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Abstract Background Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use. Methods LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients

Tumours of the central nervous system (CNS) represent the most common group of solid tumours in children and adolescents up to the age of 18 years. They comprise several biological entities, subgroups, and subtypes. These subtypes and additional factors, including age at diagnosis, location, stage, or genetic characteristics of the tumours result in a very heterogeneous spectrum of treatment-relevant strata for risk-adapted multimodal treatment recommendations, clinical courses, and long-term outcomes. Multidisciplinary teams with highly experienced members are needed to treat these children and adolescents to achieve the best possible outcome in the short and long-term. This is particularly important for the new CNS tumour entities with no established standard of care. On behalf of the Brain Tumour Group of the European Society for Paediatric Oncology, we summarize the key statements of the involved disciplines that need to cooperate in the diagnosis and risk-adapted treatment of children with CNS tumours: neuroradiology, neurosurgery, neuropathology, radiotherapy, endocrinology, neuro-ophthalmology, and quality of survival professionals, covering what should be considered standard clinical practice for diagnostic assessments, treatment modalities, and follow-up of children with CNS-tumours.

In patients with cirrhosis with severe thrombocytopenia (platelet count [PC] 100 × 109/L), intermediate (51‐100 × 109/L), and low (≤50 × 109/L). PC was also analyzed as a continuous covariate on multivariable analysis. The primary endpoint was major perioperative bleeding. The overall event rate of major perioperative bleeding was 8.9% and was not found to differ significantly between the high, intermediate, and low platelet groups (8.1% vs. 10.2% vs. 10.8%, P = 0.48). On multivariable analysis, greater age, aspartate aminotransferase, lower hemoglobin, and treatment with LR (vs. RFA) were found to be significant independent predictors of major perioperative bleeding, with associations with disease etiology and year of surgery also observed. After adjusting for these factors, the association between PC and major perioperative bleeding remained nonsignificant. Conclusion: Major perioperative bleeding was not significantly associated with PC in patients with cirrhosis undergoing surgical treatment of HCC, even when their PC was

Summary: Background: Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder, predisposing development of benign and malignant tumours. Given the oncogenic potential, long-term surveillance is important in patients with NF1. Proposals for NF1 care and its specific manifestations have been developed, but lack integration within routine care. This guideline aims to assimilate available information on NF1 associated tumours (based on evidence and/or expert opinion) to assist healthcare professionals in undertaking tumour surveillance of NF1 individuals. Methods: By comprehensive literature review, performed March 18th 2020, guidelines were developed by a NF1 expert group and patient representatives, conversant with clinical care of the wide NF1 disease spectrum. We used a modified Delphi procedure to overcome issues of variability in recommendations for specific (national) health care settings, and to deal with recommendations based on indirect (scarce) evidence. Findings: We defined proposals for personalised and targeted tumour management in NF1, ensuring appropriate care for those in need, whilst reducing unnecessary intervention. We also incorporated the tumour-related psychosocial and quality of life impact of NF1. Interpretation: The guideline reflects the current care for NF1 in Europe. They are not meant to be prescriptive and may be adjusted to local available resources at the treating centre, both within and outside EU countries. Funding: This guideline has been supported by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS). ERN GENTURIS is funded by the European Union. DGE is supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007).

The major histocompatibility complex-class I chain related proteins A and B (MICA/B) is upregulated because of cellular stress and MICA/B shedding by cancer cells causes escape from NKG2D recognition favoring the emergence of cancers. Cholangiocarcinoma (CCA) is a relatively rare, though increasingly prevalent, primary liver cancer characterized by a late clinical presentation and a dismal prognosis. We explored the NKG2D-MICA/B axis in NK cells from 41 patients with intrahepatic cholangiocarcinoma (iCCA). The MICA/B-specific 7C6 mAb was used for ex vivo antibody-dependent cytotoxicity (ADCC) experiments using circulating, non tumor liver- and tumor-infiltrating NK cells against the HuCCT-1 cell line and patient-derived primary iCCA cells as targets. MICA/B were more expressed in iCCA than in non-tumoral tissue, MICA transcription being higher in moderately-differentiated compared with poorly-differentiated cancer. Serum MICA was elevated in iCCA patients in line with higher expression of ADAM10 and ADAM17 that are responsible for proteolytic release of MICA/B from tumor. Addition of 7C6 significantly boosted peripheral, liver- and tumor-infiltrating-NK cell degranulation and IFNγ production toward MICA/B-expressing established cell lines and autologous iCCA patient target cells. Our data show that anti-MICA/B drives NK cell anti-tumor activity, and provide preclinical evidence in support of 7C6 as a potential immunotherapeutic tool for iCCA.

