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BACKGROUND An increasing interest in machine learning (ML) has been observed amongst scholars and healthcare professionals. However, while ML algorithms have been shown to be effective and have the potential to change the delivery of patient care, their implementation in healthcare organizations is complex, and several are the challenges that currently hamper their uptake in the daily practice. OBJECTIVE The aim of this systematic review is twofold: (1) to map the ML-based technologies implemented in healthcare organizations, with a focus on investigating the organizational dimensions that are relevant in the implementation process; (2) to analyze the determinants of successful uptake of ML, identifying implementation barriers and/or facilitators to these technologies. METHODS This protocol has been developed following the PRISMA-P guidelines. The search is conducted on three databases (PubMed, Scopus, and Web of Science), considering a 10-year timeframe (2013-2023). The search strategy is built around four blocks of keywords (AI, implementation, health care, study type). Detailed inclusion criteria have been defined, and only empirical studies documenting the implementation of learning-based algorithms used by healthcare professionals in clinical settings will be considered. The study protocol was registered in PROSPERO). RESULTS The review is ongoing and is expected to be completed by June 2023. Preliminary findings highlight the need to further elaborate on the determinants of successful implementation of ML technologies, to provide the management of healthcare organizations with viable indications on how to arrive to a daily use of proven health interventions. CONCLUSIONS ML algorithms involving clinical decision support and automation of clinical tasks present unique traits that add several layers of complexity compared to earlier health technologies. Our review aims at contributing to the existing literature by investigating the implementation of ML-technologies from an organizational perspective, and by systematizing a conspicuous amount of information on factors influencing implementation.

Vaccination hesitancy is a complex phenomenon influenced by numerous factors, including the communicative messages to which individuals are exposed. Policy-makers, through public communication, might contribute to shape this behaviour. In the study we report the results of an experiment in which respondents were randomly exposed to three different messages about the vaccination against the human papilloma virus (HPV) of girls. The messages were derived from the public statements (2015–2017) of the Italian Minister of Health and contained different frames of the vaccination hesitant (misinformed, antiscientific, or socially dangerous) and correspondingly policy solutions to counteract vaccination hesitancy (information campaigns, compulsory vaccination or compulsory vaccination and sanctions). Results show how framing the vaccination hesitant as antiscientific or socially dangerous, that in turn supports coercive and sanctioning policies, tends to discourage vaccination. These findings alert us to the importance of designing with great care the communication about vaccinations and avoid counterproductive effects.

This Element presents and discusses the main trajectories in the evolution of the concept of ambiguity and the most relevant theoretical contributions developed around it. It specifically elaborates on both the intrinsic perspectives on ambiguity as an inherent part of organizational decision-making processes and the more recent strategic perspectives on discursively constructed strategic ambiguity. It helps illuminate the path ahead of organizational scholars and offers new avenues for future research. This is important given the ever more pervasive presence of ambiguity in and around organizations and societies.

On 31st January 2020, the Italian cabinet declared a 6-month national emergency after the detection of the first two COVID-19 positive cases in Rome, two Chinese tourists travelling from Wuhan. Between then and the total lockdown introduced on 22nd March 2020 Italy was hit by an unprecedented crisis. In addition to being the first European country to be heavily swept by the COVID-19 pandemic, Italy was the first to introduce stringent lockdown measures. The SARS-CoV-2 outbreak and related COVID-19 pandemic have been the worst public health challenge endured in recent history by Italy. Two months since the beginning of the first wave, the estimated excess deaths in Lombardy, the hardest hit region in the country, reached a peak of more than 23,000 deaths. The extraordinary pressures exerted on the Italian Servizio Sanitario Nazionale (SSN) inevitably leads to questions about its preparedness and the appropriateness and effectiveness of responses implemented at both national and regional levels. The aim of the paper is to critically review the Italian response to the COVID-19 crisis spanning from the first early acute phases of the emergency (March–May 2020) to the relative stability of the epidemiological situation just before the second outbreak in October 2020.

The paper discusses the responses to the COVID-19 crisis in the acute phase of the first wave of the pandemic (February-May 2020) by different Italian regions in Italy, which has a decentralised healthcare system. We consider five regions (Lombardy, Veneto, Emilia-Romagna, Umbria, Apulia) which are located in the north, centre and south of Italy. These five regions differ both in their healthcare systems and in the extent to which they were hit by the first wave of COVID-19 pandemic. We investigate their different responses to COVID-19 reflecting on seven management factors: (1) monitoring, (2) learning, (3) decision-making, (4) coordinating, (5) communicating, (6) leading, and (7) recovering capacity. In light of these factors, we discuss the analogies and differences among the regions and their different institutional choices.

