Now we are 30: 10 more years of MASCC.

This paper chronicles the third decade of MASCC from 2010. There was a generational change in this decade, building on the solid foundation of the founders. It included the first female President, and a new Executive Director with a background in strategy and business development and operations as applied to healthcare. The headquarters moved from Copenhagen to Toronto. The first meeting to be held outside of Europe or North America was held in Adelaide, Australia, and the membership in the Asia Pacific region expanded. A program of international affiliates saw national supportive care organisations formally link with MASCC. In cancer supportive care, there was a raft of new toxicities to manage as immunotherapies were added to conventional cytotoxic treatment. There was also a greater emphasis on the psychosocial needs of patients and families. New MASCC groups were formed to respond to this evolution in cancer management. The MASCC journal, Supportive Care in Cancer, continued to grow in impact, and MASCC published two editions of a textbook of supportive care and survivorship. The decade ended with the challenge of the COVID-19 pandemic, but that served to highlight the importance of good supportive care to patients with cancer.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune-related adverse events: pulmonary toxicity.

The immune checkpoints associated with the CTLA-4 and PD-1 pathways are critical modulators of immune activation. These pathways dampen the immune response by providing brakes on activated T cells, thereby ensuring more uniform and controlled immune reactions and avoiding immune hyper-responsiveness and autoimmunity. Cancer cells often exploit these regulatory controls through a variety of immune subversion mechanisms, which facilitate immune escape and tumor survival. Immune checkpoint inhibitors (ICI) effectively block negative regulatory signals, thereby augmenting immune attack and tumor killing. This process is a double-edged sword in which release of regulatory controls is felt to be responsible for both the therapeutic efficacy of ICI therapy and the driver of immune-related adverse events (IrAEs). These adverse immune reactions are common, typically low-grade and may affect virtually every organ system. In the early clinical trials, lung IrAEs were rarely described. However, with ever-expanding clinical applications and more complex ICI-containing regimens, lung events, in particular, pneumonitis, have become increasingly recognized. ICI-related lung injury is clinically distinct from other types of lung toxicity and may lead to death in advanced stage disease. Thus, knowledge regarding the key characteristics and optimal treatment of lung-IrAEs is critical to good outcomes. This review provides an overview of lung-IrAEs, including risk factors and epidemiology, as well as clinical, radiologic, and histopathologic features of ICI-related lung injury. Management principles for ICI-related lung injury, including current consensus on steroid refractory pneumonitis and the use of other immune modulating agents in this setting are also highlighted.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe gastrointestinal and hepatic toxicities from checkpoint inhibitors.

