RESUMO
Azacitidine/venetoclax is an active regimen in patients with newly diagnosed acute myeloid leukemia (AML). However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL1 through activation of NOXA, and pevonedistat/azacitidine has previously shown activity in AML. To assess the tolerability and efficacy of adding pevonedistat to azacitidine/ venetoclax in relapsed/refractory AML, we conducted a phase I, multicenter, open-label study in 16 adults with relapsed/ refractory AML. Patients were treated with azacitidine, venetoclax along with pevonedistat intravenously on days 1, 3 and 5 of each 28-day cycle at doses of 10, 15 or 20 mg/m2 in successive cohorts in the dose escalation phase. The impact of treatment on protein neddylation as well as expression of pro-apoptotic BCL2 family members was assessed. The recommended phase II dose of pevonedistat was 20 mg/m2. Grade 3 or higher adverse events included neutropenia (31%), thrombocytopenia (13%), febrile neutropenia (19%), anemia (19%), hypertension (19%) and sepsis (19%). The overall response rate was 46.7% for the whole cohort including complete remission in five of seven (71.4%) patients who had not previously been treated with the hypomethylating agent/venetoclax. No measurable residual disease was detected in 80.0% of the patients who achieved complete remission. The median time to best response was 50 (range, 23-77) days. Four patients were bridged to allogeneic stem cell transplantation. The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. (NCT04172844).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Pirimidinas , Sulfonamidas , Humanos , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Azacitidina/administração & dosagem , Azacitidina/uso terapêutico , Azacitidina/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Naftiridinas/uso terapêutico , Naftiridinas/administração & dosagem , Recidiva , Resultado do Tratamento , Resistencia a Medicamentos Antineoplásicos , Idoso de 80 Anos ou mais , CiclopentanosRESUMO
BACKGROUND: The classification of acute myeloid leukemia (AML) has long been overseen by the World Health Organization (WHO) and published into a series of "Blue Books." These ledgers serve as the reference manual for AML classification and, in turn, classification-based treatment decisions. In 2022, two separate groups, each of which included hematologic oncologists, hematopathologists, and geneticists - developed and published two parallel classification systems for AML. One is from the WHO (WHO 5th edition), and a second is from an International Advisory Consortium (International Consortium Classification [ICC]). SUMMARY: Both modern classification systems originated from the revised 4th edition of the WHO Blue Books and thus share many similarities. There are never-the-less several important differences with the potential to substantially alter disease classification, access to clinical trials, and treatment decision-making. In this manuscript, we review the organization of the WHO and ICC classification systems for AML with emphasis on their similarities and differences, followed by areas in which their application to clinical scenarios may present difficulties. KEY MESSAGES: (1) The ICC and WHO 5th edition are concordant for the majority of AMLs. (2) Key differences between AML classification by the ICC and WHO 5th edition include (a) the overall framework of classification, (b) AML-defining blast threshold, definition of myelodysplasia-related AML, and (c) strategy for assigning therapy-related or germline-associated AML modifiers.
Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapiaRESUMO
Successful hematopoietic cell transplantation (HCT) depends on rapid engraftment of the progenitor and stem cells that will reestablish hematopoiesis. Rap1A and Rap1B are two closely related small GTPases that may affect platelet and neutrophil engraftment during HCT through their roles in cell adhesion and migration. ß-adrenergic signaling may regulate the participation of Rap1A and Rap1B in engraftment through their inhibition or activation. We conducted a correlative study of a randomized controlled trial evaluating the effects of the nonselective ß-antagonist propranolol on expression and prenylation of Rap1A and Rap1B during neutrophil and platelet engraftment in 25 individuals receiving an autologous HCT for multiple myeloma. Propranolol was administered for 1 week prior to and 4 weeks following HCT. Blood was collected 7 days (baseline) and 2 days (Day -2) before HCT, and 28 days after HCT (Day +28). Circulating polymorphonuclear cells (PMNC) were isolated and analyzed via immunoblotting to determine levels of prenylated and total Rap1A versus Rap1B. Twelve participants were randomized to the intervention and 13 to the control. Rap1A expression significantly correlated with Rap1B expression. Rap1B expression significantly correlated with slower platelet engraftment; however, this association was not observed in the propranolol-treated group. There were no significant associations between neutrophil engraftment and Rap1A or Rap1B expression. Post hoc exploratory analyses did not reveal an association between social health variables and Rap1A or Rap1B expression. This study identifies a greater regulatory role for Rap1B than Rap1A in platelet engraftment and suggests a possible role for ß-adrenergic signaling in modulating Rap1B function during HCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Propranolol , Adrenérgicos , Humanos , Propranolol/farmacologia , Transdução de Sinais/fisiologia , Proteínas rap de Ligação ao GTP/metabolismo , Proteínas rap1 de Ligação ao GTP/metabolismoRESUMO
