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BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell-like [ABC], germinal-center B-cell-like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. METHODS: We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations. RESULTS: and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on "chronic active" B-cell receptor signaling that is amenable to therapeutic inhibition. CONCLUSIONS: We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.).

During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. In addition, based on the current evidence we give practical guidance to the management of the cytokine release syndrome.

Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.

: By definition, an adrenal incidentaloma is an asymptomatic adrenal mass detected on imaging not performed for suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, but may also represent conditions requiring therapeutic intervention (e.g. adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastasis). The purpose of this guideline is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with adrenal incidentalomas based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions crucial for the management of adrenal incidentaloma patients, addressing these four with systematic literature searches: (A) How to assess risk of malignancy?; (B) How to define and manage low-level autonomous cortisol secretion, formerly called 'subclinical' Cushing's syndrome?; (C) Who should have surgical treatment and how should it be performed?; (D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? SELECTED RECOMMENDATIONS: (i) At the time of initial detection of an adrenal mass establishing whether the mass is benign or malignant is an important aim to avoid cumbersome and expensive follow-up imaging in those with benign disease. (ii) To exclude cortisol excess, a 1mg overnight dexamethasone suppression test should be performed (applying a cut-off value of serum cortisol ≤50nmol/L (1.8µg/dL)). (iii) For patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post 1mg dexamethasone >138nmol/L (>5µg/dL), we propose the term 'autonomous cortisol secretion'. (iv) All patients with '(possible) autonomous cortisol' secretion should be screened for hypertension and type 2 diabetes mellitus, to ensure these are appropriately treated. (v) Surgical treatment should be considered in an individualized approach in patients with 'autonomous cortisol secretion' who also have comorbidities that are potentially related to cortisol excess. (vi) In principle, the appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health and patient preference. (vii) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. Furthermore, we offer recommendations for the follow-up of patients with adrenal incidentaloma who do not undergo adrenal surgery, for those with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses and for young and elderly patients with adrenal incidentalomas.

The MYC oncogene codes for a transcription factor that is overexpressed in many human cancers. Here we show that MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface: the innate immune regulator CD47 (cluster of differentiation 47) and the adaptive immune checkpoint PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 messenger RNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pd-l1 genes. MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed, and tumors continued to grow. Thus, MYC appears to initiate and maintain tumorigenesis, in part, through the modulation of immune regulatory molecules.

Adrenocortical carcinoma (ACC) is a rare and in most cases steroid hormone-producing tumor with variable prognosis. The purpose of these guidelines is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with ACC based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions, which we judged as particularly important for the management of ACC patients and performed systematic literature searches: (A) What is needed to diagnose an ACC by histopathology? (B) Which are the best prognostic markers in ACC? (C) Is adjuvant therapy able to prevent recurrent disease or reduce mortality after radical resection? (D) What is the best treatment option for macroscopically incompletely resected, recurrent or metastatic disease? Other relevant questions were discussed within the group. Selected Recommendations: (i) We recommend that all patients with suspected and proven ACC are discussed in a multidisciplinary expert team meeting. (ii) We recommend that every patient with (suspected) ACC should undergo careful clinical assessment, detailed endocrine work-up to identify autonomous hormone excess and adrenal-focused imaging. (iii) We recommend that adrenal surgery for (suspected) ACC should be performed only by surgeons experienced in adrenal and oncological surgery aiming at a complete en bloc resection (including resection of oligo-metastatic disease). (iv) We suggest that all suspected ACC should be reviewed by an expert adrenal pathologist using the Weiss score and providing Ki67 index. (v) We suggest adjuvant mitotane treatment in patients after radical surgery that have a perceived high risk of recurrence (ENSAT stage III, or R1 resection, or Ki67 >10%). (vi) For advanced ACC not amenable to complete surgical resection, local therapeutic measures (e.g. radiation therapy, radiofrequency ablation, chemoembolization) are of particular value. However, we suggest against the routine use of adrenal surgery in case of widespread metastatic disease. In these patients, we recommend either mitotane monotherapy or mitotane, etoposide, doxorubicin and cisplatin depending on prognostic parameters. In selected patients with a good response, surgery may be subsequently considered. (vii) In patients with recurrent disease and a disease-free interval of at least 12 months, in whom a complete resection/ablation seems feasible, we recommend surgery or alternatively other local therapies. Furthermore, we offer detailed recommendations about the management of mitotane treatment and other supportive therapies. Finally, we suggest directions for future research.

Abstract Approximately 30% to 50% of adults with acute lymphoblastic leukemia (ALL) in hematologic complete remission after multiagent therapy exhibit minimal residual disease (MRD) by reverse transcriptase–polymerase chain reaction or flow cytometry. MRD is the strongest predictor of relapse in ALL. In this open-label, single-arm study, adults with B-cell precursor ALL in hematologic complete remission with MRD (≥10−3) received blinatumomab 15 µg/m2 per day by continuous IV infusion for up to 4 cycles. Patients could undergo allogeneic hematopoietic stem-cell transplantation any time after cycle 1. The primary end point was complete MRD response status after 1 cycle of blinatumomab. One hundred sixteen patients received blinatumomab. Eighty-eight (78%) of 113 evaluable patients achieved a complete MRD response. In the subgroup of 110 patients with Ph-negative ALL in hematologic remission, the Kaplan-Meier estimate of relapse-free survival (RFS) at 18 months was 54%. Median overall survival (OS) was 36.5 months. In landmark analyses, complete MRD responders had longer RFS (23.6 vs 5.7 months; P = .002) and OS (38.9 vs 12.5 months; P = .002) compared with MRD nonresponders. Adverse events were consistent with previous studies of blinatumomab. Twelve (10%) and 3 patients (3%) had grade 3 or 4 neurologic events, respectively. Four patients (3%) had cytokine release syndrome grade 1, n = 2; grade 3, n = 2), all during cycle 1. After treatment with blinatumomab in a population of patients with MRD-positive B-cell precursor ALL, a majority achieved a complete MRD response, which was associated with significantly longer RFS and OS compared with MRD nonresponders. This study is registered at www.clinicaltrials.gov as #NCT01207388.

