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Progression and persistence of malignancies are influenced by the local tumor microenvironment, and future eradication of currently incurable tumors will, in part, hinge on our understanding of malignant cell biology in the context of their nourishing surroundings. Here, we generated paired single-cell transcriptomic datasets of tumor cells and the bone marrow immune and stromal microenvironment in multiple myeloma. These analyses identified myeloma-specific inflammatory mesenchymal stromal cells, which spatially colocalized with tumor cells and immune cells and transcribed genes involved in tumor survival and immune modulation. Inflammatory stromal cell signatures were driven by stimulation with proinflammatory cytokines, and analyses of immune cell subsets suggested interferon-responsive effector T cell and CD8 + stem cell memory T cell populations as potential sources of stromal cell–activating cytokines. Tracking stromal inflammation in individuals over time revealed that successful antitumor induction therapy is unable to revert bone marrow inflammation, predicting a role for mesenchymal stromal cells in disease persistence. Multiple myeloma disease progression and therapy response are influenced by the bone marrow niche in which the tumor cells reside. To characterize this supportive niche, Cupedo and colleagues use single-cell transcriptomic analysis of bone marrow stromal cell populations from individuals with multiple myeloma. They identify a myeloma-specific inflammatory mesenchymal stromal cell (iMSC) population that spatially colocalizes with tumor cells. Anti-myeloma induction therapy does not influence iMSC presence, suggesting a role for bone marrow inflammation in myeloma persistence or relapse.

Tissue inflammation is a hallmark of tumour microenvironments. In the bone marrow, tumour-associated inflammation impacts normal niches for haematopoietic progenitor cells and mature immune cells and supports the outgrowth and survival of malignant cells residing in these niche compartments. This Review provides an overview of our current understanding of inflammatory changes in the bone marrow microenvironment of myeloid and lymphoid malignancies, using acute myeloid leukaemia and multiple myeloma as examples and highlights unique and shared features of inflammation in niches for progenitor cells and plasma cells. Importantly, inflammation exerts profoundly different effects on normal bone marrow niches in these malignancies, and we provide context for possible drivers of these divergent effects. We explore the role of tumour cells in inflammatory changes, as well as the role of cellular constituents of normal bone marrow niches, including myeloid cells and stromal cells. Integrating knowledge of disease-specific dynamics of malignancy-associated bone marrow inflammation will provide a necessary framework for future targeting of these processes to improve patient outcome.Haematological malignancies are associated with inflammation in the bone marrow. In this Review, the authors discuss how tumour-associated inflammation affects the normal functions of the bone marrow and supports the outgrowth and survival of malignant cells. Moreover, they describe how the inflammatory changes in the bone marrow differ in myeloid and lymphoid malignancies.

Human bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In individuals with multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in human marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor supportive and transcribe increased levels of IL1B and myeloma cell survival factor TNFSF13B (BAFF). Interactions with inflammatory stromal cells induce neutrophil activation, including BAFF secretion, in a STAT3-dependent manner, and once activated, neutrophils gain the ability to reciprocally induce stromal activation. After first-line myeloid-depleting antimyeloma treatment, human bone marrow retains residual stromal inflammation, and newly formed neutrophils are reactivated. Combined, we identify a neutrophil–stromal cell feed-forward loop driving tumor-supportive inflammation that persists after treatment and warrants novel strategies to target both stromal and immune microenvironments in multiple myeloma. Cupedo and colleagues show that neutrophils promote a tumor-supportive microenvironment via a self-amplifying interaction between neutrophils and bone marrow stromal cells. This scenario creates a promyeloma niche that is difficult to treat despite targeted therapies directed at the myeloma cells.

