Psychosocial care for cancer: a framework to guide practice, and actionable recommendations for Ontario.

OBJECTIVES: We set out to create a psychosocial oncology care framework and a set of relevant recommendations that can be used to improve the quality of comprehensive cancer care for Ontario patients and their families.meet the psychosocial health care needs of cancer patients and their families at both the provider and system levels. DATA SOURCES AND METHODS: The adapte process and the practice guideline development cycle were used to adapt the 10 recommendations from the 2008 U.S. Institute of Medicine standard Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs into the psychosocial oncology care framework. In addition, the evidence contained in the original document was used, in combination with the expertise of the working group, to create a set of actionable recommendations. Refinement after formal external review was conducted. DATA EXTRACTION AND SYNTHESIS: The new framework consists of 8 defining domains. Of those 8 domains, 7 were adapted from recommendations in the source document; 1 new domain, to raise awareness about the need for psychosocial support of cancer patients and their families, was added. To ensure high-quality psychosocial care and services, 31 actionable recommendations were created. The document was submitted to an external review process. More than 70% of practitioners rated the quality of the advice document as high and reported that they would recommend its use. CONCLUSIONS: This advice document advocates for a multidisciplinary approach to cancer care in response to the distress experienced by cancer patients and their families. The recommendations will be useful in future to measure performance, quality of practice, and access to psychosocial services.

A phase I clinical study of intratumorally administered VB4-845, an anti-epithelial cell adhesion molecule recombinant fusion protein, in patients with squamous cell carcinoma of the head and neck.

VB4-845 is a novel recombinant fusion protein that targets the epithelial cellular adhesion molecule (EpCAM). This initial clinical trial was conducted to determine the maximum tolerated dose of intratumoral injections in patients with advanced squamous cell carcinoma of the head and neck and to assess pharmacokinetics and immunogenicity. Twenty-four patients with advanced, recurrent squamous cell carcinoma of the head and neck received two cycles of five daily intratumoral VB4-845 injections of 20, 40, 80, 130, 200, or 280 microg. The maximum tolerated dose was established to be 280 microg administered daily for 5 days. Common adverse events were pain due to intratumoral injection and reversibly elevated liver enzymes. Of the 24 patients, 15 had detectable blood levels with a mean drug half-life of 4.0 +/- 0.3 h. VB4-845 reduced or stabilized tumors in 71.4% of epithelial cell adhesion molecule-positive patients. VB4-845 intratumoral injection therapy was well tolerated and feasible.

Differential control of autoantibodies and lymphoproliferation by Fas ligand expression on CD4+ and CD8+ T cells in vivo.

We have previously shown that the gld autoimmune syndrome is suppressed in lethally irradiated gld mice reconstituted with a mixture of normal and gld bone marrow (BM). Furthermore, in vivo depletion of normal Thy-1+ cells restores lymphoproliferation and autoantibody production in such chimeras, suggesting that T cells bearing Fas ligand are responsible for correcting the gld defect. In this study, mixed-BM chimeras lacking either normal CD4+ (B6CD4KO-B6gld) or normal CD8+ T cells (B6CD8KO-B6gld) were generated to determine the contribution of the normal T cell subsets to disease suppression. Lymphoproliferation was completely suppressed in B6CD4KO-B6gld chimeras but only modestly in B6CD8KO-B6gld chimeras. On the other hand, both types of mixed-BM chimeras had incomplete effects on the suppression of serum autoantibodies when compared with B6gld reconstituted with isologous BM. These results suggest that both T cell subsets provide Fas ligand to suppress immune cells responsible for autoantibody production; however, CD8+ T cells are mainly responsible for preventing lymphoproliferation.

The role of environmental antigens in the spontaneous development of autoimmunity in MRL-lpr mice.