Il PNRR è un documento di alta visione e di allocazione di importanti risorse di investimento per il SSN che devono garantire valore entro 5 anni, per ottenere l'effettivo riconoscimento finanziario da parte della EU e giustificare l'aumento del debito per le generazioni future. La partita attuativa è, quindi, solo iniziata e durerà 5 anni: un tempo breve in cui occorre definire la progettazione esecutiva per ogni misura, costruire pianificazioni regionali, attuare le politiche nelle singole aziende sanitarie locali. Il successo non può allora considerarsi scontato, richiedendo grande coesione di intenti, da perseguirsi con un forte impegno finalizzato a creare convergenze e collaborazione istituzionale. Nell'ottica descritta, un gruppo di studiosi di economia, management e politiche sanitarie, appartenenti a sei università, ha ritenuto di confrontarsi sul tema, ed esperire il tentativo di trovare una convergenza di visioni sul futuro del SSN (e del suo ruolo nelle politiche economiche e sociali del Paese), da consegnare alla valutazione delle istituzioni e al dibattito scientifico. Questa spontanea iniziativa ha permesso di elaborare delle proposte attuative sulla governance e sul riparto del PNRR, sull'autonomia e i vincoli per le regioni e le loro aziende, sullo sviluppo dei fattori abilitanti e sulla progettazione organizzativa e operativa delle diverse missioni del PNRR.

In spite of an increasing interest in ambiguity, our knowledge of how organizations maintain strategic ambiguity to protect themselves from public scrutiny is still in its infancy. Through an in-depth historical study of the Sicilian Mafia between 1963 and 2018, we develop a model of strategic ambiguity maintenance. We focus on three struggles between the Mafia and state representatives and show how they centered on different types of ambiguity: ambiguity as opacity, equivocality and absurdity. We elaborate on the strategies enacted by the Mafia and the responses by state representatives and their implications for ambiguity over time. The main contribution of our paper is that it advances understanding of the maintenance of strategic ambiguity by organizations that need to protect themselves from public scrutiny. More specifically, it enriches understanding of the key process dynamics, the type of struggles, and the discursive and non-discursive strategies employed in the process. Our analysis also extends research on clandestine organizations and illuminates the relationship between (strategic) ambiguity and secrecy.

Background: Primary care teams (hereafter referred to as primary care units [PCUs]) composed of general practitioners (GPs), nurses, and specialist doctors have recently been established in the Italian context, with the main aim of improving integrated care for chronic diseases. Purposes: The aim of the study was to assess whether the increased professional diversity of PCUs has resulted in an improvement in the integrated care of type II diabetes and to identify a potential mechanism mediating this effect. Methodology/Approach: We analyzed 213 PCUs, comparing their performance in integrated type II diabetes care at two time points. Using social categorization theory and a fixed effects regression analysis, we tested a mediation model in which the frequency of communication among GPs in the PCUs, that is, within-subgroup communication, mediates the relationship between PCU professional diversity and team performance in diabetes care. Findings: We show that when the professional diversity of the PCUs increases, integrated care of type II diabetes improves and better meets the standards of optimal care. Within-GP subgroup communication works as a mediating mechanism that translates the PCU professional diversity into better team performance. The mediation effect, however, is curvilinear. Beyond certain levels, within-subgroup communication can hamper PCUs' capacity to work collaboratively in integrated type II diabetes care. Practice Implications: The article suggests that, when creating interprofessional primary care teams, managers might be able to steer teams toward a better performance by encouraging communication among peers of the same profession.

The sustainability of health care systems, particularly those supporting universal health care, is a matter of current discussion among policymakers and scholars. In this article, we summarize the controversies around the economic sustainability of health care. We attempt to extend the debate by including a more comprehensive conceptualization of sustainability in relation to health care systems and by examining the dimensions of social and political sustainability. In conclusion, we argue that policymakers when taking decisions around universal health care should carefully consider issues of social, political, and economic sustainability, their interaction, and often their inherent trade-offs.