Immune-related adverse events (IrAEs) affecting the gastrointestinal (GI) tract and liver are among the most frequent and most severe inflammatory toxicities from contemporary immunotherapy. Inflammation of the colon and or small intestines (entero)colitis is the single most common GI IrAE and is an important cause of delay of discontinuation of immunotherapy. The severity of these GI IrAEs can range from manageable with symptomatic treatment alone to life-threatening complications, including perforation and liver failure. The frequency and severity of GI IrAEs is dependent on the specific immunotherapy given, with cytotoxic T lymphocyte antigen (CTLA)-4 blockade more likely to induce severe GI IrAEs than blockade of either programmed cell death protein 1 (PD-1) or PD-1 ligand (PD-L1), and combination therapy showing the highest rate of GI IrAEs, particularly in the liver. To date, we have minimal prospective data on the appropriate diagnosis and management of GI IrAEs, and recommendations are based largely on retrospective data and expert opinion. Although clinical diagnoses of GI IrAEs are common, biopsy is the gold standard for diagnosis of both immunotherapy-induced enterocolitis and hepatitis and can play an important role in excluding competing, though less common, diagnoses and ensuring optimal management. GI IrAEs typically respond to high-dose corticosteroids, though a significant fraction of patients requires secondary immune suppression. For colitis, both TNF-α blockade with infliximab and integrin inhibition with vedolizumab have proved highly effective in corticosteroid-refractory cases. Detailed guidelines have been published for the management of low-grade GI IrAEs. In the setting of more severe toxicities, involvement of a GI specialist is generally recommended. The purpose of this review is to survey the available literature and provide management recommendations focused on the GI specialist.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe dermatological toxicities from checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) frequently result in cutaneous immune-related adverse events (IrAEs). Although the majority of these events are mild-to-moderate in severity, up to 5% are severe, which may lead to morbidity and dose interruption or discontinuation of ICI therapy. In addition, up to 25% of dermatologic IrAEs are corticosteroid-refractory or corticosteroid-dependent. These 2020 MASCC recommendations cover the diagnosis and management of cutaneous IrAEs with a focus on moderate-to-severe and corticosteroid-resistant events. Although the usage of immune-suppressive therapy has been advocated in this setting, there is a lack of randomized clinical trial data to provide a compelling level of evidence of its therapeutic benefit.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune-mediated cardiovascular, rheumatic, and renal toxicities from checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have emerged as the newest pillar of cancer treatment. Immune-mediated toxicities, stemming from increased activity within the T cell lineage, range from asymptomatic or mild complications to those that are fulminant and potentially fatal. Although they are of variable occurrence, cardiovascular, rheumatic, and renal immune-mediated toxicities are among the most serious of these adverse events. We present MASCC recommendations with respect to the workup and management of cardiovascular, rheumatic, and renal immune-mediated toxicities with a focus on presentations that require treatment with immunomodulating agents.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune checkpoint inhibitor endocrinopathies and the role of advanced practice providers in the management of immune-mediated toxicities.

Immune checkpoint inhibitors (ICIs) have emerged as the newest pillar of cancer treatment, transforming outcomes in melanoma and showing benefit in a range of malignancies. Immune-mediated toxicities, stemming from increased activity within the T cell lineage, range from asymptomatic or mild complications to those that are fulminant and potentially fatal. Immune-mediated endocrinopathies include hypophysitis, thyroiditis, and insulin-dependent diabetes mellitus. These presentations, which may be vague and non-specific, can be life-threatening if not diagnosed and treated appropriately. This review considers the work-up and management of immune-mediated endocrinopathies and also considers the role of advanced practice practitioners in the management of immune-mediated toxicities. These state-of-the-art MASCC recommendations represent a comprehensive overview of the management and clinical work-up in those in whom the diagnosis should be considered.

Triglycerides/high-density lipoprotein cholesterol is a predictor similar to the triglyceride-glucose index for the diagnosis of metabolic syndrome using International Diabetes Federation criteria of insulin resistance in obese adolescents: a cross-sectional study.

Objectives Metabolic syndrome (MS) is a fatal endocrinopathy that begins with insulin resistance (IR) and causes abdominal obesity, glucose intolerance, or systemic disorders. This study was aimed to determine the cut-off values for the triglyceride (TG)/high-density lipoprotein cholesterol (TG/HDL-C) ratio, the TG glucose (TyG) index and homeostasis model assessment (HOMA-IR) for the diagnosis of MS in obese adolescents, and to compare which of the three indexes would offer a more accurate approach to diagnosis. Methods The study population comprised 1,171 obese adolescents (639 females and 532 males aged 10-16 years, Body Mass Index (BMI)>=95th percentile). Indirect measures of IR screening for MS were the TG/HDL ratio, TyG index, and HOMA-IR. The cut-off values of the TG/HDL ratio, TyG index, and HOMA-IR were obtained from receiver operation characteristic (ROC) curves. Results HOMA-IR had a significant positive correlation with the TyG index (r=0.352, p<0.001) and TG/HDL-C (r=0.291, p<.001). The TyG index and TG/HDL-C showed a strong positive correlation (r=0.901, p<0.001). The TG/HDL-C ratio showed a larger ROC Area under Curve (AUC=0.849) than HOMA-IR index (AUC=0.689), but as a predictor similar to TyG index (AUC=0.833) when screening for MS. The cut-off values for MS were as follows: TG/HDL-C ratio>2.16 (sensitivity: 88.8%; specificity: 49.7%), TyG index>8.50 (sensitivity: 85.6%; specificity: 57.0%) and HOMA-IR>2.52 (sensitivity: 83.2%; specificity: 40.4%). Conclusions Both the TyG index and TG/HDL-C ratio are better markers than HOMA-IR to determine the risk of metabolic syndrome according to IDF criteria. Besides, the TyG index and TG/HDL-C ratio have similar differentiating powers to determine this risk in obese Turkish adolescents.