It has been proposed that the "normal" stimulation of the immune system that occurs from interactions with environmental stimuli, whether infectious or dietary, is necessary for the initiation and/or continuation of autoimmunity. We tested this hypothesis by deriving a group of MRL-lpr mice into a germfree (GF) environment. At 5 mo of age, no differences between GF and conventional MRL-lpr mice were noted in lymphoproliferation, flow cytometric analysis of lymph node cells (LN), or histologic analysis of the kidneys. Autoantibody levels were comparably elevated in both groups. A second experiment tested the role of residual environmental stimuli by contrasting GF mice fed either a low m.w., ultrafiltered Ag-free (GF-AF) diet or an autoclaved natural ingredient diet (GF-NI). At 4 mo of age, both groups showed extensive lymphoproliferation and aberrant T cell formation, although the GF-AF mice had approximately 50% smaller LNs compared with sex-matched GF-NI controls. Autoantibody formation was present in both groups. Histologic analysis of the kidneys revealed that GF-AF mice had much lower levels of nephritis, while immunofluorescence analysis demonstrated no difference in Ig deposits but did reveal a paucity of C3 deposition in the kidneys of GF-AF mice. These data do not support a role for infectious agents in the induction of lymphoproliferation and B cell autoimmunity in MRL-lpr mice. Furthermore, they suggest that autoantibodies do not originate from B cells that were initially committed to exogenous Ags. They do suggest a possible contributory role for dietary exposure in the extent of lymphoproliferation and development of nephritis in this strain.

Depletion of natural killer cells from the graft reduces interferon-gamma levels and lipopolysaccharide-induced tumor necrosis factor-alpha release in F1 hybrid mice with acute graft-versus-host disease.

BACKGROUND: We wished to determine whether removal of NK1.1+ cells from the graft provides protection against acute graft-versus-host disease (GVHD) by obviating the Th1 immune response that underlies the development of this disease. METHODS: Graft-versus-host (GVH) reactions were induced in two groups of (C57BL/6 x DBA/2)F1 hybrid mice. The first received grafts harvested from polyinosinic:polycytidylic acid-stimulated, C57BL/6 donors and depleted in vitro of NK1.1+ cells. This treatment provides protection against GVHD-associated mortality and cachexia. The second received unmodified grafts. We compared interferon-gamma and interleukin-10 production as well as the levels of engraftment in these two groups. Lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha) release was also compared since TNF-alpha levels in GVH mice following injection of a sublethal dose of endotoxin provide an index of macrophage priming by Th1 cytokines. RESULTS: Interferon-gamma production was absent in recipients of NK1.1-depleted grafts at the time when high levels were seen in recipients of unmodified grafts. Following lipopolysaccharide injection, high levels of TNF-alpha were observed in recipients of unmodified grafts, whereas negligible amounts were present in recipients of NK1.1-depleted grafts. The use of NK1.1-depleted grafts did not result in a reduced level of engraftment of CD4+ or CD8+ cells. CONCLUSIONS: These results suggest that NK1.1 depletion of the graft confers protection against mortality by interfering with an immunoregulatory mechanism that results in the development of a Th1 response in GVH mice, and does not result in abortion of the graft. Because macrophage priming is prevented, recipients are also protected from the exaggerated sensitivity to endotoxin seen in mice with acute GVHD.

B cell genotype determines the fine specificity of autoantibody in lpr mice.

Anti-Sm Abs are specific markers of human systemic lupus erythematosus (SLE) and of murine models of this disease. In humans, anti-Sm Abs are mostly IgG1, and in MRL/lpr mice, IgG2a; both are T-dependent isotypes. Other lpr strains, such as B6/lpr, do not produce anti-Sm Ab spontaneously. The present study was aimed at identifying the cellular expression of background genes responsible for generation of the anti-Sm Ab response in MRL/lpr mice. We used double chimeric mice made by transferring MRL/lpr and B6/lpr bone marrows into irradiated allotype heterozygous F1 mice. Five mo after reconstitution, FACS analysis of lymph node (LN) and spleen cells revealed that both MRL/lpr and B6/lpr cells coexisted in roughly equal numbers. Ab produced by each donor could be distinguished by allotype-specific assays. IgG2a anti-Sm was made only by MRL-derived B cells despite the presence of T cells that might potentially provide help to the B6/lpr B cells. The frequency of anti-Sm Ab-producing individuals was similar to that of unmanipulated MRL/lpr mice (about 25%). IgG2a anti-chromatin and total IgG2a was mostly dominated by the MRL-derived B cells. B6-derived B cells produced more rheumatoid factor (RF) against their own IgG2b(b), while RF against IgG2a was dominated by MRL-derived B cells. This suggests that the control of the production of particular autoantibody specificities, such as anti-Sm, is determined by the expression of MRL or B6 background genes in B cells.

