High-grade osteosarcomas are the most common primary malignant tumors of bone. With complete surgical resection and multi-agent chemotherapy up to 70% of patients with high-grade osteosarcomas and localized extremity tumors can become long-term survivors. The prognosis, however, is poor for patients with nonresectable, primary metastatic or relapsed disease. Outcome is essentially unchanged for three decades. Herein, we describe selected novel insights into the genomics, biology and immunology of the disease and discuss selected strategies, which hold promise to overcome the current stagnation in the therapeutic success in childhood osteosarcoma.

Global Retinoblastoma Study Group IMPORTANCE Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale.OBJECTIVES To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. DESIGN, SETTING, AND PARTICIPANTSA total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. MAIN OUTCOMES AND MEASURESAge at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. RESULTSThe cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low-and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI,, and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI,). CONCLUSIONS AND RELEVANCEThis study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

Background Malignancy-associated hemophagocytic lymphohistiocytosis (HLH) in adults is a highly lethal disorder. Knowledge gaps have resulted in under-diagnosis or delayed diagnosis. Patients and Methods The University of Texas MD Anderson Cancer Center pathology database (1991–2014) was retrospectively interrogated for the keywords “hemophagocytosis” and/or “lymphohistiocytosis”. 77 adult patients were identified. All had an underlying malignancy. 16 patients with insufficient documentation were excluded. Results The majority of patients with pathologic evidence of hemophagocytosis/lymphohistiocytosis had incomplete work-up to confirm or refute HLH using the HLH-2004 criteria (HLH-2004 = 8 variables) and this is a common problem in adult HLH. Only 13/61 (21%) patients met the HLH-2004 diagnostic criteria based on available retrospective data. To identify potentially missed cases of HLH we reviewed published literature and selected additional variables known to be associated with adult HLH resulting in an extended diagnostic criteria of 18 variables. 35 patients met the extended criteria and 33 had follow-up data. The median OS of the 13 patients who met both the extended criteria and the HLH-2004 criteria was similar to the 20 patients who met the extended criteria but NOT the HLH-2004 criteria (1.43 vs 1.76 months, P=0.34) indicating similar underlying aggressive systemic process. 26 patients did not meet either criteria and 17 had follow-up data. The median OS of the 17 patients who had pathologic hemophagocytosis or lymphohistiocytosis but met neither criteria was significantly superior to those who met both the extended criteria and the HLH-2004 criteria or those who met the extended criteria but NOT the HLH-2004 criteria (17.27 vs 1.43 vs 1.76, P=0.002). Conclusion Addition of diagnostic laboratory variables that are more easily and rapidly available in smaller institutions and primary care settings than the HLH-2004 variables may be a good surrogate to raise early suspicion of malignancy-associated HLH. Prospective validation is warranted.

Recent years have highlighted significant progress in understanding the underlying genetic and epigenetic signatures of acute myeloid leukemia(AML). Most importantly, novel chemotherapy and targeted strategies have led to improved outcomes in selected genetic subsets. AML is a remarkably heterogeneous disease, and individualized therapies for disease-specific characteristics (considering patients’ age, cytogenetics, and mutations) could yield better outcomes. Compared with the historical 5-to 10-year survival rate of 10%, the survival of patients who undergo modern treatment approaches reaches up to 40–50%, and for specific subsets, the improvements are even more dramatic; for example, in acute promyelocytic leukemia, the use of all-trans retinoic acid and arsenic trioxide improved survival from 30–40% up to 80–90%. Similar progress has been documented in core-binding-factor-AML, with an increase in survival from 30% to 80% upon the use of high-dose cytarabine/fludarabine/granulocyte colony-stimulating factor combination regimens. AML treatment was also recently influenced by the discovery of the superiority of regimens with higher dose Ara-C and nucleoside analogues compared with the “7+3” regimen, with about a 20% improvement in overall survival. Despite these significant differences, most centers continue to use the “7+3” regimen, and greater awareness will improve the outcome. The discovery of targetable molecular abnormalities and recent studies of targeted therapies (gemtuzumab ozagomycin, FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and epigenetic therapies), future use of checkpoint inhibitors and other immune therapies such as chimeric antigen receptor T-cells, and maintenance strategies based on the minimal residual disease evaluation represent novel, exciting clinical leads aimed to improve AML outcomes in the near future.

