Harmonization Project Research Articles

Reducing CO2 Emissions by Off-Grid Photovoltaic Systems: A Case Study in the Departamento del Magdalena - Colombia

This paper presents projections on the reduction of CO2 emissions through the implementation of off-grid PV systems on 33 farms located in rural areas of the Departamento del Magdalena, where horticultural activities are performed by small local producers. To achieve this, the emission reduction was estimated for a period of 25 years using the installed PV peak power on each farm, data from the Global Solar Atlas, the emission factor in Colombia for electricity generation and information established in the harmonization project of the National Renewable Energy Laboratory (NREL). In order to compare the estimations, temperature and solar irradiance data were obtained from 10 farms near the installations, located in 8 municipalities within the department. With these data and through mathematical modeling, the energy generated by each PV system and the projection of non-emitted CO2 emissions were calculated. The results obtained demonstrated that, in both cases, the projections for emission reduction are similar, highlighting that the municipalities of Ciénaga and Sitio Nuevo contribute the highest amount of saved CO2 due to the projections of higher energy production in these locations.

Measuring bile acids: Are we all talking the same language?

In this paper, we discuss the Bile Acid Comparison and Harmonisation project, a sub-study of the Trial of URsodeoxycholic acid vs RIFampicin in early-onset severe Intrahepatic Cholestasis of pregnancy, giving an overview of the current state of affairs for total bile acid measurements.

A data harmonization project of three large prospective cardiovascular health-focused cohorts.

Few prospective studies examine multilevel resilience resources and psychosocial factors in relation to cardiovascular health and disease. Recent research indicates that resilience resources are associated with a reduction in the incidence of cardiovascular disease-related events, but few studies have examined this relationship across different racial/ethnic populations or in large cohorts. Harmonization may address these limitations because it allows data from several cohorts to be analyzed together, potentially increasing sample size and in turn power overall and in minority populations. This paper describes the process involved in combining three cardiovascular health-focused cohorts: Jackson Heart Study, Multi-Ethnic Study of Atherosclerosis, and Mediators of Atherosclerosis in South Asians Living in America Study. Using a systematic process, we identified appropriate data harmonization techniques to use in harmonizing variables across cohorts. Variables included exposures (e.g., resilience resources), outcomes (e.g., American Heart Association's Life's Simple 7), and covariates (e.g., race and ethnicity). Post harmonization examinations included psychometric analyses of the harmonized variables. A total of 13,284 participants were included in the final harmonized dataset. This project provides opportunities for future research in resilience resources and informs future studies that need to harmonize data. Results based on the harmonized dataset could inform interventions and policies.

Plasma proteins and persistent postsurgical pelvic pain among adolescents and young adults with endometriosis