Malignant plasma cells in multiple myeloma patients reside in the bone marrow and continuously interact with local immune cells. Progression and therapy response are influenced by this immune environment, highlighting the need for a detailed understanding of endogenous immune responses to malignant plasma cells. Here we used the 5TGM1 murine transfer model of multiple myeloma to dissect early immune responses to myeloma cells. We modeled stable and progressive disease by transferring 5TGM1 murine myeloma cells into C57Bl/6 mice and KaLwRij mice, respectively. We used flow cytometry and single‐cell and bulk transcriptomic analyses to characterize differential immune responses in stable and progressive disease. Transfer of 5TGM1 cells in C57Bl/6 mice led to stable disease with low tumor burden in a subset of animals. Stable disease was associated with sustained activation and expansion of NK cells, ILC1, and CD8+ T cells, a response that was lost upon disease progression. Single‐cell RNA‐sequencing of immune cells and bulk RNA sequencing of immune and mesenchymal stromal cells implicated the activation of interferon responses as a central immune pathway during stable disease. Experimentally, neutralization of IFNγ significantly increased myeloma development and progression in C57Bl/6 mice, testifying to the importance of this pathway in early disease control. In conclusion, we provide a framework for studying immune responses to multiple myeloma progression in immunocompetent and genetically modifiable mice and highlight the importance of bone marrow immunity in tumor control.

Multiple myeloma is a disease of malignant plasma cells residing in the bone marrow, where interactions with local immune cells are thought to contribute to disease pathobiology. However, since a multiple myeloma diagnosis is virtually always preceded by an asymptomatic precursor phase, identifying early alterations in the bone marrow micro-environment following occupation by multiple myeloma cells remains challenging. Here we used the 5TGM1 transfer model of murine myeloma in combination with myeloma-permissive KaLwRij mice and myeloma-resistant C57Bl/6 mice and hypothesized that differential sensitivity to myeloma in these HLA-identical mouse strains has an immunological basis and might allow for dissection of early immune responses to myeloma cells. Using flow cytometry and single-cell RNA sequencing we show that C57Bl/6 mice can restrain tumor growth for prolonged periods, associated with activation of cytotoxic immune responses that were absent from KaLwRij mice. Transcriptional analysis of immune cells and stromal cells identified a central role for IFN-signaling in tumor containment, and antibody-mediated neutralization of IFNγ increased both incidence and outgrowth of multiple myeloma in C57Bl/6 mice. Together these findings highlight the ability of a fully functional immune system to control multiple myeloma progression in an IFNγ-dependent manner and suggest that transfer of 5TGM1 cells into parental C57Bl/6 mice can serve as a faithful model to track anti-myeloma immune responses in immune competent and genetically modifiable mice.Competing Interest StatementCompeting interests A.B. consults for BMS/Celgene, Janssen, Amgen and Sanofi. P.S. is on the advisory board for Amgen, BMS/Celgene, Janssen, Seagen and Pfizer and receives research support from Janssen, BMS/Celgene and Karyopharm.

Attentional bias for substance-relevant cues has been found to contribute to the persistence of addiction. Attentional bias modification (ABM) interventions might, therefore, increase positive treatment outcome and reduce relapse rates. The current study investigated the effectiveness of a newly developed home-delivered, multi-session, internet-based ABM intervention, the Bouncing Image Training Task (BITT), as an add-on to treatment as usual (TAU). No significant differences were found between conditions with regard to substance use, craving, relapse rates, attentional bias, or physical and psychological complaints. The findings may reflect unsuccessful modification of attentional bias, the BITT not targeting the relevant process (engagement vs. disengagement bias), or may relate to the diverse treatment goals of the current sample (i.e., moderation or abstinence). The current findings provide no support for the efficacy of this ABM approach as an add-on to TAU in alcohol or cannabis use disorder. Future studies need to delineate the role of engagement and disengagement bias in the persistence of addiction, and the role of treatment goal in the effectiveness of ABM interventions.

Background The automatic tendency to attend to and focus on substance-related cues in the environment (attentional bias), has been found to contribute to the persistence of addiction. Attentional bias modification (ABM) interventions might, therefore, contribute to treatment outcome and the reduction of relapse rates. Based on some promising research findings, we designed a study to test the clinical relevance of ABM as an add-on component of regular intervention for alcohol and cannabis patients. Design/Methods The current protocol describes a study which will investigate the effectiveness and cost-effectiveness of a newly developed home-delivered, multi-session, internet-based ABM (iABM) intervention as an add-on to treatment as usual (TAU). TAU consists of cognitive behavioural therapy-based treatment according to the Dutch guidelines for the treatment of addiction. Participants ( N  = 213) will be outpatients from specialized addiction care institutions diagnosed with alcohol or cannabis dependency who will be randomly assigned to one of three conditions: TAU + iABM; TAU + placebo condition; TAU-only. Primary outcome measures are substance use, craving, and rates of relapse. Changes in attentional bias will be measured to investigate whether changes in primary outcome measures can be attributed to the modification of attentional bias. Indices of cost-effectiveness and secondary physical and psychological complaints (depression, anxiety, and stress) are assessed as secondary outcome measures. Discussion This randomized control trial will be the first to investigate whether a home-delivered, multi-session iABM intervention is (cost-) effective in reducing relapse rates in alcohol and cannabis dependency as an add-on to TAU, compared with an active and a waiting list control group. If proven effective, this ABM intervention could be easily implemented as a home-delivered component of current TAU. Trial registration Netherlands Trial Register, NTR5497 , registered on 18th September 2015.

