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BACKGROUND Thoracic spinal epidural lipomatosis (SEL) involves the pathological overgrowth of histologically normal, unencapsulated adipose tissue that can compress the spinal cord and cause myelopathy. SEL has been associated with multiple medical conditions, including Scheuermann kyphosis (SK). Optimal treatment strategies for SEL, especially in the setting of a sagittal spinal deformity, remain unclear. OBSERVATIONS In this report, the authors discussed surgical management of a patient with thoracic SEL and SK using skip hemilaminotomies for resection of the epidural adipose tissue. To the authors’ knowledge, only one other report described a similar surgical technique in a patient who did not have a spinal deformity. LESSONS When conservative efforts fail, thoracic SEL may require surgical treatment. Surgical planning must account for co-medical conditions such as SK. The described approach involving skip laminotomies, which minimizes spine destabilization, is a viable option to treat SEL spanning multiple spinal segments. Prognosis after surgical treatment varies and is impacted by multiple factors, including severity of preoperative neurological deficits.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

Abstract Background: Pts with HR-MDS unfit for hematopoietic stem cell transplant (HSCT) have poor outcomes and limited survival with single-agent hypomethylating agent (HMA) therapy. Novel treatments that provide durable responses and clinically meaningful survival benefit for pts with HR-MDS are needed. TIM-3 is a promising target in myeloid malignancies as it regulates innate and adaptive immune cells and is expressed on leukemic stem cells (LSCs) and blasts but not normal hematopoietic stem cells. Sabatolimab (MBG453) is a novel immuno-myeloid therapy that binds to TIM-3 on immune cells, facilitating antileukemic immune activation and phagocytic killing of leukemic cells. Sabatolimab also binds to TIM-3 on leukemic cells, potentially impeding self-renewal of LSCs via inhibition of TIM3-galectin-9. In an early phase (ph) trial (NCT03066648) sabatolimab + HMA therapy showed a durable clinical benefit and was well tolerated in pts with HR-MDS (Wei, EHA 2021). Study Design and Methods: The STIMULUS immuno-myeloid clinical trial program is investigating the safety, efficacy, and durability of multiple sabatolimab-based combination therapies in pts with myeloid malignancies. Additional exploration of the mechanism of action of sabatolimab and identification of potential biomarkers predictive of response is planned. This abstract summarizes the design of the 4 ongoing STIMULUS trials in previously untreated adult pts with HR-MDS who are not eligible for intensive chemotherapy (IC) or HSCT. STIMULUS-MDS1 (NCT03946670) is an international, randomized, double-blind, placebo-controlled Ph II trial evaluating sabatolimab + HMA therapy in pts with very-high, high-, or intermediate-risk (vH/H/IR)-MDS which has completed enrollment (N=127). The primary endpoints of STIMULUS-MDS1 are complete response (CR) and progression-free survival (PFS). STIMULUS-MDS2 (NCT04266301) is an ongoing, international, randomized, double-blind, placebo-controlled, Ph III trial of sabatolimab + azacitidine (AZA) in pts with vH/H/IR-MDS or chronic myelomonocytic leukemia-2. Target enrollment is ~500 pts. The primary endpoint in this trial is overall survival (OS). Key secondary endpoints are time to definitive deterioration of fatigue; duration of RBC transfusion-free interval; and improvement of fatigue, physical functioning, and emotional functioning. Other endpoints include CR, marrow CR (mCR), partial remission (PR), PFS, and leukemia-free survival (LFS). STIMULUS-MDS2 is a trial that aims to determine if sabatolimab + HMA has a statistically significant and clinically meaningful benefit in OS and quality of life vs HMA alone. STIMULUS MDS-US (NCT04878432) is a US-based, open-label, single-arm, Ph II trial investigating sabatolimab + HMAs of investigators' choice (AZA intravenous [IV] or subcutaneous, decitabine IV or oral decitabine) in pts with vH/H/IR-MDS. Target enrollment is 90 pts. Primary endpoint is safety, which will be evaluated via incidence and severity of adverse events (AEs) and serious AEs. Secondary endpoints include CR, PFS, LFS, and OS. This trial will provide further understanding of sabatolimab + HMA therapy with additional insight into the safety and efficacy of sabatolimab + oral HMA. STIMULUS-MDS3 (NCT04812548) is an international, open-label, single-arm, Ph II trial that explores triplet therapy of sabatolimab combined with AZA and the BCL-2 inhibitor venetoclax (VEN) in pts with vH/HR-MDS. Part 1 of this trial is a safety run-in comprising 2 safety cohorts with ~6 pts receiving sabatolimab 400 mg + AZA + VEN and ~12 pts receiving sabatolimab 800 mg + AZA + VEN. Primary endpoint of part 1 is safety (dose-limiting toxicities between cycle 1 day 8 and end of cycle 2). If (both 400 and 800 mg) sabatolimab + AZA and VEN are safe, the trial will progress to an expansion cohort (~58 pts) of sabatolimab 800 mg Q4W + AZA + VEN. The primary endpoint is CR. Secondary endpoints include CR + mCR rate, overall response rate (CR + mCR + PR + hematologic improvement), OS, PFS, LFS, and event-free survival. The STIMULUS immuno-myeloid clinical trial program is investigating the efficacy, safety, and improved quality of life of multiple sabatolimab-based combination therapies in pts with myeloid malignancies. The goal of ongoing STIMULUS-MDS trials is to gain insight into the promising durable benefit of sabatolimab combination therapies in pts with HR-MDS. Figure 1 Figure 1. Disclosures Zeidan: Jazz: Consultancy; Jasper: Consultancy; Pfizer: Other: Travel support, Research Funding; AstraZeneca: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Genentech: Consultancy; Epizyme: Consultancy; Daiichi Sankyo: Consultancy; Geron: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; BeyondSpring: Consultancy; Astex: Research Funding; Astellas: Consultancy; Aprea: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Agios: Consultancy; ADC Therapeutics: Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Borate: Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Cluzeau: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Agios: Honoraria; Amgen: Speakers Bureau; Jazz Pharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Astellas: Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Other: travel, accommodations, expenses; Takeda: Other: travel, accommodations, expenses. DeZern: Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Esteve: Jazz: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Giagounidis: Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Platzbecker: Celgene/BMS: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Geron: Honoraria; AbbVie: Honoraria; Takeda: Honoraria. Sallman: Kite: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Syndax: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Magenta: Consultancy. Santini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees. Sanz: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Other: Travel, accommodations, and expenses. Sekeres: Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Wei: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Van Hoef: Novartis Pharma: Current Employment. Nourry-Boulot: Novartis: Current Employment. Sadek: Novartis: Current Employment. Bengoudifa: Novartis Pharma AG: Current Employment. Sachs: Novartis Pharma AG: Current Employment. Sabo: Novartis: Current Employment, Current holder of stock options in a privately-held company. OffLabel Disclosure: Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3 and is under investigation for the treatment of patients with myeloid malignancies

