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Lymphomas of the breast are rare neoplasms that arise from breast lymphoid tissue and are characterised by neoplastic B or T cells. Breast lymphomas arising from B cells include, but are not limited to, diffuse large B cell lymphoma, follicular lymphoma, extra-nodal marginal zone lymphoma and Burkitt lymphoma. Anaplastic large cell lymphoma (ALCL) is of a T cell origin and both anaplastic lymphoma kinase (ALK)-positive and ALK-negative presentations have been noted in the breast. In addition, there is a more recently identified presentation of ALK-negative ALCL that arises around textured breast implants and is usually confined to a periprosthetic fibrous capsule. Here, we discuss the clinical presentations, histological and immunohistochemical features and treatment options for each type of primary breast lymphoma. We hope that this review will highlight the importance of the timely and accurate diagnosis of breast lymphoma in order to tailor the most appropriate treatment. We also wish to raise awareness of the breast implant-associated lymphomas, with the goal of stimulating work that will aid our understanding of their epidemiology and pathogenesis.

The European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL) was established 25 years ago with the goal to facilitate clinical trials and research collaborations in the field both within Europe and worldwide. Since its inception, much progress has been made whereby major improvements in outcomes have been achieved. In this Review, we describe the different diagnostic entities of non-Hodgkin lymphoma in children and young adults describing key features of each entity and outlining clinical achievements made in the context of the EICNHL framework. Furthermore, we provide an overview of advances in biopathology with an emphasis on the role of biological studies and how they have shaped available treatments. Finally, for each entity, we describe future goals, upcoming clinical trials, and highlight areas of research that require our focus going forward.

Mature non-Hodgkin lymphomas (NHL) in the childhood, adolescent and young adult (CAYA) population are rare and exhibit unique clinical, immunophenotypic and genetic characteristics. Application of large-scale unbiased genomic and proteomic technologies such as gene expression profiling and next generation sequencing (NGS) have led to enhanced understanding of the genetic basis for many lymphomas in adults. However, studies to investigate the pathogenetic events in CAYA population are relatively sparse. Enhanced understanding of the pathobiologic mechanisms involved in non-Hodgkin lymphomas in this unique population will allow for improved recognition of these rare lymphomas. Elucidation of the pathobiologic differences between CAYA and adult lymphomas will also lead to the design of more rational and much needed, less toxic therapies for this population. In this review, we summarize recent insights gained from the proceedings of the recent 7th International CAYA NHL Symposium held in New York City, New York October 20-23, 2022.

Simple Summary T-cell lymphoma is a cancer of the immune system. One specific sub-type of T-cell lymphoma is a malignancy called anaplastic large cell lymphoma (ALCL), which is distinct from the other forms, as in general, it has a better prognosis. Research conducted to understand why ALCL develops has shown that a specific genetic event occurs, whereby a new protein is created that drives tumour growth. This protein is called nucleophosmin–anaplastic lymphoma kinase (NPM-ALK). Our research, described here, shows that NPM-ALK regulates another protein, called BRG1, to drive proliferation of tumour cells. In turn, when the gene that leads to expression of BRG1 is inactivated, the tumour cells die. These data suggest that therapeutic targeting of BRG1 might be a novel therapy for this form of cancer. Abstract Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin–anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL.

Simple Summary In general, the non-Hodgkin lymphoma (NHL), anaplastic large cell lymphoma (ALCL) diagnosed in childhood has a good survival outcome when treated with multi-agent chemotherapy. However, side effects of treatment are common, and outcomes are poorer after relapse, which occurs in up to 30% of cases. New drugs are required that are more effective and have fewer side effects. Targeted therapies are potential solutions to these problems, however, the development of resistance may limit their impact. This review summarises the potential resistance mechanisms to these targeted therapies. Abstract Non-Hodgkin lymphoma (NHL) is the third most common malignancy diagnosed in children. The vast majority of paediatric NHL are either Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma (LL). Multi-agent chemotherapy is used to treat all of these types of NHL, and survival is over 90% but the chemotherapy regimens are intensive, and outcomes are generally poor if relapse occurs. Therefore, targeted therapies are of interest as potential solutions to these problems. However, the major problem with all targeted agents is the development of resistance. Mechanisms of resistance are not well understood, but increased knowledge will facilitate optimal management strategies through improving our understanding of when to select each targeted agent, and when a combinatorial approach may be helpful. This review summarises currently available knowledge regarding resistance to targeted therapies used in paediatric anaplastic lymphoma kinase (ALK)-positive ALCL. Specifically, we outline where gaps in knowledge exist, and further investigation is required in order to find a solution to the clinical problem of drug resistance in ALCL.