Abstract Background COVID-19 pandemic has impacted the Italian National Health Care system at many different levels, causing a complete reorganization of surgical wards. In this context, our study retrospectively analysed the management strategy for patients with acute cholecystitis. Methods We analysed all patients admitted to our Emergency Department for acute cholecystitis between February and April 2020 and we graded each case according to 2018 Tokyo Guidelines. All patients were tested for positivity to SARS-CoV-2 and received an initial conservative treatment. We focused on patients submitted to cholecystostomy during the acute phase of pandemic and their subsequent disease evolution. Results Thirty-seven patients were admitted for acute cholecystitis (13 grade I, 16 grade II, 8 grade III). According to Tokyo Guidelines (2018), patients were successfully treated with antibiotic only, bedside percutaneous transhepatic gallbladder drainage (PC) and laparoscopic cholecystectomy (LC) in 29.7%, 21.6% and 48.7% of cases respectively. Therapeutic strategy of three out of 8 cases, otherwise fit for surgery, submitted to bedside percutaneous transhepatic gallbladder drainage (37.5%), were directly modified by COVID-19 pandemic: one due to the SARS-CoV-2 positivity, while two others due to unavailability of operating room and intensive care unit for post-operative monitoring respectively. Overall success rate of percutaneous cholecystostomy was of 87.5%. The mean post-procedural hospitalization length was 9 days, and no related adverse events were observed apart from transient parietal bleeding, conservatively treated. Once discharged, two patients required readmission because of acute biliary symptoms. Median time of drainage removal was 43 days and only 50% patients thereafter underwent cholecystectomy. Conclusions Percutaneous cholecystostomy has shown to be an effective and safe treatment thus acquiring an increased relevance in the first phase of the pandemic. Nowadays, considering we are forced to live with the SARS-CoV-2 virus, PC should be considered as a virtuous, alternative tool for potentially all COVID-19 positive patients and selectively for negative cases unresponsive to conservative therapy and unfit for surgery.

The role of epigenetic deregulation in colorectal cancer (CRC) is not fully understood yet. Here the authors use patient-derived organoids, epigenomics and single-cell RNA-seq to reveal that YAP/TAZ are key regulators that bind to active enhancers in CRC and promote tumour survival.

Retinoblastoma (RB) is the most common ocular cancer, and it typically presents before the age of 5 years in over 90% of cases. In high resource countries, RB patients tend to survive and retain their sight. This is not the case in low-resource countries because of late presentation and delayed intervention arising mostly from sociocultural and socioeconomic challenges. RB has no gender or racial predilection; the incidence is estimated as 1:16,000–1:18,000 live-births or 11/1 million children under 5 years. Most of the world's RB cases are found in Asia and Africa while most RB treatment centres are in America and Europe. RB is easy to detect by caregivers as a glowing white 'cat eye reflex' at night or when captured on camera. Health workers at primary care level can detect RB in early life if red reflex test and/or squint (Hirschberg) tests are deployed as part of wellness checks done especially during routine immunisation and well-baby clinics in the first 24 months of life. In most cases of RB, biopsies for histological confirmation are not required for diagnosis and treatment decisions to be made. Clinical information, ophthalmic evaluation and imaging modalities are typically used. There have been significant changes in the management of RB using various treatment modalities such as enucleation with orbital implant, use of chemotherapy delivered through intravenous, intravitreal, periocular and intra-arterial routes and targeted treatment with laser, cryotherapy and brachytherapy. Algorithm for management and development of the national RB program within the context of a low-resource country is presented from review of data extracted from Mendeley library, PubMed library, Google Scholar and One Network; full-text articles were mostly retrieved through the American Academy of Ophthalmology.

In March 2020, northern Italy became the second country worldwide most affected by Covid-19 and the death toll overtook that in China. Hospital staff soon realized that Covid-19 was far more severe than expected from the few data available at that time. The Covid-19 pandemic forced hospitals to adjust to rapidly changing circumstances. We report our experience in a general teaching hospital in Milan, the capital of Lombardy, the most affected area in Italy. First, we briefly describe Lombardy's regional Covid-19-related health organizational changes as well as general hospital reorganization. We also provide a multidisciplinary report of the main clinical, radiological and pathological Covid-19 findings we observed in our patients.