- R. Anderson Sutton, Wim van Zanten, Ethnomusicology in the Netherlands: present situation and traces of the past. Leiden: Centre of Non-Western Studies, Leiden University, 1995, ix + 330 pp. [Oideion; The performing arts worldwide 2. Special Issue]., Marjolijn van Roon (eds.) - T.E. Behrend, Willem Remmelink, The Chinese War and the collapse of the Javanese state, 1725-1743. Leiden: KITLV Press, 1994, 297 pp. [Verhandelingen 162]. - Erik Brandt, Eric Venbrux, A death in the Tiwi Islands; Conflict, ritual and social life in an Australian Aboriginal Community. Cambridge: Cambridge University Press, 1995, xvii + 269 pp. - Madelon Djajadiningrat-Nieuwenhuis, Tineke Hellwig, In the shadow of change; Images of women in Indonesian literature. Berkeley: University of California, Centers for South and Southeast Asia Studies, 1994, xiii + 259 pp. [Monograph 35]. - M. Estellie Smith, Peter J.M. Nas, Issues in urban development; Case studies from Indonesia. Leiden: Research School CNWS, 1995, 293 pp. [CNWS Publications 33]. - Uta Gärtner, Jan Becka, Historical dictionary of Myanmar. Metuchen, N.J.: Scarecrow Press, xxii + 328 pp. [Asian Historical Dictionaries 15]. - Beatriz van der Goes, H. Slaats, Wilhelm Middendorp over de Karo Batak, 1914-1919. Deel 1. Nijmegen: Katholieke Universiteit, Faculteit der Rechtsgeleerdheid, 1994, xvii + 313 pp. [Reeks Recht en Samenleving 11]., K. Portier (eds.) - Stephen C. Headley, Janet Carsten, About the house, Lévi-Strauss and beyond. Cambridge: Cambridge University Press, 1995, xiv + 300 pp., Stephen Hugh-Jones (eds.) - Stephen C. Headley, James J. Fox, Inside Austronesian houses; Perspectives on domestic designs for living. Canberra: Department of Anthropology, Research School of Pacific Studies, The Australian National University, 1993, x + 237 pp. - M. Hekker, Helmut Buchholt, Continuity, change and aspirations; Social and cultural life in Minahasa, Indonesia. Singapore: Institute of Southeast Asian Studies, 1994, vii + 231 pp., Ulricht Mai (eds.) - Tineke Hellwig, Brigitte Müller, Op de wipstoel; De niet-gewettigde inheemse vrouw van de blanke Europeaan in Nederlands-Indië (1890-1940); Een literatuuronderzoek naar beeldvorming en werkelijkheid. Amsterdam: Vakgroep Culturele Antropologie/Sociologie der Niets-Westerse Samenlevingen, 1995, xii + 131 pp. - Jan van der Putten, Liaw Yock Fang, Standard Malay made simple. Singapore: Times Books International, 1988. - Jan van der Putten, Liaw Yock Fang, Standard Indonesian made simple, written with the assistance of Nini Tiley-Notodisuryo, Singapore: Times Books International, 1990. - Jan van der Putten, Liaw Yock Fang, Speak standard Malay; A beginner’s guide. Singapore: Times Books International, 1993, xxii + 280 pp. - Jan van der Putten, Liaw Yock Fang, Speak Indonesian; A beginner’s guide, written in collaboration with Munadi Padmadiwiria and Abdullah Hassan. Singapore: Times Books International, 1990. - Alle G. Hoekema, Chr.G.F. de Jong, Geschiedenis van de Nederlandse Zending op Zuid-Sulawesi 1852-1966; Een bronnenpublicatie. Oegstgeest: Raad voor de Zending der Nederlands Hervormde Kerk, 1995, xi + 524 pp. - George Hotze, Ronald G. Gill, De Indische stad op Java en Madura; Een morfologische studie van haar ontwikkeling. Delft: Publikatieburo Bouwkunde, Technische Universiteit Delft, 1995, 350 pp. - H.A.J. Klooster, Holk H. Dengel, Neuere Darstellung der