The article examines the implementation by the Italian Ministry of Health of performance-based funding to allocate resources for research to IRCCS (Istituti di Ricovero e Cura a Carattere Scientifico) hospitals. The analysis provides evidence that ten years from its introduction the performance-based funding system has persisted, but it has been implemented rather differently from what had been imagined by its proponents. By drawing on the theoretical frameworks of policy implementation, agency, and relational contracting, the study establishes that the overall design of the system has contributed to this final outcome only to a limited extent. Rather, the lack of procedural fairness, as well as of political leadership in linking the system to national research priorities, has undermined the basis for trust between hospitals and the Ministry of Health. The article discusses how, in this, the governance of performance-based funding and its strong ownership by the ministerial bureaucracy has been determinant.

In the mental health field, the creation of networks that can guarantee the smooth coordination of services and organizations across sectors is a priority in the policy agenda of several countries. In Italy, Departments of Mental Health (DMHs) have been designated responsible for the system of specialist mental health services, and also mandated as the conveners and leaders of interorganizational and cross-sectoral networks, by a system-wide reform. This study aims to understand how mental health networks have been assembled in this context and the factors and motivations that have shaped their scope. By combining an analysis of policies with a survey of DMH directors, we have determined that DMHs have preferentially formed collaborative relationships with social service providers (local governments) and the voluntary sector. In contrast, relationships with substance abuse and addiction services and primary care providers were weak and stifled by a lack of trust and by conflict about respective contributions to mental care. We explore the reasons for this selectivity in interorganizational relationships and propose that a lack of targeted incentives in policy guidelines, on the one hand, and the existence of a mandated network leadership, on the other, have led to a rather narrow range of collaborations.

We report on a multi-level longitudinal study investigating a population of public-private hybrid organizations in the Italian healthcare field, where a public service and quasi-market logic coexis...

In the last 20 years, orphan drug legislation (ODL) has been adopted in several countries around the world (USA, Japan, Australia, and the European Union) and has successfully promoted R&D investments to develop new pharmaceutical products for the treatment of rare diseases. Without these incentives, many life-saving new drugs would have not been developed and produced. For economic reasons, the development of medicines for the treatment of diseases prevalent in the developing world (or tropical diseases) is lagging behind. Among several factors, the low average per-capita income makes pharmaceutical markets in developing countries appear relatively unprofitable and therefore unattractive for R&D-oriented companies. The case of ODL may offer some useful insights and perspectives for the fight against neglected tropical diseases. First, the measures used in ODL may also be effective in boosting R&D for neglected tropical diseases, if appropriately adapted to this market. Second, small-sized companies, which have played a successful role in the development of orphan drugs for rare diseases, may also represent a good business strategy for the case of tropical diseases.

SummaryNew blood vessels are initially formed through the assembly or sprouting of endothelial cells, but the recruitment of supporting pericytes and vascular smooth muscle cells (mural cells) ensures the formation of a mature and stable vascular network. Defective mural-cell coverage is associated with the poorly organized and leaky vasculature seen in tumors or other human diseases. Here we report that mural cells require ephrin-B2, a ligand for Eph receptor tyrosine kinases, for normal association with small-diameter blood vessels (microvessels). Tissue-specific mutant mice display perinatal lethality; vascular defects in skin, lung, gastrointestinal tract, and kidney glomeruli; and abnormal migration of smooth muscle cells to lymphatic capillaries. Cultured ephrin-B2-deficient smooth muscle cells are defective in spreading, focal-adhesion formation, and polarized migration and show increased motility. Our results indicate that the role of ephrin-B2 and EphB receptors in these processes involves Crk-p130(CAS) signaling and suggest that ephrin-B2 has some cell-cell-contact-independent functions.

We report that targeted inactivation of the Eph receptor ligand ephrinB1 in mouse caused perinatal lethality, edema, defective body wall closure, and skeletal abnormalities. In the thorax, sternocostal connections were arranged asymmetrically and sternebrae were fused, defects that were phenocopied in EphB2/EphB3 receptor mutants. In the wrist, loss of ephrinB1 led to abnormal cartilage segmentation and the formation of additional skeletal elements. We conclude that ephrinB1 and B class Eph receptors provide positional cues required for the normal morphogenesis of skeletal elements. Another malformation, preaxial polydactyly, was exclusively seen in heterozygous females in which expression of the X-linked ephrinB1 gene was mosaic, so that ectopic EphB-ephrinB1 interactions led to restricted cell movements and the bifurcation of digital rays. Our findings suggest that differential cell adhesion and sorting might be relevant for an unusual class of X-linked human genetic disorders, in which heterozygous females show more severe phenotypes than hemizygous males.

We report on a multilevel study investigating the diffusion of robotic surgery in the Italian health care system between 1999 and 2010. A combination of qualitative and quantitative methods allowed...