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.

Adrenal incidentalomas are adrenal masses detected on imaging performed for reasons other than suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas but may also require therapeutic intervention including that for adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma, or metastases. Here, we provide a revision of the first international, interdisciplinary guidelines on incidentalomas. We followed the Grading of Recommendations Assessment, Development and Evaluation system and updated systematic reviews on 4 predefined clinical questions crucial for the management of incidentalomas: (1) How to assess risk of malignancy?; (2) How to define and manage mild autonomous cortisol secretion?; (3) Who should have surgical treatment and how should it be performed?; and (4) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? Selected Recommendations: (1) Each adrenal mass requires dedicated adrenal imaging. Recent advances now allow discrimination between risk categories: Homogeneous lesions with Hounsfield unit (HU) ≤ 10 on unenhanced CT are benign and do not require any additional imaging independent of size. All other patients should be discussed in a multidisciplinary expert meeting, but only lesions >4 cm that are inhomogeneous or have HU >20 have sufficiently high risk of malignancy that surgery will be the usual management of choice. (2) Every patient needs a thorough clinical and endocrine work-up to exclude hormone excess including the measurement of plasma or urinary metanephrines and a 1-mg overnight dexamethasone suppression test (applying a cutoff value of serum cortisol ≤50 nmol/L [≤1.8 µg/dL]). Recent studies have provided evidence that most patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post dexamethasone >50 nmol/L (>1.8 µg/dL) harbor increased risk of morbidity and mortality. For this condition, we propose the term "mild autonomous cortisol secretion" (MACS). (3) All patients with MACS should be screened for potential cortisol-related comorbidities that are potentially attributably to cortisol (eg, hypertension and type 2 diabetes mellitus), to ensure these are appropriately treated. (4) In patients with MACS who also have relevant comorbidities surgical treatment should be considered in an individualized approach. (5) The appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health, and patient preference. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. (6) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. Furthermore, we offer recommendations for the follow-up of nonoperated patients, management of patients with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses, and for young and elderly patients with adrenal incidentalomas. Finally, we suggest 10 important research questions for the future.

OBJECTIVE: Psychological distress is common in cancer patients, and awareness of its indicators is essential. We aimed to assess the prevalence of psychological distress and to identify problems indicative of high distress. METHODS: We used the distress thermometer (DT) and its 34-item problem list to measure psychological distress in 3724 cancer patients (mean age 58 years; 57% women) across major tumor entities, enrolled in an epidemiological multicenter study. To identify distress-related problems, we conducted monothetic analyses. RESULTS: We found high levels of psychological distress (DT ≥ 5) in 52% of patients. The most prevalent problems were fatigue (56%), sleep problems (51%), and problems getting around (47%). Sadness, fatigue, and sleep problems were most strongly associated with the presence of other problems. High distress was present in 81.4% of patients reporting all 3 of these problems (DT M = 6.4). When analyzing only the subset of physical problems, fatigue, problems getting around, and indigestion showed the strongest association with the remaining problems and 76.3% of patients with all 3 problems were highly distressed (DT M = 6.1). CONCLUSIONS: Our results show a high prevalence of psychological distress in cancer patients, as well as a set of problems that indicate the likely presence of other problems and high distress and can help clinicians identify distressed patients even if no routine distress screening is available.

In heart failure, alterations of Na + and Ca 2+ handling, energetic deficit, and oxidative stress in cardiac myocytes are important pathophysiological hallmarks. Mitochondria are central to these processes because they are the main source for ATP, but also reactive oxygen species (ROS), and their function is critically controlled by Ca 2+ . During physiological variations of workload, mitochondrial Ca 2+ uptake is required to match energy supply to demand but also to keep the antioxidative capacity in a reduced state to prevent excessive emission of ROS. Mitochondria take up Ca 2+ via the mitochondrial Ca 2+ uniporter, which exists in a multiprotein complex whose molecular components were identified only recently. In heart failure, deterioration of cytosolic Ca 2+ and Na + handling hampers mitochondrial Ca 2+ uptake and the ensuing Krebs cycle–induced regeneration of the reduced forms of NADH (nicotinamide adenine dinucleotide) and NADPH (nicotinamide adenine dinucleotide phosphate), giving rise to energetic deficit and oxidative stress. ROS emission from mitochondria can trigger further ROS release from neighboring mitochondria termed ROS-induced ROS release, and cross talk between different ROS sources provides a spatially confined cellular network of redox signaling. Although low levels of ROS may serve physiological roles, higher levels interfere with excitation–contraction coupling, induce maladaptive cardiac remodeling through redox-sensitive kinases, and cell death through mitochondrial permeability transition. Targeting the dysregulated interplay between excitation–contraction coupling and mitochondrial energetics may ameliorate the progression of heart failure.

