Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma.

Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.

STAT3 couples activated tyrosine kinase signaling to the oncogenic core transcriptional regulatory circuitry of anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.

Initiation and rapid titration of methadone and slow-release oral morphine (SROM) in an acute care, inpatient setting: a case series.

BACKGROUND: Methadone titration in an outpatient setting typically involves initiation with subtherapeutic doses with slow titration to mitigate the risks of respiratory depression and overdose. In pregnancy, and generally, subtherapeutic doses of methadone and slow titrations are associated with poorer outcomes in terms of treatment retention and ongoing illicit opioid use. We aim to describe rapid titration of OAT in an inpatient setting for pregnant injection opioid users with high opioid tolerance secondary to a fentanyl-based illicit drug supply. METHODS: Retrospective case series of patients admitted to a tertiary center with a primary indication of opioid withdrawal and treatment for severe opioid use disorder in pregnancy. RESULTS: Twelve women received rapid methadone titrations with or without slow-release oral morphine for opioid use disorder during a total of fifteen hospital admissions. All women included in the study were active fentanyl users (12/12). Methadone dosing was increased rapidly with no adverse events with a median dose at day 7 of 65 mg (IQR 60-70 mg) and median discharge dose of 85 mg (IQR 70-92.5 mg) during their admission for titration. Slow-release oral morphine was used in half of the titration admissions (8/15) with a median dose of 340 mg (IQR 187.5-425 mg) at discharge. The median length of admission was 12 days (IQR 9.5-15). CONCLUSIONS: A rapid titration of methadone was completed in an inpatient setting with or without slow-release oral morphine, without adverse events showing feasibility of this protocol for a pregnant population in an inpatient setting. Patients achieved therapeutic doses of methadone (and/or SROM) faster than outpatient counterparts with no known adverse events.

Directive clinique no 443b : Opioïdes aux différentes étapes de la vie des femmes : Grossesse et allaitement.

OBJECTIF: Présenter aux professionnels de la santé les données probantes concernant l'utilisation des opioïdes et la santé des femmes. Les domaines d'intérêt sont la grossesse et les soins post-partum. POPULATION CIBLE: Toutes les femmes qui utilisent des opioïdes. RéSULTATS: Un dialogue ouvert et éclairé sur l'utilisation des opioïdes améliorera les soins aux patientes. BéNéFICES, RISQUES ET COûTS: L'exploration de l'utilisation d'opioïdes par une approche tenant compte des traumatismes antérieurs donne au professionnel de la santé et à la patiente l'occasion de bâtir une alliance solide, collaborative et thérapeutique. Cette alliance permet aux femmes de faire des choix éclairés. Elle favorise le diagnostic et le traitement possible du trouble lié à l'utilisation d'opioïdes. L'utilisation ne doit pas être stigmatisée, puisque la stigmatisation affaiblit le partenariat (le partenariat entre patiente et professionnel de la santé). Les professionnels de la santé ceus-ci doivent comprendre l'effet potentiel des opioïdes sur la santé les femmes enceintes et les aider à prendre des décisions éclairées sur leur santé. DONNéES PROBANTES: Une recherche a été conçue puis effectuée dans les bases de données PubMed et Cochrane Library pour la période d'août 2018 à mars 2023 des termes MeSH et mots clés suivants (et variantes) : opioids, opioid agonist therapy, illicit drugs, fertility, pregnancy, fetal development, neonatal abstinence syndrome et breastfeeding. MéTHODES DE VALIDATION: Les auteurs ont évalué la qualité des données probantes et la force des recommandations en utilisant le cadre méthodologique GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Voir l'annexe A en ligne (tableau A1 pour les définitions et tableau A2 pour l'interprétation des recommandations fortes et conditionnelles [faibles]). PROFESSIONNELS CONCERNéS: Tous les professionnels de la santé qui prodiguent des soins aux femmes et aux nouveaux-nés. RéSUMé POUR TWITTER: La consommation d'opioïdes pendant la grossesse coïncide souvent avec des problèmes de santé mentale et est associée à des conséquences néfastes pour la mère, le fœtus et le nouveau-né ; le traitement des troubles liés à la consommation d'opioïdes par agonistes peut être sûr pendant la grossesse lorsque les risques sont plus nombreux que les avantages. DÉCLARATIONS SOMMAIRES: RECOMMANDATIONS.

Guideline No. 443a: Opioid Use Throughout Women's Lifespan: Fertility, Contraception, Chronic Pain, and Menopause.