Aim Neuroblastoma is a heterogeneous childhood cancer derived from the neural crest. The dual cell identities of neuroblastoma include Mesenchymal (MES) and Adrenergic (ADRN). These identities are conferred by a small set of tightly-regulated transcription factors (TFs) binding super enhancers, collectively forming core regulatory circuitries (CRCs). The purpose of this study was to gain a deep understanding of the role of MES and ADRN TFs in neuroblastoma and other cancers as potential indicators of disease prognosis, progression, and relapse. Methods To that end, we first investigated the expression and mutational profile of MES and ADRN TFs in neuroblastoma. Moreover, we established their correlation with neuroblastoma risk groups and overall survival while establishing their extended networks with long non-coding RNAs (lncRNAs). Furthermore, we analysed the pan-cancer expression and mutational profile of these TFs and their correlation with patient survival and finally their network connectivity, using a panel of bioinformatic tools including GEPIA2, human pathology atlas, TIMER2, Omicsnet, and Cytoscape. Results We show the association of multiple MES and ADRN TFs with neuroblastoma risk groups and overall survival and find significantly higher expression of various MES and ADRN TFs compared to normal tissues and their association with overall survival and disease-free survival in multiple cancers. Moreover, we report the strong correlation of the expression of these TFs with the infiltration of stromal and immune cells in the tumour microenvironment and with stemness and metastasis-related genes. Furthermore, we reveal extended pan-cancer networks comprising these TFs that influence the tumour microenvironment and metastasis and may be useful indicators of cancer prognosis and patient survival. Conclusion Our meta-analysis shows the significance of MES and ADRN TFs as indicators of patient prognosis and the putative utility of these TFs as potential novel biomarkers.

Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally-reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, EMT, and signalling pathways.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon T cell Non-Hodgkin Lymphoma (NHL) associated with breast implants. Raising awareness of the possibility of BIA-ALCL in anyone with breast implants and new breast symptoms is crucial to early diagnosis. The tumour begins on the inner aspect of the peri-implant capsule causing an effusion, or less commonly a tissue mass to form within the capsule, which may spread locally or to more distant sites in the body. Diagnosis is usually made by cytological, immunohistochemical and immunophenotypic evaluation of the peri-implant fluid: pleomorphic lymphocytes are characteristically anaplastic lymphoma kinase (ALK) negative and strongly positive for CD30. BIA-ALCL is indolent in most patients but can progress rapidly. Surgical removal of the implant with the intact surrounding capsule (total en-bloc capsulectomy) is usually curative. Late diagnosis may require more radical surgery and systemic therapies and although these are usually successful, poor outcomes and deaths have been reported. By adopting a structured approach, as suggested in these guidelines, early diagnosis and successful treatment will minimize the need for systemic treatments, reduce morbidity and the risk of poor outcomes. These guidelines provide an evidence-based and systematic framework for the assessment and treatment of patients with suspected or proven BIA-ALCL and are aimed at all clinicians involved in the care of people with breast implants.

Patients diagnosed with anaplastic large cell lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, we performed whole-exome sequencing of anaplastic lymphoma kinase (ALK)+ ALCL, as well as gene-set enrichment analysis. This revealed that the T-cell receptor and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK– ALCL patients’ samples. Furthermore, we demonstrated that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ- secretase inhibitors or silencing by short hairpin RNA leads to apoptosis; cotreatment in vitro with the ALK inhibitor crizotinib led to additive/synergistic antitumor activity suggesting that this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, crizotinib-resistant and -sensitive ALCL were equally sensitive to γ-secretase inhibitors. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL.

Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor–relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance–specific relapse.

Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase aberrantly expressed in a variety of tumor types, most notably in Anaplastic Large Cell Lymphoma (ALCL) where a chromosomal translocation generates the oncogenic fusion protein, Nucleophosmin-ALK (NPM-ALK). Whilst much is known regarding the mechanism of transformation by NPM-ALK, the existence of cellular defence pathways to prevent this pathological process has not been investigated. Employing the highly tractable primary murine embryonic fibroblast (MEF) system we show that cellular transformation is not an inevitable consequence of NPM-ALK activity but is combated by p53 and Rb. Activation of p53 and/or Rb by NPM-ALK triggers a potent proliferative block with features reminiscent of senescence. While loss of p53 alone is sufficient to circumvent NPM-ALK-induced senescence and permit cellular transformation, sole loss of Rb permits continued proliferation but not transformation due to p53-imposed restraints. Furthermore, NPM-ALK attenuates p53 activity in an Rb and MDM2 dependent manner but this activity is not sufficient to bypass senescence. These data indicate that senescence may constitute an effective barrier to ALK-induced malignancies that ultimately must be overcome for tumor development.

Calculating risk factors is inherently difficult when the real exposure is unknown1. This is particularly true of breast implant associated anaplastic large cell lymphoma (BIA-ALCL) whereby the true number of breast implants that make their way into human bodies is not known. As such, best estimates have been derived from sales data, rather than implant registries although with the advent of the latter, it is hoped that this will significantly improve, but of course this will be dependent on uptake in the use of registries by surgeons2. This recent publication from Australia describes data collection both retrospectively and prospectively (October 2015-May 2019) conducted to deduce the risk of BIA-ALCL with respect to the implant manufacturer, surface area and texture as well as the certification status of the practicing surgeon3. In addition, this work takes account of the number of implants received by each patient and accounts for the manufacturer of the last implant in place at the time of diagnosis. Notably, the last implant in every case (n=27 women with multiple implants) is of a textured variety with 52% being Allergan Biocell implants3.

Background: MYCN amplification (MNA) is the strongest indicator of poor prognosis in neuroblastoma (NB). This meta-analysis aims to determine the diagnostic accuracy of MNA analysis in circulating-free DNA (cfDNA) from advanced-stage NB patients. Methods: A systematic review of electronic databases was conducted to identify studies exploring the detection of MNA in plasma/serum cfDNA from NB patients at diagnosis using PCR methodology. Pooled estimates for sensitivity, specificity and diagnostic odds ratio (DOR) were calculated by conducting a bivariate/HSROC random-effects meta-analysis. Results: Seven studies, with a total of 529 advanced-stage patients, were eligible. The pooled sensitivity of cfDNA-based MNA analysis was 0.908 (95% CI, 0.818–0.956), the pooled specificity was 0.976 (0.940–0.991) and the DOR was 410.0 (−103.6 to 923.7). Sub-grouped by INSS stage, the sensitivity for stage 3 and 4 patients was 0.832 (0.677–0.921) and 0.930 (0.834–0.972), respectively. The specificity was 0.999 (0.109–1.000) and 0.974 (0.937–0.990), respectively, and the DOR was 7855.2 (−66267.0 to 81977.4) and 508.7 (−85.8 to 1103.2), respectively. Conclusions: MNA analysis in cfDNA using PCR methodology represents a non-invasive approach to rapidly and accurately determine MNA status in patients with advanced-stage NB. Standardised methodology must be developed before this diagnostic test can enter the clinic.

Summary DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also enriched in MYC-translocated diffuse large B cell lymphoma and reveal functional cooperation between mutant DDX3X and MYC. DDX3X promotes the translation of mRNA encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y chromosome homolog, the expression of which is normally restricted to the testis. These findings show that DDX3X loss of function can buffer MYC-driven proteotoxic stress and highlight the capacity of male B cell lymphomas to then compensate for this loss by ectopic DDX3Y expression.