Restraints and seclusion in psychiatry: striking a balance between protection and coercion. Critical overview of international regulations and rulings.

Restraint and seclusion (R&S) measures in psychiatric settings are applied worldwide, despite poor scientific evidence to back up their effectiveness. The medical, ethical and medico-legal implications of coercive interventions are broad-ranging and multifaceted. The review aims to shed a light on the most relevant and meaningful standards that have been laid out by international treaties, supranational institutions (United Nations, Council of Europe, World Health Organization), scientific institutions (American Medical Association, Australian Department of Health), legislative bodies and courts of law. Several court cases are herein expounded upon, with a close focus on meaningful analysis, decisions and conclusions that have laid the groundwork for a different, more restrictive and more clearly defined approach towards R&S imposed upon psychiatric patients. It is reasonable to assume that changing norms, civil rights enforcement, court rulings and new therapeutic options have influenced the use of R&S to such an extent that such measures are among the most strictly regulated in psychiatric practice; health care providers should abide by a strict set of cautionary rules when making the decision to resort to R&S, which must never be put in place as a substitute for patient-centered therapeutic planning. Case law shows that R&S should only be weighed in terms of their effectiveness towards therapeutic goals. Being able to prove that R&S was employed as part of a therapeutic path rather than used to maintain order or to exact punishment may go a long way towards shielding operators against negligence lawsuits and litigation.

Risk prediction in intrahepatic cholangiocarcinoma: Direct comparison of the MEGNA score and the 8th edition of the UICC/AJCC Cancer staging system.

BACKGROUND: External validation of prognostic risk models is essential before they are implemented in clinical practice. This study evaluated the recently developed MEGNA score for survival prediction after resection of intrahepatic cholangiocarcinoma (ICC), with a focus on the direct comparison of its prognostic value to that of the current International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) Cancer staging system. MATERIAL AND METHODS: Between 1997 and 2018, 417 consecutive patients with ICC were referred to our tertiary care centre and were retrospectively identified out of a dedicated clinical database. Of this group, 203 patients underwent surgical resection and met the inclusion criteria. Multivariate analysis was performed to assess the predictors of the recently proposed MEGNA score regarding overall survival (OS). Concordance indices (C-indices) and integrated Brier scores (IBS) were calculated to assess the ability of both the MEGNA score and the current (8th) edition of the UICC/AJCC Cancer staging system to predict individual patient outcome. RESULTS: Stratification according to the MEGNA score resulted in a median OS of 34.5 months, 26.1 months, 21.5 months, and 16.6 months for MEGNA scores 0, 1, 2, and ≥3, respectively (log rank p < 0.001). However, of the five factors that contribute to the MEGNA score, age > 60 years was not a predictor for poor OS in our cohort. The C-index for the MEGNA score was 0.58, the IBS was 0.193. The 8th edition of the UICC/AJCC system performed slightly better, with a C-index of 0.61 and an IBS of 0.186. CONCLUSION: The ability of the MEGNA score to predict individual patient outcome was only moderate in this external validation. Its prognostic value did not reach that of the more widely known and used UICC/AJCC system. However, neither scoring system performed well enough to support clear-cut clinical decisions.

An update on effects of ionizing radiation exposure on the eye.