Noninvasive biomarkers that predict surgical treatment response would inform personalized treatments and provide insight into potential biologic pathways underlying endometriosis-associated pain and symptom progression. To use plasma proteins in relation to the persistence of pelvic pain following laparoscopic surgery in predominantly adolescents and young adults with endometriosis using a multiplex aptamer-based proteomics biomarker discovery platform. We conducted a prospective analysis including 142 participants with laparoscopically-confirmed endometriosis from the Women's Health Study: From Adolescence to Adulthood observational longitudinal cohort with study enrollment from 2012-2018. Biologic samples and patient data were collected with modified World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project tools. In blood collected before laparoscopic ablation or excision of endometriosis, we simultaneously measured 1305 plasma protein levels, including markers for immunity, angiogenesis, and inflammation, using SomaScan. Worsening or persistent postsurgical pelvic pain was defined as having newly developed, persistent (ie, stable), or worsening severity, frequency, or persistent life interference of dysmenorrhea or acyclic pelvic pain at 1-year postsurgery compared with presurgery. We calculated odds ratios and 95% confidence intervals using logistic regression adjusted for age, body mass index, fasting status, and hormone use at blood draw. We applied Ingenuity Pathway Analysis and STRING analysis to identify pathophysiologic pathways and protein interactions. The median age at blood draw was 17 years (interquartile range, 15-19 years), and most participants were White (90%). All had superficial peritoneal lesions only and were treated by excision or ablation. One-year postsurgery, pelvic pain worsened or persisted for 76 (54%) of these participants with endometriosis, whereas pelvic pain improved for 66 (46%). We identified 83 proteins associated with worsening or persistent pelvic pain 1-year postsurgery (nominal P<.05). Compared with those with improved pelvic pain 1-year postsurgery, those with worsening or persistent pelvic pain had higher plasma levels of CD63 antigen (odds ratio, 2.98 [95% confidence interval, 1.44-6.19]) and CD47 (odds ratio, 2.68 [95% confidence interval, 1.28-5.61]), but lower levels of Sonic Hedgehog protein (odds ratio, 0.55 [95% confidence interval, 0.36-0.84]) in presurgical blood. Pathways related to cell migration were up-regulated, and pathways related to angiogenesis were down-regulated in those with worsening or persistent postsurgical pelvic pain compared with those with improved pain. When we examined the change in protein levels from presurgery to postsurgery and its subsequent risk of worsening or persistent postsurgical pain at 1-year follow-up, we observed increasing levels of Sonic Hedgehog protein from presurgery to postsurgery was associated with a 4-fold increase in the risk of postsurgical pain (odds ratio [quartile 4 vs 1], 3.86 [1.04-14.33]). Using an aptamer-based proteomics platform, we identified plasma proteins and pathways associated with worsening or persistent pelvic pain postsurgical treatment of endometriosis among adolescents and young adults that may aid in risk stratification of individuals with endometriosis.

Abstract A017: An analysis of 13 independently performed assays to measure homologous recombination deficiency using 90 freshly extracted high grade serous ovarian tumors: findings from the friends of cancer research hrd harmonization project

Abstract A017: An analysis of 13 independently performed assays to measure homologous recombination deficiency using 90 freshly extracted high grade serous ovarian tumors: findings from the friends of cancer research hrd harmonization project

World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: V. Physical examination standards in endometriosis research

The World Endometriosis Research Foundation established the Endometriosis Phenome and Biobanking Harmonisation Project (EPHect) to create standardized documentation tools (with common data elements) to facilitate the comparison and combination of data across different research sites and studies. In 2014, 4 data research standards were published: clinician-reported surgical data, patient-reported clinical data, and fluid and tissue biospecimen collection. Our current objective is to create an EPHect standard for the clinician-reported physical examination (EPHect-PE) for research studies. An international consortium involving 26 clinical and academic experts and patient partners from 11 countries representing 25 institutions and organizations. Two virtual workshops, followed by the development of the physical examination standards underwent multiple rounds of iterations and revisions. N/A MAIN OUTCOME MEASURE(S): N/A RESULT(S): The EPHect-PE tool provides standardized assessment of physical examination characteristics and pain phenotyping. Data elements involve examination of back and pelvic girdle; abdomen including allodynia and trigger points; vulva including provoked vestibulodynia; pelvic floor muscle tone and tenderness; tenderness on unidigital pelvic examination; presence of pelvic nodularity; uterine size and mobility; presence of adnexal masses; presence of incisional masses; speculum examination; tenderness and allodynia at an extra-pelvic site (e.g., forearm); and recording of anthropometrics. The EPHect-PE standards will facilitate the standardized documentation of the physical examination, including the assessment and documentation of examination phenotyping of endometriosis-associated pelvic pain.

Mirroring the American Bankruptcy Code? IP Licences in the European Insolvency Harmonisation Project

Abstract With the growth of the licensing of Intellectual Property rights in the global economy, the insolvency treatment of licensing agreements has also taken on greater importance. This paper analyses the treatment of intellectual property licences under the European Commission’s new Directive Proposal 2022/0408/COD, the flagship law of the European insolvency harmonisation project. The paper focuses on the Proposal’s approach in cases where the debtor’s business, or part of it, is sold as a going concern in the pre-pack context. It contrasts the European response to the US Bankruptcy Code, which serves as a significant source of inspiration, and provides examples of how some EU Member States handle such cases. In substance, the paper examines the Commission’s steps towards harmonising the treatment of IP licences in insolvency. Considering the insolvency context and the needs of the parties to the licence, it critically analyses not only the expediency of implementing specific regulations but also the effectiveness of the means employed. Finally, the paper provides some suggestions to amend the Proposal and highlights the necessity to revisit the broader debate over the treatment of IP licences in European insolvency legislation in general.