Anaplastic large cell lymphoma (ALCL) presents as one of 4 forms; systemic ALCL Anaplastic Lymphoma Kinase (ALK)-positive, systemic ALCL ALK-, cutaneous ALCL or breast implant associated ALCL (BIA-ALCL) 1. The latter 3 disease entities are all negative for ALK which is expressed in ALK-positive disease as the consequence of a chromosomal translocation1,2. Naturally, cutaneous disease is associated with skin presentation which is not an unusual feature of systemic disease but in the former case, disease is limited to the skin. In this publication, the authors report a case of ALCL associated with a burn scar on the breast whereby a palpable mass, nodules and papules were detected, with histopathology confirming an infiltration of large CD30+ cells with abundant clear cytoplasm and pleomorphic nuclei consistent with a diagnosis of ALCL (ref). The lack of ALK expression in this malignancy as well as the absence of breast implants places it firmly in the ALCL, ALK- category although an inability to detect nodal disease, involvement of the skin and a good response to therapy perhaps aligns it more with the cutaneous rather than systemic form of ALCL, yet palpable masses were seen (ref).

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a CD30-positive, anaplastic lymphoma kinase-negative T-cell lymphoma. Nearly all cases have been associated with textured implants. Most cases are of effusion-limited, indolent disease, with an excellent prognosis after implant and capsule removal. However, capsular invasion and tumor mass have a more aggressive course and a fatal outcome risk. This review summarizes the current knowledge on BIA-ALCL cell of origin and immunologic factors underlying its pathogenesis. Cytokine expression profiling of BIA-ALCL cell lines and clinical specimens reveals a predominantly type 17 helper T-cell (Th17)/Th1 signature, implicating this as its cell of origin. However, a Th2 allergic inflammatory response is suggested by the presence of IL-13, with infiltration of eosinophils and IgE-coated mast cells in clinical specimens of BIA-ALCL. The microenvironment-induced T-cell plasticity, a factor increasingly appreciated, may partially explain these divergent results. Mutations resulting in constitutive Janus kinase (JAK)-STAT activation have been detected and associated with BIA-ALCL pathogenesis in a small number of cases. One possible scenario is that an inflammatory microenvironment stimulates an immune response, followed by polyclonal expansion of Th17/Th1 cell subsets with release of inflammatory cytokines and chemokines and accumulation of seroma. JAK-STAT3 gain-of-function mutations within this pathway and others may subsequently lead to monoclonal T-cell proliferation and clinical BIA-ALCL. Current research suggests that therapies targeting JAK proteins warrant investigation in BIA-ALCL.

Despite advancements in new generations of biomaterials and medical devices, complications related to their use remain a burden for health care. In particular, healthcare-acquired infections (HAI) are a significant problem resulting in a variety of co-morbidities resulting in increased length of hospitalisation, antibiotic resistance and in more extreme cases, death.[1] Medical devices by their very nature are in contact with the body, whether that be the eye, internal tissues and/or bodily fluids such as blood and urine. The interface between the device and the biological environment is crucial and must fulfil a set of requirements to be biocompatible and safe. In particular, biofouling whereby host proteins can accumulate on the device/implant surface can result in a number of effects dependent on the site of the device/implant including thrombus formation, inflammatory responses and importantly bacterial infection leading to the aforementioned HAIs. While HAIs are largely treatable with antibiotic therapy, antibiotic resistance is a significant issue whereby the World Health Organisation (WHO) has developed a global action plan on antimicrobial resistance with a goal to reduce the incidence of infection through effective sanitation, hygiene and infection prevention measures.[2] One route towards achieving this goal is to improve our understanding of how bacteria interact with implant surfaces to develop biofilms, and thus armed with this knowledge work towards the development of preventative measures.