Persistence or recurrence of minimal residual disease (MRD) after chemotherapy results in clinical relapse in patients with acute lymphoblastic leukemia (ALL). In a phase 2 trial of B-lineage ALL patients with persistent or relapsed MRD, a T cell-engaging bispecific Ab construct induced an 80% MRD response rate. In the present study, we show that after a median follow-up of 33 months, the hematologic relapse-free survival of the entire evaluable study cohort of 20 patients was 61% (Kaplan-Meier estimate). The hema-tologic relapse-free survival rate of a subgroup of 9 patients who received allogeneic hematopoietic stem cell transplantation after blinatumomab treatment was 65% (Kaplan-Meier estimate). Of the subgroup of 6 Philadelphia chromosome-negative MRD responders with no further therapy after blinatumomab, 4 are in ongoing hematologic and molecular remission. We conclude that blinatumomab can induce long-lasting complete remission in B-lineage ALL patients with persistent or recurrent MRD. The original study and this follow-up study are registered at www.clinicaltrials.gov as NCT00198991 and NCT00198978, respectively.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Standard treatment is surgical resection. Following complete resection of the primary tumour, patients with PPGL are at risk of developing new tumoural events. The present guideline aims to propose standardised clinical care of long-term follow-up in patients operated on for a PPGL. The guideline has been developed by The European Society of Endocrinology and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles. We performed a systematic review of the literature and analysed the European Network for the Study of Adrenal Tumours (ENS@T) database. The risk of new events persisted in the long term and was higher for patients with genetic or syndromic diseases. Follow-up in the published cohorts and in the ENS@T database was neither standardised nor exhaustive, resulting in a risk of follow-up bias and in low statistical power beyond 10 years after complete surgery. To inform patients and care providers in this context of low-quality evidence, the Guideline Working Group therefore prepared recommendations on the basis of expert consensus. Key recommendations are the following: we recommend that all patients with PPGL be considered for genetic testing; we recommend assaying plasma or urinary metanephrines every year to screen for local or metastatic recurrences or new tumours; and we suggest follow-up for at least 10 years in all patients operated on for a PPGL. High-risk patients (young patients and those with a genetic disease, a large tumour and/or a paraganglioma) should be offered lifelong annual follow-up.

BACKGROUND: Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and CD3, showed promising antitumor activity in a phase 1 trial in patients with previously treated small-cell lung cancer. METHODS: In this phase 2 trial, we evaluated the antitumor activity and safety of tarlatamab, administered intravenously every 2 weeks at a dose of 10 mg or 100 mg, in patients with previously treated small-cell lung cancer. The primary end point was objective response (complete or partial response), as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Overall, 220 patients received tarlatamab; patients had previously received a median of two lines of treatment. Among patients evaluated for antitumor activity and survival, the median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% (97.5% confidence interval [CI], 29 to 52) of the patients in the 10-mg group and in 32% (97.5% CI, 21 to 44) of those in the 100-mg group. Among patients with an objective response, the duration of response was at least 6 months in 59% (40 of 68 patients). Objective responses at the time of data cutoff were ongoing in 22 of 40 patients (55%) in the 10-mg group and in 16 of 28 patients (57%) in the 100-mg group. The median progression-free survival was 4.9 months (95% CI, 2.9 to 6.7) in the 10-mg group and 3.9 months (95% CI, 2.6 to 4.4) in the 100-mg group; the estimates of overall survival at 9 months were 68% and 66% of patients, respectively. The most common adverse events were cytokine-release syndrome (in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group), decreased appetite (in 29% and 44%, respectively), and pyrexia (in 35% and 33%). Cytokine-release syndrome occurred primarily during treatment cycle 1, and events in most of the patients were grade 1 or 2 in severity. Grade 3 cytokine-release syndrome occurred less frequently in the 10-mg group (in 1% of the patients) than in the 100-mg group (in 6%). A low percentage of patients (3%) discontinued tarlatamab because of treatment-related adverse events. CONCLUSIONS: Tarlatamab, administered as a 10-mg dose every 2 weeks, showed antitumor activity with durable objective responses and promising survival outcomes in patients with previously treated small-cell lung cancer. No new safety signals were identified. (Funded by Amgen; DeLLphi-301 ClinicalTrials.gov number, NCT05060016.).

BACKGROUND: Corticotropin-independent Cushing's syndrome is caused by tumors or hyperplasia of the adrenal cortex. The molecular pathogenesis of cortisol-producing adrenal adenomas is not well understood. METHODS: We performed exome sequencing of tumor-tissue specimens from 10 patients with cortisol-producing adrenal adenomas and evaluated recurrent mutations in candidate genes in an additional 171 patients with adrenocortical tumors. We also performed genomewide copy-number analysis in 35 patients with cortisol-secreting bilateral adrenal hyperplasias. We studied the effects of these genetic defects both clinically and in vitro. RESULTS: Exome sequencing revealed somatic mutations in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase (protein kinase A [PKA]), in 8 of 10 adenomas (c.617A→C in 7 and c.595_596insCAC in 1). Overall, PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome; these mutations were not detectable in 40 patients with subclinical hypercortisolism or in 82 patients with other adrenal tumors. Among 35 patients with cortisol-producing hyperplasias, 5 (including 2 first-degree relatives) carried a germline copy-number gain (duplication) of the genomic region on chromosome 19 that includes PRKACA. In vitro studies showed impaired inhibition of both PKA catalytic subunit mutants by the PKA regulatory subunit, whereas cells from patients with germline chromosomal gains showed increased protein levels of the PKA catalytic subunit; in both instances, basal PKA activity was increased. CONCLUSIONS: Genetic alterations of the catalytic subunit of PKA were found to be associated with human disease. Germline duplications of this gene resulted in bilateral adrenal hyperplasias, whereas somatic PRKACA mutations resulted in unilateral cortisol-producing adrenal adenomas. (Funded by the European Commission Seventh Framework Program and others.).