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Key Points• Children with PCNSL and no immunodeficiency have a good outcome when treated by a histological subtype-driven and radiation-free protocol.• New treatment guidelines are needed for PCNSL in children and adolescents with an underlying immunodeficiency.

BackgroundGiant cell tumor of bone (GCT) is a rare primary bone tumor, which can metastasize and undergo malignant transformation. The standard treatment of GCT is surgery. In patients with unresectable or metastatic disease, additional therapeutic options are available. These include blocking of the receptor activator of NF-kappa B ligand (RANKL) signaling pathway, which plays a role in the pathogenesis of GCT of bone, via the anti-RANKL monoclonal antibody denosumab.Case PresentationHerein we report on a female teenager who presented in a very poor clinical condition (cachexia, diplopia, strabismus, dysphonia with palsy of cranial nerves V, VI, VIII, IX, X, XI and XII) due to progressive disease, after incomplete resection and adjuvant radiotherapy, of a GCT which affected the cervical spine (C1 and C2) as well as the skull base; and who had an impressive clinical response to denosumab therapy. To the best of our knowledge, this is the youngest patient ever reported with a skull base tumor treated with denosumab.ConclusionIn situations when surgery can be postponed and local aggressiveness of the tumor does not urge for acute surgical intervention, upfront use of denosumab in order to reduce the tumor size might be considered. Principally, the goal of denosumab therapy is to reduce tumor size as much as possible, with the ultimate goal to make local surgery (or as in our case re-surgery) amenable. However, improvement in quality of life, as demonstrated in our patient, is also an important aspect of such targeted therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13052-017-0353-0) contains supplementary material, which is available to authorized users.

War in the time of COVID-19: humanitarian catastrophe in Nagorno-Karabakh and ArmeniaAs a small country with a population of 3 million, Armenia has been severely affected by the COVID-19 pandemic, and for several months was among the countries with the highest prevalence of COVID-19. 1 On Oct 23, 2020, the number of confirmed cases was 70 836 and the number of new daily diagnosed cases reached 2484. As a result, Armenia is now the second country in the world with the highest number of new daily diagnosed cases per person (778 cases per million per day), overtaking only the Czech Republic (1321 cases per million per day). 1 The first case of COVID-19 in Armenia was registered at the beginning of March, 2020, and on March 16, the country declared a state of emergency and went into lockdown. During the next few months, the numbers rose substantially; but by the end of the summer, Armenia was able to flatten the curve. Although there was some increase in the number of cases because of the opening of schools, the number of new daily cases on Sept 26 was 328, and the country had started to overcome the threat from this global pandemic. Unfortunately, this success was short-lived, as another catastrophe began.Nagorno-Karabakh (also known as Artsakh) is a former partly self-governing region of the Soviet Union, historically inhabited by the Armenians. The status of this region has been disputed between Azerbaijan and Armenia since the collapse of the Soviet Union. Since 1991, it has been a de facto independent state, although not recognised by the UN. On Sept 27, 2020, Azerbaijan initiated a large-scale war against Nagorno-Karabakh. The conflict was complicated by the open involvement of Turkey, allied with Azerbaijan, providing substantial military and political backing, which has been independently verified by several major media outlets. 2,3 Ballistic missiles, drones, and other heavy artillery have been used, resulting in multiple civilian deaths and injuries. Hospitals, churches, kindergartens, and schools were hit during the bombardment and missile attacks, which included the use of internationally banned cluster bombs. 4 As a result of the intensive bombardment of Nagorno-Karabakh by the Azerbaijani armed forces, by October 8,