BACKGROUND: Outcomes of acute promyelocytic leukemia (APL) have significantly improved with the availability of targeted agents. It remains unclear whether the population-level outcomes of APL have improved over time. METHODS: Using the SEER database, we identified patients aged ≥20 years with pathologically confirmed APL diagnosed in 2000 through 2014 and who were actively followed. Patients were stratified by diagnosis period into 3 groups (2000-2004, 2005-2009, and 2010-2014) to assess the temporal trends in overall survival (OS), cause-specific survival (CSS), and other outcomes. RESULTS: A total of 2,962 patients with a median age of 48 years (range, 20-96 years) were included. Hispanic patients constituted 21.5% of the cohort and the largest proportion (47.9%) of uninsured patients. The incidence of APL was 0.33 cases per 100,000 population per year. Incidence varied significantly by age, sex, race/ethnicity, and diagnosis period. Survival was significantly higher for patients diagnosed in 2010 through 2014 compared with those diagnosed in 2005 through 2009 and in 2000 through 2004 (4-year OS, 73.4% vs 65.6% vs 57.3%, respectively; 4-year CSS, 78.3% vs 70.8% vs 60.8%, respectively). Early mortality improved significantly over time (2000-2004, 25.3%; 2005-2009, 20.6%; 2010-2014, 17.1%) and was higher in men and Hispanic patients. According to multivariate analysis, diagnosis before 2010 and unmarried status were associated with a higher mortality risk. Uninsured patients had a significantly higher early mortality without a significant difference in post-30-day CSS. No significant changes were noted in risk of secondary malignancies. CONCLUSIONS: Population-level outcomes of APL have continued to improve over time. However, significant discrepancies in disease outcomes continue to exist, highlighting the need for more research.
Assuntos
Biomarcadores Tumorais/análise , Leucemia Promielocítica Aguda/terapia , Segunda Neoplasia Primária/epidemiologia , Cuidados Paliativos/métodos , Terapia de Salvação/métodos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/antagonistas & inibidores , Feminino , Seguimentos , Humanos , Incidência , Estimativa de Kaplan-Meier , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Programa de SEER/estatística & dados numéricos , Fatores Sexuais , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Atorvastatin administration to both the donors and recipients of matched related donor (MRD) allogeneic hematopoietic cell transplantation (allo-HCT) as acute graft-versus-host disease (GVHD) prophylaxis has been shown to be safe and effective. However, its efficacy as acute GVHD prophylaxis when given only to allo-HCT recipients is unknown. We conducted a phase II study to evaluate the safety and efficacy of atorvastatin-based acute GVHD prophylaxis given only to the recipients of MRD (n = 30) or matched unrelated donor (MUD) (n = 39) allo-HCT, enrolled in 2 separate cohorts. Atorvastatin (40 mg/day) was administered along with standard GVHD prophylaxis consisting of tacrolimus and methotrexate. All patients were evaluable for acute GVHD. The cumulative incidences of grade II to IV acute GVHD at day +100 in the MRD and MUD cohorts were 9.9% (95% confidence interval [CI], 0 to 20%) and 29.6% (95% CI,15.6% to 43.6%), respectively. The cumulative incidences of grade III and IV acute GVHD at day +100 in the MRD and MUD cohorts were 3.4% (95% CI, 0 to 9.7%) and 18.3% (95% CI, 6.3% to 30.4%), respectively. The corresponding rates of moderate/severe chronic GVHD at 1 year were 28.1% (95% CI, 11% to 45.2%) and 38.9% (95% CI, 20.9% to 57%), respectively. In the MRD cohort, the 1-year nonrelapse mortality, relapse rate, progression-free survival, and overall survival were 6.7% (95% CI, 0 to 15.4%), 43.3% (95% CI, 24.9% to 61.7%), 50% (95% CI, 32.1% to 67.9%), and 66.7% (95% CI, 49.8% to 83.6%), respectively. The respective figures for the MUD cohort were 10.3% (95% CI, 8% to 19.7%), 20.5% (95% CI, 7.9% to 33.1%), 69.2% (95% CI, 54.7% to 83.7%), and 79.5% (95% CI, 66.8% to 92.2%), respectively. No grade 4 toxicities attributable to atorvastatin were seen. In conclusion, the addition of atorvastatin to standard GVHD prophylaxis in only the recipients of MRD and MUD allo-HCT appears to be feasible and safe. The preliminary efficacy seen here warrants confirmation in randomized trials.
