CI, 0.35-0.93; P = .03) and a controlled primary tumor (HR, 0.59; 95% CI, 0.39-0.92; P = .02) were significant in the multivariate analysis. To date, this cohort study includes one of the largest series of patients with brain metastases and postoperative HSRT and appears to confirm an excellent risk-benefit profile of local HSRT to the resection cavity. Additional studies will help determine radiation dose-volume parameters and provide a better understanding of synergistic effects with systemic and immunotherapies.

Trusted Decision-Making: Data Governance for Creating Trust in Data Science Decision Outcomes

Organizations are increasingly introducing data science initiatives to support decision-making. However, the decision outcomes of data science initiatives are not always used or adopted by decision-makers, often due to uncertainty about the quality of data input. It is, therefore, not surprising that organizations are increasingly turning to data governance as a means to improve the acceptance of data science decision outcomes. In this paper, propositions will be developed to understand the role of data governance in creating trust in data science decision outcomes. Two explanatory case studies in the asset management domain are analyzed to derive boundary conditions. The first case study is a data science project designed to improve the efficiency of road management through predictive maintenance, and the second case study is a data science project designed to detect fraudulent usage of electricity in medium and low voltage electrical grids without infringing privacy regulations. The duality of technology is used as our theoretical lens to understand the interactions between the organization, decision-makers, and technology. The results show that data science decision outcomes are more likely to be accepted if the organization has an established data governance capability. Data governance is also needed to ensure that organizational conditions of data science are met, and that incurred organizational changes are managed efficiently. These results imply that a mature data governance capability is required before sufficient trust can be placed in data science decision outcomes for decision-making.

Mature forests hold maximum live biomass stocks

The important role that forests play in the global carbon cycle has led to the implementation of management practices to enhance long-term carbon storage in forests. Obtaining information about how forest biomass varies at different successional stages is therefore essential. In this study, we aimed (i) to determine the relationship between stand live biomass and the degree of naturalness (i.e. the degree to which forests dynamics are driven by natural processes in the absence of anthropogenic influences) in undisturbed, mature forests, and (ii) to establish the upper threshold of live biomass stock that is dependent on site quality, by using the site form (SF) index (dominant height-diameter relationship). We assessed live biomass stocks in a total of 10 undisturbed mixed and pure mature silver fir (Abies alba Mill.) and European beech (Fagus sylvatica L.) stands across the Spanish Pyrenees. We used dendrochronology and chrono-functional indicators to assess the degree of naturalness and to detect growth releases as proxies for past disturbance. We compared data from the mature plots and data from the Spanish National Forest Inventory (NFI), for similar forest types and SF values, to determine whether maximum live biomass values were reached in the plots. We observed that live biomass stock was generally independent of naturalness. The forests characterized by the lowest degrees of naturalness held similar amounts of live tree biomass as those characterized by the highest degrees of naturalness, including old-growth forests. Although some stands had undergone severe disturbance in the past, in all but two plots the live biomass stocks reached maximum values at the respective SF values, unlike in the NFI plots. The study findings contribute to the body of evidence supporting the existence of an upper threshold of live biomass stock represented by undisturbed mature stands. Maximum live carbon stock appears to be reached at earlier stages than the old-growth stage. This finding has consequences for biomass and carbon management and may be useful for developing forest policies involving carbon sequestration aimed at mitigating climate change.

Geochemistry and organic petrology of the permian whitehill formation, Karoo Basin (RSA) and the Devonian/Carboniferous shale of the Appalachian Basin (USA)