Pancreatic beta cell lines may offer an abundant source of cells for beta-cell replacement in type I diabetes. Using regulatory elements of the bacterial tetracycline (tet) operon for conditional expression of SV40 T antigen oncoprotein in transgenic mouse beta cells, we have shown that reversible immortalization is an efficient approach for regulated beta-cell expansion, accompanied by enhanced cell differentiation upon growth arrest. The original system employed the tet-off approach, in which the cells proliferate in the absence of tet ligands and undergo growth arrest in their presence. The disadvantage of this system is the need for continuous treatment with the ligand in vivo for maintaining growth arrest. Here we utilized the tet-on regulatory system to generate beta cell lines in which proliferation is regulated in reverse: these cells divide in the presence of tet ligands, and undergo growth arrest in their absence, as judged by [3H]thymidine and BrdU incorporation assays. These cell lines were derived from insulinomas, which heritably developed in transgenic mice continuously treated with the tet derivative doxycycline (dox). The cells produce and secrete high amounts of insulin, and can restore and maintain euglycemia in syngeneic streptozotocin-induced diabetic mice in the absence of dox. Such a system is more suitable for transplantation, compared with cells regulated by the tet-off approach, because ligand treatment is limited to cell expansion in culture and is not required for long-term maintenance of growth arrest in vivo.

Growth factor–induced signaling by receptor tyrosine kinases (RTKs) plays a central role in embryonic development and in pathogenesis and, hence, is tightly controlled by several regulatory proteins. Recently, Sprouty, an inhibitor of Drosophila development-associated RTK signaling, has been discovered. Subsequently, four mammalian Sprouty homologues (Spry-1–4) have been identified. Here, we report the functional characterization of two of them, Spry-1 and -2, in endothelial cells. Overexpressed Spry-1 and -2 inhibit fibroblast growth factor– and vascular endothelial growth factor–induced proliferation and differentiation by repressing pathways leading to p42/44 mitogen-activating protein (MAP) kinase activation. In contrast, although epidermal growth factor–induced proliferation of endothelial cells was also inhibited by Spry-1 and -2, activation of p42/44 MAP kinase was not affected. Biochemical and immunofluorescence analysis of endogenous and overexpressed Spry-1 and -2 reveal that both Spry-1 and -2 are anchored to membranes by palmitoylation and associate with caveolin-1 in perinuclear and vesicular structures. They are phosphorylated on serine residues and, upon growth factor stimulation, a subset is recruited to the leading edge of the plasma membrane. The data indicate that mammalian Spry-1 and -2 are membrane-anchored proteins that negatively regulate angiogenesis-associated RTK signaling, possibly in a RTK-specific fashion.

Tumour development is a multi-step process during which genetic and epigenetic events determine the transition from a normal to a malignant cellular state. In the past decade, extensive effort has been made not only to define the molecular mechanisms underlying progression to malignancy but also to predict the development of the disease and to identify possible molecular targets for therapy. Common to most tumours, several regulatory circuits are altered during multistage tumour progression, most importantly, the control of proliferation, the balance between cell survival and programmed cell death (apoptosis), the communication with neighbouring cells and the extracellular matrix, the induction of tumour neovascularization (angiogenesis) and, finally, tumour cell migration, invasion and metastatic dissemination. De-regulation of each of these processes represents a rate-limiting step for tumour development and, hence, has to be achieved by tumour cells in a highly selective manner during tumour progression. In this review we summarize recent advances in cancer research that have provided new insights in the molecular mechanisms underlying the transition between one tumour stage and the next and into their concerted action during tumour progression. Cultured human tumour cell lines as well as transgenic and knock-out mouse models of tumorigenesis have been instrumental in these experimental approaches. © 2000 Cancer Research Campaign

Multiprofessional primary care models promise to deliver better care and reduce waste. This study evaluates the impact of such a model, the primary care unit (PCU), on three outcomes. A multilevel analysis within a “pre- and post-PCU” study design and a cross-sectional analysis were conducted on 215 PCUs located in the Emilia-Romagna region in Italy. Seven dimensions captured a set of processes and services characterizing a well-functioning PCU, or its degree of vitality. The impact of each dimension on outcomes was evaluated. The analyses show that certain dimensions of PCU vitality (i.e., the possibility for general practitioners to meet and share patients) can lead to better outcomes. However, dimensions related to the interaction and the joint works of general practitioners with other professionals tend not to have a significant or positive impact. This suggests that more effort needs to be invested to realize all the potential benefits of the PCU’s multiprofessional approach to care.