Assuntos
Atorvastatina/administração & dosagem , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Fatores Imunológicos/administração & dosagem , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida , Tacrolimo/administração & dosagemAssuntos
Aminopiridinas/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Isocitrato Desidrogenase/antagonistas & inibidores , Cetose/induzido quimicamente , Leucemia Mieloide Aguda/tratamento farmacológico , Triazinas/efeitos adversos , Idoso , Aminopiridinas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Humanos , Masculino , Triazinas/uso terapêuticoRESUMO
This is a case of a spontaneous haemoperitoneum occurring in the second trimester of pregnancy which was managed with interventional radiology to avoid laparotomy and its potential consequences. We aim to raise awareness of this condition in pregnancy because the perinatal mortality rate is as high as 36%. Spontaneous haemoperitoneum in pregnancy (SHiP) has frequently been associated with vascular rupture from pre-existing endometriosis. Most cases of SHiP have been managed with laparotomy. However, transcatheter embolisation can impart lifesaving alternatives to more invasive interventions when caring for pregnant patients. More judicious use of imaging procedures may also help improve diagnostic and therapeutic pathways with SHiP. We recommend that high-risk pregnancies are managed in level IV regional perinatal healthcare centres, when possible, where subspecialists and alternative measures of management exist.
Assuntos
Endometriose , Complicações na Gravidez , Gravidez , Feminino , Humanos , Segundo Trimestre da Gravidez , Complicações na Gravidez/etiologia , Hemoperitônio/diagnóstico por imagem , Hemoperitônio/etiologia , Hemoperitônio/terapia , Endometriose/complicações , Gravidez de Alto RiscoRESUMO
Energy conservation associated with hibernation is maximized at the intersection of low body temperature (Tb), long torpor bouts, and few interbout arousals. In the arctic ground squirrel (Urocitellus parryii), energy conservation during hibernation is best achieved at ambient temperatures (Ta) around 0 °C; however, they spend the majority of hibernation at considerably lower Ta. Because arctic ground squirrels switch to mixed fuel metabolism, including protein catabolism, at extreme low Ta of hibernation, we sought to investigate how microbial urea-nitrogen recycling is used under different thermal conditions. Injecting squirrels with isotopically labeled urea (13C/15N) during hibernation at Ta's of - 16 °C and 2 °C and while active and euthermic allowed us to assess the ureolytic activity of gut microbes and the amount of liberated nitrogen incorporated into tissues. We found greater incorporation of microbially-liberated nitrogen into tissues of hibernating squirrels. Although ureolytic activity appears higher in euthermic squirrels, liberated nitrogen likely makes up a smaller percentage of the available nitrogen pool in active, fed animals. Because non-lipid fuel is a limiting factor for torpor at lower Ta in this species, we hypothesized there would be greater incorporation of liberated nitrogen in animals hibernating at - 16 °C. However, we found higher microbial-ureolytic activity and incorporation of microbially-liberated nitrogen, particularly in the liver, in squirrels hibernating at 2 °C. Likely this is because squirrels hibernating at 2 °C had higher Tb and longer interbout arousals, a combination of factors creating more favorable conditions for gut microbes to thrive and maintain greater activity while giving the host more time to absorb microbial metabolites.
Assuntos
Hibernação , Nitrogênio , Sciuridae , Ureia , Animais , Sciuridae/fisiologia , Sciuridae/metabolismo , Hibernação/fisiologia , Ureia/metabolismo , Nitrogênio/metabolismo , Microbioma Gastrointestinal/fisiologia , Regiões Árticas , Isótopos de Nitrogênio , Temperatura , Masculino , Isótopos de Carbono , FemininoRESUMO
Of the many innovations in health care delivery proposed in the context of health reform for those with chronic diseases such as diabetes, the group visit model is relatively easy to implement and is effective for improving health outcomes and patient and provider satisfaction, with a neutral to positive effect on health care costs. This article describes the evolution of group visits for those with diabetes, the theory underlying group visits for patients with chronic medical conditions, and the existing evidence for the effectiveness of this model. It also addresses implementation of groups in practice, with an emphasis on the practical aspects of program implementation, integration of behavioral expertise into medical groups, individualization in various practice settings, and reimbursement issues.