Geschichte Indonesiens in Bahasa Inonesia; Entwicklung und Tendenzen der indonesischen Historiographie. Stuttgart: Steiner, 1994, vii + 269 pp. - Harry A. Poeze, Hans Antlöv, Imperial policy and Southeast Asian nationalism 1930-1957. Richmond: Curzon Press, 1995, xiii + 323 pp., Stein Tonnesson (eds.) - P.W. Preston, Michael Hill, The politics of nation building and citizenship in Singapore. London: Routledge, 1995, x + 285 pp., Lian Kwen Fee (eds.) - J.W. (Pim) Schoorl, Michael Southon, The navel of the perahu; Meaning and values in the maritime trading economy of a Butonese village. Canberra: Department of Anthropology, Research School of Pacific and Asian Studies, The Australian National University, 1995, xiv + 150 pp. - Henk Schulte Nordholt, Geoffrey Robinson, The dark side of paradise; Political violence in Bali. Ithaca/London: Cornell University Press, 1995, xxii + 341 pp. - Herman A.O. de Tollenaere, Th. Stevens, Vrijmetselarij en samenleving in Nederlands-Indië en Indonesië 1764-1962. Hilversum: Verloren, 1994, 400 pp. - Donald E. Weatherbee, Mpu Prapañca, Desawarnana (Nagarakrtagama) by Mpu Prapañca, translated and edited by Stuart Robson. Leiden: KITLV Press, 1995, viii + 158 pp. [Verhandelingen 169]. - E.P. Wieringa, Jennifer Lindsay, Kraton Yogyakarta. Diterjemahkan oleh R.M. Soetanto dan T.E. Behrend. Jakarta: Yayasan Obor Indonesia, 1994, xvi + 330 pp. [Seri katalog Induk Naskah-Naskah Nusantara 2]., R.M. Soetanto, Alan Feinstein (eds.) - E.P. Wieringa, Wouter Smit, De islam binnen de horizon; Een missiologische studie over de benadering van de islam door vier Nederlandse zendingscorporaties (1797-1951). Zoetermeer: Boekencentrum, 1995, xix + 312 pp. [MISSION 11].

R. Anderson Sutton, Wim van Zanten, Ethnomusicology in the Netherlands: present situation and traces of the past. Leiden: Centre of Non-Western Studies, Leiden University, 1995, ix + 330 pp. [Oideion; The performing arts worldwide 2. Special Issue]., Marjolijn van Roon (eds.) - T.E. Behrend, Willem Remmelink, The Chinese War and the collapse of the Javanese state, 1725-1743. Leiden: KITLV Press, 1994, 297 pp. [Verhandelingen 162]. - Erik Brandt, Eric Venbrux, A death in the Tiwi Islands; Conflict, ritual and social life in an Australian Aboriginal Community. Cambridge: Cambridge University Press, 1995, xvii + 269 pp. - Madelon Djajadiningrat-Nieuwenhuis, Tineke Hellwig, In the shadow of change; Images of women in Indonesian literature. Berkeley: University of California, Centers for South and Southeast Asia Studies, 1994, xiii + 259 pp. [Monograph 35]. - M. Estellie Smith, Peter J.M. Nas, Issues in urban development; Case studies from Indonesia. Leiden: Research School CNWS, 1995, 293 pp. [CNWS Publications 33]. - Uta Gärtner, Jan Becka, Historical dictionary of Myanmar. Metuchen, N.J.: Scarecrow Press, xxii + 328 pp. [Asian Historical Dictionaries 15]. - Beatriz van der Goes, H. Slaats, Wilhelm Middendorp over de Karo Batak, 1914-1919. Deel 1. Nijmegen: Katholieke Universiteit, Faculteit der Rechtsgeleerdheid, 1994, xvii + 313 pp. [Reeks Recht en Samenleving 11]., K. Portier (eds.) - Stephen C. Headley, Janet Carsten, About the house, Lévi-Strauss and beyond. Cambridge: Cambridge University Press, 1995, xiv + 300 pp., Stephen Hugh-Jones (eds.) - Stephen C. Headley, James J. Fox, Inside Austronesian houses; Perspectives on domestic designs for living. Canberra: Department