BACKGROUND: The growing burden of chronic diseases encourages health care systems to shift services and resources toward primary care. In this sector, general practitioners (GPs) play a key role, and several collaborative organizational models have been implemented in the attempt to improve the clinical effectiveness of GPs, their adherence to evidence-based guidelines, and their capacity to work in multiprofessional teams. However, evidence of the impact of different organizational models is sparse, and little is known about the contribution of these models to the good management of chronic diseases. PURPOSE: The aim of this study was to examine the relationship of individual sociodemographic characteristics of GPs and collaborative organizational models with the adherence of physicians to evidence-based guidelines for four major chronic diseases (diabetes, heart failure, stroke, and post-acute myocardial infarction). METHODOLOGY: Evidence-based indicators for the management of the selected chronic diseases were identified on the basis of the most recent international guidelines. Multilevel logistic regression models were used to identify the correlates of adherence to guidelines, taking into account patient characteristics and comorbidities. FINDINGS: Participation in group practice was associated with different indicators of adherence to guidelines for the management of diabetes and one indicator of post-acute myocardial infarction, whereas other organizational arrangements were linked to GPs' clinical behavior to a lesser degree. Female gender and younger age of GPs were associated with good management of diabetes. PRACTICE IMPLICATIONS: The relative impact of efforts at organizational design in primary care should be evaluated in more detail before further investments are made in this direction. Our findings suggest that the professional attitude of GPs (of which gender and age can be considered proxies) is equally, if not more, important than their organizational arrangement. Hence, attention should be paid to how organizations and managerial tools can support the consolidation and spread of this attitude.

The approval (2003) and enforcement (2005) of a smoking ban in Italy have been viewed by many as an unexpectedly successful example of policy change. The present paper, by applying a processualist approach, concentrates on two policy cycles between 2000 and 2005. These had opposing outcomes: an incomplete decisional stage and an authoritative decision, enforced two years later. Through the analysis of the different phases of agenda setting, alternative specification and decision making, we have compared the quality of participation of policy entrepreneurs in the two cycles, their political strategies and, in these, the relevance of issue image. The case allows us to direct the attention of scholars and practitioners to an early phase of the policy implementation process ‐ which we have named ‘transition to practice’. This, managed with political strategy, might have strongly contributed to the final successful policy outcome.

This study examines the key mental health policy agendas of seven countries, each involved in some effort at reform, if not transformation, of the mental health system. Utilizing the Institute of M...

Objectives:The study aims at evaluating the economic evidence related to testing for genetic variants of the drug-metabolizing enzyme, TPMT. Detecting TPMT genetic variants before the administration of azathioprine (AZA) has the potential to prevent serious and costly adverse drug reactions (ADRs), such as neutropenia. In particular, our analysis concentrated on assessing the reliability of data on costs of neutropenia and performing the tests, the two main cost categories that could inform an economic evaluation of TPMT pharmacogenetic testing.Methods:A systematic literature review was performed to gather evidence on the costs of testing and neutropenia. Articles were critically appraised for their comprehensiveness and quality. To better estimate costs of TPMT tests, a small-scale survey of European diagnostic laboratories was conducted.Results:Only seven articles were retrieved specifying the costs associated with the management and treatment of AZA-induced neutropenia. Most of these studies are based on theoretical modeling reconstructed with key-informants or on very few cases of ADRs, and either the methodology for cost calculation is not specified or costs are based on national cost databases and tariffs. After critical appraisal of these studies, we considered €2,116 as the most reliable estimate for the cost of a case of neutropenia. Literature review accompanied by the survey of several diagnostic laboratories also provided an estimate (€68) for TPMT testing. Based on these values, the net cost per prevented case of neutropenia equals to €5,300.Conclusions:Solid economic considerations related to TPMT pharmacogenetic testing are still limited by underreporting of ADRs and high level of approximation related to cost data. Ad hoc observational studies and the ADR recording process embedded in pharmacovigilance systems, established across Europe, should represent more reliable sources of cost data in the future.

The paper explores the case of persistent institutional heterodoxy and the mechanisms that allow it to be sustained over a long time and against all odds, a condition that institutional theory tend...