Molecular analysis of nucleic acid and protein biomarkers is becoming increasingly common in paediatric oncology for diagnosis, risk stratification and molecularly targeted therapeutics. However, many current and emerging biomarkers are based on analysis of tumour tissue, which is obtained through invasive surgical procedures and in some cases may not be accessible. Over the past decade, there has been growing interest in the utility of circulating biomarkers such as cell-free nucleic acids, circulating tumour cells and extracellular vesicles as a so-called liquid biopsy of cancer. Here, we review the potential of emerging circulating biomarkers in the management of neuroblastoma and highlight challenges to their implementation in the clinic.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) may occur after reconstructive or aesthetic breast surgery. Worldwide, approximately 1.7 million breast implant surgeries are performed each year. To date, over 500 cases of BIA-ALCL have been reported around the world, with 16 women having died. This review highlights the most important facts surrounding BIA-ALCL. There is no consensus regarding the true incidence rate of BIA-ALCL as it varies between countries, is probably significantly under-reported and is difficult to estimate due to the true number of breast prostheses used largely being unknown. BIA-ALCL develops in the breast mostly as a seroma surrounding the implant, but contained within the fibrous capsule, or more rarely as a solid mass that can become invasive infiltrating the chest wall and muscle, in some instances spreading to adjacent lymph nodes, in these cases having a far worse prognosis. The causation of BIA-ALCL remains to be established, but it has been proposed that chronic infection and/or implant toxins may be involved. What is clear is that complete capsulectomy is required for treatment of BIA-ALCL, which for early-stage disease leads to cure, whereas chemotherapy is needed for advanced-stage disease, whereby improved results have been reported with the use of brentuximab. A worldwide database for BIA-ALCL and implants should be supported by local governments.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon and emerging entity. It is a T-cell lymphoma that is usually localised within a late-onset peri-implant seroma that develops, on average, at 10 years after implant placement. In those cases limited to the seroma fluid, treatment in the form of complete capsulectomy by surgical excision may be curative1. However, for some patients, disease presents as a solid mass extending beyond the implant capsule and/or involving lymph nodes. These patients, in addition to surgery, require conventional chemotherapy and the antibody-drug conjugate brentuximab vedotin, which selectively targets tumor cells expressing the CD30 antigen has been shown to have superior activity in some cases2,3.

The Activator Protein-1 (AP-1) transcription factor (TF) family, composed of a variety of members including c-JUN, c-FOS and ATF, is involved in mediating many biological processes such as proliferation, differentiation and cell death. Since their discovery, the role of AP-1 TFs in cancer development has been extensively analyzed. Multiple in vitro and in vivo studies have highlighted the complexity of these TFs, mainly due to their cell-type specific homo- or hetero-dimerization resulting in diverse transcriptional response profiles. However, as a result of the increasing knowledge of the role of AP-1 TFs in disease, these TFs are being recognized as promising therapeutic targets for various malignancies. In this review, we focus on the impact of deregulated expression of AP-1 TFs in CD30-positive lymphomas including Classical Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma.

Patients with Nucleophosmin (NPM)- Anaplastic Lymphoma Kinase (ALK) fusion positive Anaplastic Large Cell Lymphoma produce autoantibodies against ALK indicative of an immune response against epitopes of the chimeric fusion protein. We asked whether ALK-expression in other malignancies induces specific antibodies. Antibodies against ALK were detected in sera of one of 50 analysed ALK-expressing neuroblastoma patients, 13 of 21 ALK positive non-small cell lung carcinoma (NSCLC) patients, 13 of 22 ALK translocation-positive, but NPM-ALK-negative lymphoma patients and one of one ALK-positive rhabdomyosarcoma patient, but not in 20 healthy adults. These data suggest that boosting a pre-existent anti-ALK immune response may be more feasible for patients with ALK-positive NSCLC, lymphomas and rhabdomyosarcomas than for tumours expressing wild-type ALK.

T-cell non-Hodgkin lymphoma is a heterogeneous disease ranging from malignancies arising from thymic T cells halted in development, through to mature, circulating peripheral T cells. The latter cases are diagnostically problematic with many entering the category of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). Anaplastic large cell lymphoma (ALCL) is one of the exceptions to this whereby aberrant expression of anaplastic lymphoma kinase (ALK) and the distinctive presence of cell surface CD30 places this entity in its own class. Besides the expression of a well-studied oncogenic translocation, ALCL, ALK+ may also have a unique pathogenesis with a thymic origin like T lymphoblastic lymphoma but a peripheral presentation akin to PTCL. This perspective discusses evidence towards the potential origin of ALCL, ALK+, and mechanisms that may give rise to its unique phenotype.

Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM–ALK) fusion protein (ALCL ALK+). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK−), which is characterized by a worse prognosis. We found that ALCL ALK−, in contrast to ALCL ALK+, lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK+ cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK−, we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK− and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1). © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The p53 tumor suppressor is inactivated in most cancers, thus suggesting that loss of p53 is a prerequisite for tumor growth. Therefore, its reintroduction through different means bears great clinical potential. After a brief introduction to current knowledge of p53 and its regulation by the ubiquitin-ligases MDM2/MDMX and post-translational modifications, we will discuss small molecules that are able to reactivate specific, frequently observed mutant forms of p53 and their applicability for clinical purposes. Many malignancies display amplification of MDM genes encoding negative regulators of p53 and therefore much effort to date has concentrated on the development of molecules that inhibit MDM2, the most advanced of which are being tested in clinical trials for sarcoma, glioblastoma, bladder cancer and lung adenocarcinoma. These will be discussed as will recent findings of MDMX inhibitors: these are of special importance as it has been shown that cancers that become resistant to MDM2 inhibitors often amplify MDM4. Finally, we will also touch on gene therapy and vaccination approaches; the former of which aims to replace mutated TP53 and the latter whose goal is to activate the body's immune system toward mutant p53 expressing cells. Besides the obvious importance of MDM2 and MDMX expression for regulation of p53, other regulatory factors should not be underestimated and are also described. Despite the beauty of the concept, the past years have shown that many obstacles have to be overcome to bring p53 reactivation to the clinic on a broad scale, and it is likely that in most cases it will be part of a combined therapeutic approach. However, improving current p53 targeted molecules and finding the best therapy partners will clearly impact the future of cancer therapy.

Most of the anaplastic large-cell lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces the fusion protein NPM-ALK (nucleophosmin-anaplastic lymphoma kinase). NPM-ALK-deregulated kinase activity drives several pathways that support malignant transformation of lymphoma cells. We found that in ALK-rearranged ALCL cell lines, NPM-ALK was distributed in equal amounts between the cytoplasm and the nucleus. Only the cytoplasmic portion was catalytically active in both cell lines and primary ALCL, whereas the nuclear portion was inactive because of heterodimerization with NPM1. Thus, about 50% of the NPM-ALK is not active and sequestered as NPM-ALK/NPM1 heterodimers in the nucleus. Overexpression or relocalization of NPM-ALK to the cytoplasm by NPM genetic knockout or knockdown caused ERK1/2 (extracellular signal-regulated protein kinases 1 and 2) increased phosphorylation and cell death through the engagement of an ATM/Chk2- and γH2AX (phosphorylated H2A histone family member X)-mediated DNA-damage response. Remarkably, human NPM-ALK-amplified cell lines resistant to ALK tyrosine kinase inhibitors (TKIs) underwent apoptosis upon drug withdrawal as a consequence of ERK1/2 hyperactivation. Altogether, these findings indicate that an excess of NPM-ALK activation and signaling induces apoptosis via oncogenic stress responses. A 'drug holiday' where the ALK TKI treatment is suspended could represent a therapeutic option in cells that become resistant by NPM-ALK amplification.

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19ARF as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF–Mdm2–p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14ARF expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition., IL6-STAT3 signaling is activated in prostate cancer, however inhibiting this pathway has not lead to a survival advantage in patients. Here, Pencik et al. show that loss of the IL6-STAT3 axis in mice and humans leads to metastasis due to loss of ARF, unravelling STAT3 and ARF as potential prognostic markers in prostate cancer.

Purpose To establish whether the association between milk intake and prostate cancer operates via the insulin-like growth factor (IGF) pathway (including IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3). Methods Systematic review, collating data from all relevant studies examining associations of milk with IGF, and those examining associations of IGF with prostate cancer risk and progression. Data were extracted from experimental and observational studies conducted in either humans or animals, and analyzed using meta-analysis where possible, with summary data presented otherwise. Results One hundred and seventy-two studies met the inclusion criteria: 31 examining the milk–IGF relationship; 132 examining the IGF–prostate cancer relationship in humans; and 10 animal studies examining the IGF–prostate cancer relationship. There was moderate evidence that circulating IGF-I and IGFBP-3 increase with milk (and dairy protein) intake (an estimated standardized effect size of 0.10 SD increase in IGF-I and 0.05 SD in IGFBP-3 per 1 SD increase in milk intake). There was moderate evidence that prostate cancer risk increased with IGF-I (Random effects meta-analysis OR per SD increase in IGF-I 1.09; 95% CI 1.03, 1.16; n = 51 studies) and decreased with IGFBP-3 (OR 0.90; 0.83, 0.98; n = 39 studies), but not with other growth factors. The IGFBP-3 -202A/C single nucleotide polymorphism was positively associated with prostate cancer (pooled OR for A/C vs. AA = 1.22; 95% CI 0.84, 1.79; OR for C/C vs. AA = 1.51; 1.03, 2.21, n = 8 studies). No strong associations were observed for IGF-II, IGFBP-1 or IGFBP-2 with either milk intake or prostate cancer risk. There was little consistency within the data extracted from the small number of animal studies. There was additional evidence to suggest that the suppression of IGF-II can reduce tumor size, and contradictory evidence with regards to the effect of IGFBP-3 suppression on tumor progression. Conclusion IGF-I is a potential mechanism underlying the observed associations between milk intake and prostate cancer risk. Electronic supplementary material The online version of this article (doi:10.1007/s10552-017-0883-1) contains supplementary material, which is available to authorized users.