Assuntos
Diabetes Mellitus , Atenção Primária à Saúde , Humanos , AutocuidadoAssuntos
Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/genética , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Marcadores Genéticos , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Razão de Chances , Adulto JovemRESUMO
BACKGROUND: It is important for nursing faculty to consider the variability in learning style among nursing students. AIM: The researchers sought to compare differences in perceived learning benefits among nursing students who had different learning styles and in frequency of use of a virtual community learning intervention. METHOD Using a comparative approach, learning style was measured with the Kolb Learning Style Inventory. Frequency of use and benefit were measured with an exit survey. RESULTS: No differences in perceived benefit were found according to learning style. Subjects with frequent use of the virtual community reported significantly greater learning benefits than those with infrequent use, regardless of learning style. Also found was a statistically significant relationship between Kolb learning-style scores and race or ethnicity. CONCLUSION: All nursing students may potentially benefit from virtual community use.
Assuntos
Redes Comunitárias , Instrução por Computador/métodos , Características Culturais , Bacharelado em Enfermagem/métodos , Etnicidade/psicologia , Estudantes de Enfermagem/psicologia , Interface Usuário-Computador , Adulto , Docentes de Enfermagem , Feminino , Humanos , Aprendizagem , Masculino , Pessoa de Meia-Idade , Avaliação de Programas e Projetos de Saúde , Estados Unidos , Adulto JovemRESUMO
Many conditions that affect a woman's health can be evaluated through the pelvic examination. Early detection and treatment of a range of gynaecologic and non-gynaecological conditions, including unusual pelvic masses, may decrease a woman's morbidity and mortality. Here, we have a female patient in her early 20s who was found to have a mass on her first screening pelvic examination. Subsequent imaging followed by surgical resection were performed with the final diagnosis of a pelvic meningioma. Routine pelvic examinations in asymptomatic women may be more useful than merely screening for cervical cancer and sexually transmitted infections. Once detected, the differential diagnosis of a pelvic mass may include aetiologies outside of the gynaecological organ system.
Assuntos
Neoplasias Meníngeas , Meningioma , Feminino , Humanos , Exame Ginecológico , Meningioma/diagnóstico por imagem , Meningioma/cirurgia , Pelve/diagnóstico por imagem , Diagnóstico Diferencial , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/cirurgiaRESUMO
This case involves a pregnant patient in her late 20s whose pregnancy was complicated by placentamegaly and early-onset, severe fetal growth restriction (FGR). Investigations ruled out genetic and infectious aetiologies. The pregnancy eventually was further complicated by abnormal umbilical artery blood flow. Shared decision-making with the patient and obstetrical team led to delivery by caesarean section at 28 weeks and 4 days. The baby was admitted to the neonatal intensive care unit but, overall, did well. Placental pathology revealed a massive subchorionic thrombohaematoma (MST). This case highlights the importance of early detection, evaluation and management of pregnancies complicated by severe FGR as well as the significance of shared decision-making with patients. We aim to increase the awareness of MST in the differential diagnosis of placentamegaly, as this finding in combination with early and severe FGR has been shown to be a poor prognostic factor for the fetus.
Assuntos
Doenças Placentárias , Placenta , Recém-Nascido , Gravidez , Humanos , Feminino , Placenta/patologia , Cesárea , Feto/patologia , Doenças Placentárias/diagnóstico , Doenças Placentárias/patologia , Retardo do Crescimento FetalRESUMO
Myeloid sarcomas (MS), commonly referred to as chloromas, are extramedullary tumors of acute myeloid leukemia (AML) with varying incidence and influence on outcomes. Pediatric MS has both a higher incidence and unique clinical presentation, cytogenetic profile, and set of risk factors compared to adult patients. Optimal treatment remains undefined, yet allogeneic hematopoietic stem cell transplantation (allo-HSCT) and epigenetic reprogramming in children are potential therapies. Importantly, the biology of MS development is poorly understood; however, cell-cell interactions, epigenetic dysregulation, cytokine signaling, and angiogenesis all appear to play key roles. This review describes pediatric-specific MS literature and the current state of knowledge about the biological determinants that drive MS development. While the significance of MS remains controversial, the pediatric experience provides an opportunity to investigate mechanisms of disease development to improve patient outcomes. This brings the hope of better understanding MS as a distinct disease entity deserving directed therapeutic approaches.