Visualized peritoneal fluid variation in adolescents and young adults with endometriosis: is there more to it?

Peritoneal fluid is a medium for endometriosis-associated biomarker discovery from which the local peritoneal environment and pathophysiologic pathways are often inferred. Therefore, we evaluated the associations between peritoneal fluid color and volume at time of endometriosis-related laparoscopic surgery with patient characteristics, endometriosis type and lesion location in adolescents and young adults with endometriosis. We conducted a cross-sectional analysis among 545 patients undergoing surgery for endometriosis who enrolled in the Women's Health Study: from Adolescence to Adulthood cohort study. Patient characteristics, surgically visualized endometriosis phenotypes, and gross characteristics of peritoneal fluid were collected in compliance with World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project (EPHect) tools. Chi-square or Fisher's exact tests were applied to test for differences across categories. Most of the patients were adolescents or young adults (86% age <25 years) of white race (89%), with only superficial peritoneal lesions and rASRM stage = I/II observed at surgery (both 95%). We observed variation in peritoneal fluid color across different menstrual cycle phases at time of surgery (p = 0.006). Among those who were cycling at time of surgery, endometriosis patients with red peritoneal fluid were most likely to be in the proliferative phase (49%) compared to the secretory phase (27%), while those with yellow or orange peritoneal fluid were most likely to be in the secretory phase (57% and 86% respectively). Yellow color was significantly less common in those taking combined oral contraceptives but much more common with progesterone only formulation exposure (p = 0.002). Peritoneal fluid volume did not differ by cycle phase but was more likely to be low (≤6 ml) for those exposed to hormones at time of surgery (p = 0.01). Those with acyclic pelvic pain were less likely to have red peritoneal fluid (p = 0.001) but had greater volume (p = 0.02) compared to those without. Our findings highlight the importance of accounting for menstrual cycle phase and hormonal exposures when designing research using peritoneal fluid samples and inferring from biomarker results intended to advance our understanding of endometriosis and associated symptom pathophysiology.

The Use of Next Generation Flow in Multiple Myeloma Patients: A Preliminary Real-Life Multicenter MRD Harmonization Experience