OBJECTIVE: To provide health care providers with the best evidence on opioid use and women's health. Areas of focus include general patterns of opioid use and safety of use; care of women who use opioids; stigma, screening, brief intervention, and referral to treatment; hormonal regulation; reproductive health, including contraception and fertility; sexual function; perimenopausal and menopausal symptoms; and chronic pelvic pain syndromes. TARGET POPULATION: The target population includes all women currently using or contemplating using opioids. OUTCOMES: Open, evidence-informed dialogue about opioid use will lead to improvements in patient care and overall health. BENEFITS, HARMS, AND COSTS: Exploring opioid use through a trauma-informed approach offers the health care provider and patient with an opportunity to build a strong, collaborative, and therapeutic alliance. This alliance empowers women to make informed choices about their own care. It also allows for the diagnosis and possible treatment of opioid use disorders. Use should not be stigmatized, as stigma leads to poor "partnered care" (i.e., the partnership between the patient and care provider). Therefore, health care providers and patients must understand the potential role of opioids in women's health (both positive and negative) to ensure informed decision-making. EVIDENCE: A literature search was designed and carried out in PubMed and the Cochrane Library databases from August 2018 until March 2023 using following MeSH terms and keywords (and variants): opioids, illicit drugs, fertility, pregnancy, breastfeeding, and aging. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). INTENDED AUDIENCE: All health care providers who care for women. TWEETABLE ABSTRACT: Opioid use can affect female reproductive function; health care providers and patients must understand the potential role of opioids in women's health to ensure informed decision-making. SUMMARY STATEMENTS: RECOMMENDATIONS.

Guideline No. 443b: Opioid Use Throughout Women's Lifespan: Opioid Use in Pregnancy and Breastfeeding.

OBJECTIVE: To provide health care providers the best evidence on opioid use and women's health. Areas of focus include pregnancy and postpartum care. TARGET POPULATION: The target population includes all women currently using or contemplating using opioids. OUTCOMES: Open, evidence-informed dialogue about opioid use will improve patient care. BENEFITS, HARMS, AND COSTS: Exploring opioid use through a trauma-informed approach provides the health care provider and patient with an opportunity to build a strong, collaborative, and therapeutic alliance. This alliance empowers women to make informed choices about their own care. It also allows for the diagnosis and possible treatment of opioid use disorders. Opioid use should not be stigmatized, as stigma leads to poor "partnered care" (i.e., the partnership between the patient and care provider). Health care providers need to understand the effect opioids can have on pregnant women and support them to make knowledgeable decisions about their health. EVIDENCE: A literature search was designed and carried out in PubMed and the Cochrane Library databases from August 2018 until March 2023 using following MeSH terms and keywords (and variants): opioids, opioid agonist therapy, illicit drugs, fertility, pregnancy, fetal development, neonatal abstinence syndrome, and breastfeeding. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations). INTENDED AUDIENCE: All health care providers who care for pregnant and/or post-partum women and their newborns. TWEETABLE ABSTRACT: Opioid use during pregnancy often co-occurs with mental health issues and is associated with adverse maternal, fetal, and neonatal outcomes; treatment of opioid use disorder with agonist therapy for pregnant women can be safe during pregnancy where the risks outnumber the benefits. SUMMARY STATEMENTS: RECOMMENDATIONS.

Chimeric kinase ALK induces expression of NAMPT and selectively depends on this metabolic enzyme to sustain its own oncogenic function.

As we show in this study, NAMPT, the key rate-limiting enzyme in the salvage pathway, one of the three known pathways involved in NAD synthesis, is selectively over-expressed in anaplastic T-cell lymphoma carrying oncogenic kinase NPM1::ALK (ALK + ALCL). NPM1::ALK induces expression of the NAMPT-encoding gene with STAT3 acting as transcriptional activator of the gene. Inhibition of NAMPT affects ALK + ALCL cells expression of numerous genes, many from the cell-signaling, metabolic, and apoptotic pathways. NAMPT inhibition also functionally impairs the key metabolic and signaling pathways, strikingly including enzymatic activity and, hence, oncogenic function of NPM1::ALK itself. Consequently, NAMPT inhibition induces cell death in vitro and suppresses ALK + ALCL tumor growth in vivo. These results indicate that NAMPT is a novel therapeutic target in ALK + ALCL and, possibly, other similar malignancies. Targeting metabolic pathways selectively activated by oncogenic kinases to which malignant cells become "addicted" may become a novel therapeutic approach to cancer, alternative or, more likely, complementary to direct inhibition of the kinase enzymatic domain. This potential therapy to simultaneously inhibit and metabolically "starve" oncogenic kinases may not only lead to higher response rates but also delay, or even prevent, development of drug resistance, frequently seen when kinase inhibitors are used as single agents.

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.

The Pioneer platform: A novel approach for selection of selective anti-cancer cytotoxic activity in bacteria through co-culturing with engineered human cells.