In Italy, the process of power decentralization to Regional Governments has particularly affected pharmaceutical care policies. Regions are experimenting with various strategies to govern drugs utilization and expenditure, and differentiating their approaches, leading to an ever-changing and complex institutional scenario. Pharmaceutical companies have created new professional roles, the Regional Affairs Managers (RAM), with the mandate to monitor the different regional contexts and measures, and to establish relationships with the public actors in charge of pharmaceutical policies. This analysis shows how public affairs/lobbying actions at regional level and the creation of a solid political competence within companies are still in an early phase. The activities carried out by RAMs remain limited to an exchange of information and only rarely are perceived by Regional public servants (RRs) as giving support to their work or influence decisions. The interaction with RAMs is often seen as little relevant and still too concentrated on products and a marketing/commercial approach rather than on broader issues of interest to RRs who need to manage the pharmaceutical care system at large. The level of acceptance of this type of activity is also variable and RRs’ attitudes alternate between diffidence, polite tolerance, and openness to a constructive dialogue about pharmaceuticals and their management in a regional healthcare system. © 2008 Elsevier Ireland Ltd. All rights reserved.

The field of mental health has long suffered from a lack of convergence of disciplines that deal with the mind, the brain, and behavior. This mind–brain dualism has been particularly detrimental for consumers and their families who daily face stigma and discrimination. The understanding of the brain and its dysfunctions has benefited from the study of the human genome and, in particular, of the mutations and variations in its code. This analysis permits a better understanding of the biological basis of mental disease and will soon inform a generation of new diagnostic tools and individualized pharmacological therapies. A biological perspective on mental illness will be complemented by the analysis of the social factors influencing people's behavior and their impact on brain biology and gene function. Neurobiology has progressed to a level for which the knowledge that is generated, even if still colored with uncertainty, could represent a catalyst for the creation of an alliance between neuroscientists and consumers. This partnership has the potential to benefit both parties but will require some concrete steps that might be outside of the usual courses of action for both consumers and scientists. It is by building collaborations based on personal contact and information sharing that a transformation of the mental health care system can occur.

A common theme is emerging in sentinel reports on the United States health care system. Consumer relevance and demands on service systems and practices are influencing how mental health care is delivered and how systems will be shaped in the future.The present report seeks to assemble a confluence of consumer-driven themes from noteworthy reports on the state of the mental health system in the U.S. It also explores innovative efforts, promising practices, collaborative efforts, as well as identification of barriers to consumer-directed care, with possible solutions.The report reviews the relevant public mental health policy and data used in published work.The findings indicate an increasing public and private interest in promoting consumer-driven care, even though historical systems of care predominate, and often create, barriers to wide-spread redesign of a consumer-centered mental health care system. Innovative consumer-driven practices are increasing as quality, choice, and self-determination become integral parts of a redesigned U.S. mental health care system.The use of consumer-driven approaches in mental health is limited at best. These programs challenge industry norms and traditional practices. Limitations include the need for additional and thorough evaluations of effectiveness (cost and clinical) and replicability of consumer-directed programs.Consumer-driven services indicate that mental health consumers are expecting to be more participative in their mental health care. This expectation will influence how traditional mental health services and providers become more consumer-centric and meet the demand.Public and private interest in consumer-driven health care range from creating cost-conscious consumers to individualized control of recovery. The health care sector should seek to invest more resources in the provision of consumer-driven health care programs. The results of this study have implications and are informative for other countries where consumer-directed care is delivered in either the private or public health care systems.More research is needed to obtain further evidence on the use of consumer-driven services and their overall effectiveness.

Metastasis is a frequent and lethal complication of cancer. Vascular endothelial growth factor-C (VEGF-C) is a recently described lymphangiogenic factor. Increased expression of VEGF-C in primary tumours correlates with dissemination of tumour cells to regional lymph nodes. However, a direct role for VEGF-C in tumour lymphangiogenesis and subsequent metastasis has yet to be demonstrated. Here we report the establishment of transgenic mice in which VEGF-C expression, driven by the rat insulin promoter (Rip), is targeted to beta-cells of the endocrine pancreas. In contrast to wild-type mice, which lack peri-insular lymphatics, RipVEGF-C transgenics develop an extensive network of lymphatics around the islets of Langerhans. These mice were crossed with Rip1Tag2 mice, which develop pancreatic beta-cell tumours that are neither lymphangiogenic nor metastatic. Double-transgenic mice formed tumours surrounded by well developed lymphatics, which frequently contained tumour cell masses of beta-cell origin. These mice frequently developed pancreatic lymph node metastases. Our findings demonstrate that VEGF-C-induced lymphangiogenesis mediates tumour cell dissemination and the formation of lymph node metastases.