Introduction: Minimal residual disease (MRD) detection represents a sensitive tool to appropriately measure response in MM. The major concern about MRD detection in real-world setting is the reproducibility of results among different laboratories possibly due to methodological discrepancies. Therefore, a harmonized approach, according to criteria of Next generation Flow (NGF)/ Next generation sequencing (NGS) established by IMWG (Kumar S et al. Lancet Oncol 2016), is warranted. The aim of this project was to create an “Italian MM MRD network” using standardized NGF and NGS-MRD approach; here we report preliminary results of the NGF part. Methods: The “NGF harmonization project” includes 7 Italian Laboratories willing to commit to EuroFlow protocols after an initial MRD survey: Brescia (L1), Catania (L2), Padova (L3), Roma 1 (L4), Roma 2 (L5), S. Giovanni Rotondo (L6) and Torino (L7). Standardization of all flow cytometers settings was performed by implementation of the EuroFlow Standard Operating Protocol (SOP) for instrument setup and compensation for BD FASCCanto II, BD FACSLyric, BC Navios and BC DxFlex flow cytometers (www.euroflow.org). Bone marrow (BM) aspirates were collected from newly diagnosed MM patients treated with 4 cycles of Dara-VTD (Daratumumab, bortezomib, thalidomide, dexamethasone) induction followed by autologous stem cell transplantation (ASCT) in complete-response/very-good-partial-response at day 100 (+/- 15 days) after ASCT. Anonymized samples were split equally and shipped at room temperature to the participati ng laboratories and simultaneously analyzed. Analyses were carried out following NGF methodology (Flores-Montero J et al. Leukemia 2017) by using a two-tube 8-color antibody panel for monoclonal plasma cells identification (Tube 1:CD27, CD138, CD38, CD56, CD45, CD19, CD117, CD81 and Tube 2: CD27, CD138, CD38, CD56, CD45, CD19, cytoplasmic κ and λ light-chain). We aimed to acquire ≥ 3,000,000 events per tube for a sensitivity of at least 1 x 10 -5; a sample was considered MRD positive when ≥ 20 monoclonal plasma cells were detected. Intraclass Correlation Coefficient (ICC) was performed to evaluate degree of correlation and agreement between measurements; standard deviation (SD) and Coefficient of variation (CV) to measure variability of the dataset. Results. In stage 1 of the study, before starting MRD evaluation on freshsamples, 4 laboratories (L1, L2, L3, L7) performed a blinded analysis of the same 5 anonymous flow-cytometry files from a retrospective data repository of MM patients with/without MRD, to evaluate the inter-operator variability: 100% of the participants were concordant that samples #1, #2 and #4 were MRD positive. Sample #3 was considered MRD positive by 75% of participants whereas 75% considered sample #5 as MRD negative (ICC=0.91, 95% CI 0.69-0.98, p&amp;lt;0.001). In stage 2, a total of 7 samples have been distributed and processed after 48 hours from specimen collection, due to different shipping time in all laboratories. The inter-laboratory correlation study showed a concordance of 100 % for the sample #1 and sample #3 considered as MRD positive, 100% of the participants considered sample #5 and sample #6 as MRD negative, sample #2 was considered MRD positive by 71% of participants whereas sample #4 was considered MRD negative by 86 % of participants. Sample #7 was considered as not evaluable from all participants due to a high percentage of dead cells. (ICC=0.61, 95% CI 0.31-0.91, p&amp;lt;0.001) (Fig. 1). The highest difference in term of antigen expression of monoclonal plasma cells was recorded for CD45 and CD27. We obtained a median of 7 x 10 -6 of Limit of detection (LOD, range 6 x 10 -5 - 2 x 10 -6) and 1 x 10 -5 Limit of Quantification (LOQ, range 1 x 10 -4- 5 x 10 -6) for all samples. A centralized revision (in L7 lab) of all FCS files is ongoing to confirm our preliminary results; moreover, the study will be corroborated increasing the number of fresh samples. Conclusion: our preliminary results demonstrate the importance of a harmonized NGF-MRD assessment to improve the accuracy and comparability of MM-MRD testing among different laboratories. Major discrepancies have been found in fresh samples vs the retrospective dataset suggesting an impact of the transportation time and sample processing on the concordance of our results.

Registration of essential medicines in Kenya, Tanzania and Uganda: a retrospective analysis.

To audit national drug registers (NDRs) in Kenya, United Republic of Tanzania and Uganda with respect to national Essential Medicine Lists (EMLs) and to conduct an analysis of highly registered products including a sub-analysis of highly registered antimicrobial products. Retrospective analysis of registration of essential medicines and medicinal products on NDRs as of February 2018. Not applicable. None. Registration status of essential medicines by country, essential medicine status of registered products by country and medicines with more than 50 registrations across all three countries. A high proportion of essential medicines are not registered: Kenya 28% (175/632), United Republic of Tanzania 50% (400/797) and Uganda 40% (266/663). Of registered products on the NDRs, more than half are not essential: Kenya 71% (4350/6151), United Republic of Tanzania 64% (2278/3590) and Uganda 58% (2268/3896). When the three NDRs were combined, there were 42 medicines with over 50 registered products, accounting for 30% (4153/13637) of products, many of which were non-essential. Non-registration of essential medicines is a barrier to availability. Over-registration of medicines, particularly non-essential medicines, diverts regulatory resources towards registering non-priority and, sometimes, clinically sub-optimal medicines. The East African Community Medicines Registration Harmonization Project has the potential to improve access to key medicines if registration of essential medicines is prioritised and registration of non-essential medicines is restricted.