Suppression and reversal of gld disease by parabiosis with normal mice.

The disruption of the Fas receptor or Fas ligand by the lpr or gld mutations, respectively, results in severe autoimmune and lymphoproliferative disease due to the failure of Fas-mediated deletion of self-reactive lymphocytes. Recently, we have shown in mixed chimeras that gld-induced autoimmunity could be corrected by normal bone marrow, in particular by normal T cells. In contrast, lpr-mediated autoimmunity could not be influenced by normal bone marrow-derived cells. In the present report, we have studied the role of normal lymphocytes in suppressing or reversing gld-induced autoimmunity by parabiosis with normal mice. Our results show a suppression of lymphadenopathy, fewer CD4-CD8- T cells, and lower levels of autoantibody production in gld mice parabiosed with normal mice at 4-6 weeks of age. The gld mice parabiosed with normal mice at 4 months of age also exhibited a substantial reduction of both total and CD4-CD8- T cells in the periphery 2 months after surgery. However, they showed little reduction of autoantibodies compared to gld mice parabiosed with gld mice. In contrast, older lpr mice did not exhibit any reduction in lymphadenopathy or autoantibody production after parabiosis with normal mice. The prevention or reversal of lymphadenopathy in parabiosed gld mice suggests that ongoing Fas-mediated deletion in the periphery may play an important role in maintaining self-tolerance. The relative irreversibility of autoantibody synthesis in older parabiosed gld mice suggests that autoantibody-producing B cells or their committed precursors are long lived and do not express functional Fas receptor.

Gamma delta T cells in the pathobiology of murine acute graft-versus-host disease. Evidence that gamma delta T cells mediate natural killer-like cytotoxicity in the host and that elimination of these cells from donors significantly reduces mortality.

NK-like cytotoxicity in F1-hybrid mice with acute GVH disease is mediated by donor-derived CD3+/CD4-/CD8- cells that can lyse both NK-sensitive YAC-1 target cells as well as NK-resistant targets such as BW1100 and P815. Our objective was to determine whether this activity is mediated by gamma delta TCR+ cells. We showed that NK-like cytotoxic activity in the spleen and lymph nodes of mice with acute GVH disease could be depleted by indirect complement-mediated lysis using an Ab against gamma delta TCR. When purified NK1.1+ spleen cells that had been positively selected on a magnetic cell separator were used as effector cells, we found that NK-like cytotoxicity was mediated only by gamma delta TCR+ cells, suggesting that cells with NK-like activity are gamma delta TCR+/NK1.1+. We showed by flow cytometry experiments that coexpression of NK1.1 and TCR-gamma delta occurred on a large proportion of large granular lymphocytes in the spleens of GVH mice, but was not detectable in normal control mice. In GVH mice, fewer than 10% of small agranular NK1.1+ lymphocytes coexpressed NK1.1+ and gamma delta TCR+. On the basis of this hypothesis, we postulate that graft-derived large granular lymphocytes develop the NK1.1+/gamma delta TCR+ phenotype during the reaction, and that these cells play a role in the pathogenesis of acute GVH disease. We performed experiments to determine whether depletion of gamma delta T cells from donor mice affected the outcome of lethal GVH disease and found that there was a significant reduction in mortality.

In vivo depletion of Thy-1-positive cells originating from normal bone marrow abrogates the suppression of gld disease in normal-gld mixed bone marrow chimeras.

Mice homozygous for gld develop an autoimmune syndrome characterized by hypergammaglobulinemia, massive accumulation of abnormal T cells and the production of autoantibodies. Previous studies in our laboratory have shown that reconstitution of lethally irradiated B6/gld recipients with a mixture of normal and gld bone marrow (BM) suppresses the gld-induced syndrome. In this report we extend this observation by demonstrating that the depletion of normal Thy-1+ cells, but not normal B cells, restores gld disease in mixed BM chimeras congenic for Thy-1 and IgH alleles. These results strongly suggest that normal T cells suppress the development of gld-related abnormalities. It is probable that the mechanism by which normal Thy-1+ cells mediate the suppression is Fas ligand dependent.