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The highly conserved MicroRNA-9 (miR-9) family consists of three members. We discovered that miR-9-1 deletion reduced mature miR-9 expression, causing 43% of the mice to display smaller size and postweaning lethality. MiR-9-1-deficient mice with growth defects experienced severe lymphopenia, but other blood cells were unaffected. The lymphopenia wasn't due to defects in hematopoietic progenitors, as mutant bone marrow (BM) cells underwent normal lymphopoiesis after transplantation into wild-type recipients. Additionally, miR-9-1-deficient mice exhibited impaired osteoblastic bone formation, as mutant mesenchymal stem cells (MSCs) failed to differentiate into osteoblastic cells (OBs). RNA sequencing revealed reduced expression of master transcription factors for osteoblastic differentiation, Runt-related transcription factor 2 (Runx2) and Osterix (Osx), and genes related to collagen formation, extracellular matrix organization, and cell adhesion, in miR-9-1-deficient MSCs. Follistatin (Fst), an antagonist of bone morphogenetic proteins (BMPs), was found to be a direct target of miR-9-1. Its deficiency led to the up-regulation of Fst, inhibiting BMP signaling in MSCs, and reducing IL-7 and IGF-1. Thus, miR-9-1 controls osteoblastic regulation of lymphopoiesis by targeting the Fst/BMP/Smad signaling axis.
Assuntos
Linfopenia , MicroRNAs , Animais , Camundongos , Linfopoese/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular , MicroRNAs/genética , MicroRNAs/metabolismo , Osteogênese/genética , Osteoblastos/metabolismoRESUMO
Recurrent mutations in TP53, RAS pathway and JAK2 genes were shown to be highly prognostic of allogeneic hematopoietic cell transplant (alloHCT) outcomes in myelodysplastic syndromes (MDS). However, a significant proportion of MDS patients has no such mutations. Whole-genome sequencing (WGS) empowers the discovery of novel prognostic genetic alterations. We conducted WGS on pre-alloHCT whole-blood samples from 494 MDS patients. To nominate genomic candidates and subgroups that are associated with overall survival, we ran genome-wide association tests via gene-based, sliding window and cluster-based multivariate proportional hazard models. We used a random survival forest (RSF) model with build-in cross-validation to develop a prognostic model from identified genomic candidates and subgroups, patient-, disease- and HCT-related clinical factors. Twelve novel regions and three molecular signatures were identified with significant associations to overall survival. Mutations in two novel genes, CHD1 and DDX11, demonstrated a negative impact on survival in AML/MDS and lymphoid cancer data from the Cancer Genome Atlas (TCGA). From unsupervised clustering of recurrent genomic alterations, genomic subgroup with TP53/del5q is characterized with the significant association to inferior overall survival and replicated by an independent dataset. From supervised clustering of all genomic variants, more molecular signatures related to myeloid malignancies are characterized from supervised clustering, including Fc-receptor FCGRs, catenin complex CDHs and B-cell receptor regulators MTUS2/RFTN1. The RSF model with genomic candidates and subgroups, and clinical variables achieved superior performance compared to models that included only clinical variables.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas , Humanos , Estudo de Associação Genômica Ampla , Síndromes Mielodisplásicas/genética , Mutação , Prognóstico , DNA Helicases/genética , RNA Helicases DEAD-box/genéticaAssuntos
Mortalidade Hospitalar , Hospitais de Ensino/estatística & dados numéricos , Leucemia Mieloide Aguda/mortalidade , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Bases de Dados Factuais , Coagulação Intravascular Disseminada/epidemiologia , Coagulação Intravascular Disseminada/etiologia , Diagnóstico Precoce , Feminino , Hemorragia Gastrointestinal/epidemiologia , Hemorragia Gastrointestinal/etiologia , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
The rapid renewal of the epithelial gut lining is fuelled by stem cells that reside at the base of intestinal crypts. The signal transduction pathways and morphogens that regulate intestinal stem cell self-renewal and differentiation have been extensively characterised. In contrast, although extracellular matrix (ECM) components form an integral part of the intestinal stem cell niche, their direct influence on the cellular composition is less well understood. We set out to systematically compare the effect of two ECM classes, the interstitial matrix and the basement membrane, on the intestinal epithelium. We found that both collagen I and laminin-containing cultures allow growth of small intestinal epithelial cells with all cell types present in both cultures, albeit at different ratios. The collagen cultures contained a subset of cells enriched in fetal-like markers. In contrast, laminin increased Lgr5+ stem cells and Paneth cells, and induced crypt-like morphology changes. The transition from a collagen culture to a laminin culture resembled gut development in vivo. The dramatic ECM remodelling was accompanied by a local expression of the laminin receptor ITGA6 in the crypt-forming epithelium. Importantly, deletion of laminin in the adult mouse resulted in a marked reduction of adult intestinal stem cells. Overall, our data support the hypothesis that the formation of intestinal crypts is induced by an increased laminin concentration in the ECM.