Establishing the Australian National Endometriosis Clinical and Scientific Trials (NECST) Registry: A protocol paper.

Endometriosis is a common yet under-recognised chronic inflammatory disease, affecting 176 million women, trans and gender diverse people globally. The National Endometriosis Clinical and Scientific Trials (NECST) Registry is a new clinical registry, collecting and tracking diagnostic and treatment data, and patient-reported outcomes on people with endometriosis. The registry is a research priority action item from the 2018 National Action Plan for Endometriosis and aims to provide, large-scale, national and longitudinal population-based data on endometriosis. Working groups (consisting of patients with endometriosis, clinicians and researchers) developing the NECST Registry data dictionary and data collection platform started in 2019. Our data dictionary was developed based on existing and validated questionnaires, tools, meta-data and data cubes - World Endometriosis Research Foundation (WERF) Endometriosis Phenome and Biobanking Harmonisation Project (EPHect), endometriosis CORE outcomes set, patient-reported outcome measures, the International Statistical Classification of Diseases-10th Revision Australian Modification diagnosis codes, and Australian Government datasets: Australian Institute for Health and Welfare (for sociodemographic data), Medicare Benefits Schedule (MBS; for medical procedures) and the Pharmaceutical Benefits Scheme (PBS; for medical therapies). The resulting NECST Registry is an online, secure cloud-based database; prospectively collecting minimum core clinical and health data across eight patient and clinician modules and longitudinal data tracking disease life course. The NECST Registry has ethics approval (HREC/62508/MonH-2020) and is registered on the Australian New Zealand Clinical Trials Registry (ACTRN12622000987763).

Danish translation, cross-cultural adaptation, and electronic migration of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project Endometriosis Patient Questionnaire.

This study aims to translate and cross-culturally adapt the standard version of the World Endometriosis Research Foundation (WERF) EPHect Endometriosis Patient Questionnaire (EPQ) into Danish and to ensure equivalence of a Danish electronic version. The translation, cultural adaption, and electronic migration followed recommendations from the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the Critical Path Institute. Ten women with endometriosis were enrolled for cognitive debriefing of the paper version (pEPQ) after translation and back translation. The questionnaire was then migrated into an electronic version (eEPQ) and subsequently tested for usability and measurement equivalence by five women with endometriosis. Cross-cultural alterations were needed for medical terms, response options for ethnicity, the educational system, and measurement units. Thirteen questions were altered after back translation, while 21 underwent minor changes after cognitive debriefing. After testing the eEPQ, 13 questions were altered. Questions tested for measurement equivalence across the two modes of administration were found comparable. The median time-to-complete the pEPQ and eEPQ was 62 min (range: 29-110) and 63 min (range: 31-88), respectively. General comments included the questionnaire being relevant but long and repetitive. We find the the Danish pEPQ and eEPQ similar and comparable to the original English instrument. However, attention must be drawn to questions regarding measurement units, ethnicity, and educational systems before cross-country comparison. The Danish pEPQ and eEPQ are suitable for obtaining subjective data on women with endometriosis.

Harmonica consensus, controversies, and future directions in radiotherapy for pediatric Wilms tumors.

Radiotherapy (RT) is essential for multimodality treatment of pediatric renal tumors, particularly in higher-risk and metastatic disease. Despite decades of use, particularly for Wilms tumor, there remain controversies regarding RT indications, timing, dose, and targets. To align global management, we address these issues in this international HARMONIsation and CollAboration (HARMONICA) project. There are multiple knowledge gaps and opportunities for future research including: (1) utilization of advanced RT technologies, including intensity-modulated RT, proton beam therapy, combined with image-guided RT to reduce target volumes; (2) impact of molecular biomarkers including loss of heterozygosity at 1p, 16q, and 1q gain on RT indications; (3) mitigation of reproductive toxicity following RT; (4) promotion of RT late effects research; and (5) support to overcome challenges in RT utilization in low- and middle-income countries where 90% of the world's children reside. Here, we outline current status and future directions for RT in pediatric renal tumors.