PURPOSE: Blinatumomab is a CD19/CD3 BiTE (bispecific T-cell engager) antibody construct for the treatment of Philadelphia chromosome-negative acute B-lymphoblastic leukemia. We evaluated blinatumomab in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: This 3 + 3 design, phase I dose-escalation study determined adverse events and the maximum tolerated dose (MTD) of continuous intravenous infusion blinatumomab in patients with relapsed/refractory NHL. Blinatumomab was administered over 4 or 8 weeks at seven different dose levels (0.5 to 90 μg/m(2)/day). End points were incidence of adverse events, pharmacokinetics, pharmacodynamics, and overall response rate. RESULTS: Between 2004 and 2011, 76 heavily pretreated patients with relapsed/refractory NHL, who included 14 with diffuse large B-cell lymphoma, were enrolled; 42 received treatment in the formal dose-escalation phase. Neurologic events were dose limiting, and 60 μg/m(2)/day was established as the MTD. Thirty-four additional patients were recruited to evaluate antilymphoma activity and strategies for mitigating neurologic events at a prespecified MTD. Stepwise dosing (5 to 60 μg/m(2)/day) plus pentosan polysulfate SP54 (n = 3) resulted in no treatment discontinuations; single-step (n = 5) and double-step (n = 24) dosing entailed two and seven treatment discontinuations due to neurologic events, respectively. Grade 3 neurologic events occurred in 22% of patients (no grade 4/5). Among patients treated at 60 μg/m(2)/day (target dose; n = 35), the overall response rate was 69% across NHL subtypes and 55% for diffuse large B-cell lymphoma (n = 11); median response duration was 404 days (95% CI, 207 to 1,129 days). CONCLUSION: In this phase I study of relapsed/refractory NHL, continuous infusion with CD19-targeted immunotherapy blinatumomab at various doses and schedules was feasible, with an MTD of 60 μg/m(2)/day. Single-agent blinatumomab showed antilymphoma activity.