Mastocytosis is a hematologic neoplasm characterized by expansion and focal accumulation of neoplastic mast cells (MC) in diverse organs, including the skin, bone marrow (BM), spleen, liver, and gastrointestinal tract. The World Health Organization classification divides the disease into prognostically distinct variants of cutaneous mastocytosis (CM) and systemic mastocytosis (SM). Although this classification remains valid, recent developments in the field and the advent of new diagnostic and prognostic parameters created a need to update and refine definitions and diagnostic criteria in MC neoplasms. In addition, MC activation syndromes (MCAS) and genetic features predisposing to SM and MCAS have been identified. To discuss these developments and refinements in the classification, we organized a Working Conference comprised of experts from Europe and the United States in August 2020. This article reports on outcomes from this conference. Of particular note, we propose adjustments in the classification of CM and SM, refinements in diagnostic criteria of SM variants, including smoldering SM and BM mastocytosis (BMM), and updated criteria for MCAS and other conditions involving MC. CD30 expression in MC now qualifies as a minor SM criterion, and BMM is now defined by SM criteria, absence of skin lesions and absence of B- and C-findings. A basal serum tryptase level exceeding 20 ng/mL remains a minor SM criterion, with recognition that hereditary alpha-tryptasemia and various myeloid neoplasms may also cause elevations in tryptase. Our updated proposal will support diagnostic evaluations and prognostication in daily practice and the conduct of clinical trials in MC disorders.