The International Commission on Radiological Protection (ICRP) has considered for over 60 years that the lens of the eye is among the most radiosensitive tissues, and has recommended dose limits for the lens to prevent occurrence of vision impairing cataracts (VICs). Epidemiological evidence that doses much lower than previously thought produce cataracts led ICRP to recommend reducing dose threshold for VICs and reducing an occupational equivalent dose limit for the lens in 2011, when only a single threshold of 0.5 Gy was recommended. On the basis of epidemiological evidence, ICRP assumed progression of minor opacities into VICs and no dose rate effect. This contrasts with previously recommended separate thresholds for minor opacities and VICs, and for different exposure scenarios. Progression was assumed based on similar risks of cataracts and cataract surgery in Japanese atomic bomb survivors. The absence of dose rate effect derived from the observed similar thresholds for protracted exposures in Chernobyl cleanup workers and in atomic bomb survivors. Since 2011, there has been an increasing body of epidemiological evidence relating to cataracts and other ocular diseases (i.e. glaucoma and macular degeneration), particularly at low doses and low dose rates. This review paper gives an overview of the scientific basis of the 2011 ICRP recommendation, discusses the plausibility of these two assumptions in the light of emerging scientific evidence, and considers the radiosensitivity of the lens among ocular structures.

Do all the linear accelerators comply with the ICRU 91's constraints for stereotactic body radiation therapy treatments?

Recent technological developments in linear accelerators (linacs) and their imaging systems have made it possible to routinely perform stereotactic radiotherapy (SRT) treatments. To ensure the security and quality of the treatments, national and international recommendations have been written. This review focuses on the recommendations of the report 91 of the International Commission on Radiation Units (ICRU) on stereotactic treatments with small photon beams and proposes to answer the question of the eligibility of the commercially available accelerators for the treatment of extra-cranial SRT (SBRT). The ICRU 91 report outlines important features needed to respect the constraints, which are high intensity photon beam, integrated image-guidance, high mechanical accuracy of the linac, multileaf collimator with reduced leaf width, bundled motion management and bundled 6 Dimensional "robotic" couch tabletop. Most of the contemporary linacs meet these recommendations, in particular, stereotactic dedicated linacs, or modern gantry-based linacs equipped with 3 dimensional cone-beam CT imaging and 2D-stereoscopic planar imaging. Commercially available ring-based linacs have some limitations: they offer only coplanar treatments, and couch movements are limited to translations and, some have limited imaging equipment and no ability to manage intrafraction motion. However, for performing SBRT, non-coplanar irradiations are not mandatory, contrarily to intracranial stereotactic irradiations. Furthermore, patients' rotations can be corrected, thanks to real-time adaptive radiotherapy available on MRI-linacs. Finally, significant improvements are expected in the short term to compensate the weaknesses of the current devices.

Evidential Proximity, Independence, and the evaluation of carcinogenicity.

This paper analyses the methods of the International Agency for Research on Cancer (IARC) for evaluating the carcinogenicity of various agents. I identify two fundamental evidential principles that underpin these methods, which I call Evidential Proximity and Independence. I then show, by considering the 2018 evaluation of the carcinogenicity of styrene and styrene-7,8-oxide, that these principles have been implemented in a way that can lead to inconsistency. I suggest a way to resolve this problem: admit a general exception to Independence and treat the implementation of Evidential Proximity more flexibly where this exception applies. I show that this suggestion is compatible with the general principles laid down in the 2019 version of IARC's methods guide, its Preamble to the Monographs.

Computation Speeds and Memory Requirements of Mesh-Type ICRP Reference Computational Phantoms in Geant4, MCNP6, and PHITS.