•This updated ESMO Clinical Practice Guideline provides key recommendations on the management of adrenal cancer.•Authorship includes a multidisciplinary group of experts from different institutions and countries in Europe.•Detailed guidance on diagnosis, classification, treatment and follow-up is provided for both adrenocortical carcinoma and malignant phaeochromocytoma.•Recommendations are provided in the text, including levels of evidence and grades of recommendation, where applicable.•Due to the rarity of the adrenocortical carcinoma and malignant phaeochromocytoma, there is a clear recommendation to consult expert centres. Two different primary malignancies can arise from the adrenal gland: adrenocortical carcinoma (ACC) from the adrenal cortex and malignant phaeochromocytoma from the adrenal medulla. Both malignancies are rare. ACC has an estimated incidence of ∼0.5-2 new cases per million people per year.1Kerkhofs T.M. Verhoeven R.H. Van der Zwan J.M. et al.Adrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993.Eur J Cancer. 2013; 49: 2579-2586Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar,2Kebebew E. Reiff E. Duh Q.Y. et al.Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress?.World J Surg. 2006; 30: 872-878Crossref PubMed Scopus (318) Google Scholar Phaeochromocytomas are catecholamine-producing neuroendocrine tumours arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia. The latter are usually called paraganglioma, leading to the combined term phaeochromocytomas and paragangliomas (PPGLs). The detected incidence of PPGLs is commonly reported at 2-8 per million per year3Pacak K. Eisenhofer G. Ahlman H. et al.Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005.Nat Clin Pract Endocrinol Metab. 2007; 3: 92-102Crossref PubMed Scopus (517) Google Scholar (supplementary information, available at https://doi.org/10.1016/j.annonc.2020.08.2099). All patients with suspected and proven ACC or PPGL should be discussed in a multidisciplinary expert team meeting, at least at the time of initial diagnosis (ideally before surgery) and in case of progressive disease. Every patient with (suspected) ACC or PPGL should undergo careful clinical assessment, including case history, clinical examination for symptoms and signs of adrenal hormone excess. For more details on this topic, we refer to more comprehensive guidelines and reviews.3Pacak K. Eisenhofer G. Ahlman H. et al.Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005.Nat Clin Pract Endocrinol Metab. 2007; 3: 92-102Crossref PubMed Scopus (517) Google Scholar, 4Fassnacht M. Dekkers O.M. Else T. et al.European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2018; 179: G1-G46Crossref PubMed Scopus (403) Google Scholar, 5Lenders J.W. Duh Q.Y. Eisenhofer G. et al.Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.J Clin Endocrinol Metab. 2014; 99: 1915-1942Crossref PubMed Scopus (1471) Google Scholar, 6Amar L. Servais A. Gimenez-Roqueplo A.P. et al.Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma.J Clin Endocrinol Metab. 2005; 90: 2110-2116Crossref PubMed Scopus (283) Google Scholar, 7Fassnacht M. Libe R. Kroiss M. Allolio B. Adrenocortical carcinoma: a clinician's update.Nat Rev Endocrinol. 2011; 7: 323-335Crossref PubMed Scopus (302) Google Scholar, 8Mansmann G. Lau J. Balk E. et al.The clinically inapparent adrenal mass: update in diagnosis and management.Endocr Rev. 2004; 25: 309-340Crossref PubMed Scopus (602) Google Scholar The aims of hormonal evaluation are multiple: (i) hormone assays provide orientation to the nature of the adrenal mass and can be useful to assess presence of malignancy; (ii) a phaeochromocytoma should always be ruled out, because these tumours can induce life-threatening crises, requiring specific management before any intervention; (iii) massive adrenocortical steroid excess can impact short-term survival and quality of life (QoL), requiring specific treatments to block impacts of hormonal excess; (iv) abnormal hormone secretions may serve as biological markers for the follow-up of patients; (v) in case of large bilateral adrenal masses, a systematic assessment of adrenal function is recommended to rule out adrenal insufficiency. Precise hormone assays have been detailed in recent guideline statements,4Fassnacht M. Dekkers O.M. Else T. et al.European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2018; 179: G1-G46Crossref PubMed Scopus (403) Google Scholar,5Lenders J.W. Duh Q.Y. Eisenhofer G. et al.Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.J Clin Endocrinol Metab. 2014; 99: 1915-1942Crossref PubMed Scopus (1471) Google Scholar,9Plouin P.F. Amar L. Dekkers O.M. et al.European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma.Eur J Endocrinol. 2016; 174: G1-G10Crossref PubMed Scopus (251) Google Scholar,10Fassnacht M. Arlt W. Bancos I. et al.Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2016; 175: G1-G34Crossref PubMed Scopus (853) Google Scholar and are summarised in Table 1.Table 1Diagnostic work-up of (suspected) adrenal- or paraganglioma-related malignanciesSpecific questionAssaysIndication(Suspected) ACC Exclusion of glucocorticoid excess?1 mg dexamethasone suppression testAll adrenal masses with no overt Cushing (clinically) Characterisation of glucocorticoid excess?1 mg dexamethasone suppression testFree cortisol in 24-h urineBasal ACTH (plasma)Adrenal masses with clinical signs of Cushing or pathological 1 mg dexamethasone test Sex steroids and steroid precursors excess?DHEA-S17-OH progesteroneAndrostenedioneTestosterone (only in women)17-beta-oestradiol (only in men and postmenopausal women)11-deoxycortisol (if available)Any adrenal mass suspected to be an ACC Mineralocorticoid excess?PotassiumAldosterone/renin ratioAny adrenal masses with hypertension and/or hypokalaemia Extension of the adrenal tumour and evidence for metastases?CT or MRI of abdomen, pelvis and chest (or FDG-PET/CT including full-dose CT)All suspected ACCs Evidence of cerebral metastases?Cerebral MRTOnly if cerebral metastases are suspected Evidence of bone metastasesFDG-PET/CT, bone scan, bone CT or bone MRIOnly if skeletal metastases are suspected(Suspected) PPGL Catecholamine excess?Fractionated metanephrines in 24-h urine or plasma-free metanephrines and methoxytyramineAll adrenal masses and all paraganglioma Extension of the adrenal tumour?CT or MRI of abdomenAll biochemically confirmed phaeochromocytoma Evidence of thoracic metastases?Chest CT (or PET/CT including full-dose CT)All PPGL patients with a 'high risk of metastases'aThe authors suggest being at a 'high risk of metastases' applies to all patients who fulfil one or more of the following criteria: adrenal phaeochromocytoma ≥5 cm or any extra-adrenal paraganglioma or known SDHB germline mutation or plasma methoxytyramine more than threefold above the upper reference limit. Evidence of cerebral metastases?Cerebral MRTOnly if cerebral metastases are suspected Evidence of bone metastasesFDG-PET/CT, DOTATATE-PET/CT, bone scan, bone CT or bone MRIOnly if skeletal metastases are suspectedbSome authors are in favour of carrying out functional imaging to detect bone metastases in all PPGL patients. Additional functional imaging?At least one functional whole-body imaging (i.e. FDG-PET, DOTATATE-PET, MIBG scintigraphy)In all PPGL patients with a 'high risk of metastases'aThe authors suggest being at a 'high risk of metastases' applies to all patients who fulfil one or more of the following criteria: adrenal phaeochromocytoma ≥5 cm or any extra-adrenal paraganglioma or known SDHB germline mutation or plasma methoxytyramine more than threefold above the upper reference limit. Radionuclide therapy possible?MIBG scintigraphy and somatostatin-based imaging (e.g. DOTATATE-PET/CT)In all PPGL patients with evidence for metastases17-OH, 17-hydroxy; ACC, adrenocortical carcinoma; ACTH, adrenocorticotropic hormone; CT, computed tomography; DHEA-S, dehydroepiandrosterone sulfate; FDG-PET, 2-fluoro-2-deoxy-d-glucose-positron electron tomography; MIBG, meta-iodobenzylguanidine; MRI, magnetic resonance imaging; MRT, magnetic resonance tomography; PPGL, phaeochromocytoma and paraganglioma; SDHB, succinate dehydrogenase complex iron sulfur subunit B.a The authors suggest being at a 'high risk of metastases' applies to all patients who fulfil one or more of the following criteria: adrenal phaeochromocytoma ≥5 cm or any extra-adrenal paraganglioma or known SDHB germline mutation or plasma methoxytyramine more than threefold above the upper reference limit.b Some authors are in favour of carrying out functional imaging to detect bone metastases in all PPGL patients. Open table in a new tab 17-OH, 17-hydroxy; ACC, adrenocortical carcinoma; ACTH, adrenocorticotropic hormone; CT, computed tomography; DHEA-S, dehydroepiandrosterone sulfate; FDG-PET, 2-fluoro-2-deoxy-d-glucose-positron electron tomography; MIBG, meta-iodobenzylguanidine; MRI, magnetic resonance imaging; MRT, magnetic resonance tomography; PPGL, phaeochromocytoma and paraganglioma; SDHB, succinate dehydrogenase complex iron sulfur subunit B. For all adrenal masses, the diagnosis of phaeochromocytoma should be systematically assessed by measuring plasma-free or urinary-fractionated metanephrines [V, A].5Lenders J.W. Duh Q.Y. Eisenhofer G. et al.Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.J Clin Endocrinol Metab. 2014; 99: 1915-1942Crossref PubMed Scopus (1471) Google Scholar,10Fassnacht M. Arlt W. Bancos I. et al.Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2016; 175: G1-G34Crossref PubMed Scopus (853) Google Scholar Additional measurements of plasma methoxytyramine, a biomarker now increasingly available, provide useful information to assess the likelihood of malignancy.11Eisenhofer G. Lenders J.W. Siegert G. et al.Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status.Eur J Cancer. 2012; 48: 1739-1749Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar In cases of suspected ACC, an extensive steroid hormone work-up is recommended, assessing gluco-, mineralo-, sex- and precursor-steroids ([V, B] (Table 1)).12Arlt W. Biehl M. Taylor A.E. et al.Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors.J Clin Endocrinol Metab. 2011; 96: 3775-3784Crossref PubMed Scopus (305) Google Scholar, 13Taylor D.R. Ghataore L. Couchman L. et al.A 13-steroid serum panel based on LC-MS/MS: use in detection of adrenocortical carcinoma.Clin Chem. 2017; 63: 1836-1846Crossref PubMed Scopus (66) Google Scholar, 14Hines J.M. Bancos I. Bancos C. et al.High-resolution, accurate-mass (HRAM) mass spectrometry urine steroid profiling in the diagnosis of adrenal disorders.Clin Chem. 2017; 63: 1824-1835Crossref PubMed Scopus (63) Google Scholar, 15Schweitzer S. Kunz M. Kurlbaum M. et al.Plasma steroid metabolome profiling for the diagnosis of adrenocortical carcinoma.Eur J Endocrinol. 2018; 180: 117-125Crossref Scopus (40) Google Scholar, 16Kerkhofs T.M. Kerstens M.N. Kema I.P. et al.Diagnostic value of urinary steroid profiling in the evaluation of adrenal tumors.Horm Cancer. 2015; 6: 168-175Crossref PubMed Scopus (65) Google Scholar For best patient care, adequate visualisation of the tumour and potential metastases is essential. For differential diagnosis of an adrenal mass, computed tomography (CT) and magnetic resonance imaging (MRI) are both effective [IV, A]. Although these methods cannot determine the exact entity of the mass, both are able to correctly diagnose a subset of benign tumours—at least when carried out according to state-of-the-art criteria. The single best criterion to diagnose a benign tumour (e.g. adenoma) remains Hounsfield units ≤10 in an unenhanced CT.17Dinnes J. Bancos I. Ferrante di Ruffano L. et al.Management of endocrine disease: imaging for the diagnosis of malignancy in incidentally discovered adrenal masses: a systematic review and meta-analysis.Eur J Endocrinol. 2016; 175: R51-R64Crossref PubMed Scopus (113) Google Scholar However, other imaging criteria, such as rapid washout in 10- or 15-min delayed contrast-enhanced CT, signal intensity loss using opposed-phase MRI, and low 2-fluorine-18 [18F]fluoro-2-deoxy-d-glucose (FDG) uptake in [18F]FDG-positron electron tomography (PET)/CT are also suggestive of a benign tumour. Most ACCs show an inhomogeneous appearance in CT or MRI with irregular margins and irregular enhancement of solid components after intravenous injection of contrasted agent. Detection of local invasion or tumour extension into the inferior vena cava, as well as lymph node or other metastases—including lung and liver—is mandatory before planning any surgery. Therefore, cross-sectional imaging of the chest, abdomen and pelvis is required preoperatively [V, A]. For PPGLs, conventional radiological imaging can be important to determine the presence of metastases. However, neither CT nor MRI can be used to determine whether PPGLs are benign or malignant. Malignancy can only be determined from the presence of metastatic lesions at sites where chromaffin cells are normally absent. Without such evidence, all PPGLs should be considered potentially malignant, with risk dependent on several factors as outlined below. There are a number of functional imaging modalities available for patients with PPGLs (supplementary File, available at https://doi.org/10.1016/j.annonc.2020.08.2099). The indication is twofold: (i) best tumour staging in patients with suspected metastases (e.g. by conventional imaging) or with presumably high risk for metastases; (ii) to evaluate the option of a radionuclide-based therapy in patients with nonresectable PPGL. For assessments of metastatic risk for the first indication the authors suggest the presence of one or more of the following criteria:•tumour size ≥5 cm;•any extra-adrenal paraganglioma;•known succinate dehydrogenase complex iron sulfur subunit B (SDHB) germline mutation; or•plasma methoxytyramine more than threefold above the upper cut-offs of reference intervals. For imaging-based diagnosis of metastatic PPGLs, it is important to avoid confusing metastases with multiple primary tumours that often occur in patients with hereditary PPGL syndromes. Additionally, local recurrences should not be misdiagnosed as metastases. Biopsy of adrenal tumours is usually contraindicated because of the risk of tumour spillage, poor diagnostic power to discriminate benign from malignant adrenocortical tumours and risk of hypertensive crises in phaeochromocytoma. However, a biopsy might be indicated in an adrenal mass without any hormone excess in patients with a history of extra-adrenal cancers to exclude or prove an adrenal metastasis of an extra-adrenal malignancy, and in patients in whom tumour sequencing is desired. The pathological differential diagnosis of adrenal neoplasias in both biopsied and resected specimens is primarily based on morphological features requiring an experienced pathologist [IV, A]. Preferably, a panel of immunohistochemical markers should be applied to aid diagnosis; for example, steroidogenesis factor 1 (SF1) or, alternatively, inhibin-alpha, calretinin and melan-A for identification of adrenocortical tumours and chromogranin A for identification of PPGL [IV, A]. Staining for tyrosine hydroxylase and synaptophysin may also be helpful to highlight PPGL, but positive results for synaptophysin are also possible in adrenocortical tumours. The differential diagnosis between ACC and adenoma may be challenging as no single marker indicates malignancy. The most widely used diagnostic score has been introduced by Weiss18Weiss L.M. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors.Am J Surg Pathol. 1984; 8: 163-169Crossref PubMed Scopus (768) Google Scholar,19Weiss L.M. Medeiros L.J. Vickery Jr., A.L. Pathologic features of prognostic significance in adrenocortical carcinoma.Am J Surg Pathol. 1989; 13: 202-206Crossref PubMed Scopus (653) Google Scholar and includes nine parameters (supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.08.2099) [IV, A]. A score of ≥3 suggests malignancy. In addition, the Ki-67 labelling index, as a marker of proliferative activity, may be useful and is very helpful for prognostic purposes (supplementary Tables S2 and S3, available at https://doi.org/10.1016/j.annonc.2020.08.2099). For phaeochromocytomas, the situation is similarly demanding. Tumour size, SDHB mutation status, extra-adrenal location and plasma methoxytyramine may all be used to indicate risk of metastasis. However, there is no single histological or immunohistochemical parameter that can predict the clinical behaviour of PPGL. Nevertheless, several histological scoring systems have been developed.20Thompson L.D. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases.Am J Surg Pathol. 2002; 26: 551-566Crossref PubMed Scopus (494) Google Scholar, 21Kimura N. Takayanagi R. Takizawa N. et al.Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma.Endocr Relat Cancer. 2014; 21: 405-414Crossref PubMed Scopus (193) Google Scholar, 22Koh J.M. Ahn S.H. Kim H. et al.Validation of pathological grading systems for predicting metastatic potential in pheochromocytoma and paraganglioma.PLoS One. 2017; 12: e0187398Crossref PubMed Scopus (45) Google Scholar, 23Pierre C. Agopiantz M. Brunaud L. et al.COPPS, a composite score integrating pathological features, PS100 and SDHB losses, predicts the risk of metastasis and progression-free survival in pheochromocytomas/paragangliomas.Virchows Arch. 2019; 474: 721-734Crossref PubMed Scopus (19) Google Scholar All these scores have value but none of them has reached general acceptance. Therefore, according to the current World Health Organization (WHO) classification, all PPGLs should be considered to have some malignant potential.24Lloyd R.V. Osamura R.Y. Klöppel G. Rosai J. WHO Classification of Tumours of Endocrine Organs. IARC, Lyon, France2017Google Scholar A definitive diagnosis of malignancy can only be made by the presence of metastases at sites where chromaffin tissue is normally absent (e.g. liver, bone, lungs or lymph nodes), assessed by pathology or imaging, in particular functional imaging. Molecular characterisation of ACC (supplementary File, available at https://doi.org/10.1016/j.annonc.2020.08.2099) and PPGL is an active area of ongoing research. The gene encoding subunit B of the SDHB complex is by far the most important molecular contributor to malignant PPGL, with at least 40% of all cases of metastatic PPGLs carrying mutations of this gene.25Brouwers F.M. Eisenhofer G. Tao J.J. et al.High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing.J Clin Endocrinol Metab. 2006; 91: 4505-4509Crossref PubMed Scopus (256) Google Scholar Inactivation of SDHB reduces function of the succinate dehydrogenase complex, leading to activation of the hypoxia-inducible pathway and a pseudohypoxic state characterised by increased angiogenesis, growth and expression of mitogenic factors,26Jochmanova I. Yang C. Zhuang Z. Pacak K. Hypoxia-inducible factor signaling in pheochromocytoma: turning the rudder in the right direction.J Natl Cancer Inst. 2013; 105: 1270-1283Crossref PubMed Scopus (126) Google Scholar but also to DNA hypermethylation, which is believed to provide a further drive to metastatic progression.27Letouze E. Martinelli C. Loriot C. et al.SDH mutations establish a hypermethylator phenotype in paraganglioma.Cancer Cell. 2013; 23: 739-752Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar At least 35% of PPGLs result from germline mutations of over 18 tumour-susceptibility genes identified to date,28Dahia P.L. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic Rev Cancer. 2014; PubMed Scopus Google Scholar, Jr., T. et of the practice in the diagnosis and management of Relat Cancer. 2018; 25: PubMed Scopus Google Scholar, J. Pacak K. on pheochromocytoma and paraganglioma: a molecular Rev. 2017; PubMed Scopus Google Scholar, N. A. et on diagnostic of hereditary phaeochromocytomas and Rev Endocrinol. 2017; 13: PubMed Scopus Google Scholar, L. J. K. update on the of it to 2019; PubMed Scopus Google Scholar, J. A. S. et in pheochromocytoma and paraganglioma.Endocr Relat Cancer. 2019; 26: PubMed Scopus (63) Google Scholar with in of hypoxia-inducible factors and and carrying a risk of metastatic disease than to other mutations (supplementary Table available at https://doi.org/10.1016/j.annonc.2020.08.2099). is in patients with PPGL to mutations in the SDHB L. J. E. et in pheochromocytoma or functional paraganglioma.J Clin 2005; 23: PubMed Scopus Google Scholar The of all metastatic PPGLs, including disease to SDHB from or PPGLs with Nevertheless, a of of metastatic PPGLs from adrenal tumours that are characterised by of as by increased plasma or urinary M. et of of SDHB mutation in metastatic J Endocrinol. 2015; PubMed Scopus Google Scholar metastatic disease may only after the primary tumour is and in some patients of disease the of recommendations for follow-up of all patients with resected P.F. Amar L. Dekkers O.M. et al.European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma.Eur J Endocrinol. 2016; 174: G1-G10Crossref PubMed Scopus (251) Google Scholar patients with an adrenal tumour suspected to be an ACC or a phaeochromocytoma should undergo careful clinical assessment for signs of adrenal hormone patients with suspected and proven ACC or PPGL should be discussed in a multidisciplinary expert team meeting, at least at the time of initial diagnosis and in case of progressive patients with suspected ACC a comprehensive endocrine work-up to potential excess of and adrenocortical steroid hormone precursors [IV, imaging for patients with suspected ACC includes at least CT or MRI and chest CT (or [IV, of suspected ACC are usually not and should be ACC is by a score ≥3 [IV, A]. diagnosis should be carried out by an experienced endocrine Ki-67 to the risk of patients with suspected PPGL the of plasma or urinary metanephrines [V, A]. of disease is primarily based on (i) the presence of symptoms or other of excess; (ii) adrenal or (iii) to high risk with hereditary or history of all patients with 'high risk of metastases' a chest CT and at least one functional whole-body imaging FDG-PET, DOTATATE-PET, is recommended in to of suspected PPGL are contraindicated in most PPGLs are by the presence of metastasis. However, all PPGLs are considered to have some malignant In the assessment of disease the authors the metastasis by the European Network for the Study of Adrenal Tumours (supplementary Table available at https://doi.org/10.1016/j.annonc.2020.08.2099) [IV, M. S. M. et prognostic value of the International Cancer staging for adrenocortical carcinoma: for a PubMed Scopus (503) Google Scholar because this to be to other staging systems and is by the for International Cancer and R.V. Osamura R.Y. Klöppel G. Rosai J. WHO Classification of Tumours of Endocrine Organs. IARC, Lyon, France2017Google Scholar indicated above for at least a CT of the chest, abdomen and pelvis (or FDG-PET/CT including full-dose is suggest that lymph node with than R. I. et factors in adrenocortical an European Network for the Study of Adrenal 2015; 26: Full Text Full Text PDF PubMed Scopus Google Scholar the of ACC is However, suggest that in patients with of a tumour survival can be as high as M. S. W. et survival in patients with adrenocortical carcinoma by Clin Endocrinol Metab. PubMed Scopus Google Scholar In metastatic ACC, survival is However, in this there is a of patients with long-term M. S. M. et prognostic value of the International Cancer staging for adrenocortical carcinoma: for a PubMed Scopus (503) Google R. I. et factors in adrenocortical an European Network for the Study of Adrenal 2015; 26: Full Text Full Text PDF PubMed Scopus Google Scholar is well established that disease and are the most important prognostic factors in For the European Society of Endocrinology a comprehensive for prognostic factors has been carried out and only the marker Ki-67 and glucocorticoid excess a with [IV, (supplementary Table available at M. Dekkers O.M. Else T. et al.European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2018; 179: G1-G46Crossref PubMed Scopus (403) Google T. M. G. Dekkers O.M. of hormonal functional on survival in adrenocortical carcinoma: systematic review and meta-analysis.Eur J Endocrinol. 2018; 179: PubMed Scopus Google Scholar other markers for and survival have been but clinical use In the WHO a tumour staging for PPGL (supplementary Table available at R.V. Osamura R.Y. Klöppel G. Rosai J. WHO Classification of Tumours of Endocrine Organs. IARC, Lyon, France2017Google Scholar Although this staging remains to be the authors