On the relationships between covariance and the decoherence-free subalgebra of a quantum Markov semigroup

In this paper, we investigate if the presence of symmetries in the evolution of an open quantum system gives information about the invariant subspaces. Unfortunately, the answer is, in general, negative, but under suitable conditions we can observe that the representation through which we describe the symmetry determines a privileged family of orthogonal projections strongly correlated with the structure of the decoherence-free sub-algebra and, as a consequence, with harmonic projections.

Assessment of the effectiveness and efficiency of the West Africa medicines regulatory harmonization initiative by the member countries.

Background: The West Africa Health Organization launched the West Africa Medicines Regulatory Harmonization Project (WA-MRH) in 2017 with the overarching objective to improve the availability of high-quality, safe and effective medicines and vaccines by the 15 countries in the Economic Community of West African States region. Although this project has made significant progress towards the realisation of its goals, challenges still remain. The aims of this study were to evaluate the effectiveness and efficiency of the WA-MRH, examine what challenges are being encountered and identify strategies that would strengthen the process for realising the initiative's goals. Methods: The Process Effectiveness and Efficiency Rating (PEER) questionnaire was used to collect data from assessors representing the seven active NMRAs in the joint assessment procedure that identified the benefits, challenges and recommendations for improving the performance of the WA-MRH project. Results: The benefits of the joint assessment procedure include time savings to manufacturers resulting from submitting one dossier and the same response package to multiple countries resulting in access to the multiple African markets within the same timeframe. Additionally, some of the NMRAs have been able to strengthen their technical capacity as a result of this initiative. Key challenges to the project include the lack of a robust information technology system that would enable dossier tracking and constraints in human resources needed to support dossier submissions and the assessment process. Conclusion: This study identified the strengths of the WA-MRH initiative as well as strategies for improvement and achievement of its objectives. The centralised submission of a dossier and its tracking is key to the regulatory assessment process. This research has demonstrated that amongst other considerations, a robust information technology system, coupled with the necessary human resource capacity would greatly enhance the effectiveness and efficiency of the WA-MRH initiative.

Harmonized retrieval of middle atmospheric ozone from two microwave radiometers in Switzerland

Abstract. We present new harmonized ozone time series from two ground-based microwave radiometers in Switzerland: GROMOS and SOMORA. Both instruments have measured hourly ozone profiles in the middle atmosphere (20–75 km) for more than 2 decades. As inconsistencies in long-term trends derived from these two instruments were detected, a harmonization project was initiated in 2019. The goal was to fully harmonize the data processing of GROMOS and SOMORA to better understand and possibly reduce the discrepancies between the two data records. The harmonization has been completed for the data from 2009 until 2022 and has been successful at reducing the differences observed between the two time series. It also explains the remaining differences between the two instruments and flags their respective anomalous measurement periods in order to adapt their consideration for future trend computations. We describe the harmonization and the resulting time series in detail. We also highlight the improvements in the ozone retrievals with respect to the previous data processing. In the stratosphere and lower mesosphere, the seasonal ozone relative differences between the two instruments are now within 10 % and show good correlation (R &gt; 0.7) (except during summertime). We also perform a comparison of these new data series against measurements from the Microwave Limb Sounder (MLS) and Solar Backscatter Ultraviolet Radiometer (SBUV) satellite instruments over Switzerland. Seasonal mean differences with MLS and SBUV are within 10 % in the stratosphere and lower mesosphere up to 60 km and increase rapidly above that point.