Objectives: Multicenter data on the characteristics and outcomes of children hospitalized with coronavirus disease 2019 are limited. Our objective was to describe the characteristics, ICU admissions, and outcomes among children hospitalized with coronavirus disease 2019 using Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: Coronavirus Disease 2019 registry. Design: Retrospective study. Setting: Society of Critical Care Medicine Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) registry. Patients: Children (< 18 yr) hospitalized with coronavirus disease 2019 at participating hospitals from February 2020 to January 2021. Interventions: None. Measurements and Main Results: The primary outcome was ICU admission. Secondary outcomes included hospital and ICU duration of stay and ICU, hospital, and 28-day mortality. A total of 874 children with coronavirus disease 2019 were reported to Viral Infection and Respiratory Illness Universal Study registry from 51 participating centers, majority in the United States. Median age was 8 years (interquartile range, 1.25–14 yr) with a male:female ratio of 1:2. A majority were non-Hispanic (492/874; 62.9%). Median body mass index (n = 817) was 19.4 kg/m2 (16–25.8 kg/m2), with 110 (13.4%) overweight and 300 (36.6%) obese. A majority (67%) presented with fever, and 43.2% had comorbidities. A total of 238 of 838 (28.2%) met the Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children, and 404 of 874 (46.2%) were admitted to the ICU. In multivariate logistic regression, age, fever, multisystem inflammatory syndrome in children, and pre-existing seizure disorder were independently associated with a greater odds of ICU admission. Hospital mortality was 16 of 874 (1.8%). Median (interquartile range) duration of ICU (n = 379) and hospital (n = 857) stay were 3.9 days (2–7.7 d) and 4 days (1.9–7.5 d), respectively. For patients with 28-day data, survival was 679 of 787, 86.3% with 13.4% lost to follow-up, and 0.3% deceased. Conclusions: In this observational, multicenter registry of children with coronavirus disease 2019, ICU admission was common. Older age, fever, multisystem inflammatory syndrome in children, and seizure disorder were independently associated with ICU admission, and mortality was lower among children than mortality reported in adults.

Abstract To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin. Napabucasin's efficacy was mediated through reactive oxygen species and inhibition of translation initiation, and specific inhibition of eIF4A was effective. The sensitivity of each PDX line inversely correlated with expression of the antiapoptotic protein Bcl-xL, and inhibition of Bcl-xL synergized with other drugs. Screening directly on cells dissociated from patient resections validated these results. This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable. Significance: Therapeutics informed by genomics have not yielded effective therapies for FLC. A functional screen identified TOPO1, HDAC inhibitors, and napabucasin as efficacious and synergistic with inhibition of Bcl-xL. Validation on cells dissociated directly from patient tumors demonstrates the ability for functional precision medicine in a solid tumor. This article is highlighted in the In This Issue feature, p. 2355

e23014 Background: The number of annual global cancer deaths is rising and the majority of this burden, for a multitude of reasons, falls in low- and middle- income countries (LMICs). With the United Nations’ 3rd and 17th Sustainable Development Goals in mind (which include by 2030 “reduce by one third premature mortality from non-communicable diseases” and “partnership for the goals”) a survey was undertaken at the UK’s two largest comprehensive cancer centres to scope individual and team endeavours to work with colleagues in less well-resourced countries. Methods: Employees at the Royal Marsden Foundation Trust (RM) and Institute of Cancer Research (ICR) in London and Surrey, UK and The Christie NHS Foundation Trust (Christie), Manchester were invited to complete a survey to capture collaborative clinical care, research, education and training. Results: Responses were received from 520 multidisciplinary individuals across the 2 centres to two similar questionnaires. A large number had experience of working in some capacity in, or in collaboration with an LMIC. At the RM 14.62% of respondees were currently working with colleagues in LMICs. At The Christie 13.22% of staff had experience of working in LMICs in a supportive capacity. Those currently collaborating with colleagues in LMICs were working in a wide range of countries across Asia, Africa and South America in a range of initiatives spanning clinical care, research, education and training. Of those who answered the survey 64% at The Christie said they’d like to hear more about opportunities to be involved in supporting global health care, and 89% at RM/ICR said they’d be interested in joining a collaborative group working on global oncology initiatives at the institutions. Conclusions: This survey highlights the body of willing, interested individuals keen to work with colleagues in LMICs to improve cancer outcomes. The launch of the UK Global Cancer Network in 2020 will build upon these two surveys with a planned national survey of global health and cancer work undertaken by individuals in 2021.

Creatine is one of the most studied and popular ergogenic aids for athletes and recreational weightlifters seeking to improve sport and exercise performance, augment exercise training adaptations, and mitigate recovery time. Studies consistently reveal that creatine supplementation exerts positive ergogenic effects on single and multiple bouts of short-duration, high-intensity exercise activities, in addition to potentiating exercise training adaptations. In this respect, supplementation consistently demonstrates the ability to enlarge the pool of intracellular creatine, leading to an amplification of the cell’s ability to resynthesize adenosine triphosphate. This intracellular expansion is associated with several performance outcomes, including increases in maximal strength (low-speed strength), maximal work output, power production (high-speed strength), sprint performance, and fat-free mass. Additionally, creatine supplementation may speed up recovery time between bouts of intense exercise by mitigating muscle damage and promoting the faster recovery of lost force-production potential. Conversely, contradictory findings exist in the literature regarding the potential ergogenic benefits of creatine during intermittent and continuous endurance-type exercise, as well as in those athletic tasks where an increase in body mass may hinder enhanced performance. The purpose of this review was to summarize the existing literature surrounding the efficacy of creatine supplementation on exercise and sports performance, along with recovery factors in healthy populations.

AbstractCSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow‐up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.