Recently, Task Group 103 of the International Commission on Radiological Protection completed the development of new adult male and female mesh-type reference computational phantoms, which are planned for use in future International Commission on Radiological Protection dose coefficient calculations. In the present study, the performance of major Monte Carlo particle transport codes, i.e., Geant4, MCNP6, and PHITS, were investigated for the mesh-type reference computational phantoms by performing transport simulations of photons, electrons, neutrons, and helium ions for some external and internal exposures, and simultaneously measuring the memory usage, initialization time, and computation speed of the adult male mesh-type reference computational phantom in the codes. The measured results were then compared with the values measured with the current adult male voxel-type reference computational phantom in International Commission on Radiological Protection Publication 110 as well as five voxel phantoms produced from the adult male mesh-type reference computational phantom with different voxel resolutions, i.e., 0.1 × 0.1 × 0.1 mm, 0.6 × 0.6 × 0.6 mm, 1 × 1 × 1 mm, 2 × 2 × 2 mm, and 4 × 4 × 4 mm. From the results, it was found that in all of the codes, the memory usage of the mesh-type reference computational phantom is greater than that of the voxel-type reference computational phantom and the lowest resolution voxelized phantom, but it is sufficiently lower than the maximum memory, 64 GB, that can be installed in a personal computer. The required initialization time of the mesh-type reference computational phantom and of the voxel-type reference computational phantom and voxelized phantoms in resolutions lower than 0.6 × 0.6 × 0.6 mm was less than a few minutes in all of the codes. As for the computation speed among the codes, MCNP6 showed the worst performance for the mesh-type reference computational phantom, which was slower than that for the voxel-type reference computational phantom by up to ~50 times and slower than that for all of the voxelized phantoms by up to ~40 times. By contrast, PHITS showed the best performance for the mesh-type reference computational phantom, which was faster than that for the voxel-type reference computational phantom by up to ~3 times and faster than that for all of the voxelized phantoms by up to ~20 times. This high performance of PHITS is indeed encouraging considering that it is used nowadays by the International Commission on Radiological Protection for most dose coefficient calculations.

Moral entrepreneurship, the power-knowledge nexus, and the Cochrane "crisis".

BACKGROUND: In 2018, a so-called crisis developed in the international network of systematic reviewers known as Cochrane. It was widely depicted in terms of two competing narratives-"bad behaviour" by one member of Cochrane's Governing Board and scientific and moral decline within Cochrane. OBJECTIVE: Our goal was to distil insights on the structural issues underpinning the crisis, without taking a definitive position on the accuracy of either narrative. APPROACH AND DATASET: In this paper, we draw on (among other theories) Becker's notion of moral entrepreneurship and Foucault's conceptualisation of power to analyse the claims and counterclaims made by different parties. Our dataset consisted of publicly available materials (blogs, journal articles, newspaper articles) to end 2018, notably those relating to the expulsion of one Governing Board member. MAIN FINDINGS: Both narratives include strong moral claims about the science of systematic review and the governance of scientific organizations. The expelled individual and his supporters defined good systematic reviews in terms of a particular kind of methodological rigour and elimination of bias, and good governance largely in terms of measures to achieve independence from industry influence. Most of Cochrane's Governing Board and their sympathizers evaluated systematic reviews according to a broader range of criteria, incorporating factors such as attention to relationships among reviewers and reflexivity and dialogue around scientific and other judgements. They viewed governance partly in terms of accountability to an external advisory group. Power-knowledge alignments in Cochrane have emerged from, and contributed to, a particular system of meaning which is now undergoing evolution and challenge. CONCLUSION: Polarizing Cochrane's "crisis" into two narratives, only one of which is true, is less fruitful than viewing it in terms of a duality consisting of tensions between the two positions, each of which has some validity. Having framed the conflict as primarily philosophical and political rather than methodological and procedural, we suggest how Cochrane and its supporters and critics might harness their tensions productively.

Institutionalizing One Health: From Assessment to Action.

A One Health approach is critical to strengthening health security at country, regional, and global levels. However, operationally its uptake remains limited. Recent momentum in assessing capacity to effectively prevent, detect, and respond to disease threats has resulted in identification of gaps that require dedicated action. This article highlights relevant tools, standards, and guidance to assist countries and institutions in meeting the collective vision articulated at the 2018 Prince Mahidol Award Conference on "Making the World Safe from the Threats of Emerging Infectious Diseases." Taking stock of assessment findings, resources, priorities, and implementation initiatives across human and animal health, environment and disaster risk reduction sectors can help expand participation in global health security, target risk drivers, and form synergies for collective action and shared gains for both emerging and endemic disease challenges. In addition to health security gains, a multisectoral, One Health approach can drive benefits for wider health sector and global development goals.