Globally, there is significant economic interest in shale gas as a hydrocarbon resource. The success of unconventional shale gas exploration in the United State of America (USA) has raised interests for potential shale gas development in the Karoo Basin of South Africa. The Karoo Basin technically recoverable shale gas resource is estimated to be 13 Tcf, with 19–23 Tcf recoverable free gas. Due to the potential importance of the South African resource, this study characterized the Lower Permian Ecca Group shale and compared its geochemical and organic petrology properties with those of Devonian/Carboniferous shales of the Appalachian Basin, USA. The comparison of research data will aid in the understanding of shale gas potential of the Karoo Basin. Horizons from two boreholes (KZF-01 and KWV-01) drilled in the southern and southeastern Karoo Basin were evaluated and compared with samples of the Late Devonian Ohio and Early Carboniferous Sunbury Shales from the central Appalachian Basin, USA. Total organic carbon (TOC), total sulphur (TS), and organic petrology (bitumen and vitrinite reflectance, and maceral analysis) were used to assess organic richness and thermal maturity of the shale samples. In addition, the samples were evaluated for mineralogical content using X-Ray Diffraction (XRD). Data indicates that the Whitehill Formation of the Karoo Basin has good to excellent shale source potential, with an average TOC of 4.35 wt%. However, thermal maturity data of the Whitehill Formation shows the organic matter to be overmature, with vitrinite reflectance equivalent values greater than 3% RoV. Total sulphur data for the Whitehill Formation and the Devonian/Carboniferous shales suggests that both were influenced by marine environments. Both the KWV-01 and Ohio/Sunbury shale samples contain high amounts of quartz, with clay mineral contents greater than 40% being observed in borehole KWV-01 samples. Collectively, this research study provides valuable data for shale gas exploration and development in the Karoo Basin, South Africa.

Spatiotemporal variation in maturation: a case study with American plaice (Hippoglossoides platessoides) on the Grand Bank off Newfoundland

Fisheries management usually does not explicitly account for spatial variation in life history traits within populations. However, for some stocks this spatial variation may be substantial. We develop a spatiotemporal generalized linear model and fit the model to a long time series of maturation data for American plaice (Hippoglossoides platessoides) on the Grand Bank off Newfoundland and Labrador. The spatiotemporal correlation structure improves estimation of small-scale spatiotemporal variation in maturity across locations and times with limited or few samples. We test how American plaice maturity varies at three different spatial resolutions. We find improvements in model fit when decreasing spatial scales for higher spatial resolution due to high levels of spatial heterogeneity in American plaice maturity at age and size. Modeling variation in life history traits at the appropriate spatial and temporal scales is necessary for understanding population dynamics and developing appropriate fisheries management strategies.

Agricultural adaptation in the native North American weed waterhemp, Amaranthus tuberculatus (Amaranthaceae).

There is increasing interest in documenting adaptation of weedy plant species to agricultural ecosystems, beyond the evolution of herbicide resistance. Waterhemp (Amaranthus tuberculatus) is a native plant of the Midwestern U.S. that began infesting agricultural fields in the 20th century within the central portion of its range. We hypothesized that the vegetative growth and reproductive traits of waterhemp from this heavily infested central region provide differential fitness benefits in agricultural environments. We collected seeds from across the species’ native range, representing regions with varying degrees of waterhemp infestation, and planted them together in common garden soybean plots. A 2010 common garden experiment was conducted within the range of agriculturally weedy waterhemp (in Missouri), and a 2011 common garden experiment was conducted outside of this range (in Ohio). Days to flowering and flowering plant height, mature plant size data (height, number of branches, and length of the longest branch), and above-ground biomass were measured to estimate relative fitness. In both common garden locations, plants from regions where waterhemp occurs as an agricultural weed — including those from the heavily infested Mississippi Valley region (Iowa, Illinois, and Missouri) and the less severely infested Plains region (Nebraska, Kansas, and Oklahoma) — had higher relative performance in almost all fitness-related measures than plants from the Northeast region (Ohio, Michigan, and Ontario), which had little to no agriculturally weedy waterhemp at the time of our study. Further analysis revealed that fewer days to flowering in the Northeast populations can be largely accounted for by latitude of origin, suggesting a strong genetic influence on this reproductive trait. These findings suggest intraspecific variation in agricultural adaptation in a native U.S. weed, and support the use of agricultural weeds to study adaptation.