Governmental accounting and budgeting in Malta and Poland – a different dance to the same tune

PurposeThis paper compares governmental accounting and budgeting in two European Union (EU) member states, analysing the developments in each country as to how they “fit” into the EU's harmonization project and the push towards the implementation of accrual accounting compliant with the International Public Sector Accounting Standards (IPSAS).Design/methodology/approachAn explanatory multiple case study is used to describe the structures and changes in governmental systems (accounting and budgetary) in Malta and Poland. The methodology takes a qualitative interpretative approach, examining the underlying legislations and related ministerial publications as secondary sources.FindingsFocusing on the output from financial accounting and budgetary systems, the results illustrate how organizations respond in a different manner to similar institutional pressures. In particular, Poland shows no inclination to adopt the IPSAS, but emerges with a sophisticated budgeting system while Malta is more focused on developing its financial reporting in line with the IPSAS. The theoretical lens highlights that while both countries tend towards pragmatic legitimacy, Poland appears more inclined towards exchange legitimacy, and Malta is more subject to influence legitimacy.Research limitations/implicationsAt a practical level, this study should be read by public sector accounting standard setters. It illustrates how EU member states are engaging with the IPSAS, emphasizing the ambitious nature of the EU's harmonization project, in spite of the structural legitimacy that the EU institution emanates.Originality/valuePrevious comparative international governmental accounting studies have examined accounting reform processes and developed or applied various theoretical models to try to understand the process. This study looks at the output from such reform processes. The two countries are seemingly experiencing the same type of pressures exerted by the demands of EU membership. However, the translation of the same external macro-forces at macro-level to micro (organizational)-level results in different compliance with the desired harmonization of governmental accounting systems.

The value of FDG PET/CT imaging in outcome prediction and response assessment of lymphoma patients treated with immunotherapy: a meta-analysis and systematic review

PurposeTreatment strategies of lymphoid malignancies have been revolutionized by immunotherapy. Because of the inherent property of Hodgkin lymphoma and some subtypes of non-Hodgkin lymphoma as a highly FDG-avid tumor, functional 18F-FDG PET/CT imaging is already embedded in their routine care. Nevertheless, the question is whether it is still valuable in the context of these tumors being treated with immunotherapy. Herein, we will review the value of 18F-FDG PET/CT imaging lymphoid tumors treated with immunotherapy regimens.MethodsA comprehensive literature search of the PubMed database was conducted on the value of the 18F-FDG PET/CT for immunotherapy response monitoring of patients with malignant lymphoma. The articles were considered eligible if they met all of the following inclusion criteria: (a) clinical studies on patients with different types of malignant lymphoma, (b) treatment with anti-CD20 antibodies, immune checkpoint inhibitors or immune cell therapies, (c) and incorporated PET/CT with 18F-FDG as the PET tracer.ResultsFrom the initial 1488 papers identified, 91 were ultimately included in our study. In anti-CD20 therapy, the highest pooled hazard ratios (HRs) of baseline, early, and late response monitoring parameters for progression-free survival (PFS) belong to metabolic tumor volume (MTV) (3.19 (95%CI: 2.36–4.30)), maximum standardized uptake value (SUVmax) (3.25 (95%CI: 2.08–5.08)), and Deauville score (DS) (3.73 (95%CI: 2.50–5.56)), respectively. These measurements for overall survival (OS) were MTV (4.39 (95%CI: 2.71–7.08)), DS (3.23 (95%CI: 1.87–5.58)), and DS (3.64 (95%CI: 1.40–9.43)), respectively. Early and late 18F-FDG PET/CT response assessment in immune checkpoint inhibitors (ICI) and immune cell therapy might be an effective tool for prediction of clinical outcome.ConclusionFor anti-CD20 therapy of lymphoma, the MTV as a baseline 18F-FDG PET/CT-derived parameter has the highest HRs for PFS and OS. The DS as visual criteria in early and late response assessment has higher HRs for PFS and OS compared to the international harmonization project (IHP) visual criteria in anti-CD20 therapy. Early changes in 18F-FDG PET parameters may be predictive of response to ICIs and cell therapy in lymphoma patients.

Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study

Mosunetuzumab is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. In a phase 1 study, mosunetuzumab was well tolerated and active in patients with relapsed or refractory B-cell lymphoma. We, therefore, aimed to evaluate the safety and anti-tumour activity of fixed-duration mosunetuzumab in patients with relapsed or refractory follicular lymphoma who had received two or more previous therapies. We conducted a single-arm, multicentre, phase 2 study at 49 centres in seven countries (Australia, Canada, Germany, South Korea, Spain, UK, and USA). All patients were aged 18 years or older with histologically confirmed follicular lymphoma (grade 1-3a) and an Eastern Cooperative Oncology Group performance status of 0-1. Patients had disease that was relapsed or refractory to two or more previous lines of treatment, including an anti-CD20 therapy and an alkylating agent. Intravenous mosunetuzumab was administered in 21-day cycles with cycle 1 step-up dosing: 1 mg on cycle 1 day 1, 2 mg on cycle 1 day 8, 60 mg on cycle 1 day 15 and cycle 2 day 1, and 30 mg on day 1 of cycle 3 and onwards. Patients with a complete response by investigator assessment using the International Harmonisation Project criteria completed treatment after cycle 8, whereas patients with a partial response or stable disease continued treatment for up to 17 cycles. The primary endpoint was independent review committee-assessed complete response rate (as best response) in all enrolled patients; the primary efficacy analysis compared the observed IRC-assessed complete response rate with a 14% historical control complete response rate in a similar patient population receiving the pan class I PI3K inhibitor copanlisib. Safety was assessed in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02500407, and is ongoing. Between May 2, 2019, and Sept 25, 2020, we enrolled 90 patients. As of the data cutoff date (Aug 27, 2021), the median follow-up was 18·3 months (IQR 13·8-23·3). According to independent review committee assessment, a complete response was recorded in 54 patients (60·0% [95% CI 49·1-70·2]). The observed complete response rate was significantly higher than the historical control complete response rate with copanlisib of 14% (p<0·0001), thereby meeting the primary study endpoint. Cytokine release syndrome was the most common adverse event (40 [44%] of 90 patients) and was predominantly grade 1 (23 [26%] of 90) and grade 2 (15 [17%]), and primarily confined to cycle 1. The most common grade 3-4 adverse events were neutropenia or neutrophil count decreased (24 [27%] of 90 patients), hypophosphataemia (15 [17%]), hyperglycaemia (seven [8%]), and anaemia (seven [8%]). Serious adverse events occurred in 42 (47%) of 90 patients. No treatment-related grade 5 (ie, fatal) adverse event occurred. Fixed-duration mosunetuzumab has a favourable safety profile and induces high rates of complete remissions, allowing potential administration as an outpatient regimen, in patients with relapsed or refractory follicular lymphoma and two or more previous therapies. F Hoffmann-La Roche and Genentech.

Contract Negotiations and the Common Law: A Move to Good Faith in Commercial Contracting?

Classically a duty to negotiate commercial contracts in good faith has been seen as part of the civil, not the common, law world. Common law commercial lawyers have long resisted the lure of “good faith” as a contractual concept, despite engagement with civil law principles in harmonisation projects, by virtue of membership of the European Union and their use in international conventions such as the United Nations Convention on Contracts for the International Sale of Goods (CISG). This paper will examine whether this situation is changing, focusing on two common law jurisdictions—England and Wales and Canada. In England and Wales and the common law of Canada, case-law in the last 10 years has indicated a movement towards acceptance of express and implied duties of good faith in relation to contractual performance, see e.g. Yam Seng Pte Limited v International Trade Corporation Limited [2013] EWHC 111 (QB) and, most recently, Essex CC v UBB Waste (Essex) Ltd (No. 2) [2020] EWHC 1581 (TCC) in England and Wales; Bhasin v Hrynew 2014 SCC 71 and Callow v Zollinger 2020 SCC 45 in Canada. This paper will examine the extent to which these cases may open the way more generally for a duty to negotiate commercial contracts in good faith. It will examine the reception of these cases and whether they indicate (i) greater acceptance of “good faith” as part of contract law thinking and (ii) a possible extension of good faith into the pre-contractual period.