Most of the small-molecule drugs approved for the treatment of cancer over the past 40 years are based on natural compounds. Bacteria provide an extensive reservoir for the development of further anti-cancer therapeutics to meet the challenges posed by the diversity of these malignant diseases. While identifying cytotoxic compounds is often easy, achieving selective targeting of cancer cells is challenging. Here we describe a novel experimental approach (the Pioneer platform) for the identification and development of 'pioneering' bacterial variants that either show or are conduced to exhibit selective contact-independent anti-cancer cytotoxic activities. We engineered human cancer cells to secrete Colicin M that repress the growth of the bacterium Escherichia coli, while immortalised non-transformed cells were engineered to express Chloramphenicol Acetyltransferase capable of relieving the bacteriostatic effect of Chloramphenicol. Through co-culturing of E. coli with these two engineered human cell lines, we show bacterial outgrowth of DH5α E. coli is constrained by the combination of negative and positive selection pressures. This result supports the potential for this approach to screen or adaptively evolve 'pioneering' bacterial variants that can selectively eliminate the cancer cell population. Overall, the Pioneer platform demonstrates potential utility for drug discovery through multi-partner experimental evolution.

Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma.

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. Although resistance mechanisms have been studied extensively in ALK-driven non-small cell lung cancer, 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 phosphatidylinositol 3-kinase γ (PI3K-γ) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kγ expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kγ, and PI3Kδ were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kγ isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kγ/δ inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kγ or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.

Patient-derived xenograft models of ALK+ ALCL reveal preclinical promise for therapy with brigatinib.

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.

To Waste or Not to Waste: Questioning Potential Health Risks of Micro- and Nanoplastics with a Focus on Their Ingestion and Potential Carcinogenicity.

Micro- and nanoplastics (MNPs) are recognized as emerging contaminants, especially in food, with unknown health significance. MNPs passing through the gastrointestinal tract have been brought in context with disruption of the gut microbiome. Several molecular mechanisms have been described to facilitate tissue uptake of MNPs, which then are involved in local inflammatory and immune responses. Furthermore, MNPs can act as potential transporters ("vectors") of contaminants and as chemosensitizers for toxic substances ("Trojan Horse effect"). In this review, we summarize current multidisciplinary knowledge of ingested MNPs and their potential adverse health effects. We discuss new insights into analytical and molecular modeling tools to help us better understand the local deposition and uptake of MNPs that might drive carcinogenic signaling. We present bioethical insights to basically re-consider the "culture of consumerism." Finally, we map out prominent research questions in accordance with the Sustainable Development Goals of the United Nations.

Improving outcomes of childhood and young adult non-Hodgkin lymphoma: 25 years of research and collaboration within the framework of the European Intergroup for Childhood Non-Hodgkin Lymphoma.

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.

Biopathology of childhood, adolescent and young adult non-Hodgkin lymphoma.

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.

Evaluating the baseline survival outcomes of the "six Global Initiative for Childhood Cancer index cancers" in Africa.

Limited survival data for the six Global Initiative for Childhood Cancer (GICC) priority cancers are available in Africa. Management of pediatric malignancies in Africa is challenging due to lack of resources, setting-specific comorbidities, high rates of late presentation and treatment abandonment. Reporting of outcome data is problematic due to the lack of registries. With the aim of evaluating the feasibility of baseline outcomes for the six index cancers, we present a descriptive analysis of respective survival rates in Africa. The survival rates were between 18% (lower middle-income countries) to 82.3% (upper middle-income countries) for acute lymphoblastic leukemia, between 26.9% (low-income countries) to 77.9% (upper middle-income countries) for nephroblastoma, between 23% (low-income countries) to 100% (upper middle-income countries), for retinoblastoma, 45% (low-income countries) to 95% (upper middle-income countries) for Hodgkin lymphoma and 28% (low-income countries) to 76% (upper middle-income countries) for Burkitt lymphoma. Solutions to improve survival rates and reported outcomes include establishing and funding sustainable registries, training and to actively include all countries in consortia from different African regions.HighlightsContinental differences in childhood cancer management such lack of resources, setting-specific comorbidities, high rates of late presentation and treatment abandonment, present challenges to the achievement of Global Initiative for Childhood Cancer goals.The available data registries do not adequately inform on the true incidences and outcomes of childhood cancers in Africa.The pathophysiology of some childhood cancers in Africa are associated with high-risk prognostic factors.Outcomes can be improved by greater regional collaboration to manage childhood cancer based on local resources and tumor characteristics.Some individual countries have reached the Global Initiative for Childhood Cancer goals for single cancers and it should be possible for more African countries to follow suit.