of Anthropology, Research School of Pacific Studies, The Australian National University, 1993, x + 237 pp. - M. Hekker, Helmut Buchholt, Continuity, change and aspirations; Social and cultural life in Minahasa, Indonesia. Singapore: Institute of Southeast Asian Studies, 1994, vii + 231 pp., Ulricht Mai (eds.) - Tineke Hellwig, Brigitte Müller, Op de wipstoel; De niet-gewettigde inheemse vrouw van de blanke Europeaan in Nederlands-Indië (1890-1940); Een literatuuronderzoek naar beeldvorming en werkelijkheid. Amsterdam: Vakgroep Culturele Antropologie/Sociologie der Niets-Westerse Samenlevingen, 1995, xii + 131 pp. - Jan van der Putten, Liaw Yock Fang, Standard Malay made simple. Singapore: Times Books International, 1988. - Jan van der Putten, Liaw Yock Fang, Standard Indonesian made simple, written with the assistance of Nini Tiley-Notodisuryo, Singapore: Times Books International, 1990. - Jan van der Putten, Liaw Yock Fang, Speak standard Malay; A beginner’s guide. Singapore: Times Books International, 1993, xxii + 280 pp. - Jan van der Putten, Liaw Yock Fang, Speak Indonesian; A beginner’s guide, written in collaboration with Munadi Padmadiwiria and Abdullah Hassan. Singapore: Times Books International, 1990. - Alle G. Hoekema, Chr.G.F. de Jong, Geschiedenis van de Nederlandse Zending op Zuid-Sulawesi 1852-1966; Een bronnenpublicatie. Oegstgeest: Raad voor de Zending der Nederlands Hervormde Kerk, 1995, xi + 524 pp. - George Hotze, Ronald G. Gill, De Indische stad op Java en Madura; Een morfologische studie van haar ontwikkeling. Delft: Publikatieburo Bouwkunde, Technische Universiteit Delft, 1995, 350 pp. - H.A.J. Klooster, Holk H. Dengel, Neuere Darstellung der Geschichte Indonesiens in Bahasa Inonesia; Entwicklung und Tendenzen der indonesischen Historiographie. Stuttgart: Steiner, 1994, vii + 269 pp. - Harry A. Poeze, Hans Antlöv, Imperial policy and Southeast Asian nationalism 1930-1957. Richmond: Curzon Press, 1995, xiii + 323 pp., Stein Tonnesson (eds.) - P.W. Preston, Michael Hill, The politics of nation building and citizenship in Singapore. London: Routledge, 1995, x + 285 pp., Lian Kwen Fee (eds.) - J.W. (Pim) Schoorl, Michael Southon, The navel of the perahu; Meaning and values in the maritime trading economy of a Butonese village. Canberra: Department of Anthropology, Research School of Pacific and Asian Studies, The Australian National University, 1995, xiv + 150 pp. - Henk Schulte Nordholt, Geoffrey Robinson, The dark side of paradise; Political violence in Bali. Ithaca/London: Cornell University Press, 1995, xxii + 341 pp. - Herman A.O. de Tollenaere, Th. Stevens, Vrijmetselarij en samenleving in Nederlands-Indië en Indonesië 1764-1962. Hilversum: Verloren, 1994, 400 pp. - Donald E. Weatherbee, Mpu Prapañca, Desawarnana (Nagarakrtagama) by Mpu Prapañca, translated and edited by Stuart Robson. Leiden: KITLV Press, 1995, viii + 158 pp. [Verhandelingen 169]. - E.P. Wieringa, Jennifer Lindsay, Kraton Yogyakarta. Diterjemahkan oleh R.M. Soetanto dan T.E. Behrend. Jakarta: Yayasan Obor Indonesia, 1994, xvi + 330 pp. [Seri katalog Induk Naskah-Naskah Nusantara 2]., R.M. Soetanto, Alan Feinstein (eds.) - E.P. Wieringa, Wouter Smit, De islam binnen de horizon; Een missiologische studie over de benadering van de islam door vier Nederlandse zendingscorporaties (1797-1951). Zoetermeer: Boekencentrum, 1995, xix + 312 pp. [MISSION 11].