Mesenchymal stem cells (MSCs) are multipotent cells able to differentiate into multiple cell types, including adipocytes, osteoblasts, and chondrocytes. The role of adipose-derived stem cells (ADSCs) in cancers is significantly relevant. They seem to be involved in the promotion of tumour development and progression and relapse processes. For this reason, investigating the effects of breast cancer microenvironment on ADSCs is of high importance in order to understand the relationship between tumour cells and the surrounding stromal cells. With the current study, we aimed to investigate the specific characteristics of human ADSCs isolated from the adipose tissue of breast tumour patients. We compared ADSCs obtained from periumbilical fat (PF) of controls with ADSCs obtained from adipose tissue of breast cancer- (BC-) bearing patients. We analysed the surface antigens and the adipogenic differentiation ability of both ADSC populations. C/EBPδ expression was increased in PF and BC ADSCs induced to differentiate compared to the control while PPARγ and FABP4 expressions were enhanced only in PF ADSCs. Conversely, adiponectin expression was reduced in PF-differentiated ADSCs while it was slightly increased in differentiated BC ADSCs. By means of Oil Red O staining, we further observed an impaired differentiation capability of BC ADSCs. To investigate this aspect more in depth, we evaluated the effect of selective PPARγ activation and nutritional supplementation on the differentiation efficiency of BC ADSCs, noting that it was only with a strong differentiation stimuli that the process took place. Furthermore, we observed no response in BC ADSCs to the PPARγ inhibitor T0070907, showing an impaired activation of this receptor in adipose cells surrounding the breast cancer microenvironment. In conclusion, our study shows an impaired adipogenic differentiation capability in BC ADSCs. This suggests that the tumour microenvironment plays a key role in the modulation of the adipose microenvironment located in the surrounding tissue.

Barrett’s esophagus is a condition in which the normal squamous lining of the esophagus has been replaced by columnar epithelium containing intestinal metaplasia induced by recurrent mucosal injury related to gastroesophageal reflux disease. Barrett’s esophagus is a premalignant condition that can progress through a dysplasia-carcinoma sequence to esophageal adenocarcinoma. Multiple endoscopic ablative techniques have been developed with the goal of eradicating Barrett’s esophagus and preventing neoplastic progression to esophageal adenocarcinoma. For patients with high-grade dysplasia or intramucosal neoplasia, radiofrequency ablation with or without endoscopic resection for visible lesions is currently the most effective and safe treatment available. Recent data demonstrate that, in patients with Barrett’s esophagus and low-grade dysplasia confirmed by a second pathologist, ablative therapy results in a statistically significant reduction in progression to high-grade dysplasia and esophageal adenocarcinoma. Treatment of dysplastic Barrett’s esophagus with radiofrequency ablation results in complete eradication of both dysplasia and of intestinal metaplasia in a high proportion of patients with a low incidence of adverse events. A high proportion of treated patients maintain the neosquamous epithelium after successful treatment without recurrence of intestinal metaplasia. Following successful endoscopic treatment, endoscopic surveillance should be continued to detect any recurrent intestinal metaplasia and/or dysplasia. This paper reviews all relevant publications on the endoscopic management of Barrett’s esophagus using radiofrequency ablation.

Rectal syphilis is a rare expression of the widely recognised sexual transmitted disease, also known as the great imitator for its peculiarity of being confused with mild anorectal diseases because of its vague symptoms or believed rectal malignancy, with the concrete risk of overtreatment. We present the case of a male patient with primary rectal syphilis, firstly diagnosed as rectal cancer; the medical, radiological, and endoscopic features are discussed below.

Hamartoma is a rare splenic benign tumor usually accidentally detected as a radiologic finding. Preoperative diagnosis poses a challenge and thus surgery becomes necessary to confirm the clinical suspicion. Laparoscopic splenectomy has gained consensus as a standard surgical procedure particularly for autoimmune hematological diseases. This former experience has allowed this technique to be extended to other splenic pathologies. Here we report a case of total laparoscopic splenectomy for a bulky splenic hamartoma in a young male patient.