Adrenocortical carcinoma (ACC) is an orphan malignancy that has attracted increasing attention during the last decade. Here we provide an update on advances in the field since our last review published in this journal in 2006. The Wnt/β-catenin pathway and IGF-2 signaling have been confirmed as frequently altered signaling pathways in ACC, but recent data suggest that they are probably not sufficient for malignant transformation. Thus, major players in the pathogenesis are still unknown. For diagnostic workup, comprehensive hormonal assessment and detailed imaging are required because in most ACCs, evidence for autonomous steroid secretion can be found and computed tomography or magnetic resonance imaging (if necessary, combined with functional imaging) can differentiate benign from malignant adrenocortical tumors. Surgery is potentially curative in localized tumors. Thus, we recommend a complete resection including lymphadenectomy by an expert surgeon. The pathology report should demonstrate the adrenocortical origin of the lesion (eg, by steroidogenic factor 1 staining) and provide Weiss score, resection status, and quantitation of the proliferation marker Ki67 to guide further treatment. Even after complete surgery, recurrence is frequent and adjuvant mitotane treatment improves outcome, but uncertainty exists as to whether all patients benefit from this therapy. In advanced ACC, mitotane is still the standard of care. Based on the FIRM-ACT trial, mitotane plus etoposide, doxorubicin, and cisplatin is now the established first-line cytotoxic therapy. However, most patients will experience progress and require salvage therapies. Thus, new treatment concepts are urgently needed. The ongoing international efforts including comprehensive "-omic approaches" and next-generation sequencing will improve our understanding of the pathogenesis and hopefully lead to better therapies.

BACKGROUND: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. METHODS: ). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. FINDINGS: molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. INTERPRETATION: because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. FUNDING: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.

The Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP–RTSG) has developed a new protocol for the diagnosis and treatment of childhood renal tumours, the UMBRELLA SIOP–RTSG 2016 (the UMBRELLA protocol). In this Consensus Statement, members of SIOP–RTSG outline the rationale for the recommendations in the protocol. The Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP–RTSG) has developed a new protocol for the diagnosis and treatment of childhood renal tumours, the UMBRELLA SIOP–RTSG 2016 (the UMBRELLA protocol), to continue international collaboration in the treatment of childhood renal tumours. This protocol will support integrated biomarker and imaging research, focussing on assessing the independent prognostic value of genomic changes within the tumour and the volume of the blastemal component that survives preoperative chemotherapy. Treatment guidelines for Wilms tumours in the UMBRELLA protocol include recommendations for localized, metastatic, and bilateral disease, for all age groups, and for relapsed disease. These recommendations have been established by a multidisciplinary panel of leading experts on renal tumours within the SIOP–RTSG. The UMBRELLA protocol should promote international collaboration and research and serve as the SIOP–RTSG best available treatment standard.