Summary Aberrant DNA methylation patterns in malignant cells allow insight into tumor evolution and development and can be used for disease classification. Here, we describe the genome-wide DNA methylation signatures of NPM-ALK-positive (ALK+) and NPM-ALK-negative (ALK−) anaplastic large-cell lymphoma (ALCL). We find that ALK+ and ALK− ALCL share common DNA methylation changes for genes involved in T cell differentiation and immune response, including TCR and CTLA-4, without an ALK-specific impact on tumor DNA methylation in gene promoters. Furthermore, we uncover a close relationship between global ALCL DNA methylation patterns and those in distinct thymic developmental stages and observe tumor-specific DNA hypomethylation in regulatory regions that are enriched for conserved transcription factor binding motifs such as AP1. Our results indicate similarity between ALCL tumor cells and thymic T cell subsets and a direct relationship between ALCL oncogenic signaling and DNA methylation through transcription factor induction and occupancy.

BACKGROUND Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare, Non-Hodgkin lymphoma arising in the capsule of breast implants. BIA-ALCL presents as a recurrent effusion and/or mass. Tumours exhibit CD30 expression and are negative for Anaplastic Lymphoma Kinase (ALK). We report the multi-disciplinary management of the UK series and how the stage of disease may be used to stratify treatment. METHODS Between 2012 and 2016, 23 cases of BIA-ALCL were diagnosed in 15 regional centres throughout the UK. Data on breast implant surgeries, clinical features, treatment and follow-up were available for 18 patients. RESULTS The mean lead-time from initial implant insertion to diagnosis was 10 years (range: 3-16). All cases were observed in patients with textured breast implants or expanders. Fifteen patients with breast implants presented with stage I disease (capsule confined), and were treated with implant removal and capsulectomy. One patient received adjuvant chest-wall radiotherapy. Three patients presented with extra-capsular masses (stage IIA). In addition to explantation, capsulectomy and excision of the mass, all patients received neo-/adjuvant chemotherapy with CHOP as first line. One patient progressed on CHOP but achieved pathological complete response (pCR) with Brentuximab Vedotin. After a mean follow-up of 23 months (range: 1-56) all patients reported here remain disease-free. DISCUSSION BIA-ALCL is a rare neoplasm with a good prognosis. Our data support the recommendation that stage I disease be managed with surgery alone. Adjuvant chemotherapy may be required for more invasive disease and our experience has shown the efficacy of Brentuximab as a second line treatment.

Anaplastic Lymphoma Kinase (ALK) tyrosine kinase inhibitors (TKIs) show potent efficacy in several ALK-driven tumors, but the development of resistance limits their long-term clinical impact. While resistance mechanisms have been studied extensively in ALK-driven non-small cell lung cancer (NSCLC), they are poorly understood in ALK-driven anaplastic large cell lymphoma (ALCL). Here we identify a survival pathway supported by the tumor microenvironment that activates PI3K signaling through the CCR7 chemokine receptor. We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3K expression was predictive of lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3K, and PI3K were upregulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3K isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a 3D microfluidic chip, endothelial cells, that produce the CCR7 ligands CCL19/CCL21, protected ALCL cells from apoptosis induced by crizotinib. The PI3K/ inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts (PDXs). Further, genetic deletion of CCR7 blocked the central nervous system (CNS) dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3K or CCR7 signaling together with ALK TKI treatment reduces primary resistance as well as the survival of persister lymphoma cells in ALCL.