Prevention of acute lethal graft-versus-host disease in F1 hybrid mice by pretreatment of the graft with anti-NK-1.1 and complement.

We studied the effect of depleting NK1.1+ cells from an allograft of lymph node and spleen cells on the outcome of GVH disease in the parent----F1-hybrid combination C57BL/6----(C57BL/6xDBA/2)F1. Four treatment groups were established: group I mice were transplanted with an unmodified graft from normal donors; group II mice were transplanted with an NK1.1-depleted graft that had been harvested from normal donors; group III mice received grafts from donors that had been injected with Poly I:C (100 micrograms i.p.) 18 hr prior to harvesting (These grafts were incubated with complement, but no antibody.); group IV mice were transplanted with depleted grafts harvested from donors that had received Poly I:C. Recipients in each group were monitored for splenomegaly, mitogen responsiveness, NK and CTL activity, histopathology, weight loss, and mortality. Results showed that recipients in all four groups developed splenomegaly and unresponsiveness to LPS, PHA, and Con A by day 12. Augmented host-derived NK activity and graft-derived antihost CTL activity was also demonstrated. Group IV showed little or no weight loss, minimal histopathological changes and a marked reduction in mortality. Recipients in all other groups developed features characteristic of GVH disease and exhibited a steady decline in body weight beginning by day 12. Mortality generally began on day 18 and reached 75-90% by day 60. We postulate that anti-NK1.1 depletes cells from the graft are intimately connected with the effector mechanism in acute GVH disease.

Natural killer (NK) cell activity in mice with acute graft-versus-host reactions: characterization of a Thy-1+ NK-like cell with a broadened spectrum of lytic activity in the spleen and lymph nodes.

We have shown that acute (GVH) reactions produced in the parental-F1 hybrid combination, A/J----(C57BL/6 x A/J)F1 result in the activation of two cytotoxic cell populations: a host-derived Thy-1+/- natural killer (NK) cell with a lytic spectrum confined to YAC-1 targets, and a donor-derived Thy-1+ NK-like cell that has the ability to lyse target cells that are normally insensitive to lysis by NK cells. Cold-target inhibition (CTI) experiments have shown that the greater range of target cell killing seen in the NK-like population is mediated by a single effector cell with a broadened lytic repertoire. Percoll density fractionation studies have revealed that NK and NK-like cells co-fractionate, suggesting that both are large granular lymphocytes. We we have also shown that NK-like cells do not express either Lyt-2 or L3T4 markers. We have also observed that there is a close temporal relationship between elevated levels of interleukin-2 (IL-2) secretion by spleen cell cultures from mice with GVH disease and the subsequent emergence of splenic NK activity in both acute [A/J----(C57BL/6 x A/J)F1] and chronic (A/J----CBA x A/J)F1 GVH reactions. We have also noted that, despite high levels of IL-2 secretion, mice with chronic GVH reactions do not generate NK-like activity. Interferon (IFN) measurements have shown that, although increased IFN activity can be detected in both acute and chronic models, a preponderance of IFN-alpha/beta and some IFN-gamma is produced in the acute reaction, whereas only IFN-gamma can be detected in the chronic model. These results suggest that, although IL-2 may participate in augmenting conventional NK activity, IL-2 by itself does not generate NK-like activity. We suggest that IFN-alpha/beta may be the cytokine that, either alone or in concert with IL-2, triggers the NK-like cell response. The NK-like cell described in our study resembles a phenotypically identical, donor-derived large granular lymphocyte, identified by others, in close proximity to dead or dying epithelial cells in mice with GVH disease [14]. It has been suggested that these cells may mediate tissue injury. If in fact these graft-derived NK-like cells are involved in the pathogenesis of acute GVH disease, our present findings suggest that they must first be activated by an appropriate complement of cytokines that includes IFN-alpha/beta.(ABSTRACT TRUNCATED AT 400 WORDS)

Fibronectin in foreign body-induced sarcomas and preneoplastic cells.

Foreign body (FB)-induced murine sarcoma cells and advanced preneoplastic cells as well as normal fibroblasts produce fibronectin (FN) in primary culture; cells at early preneoplasia do not. Hence, the neoplastic properties of FB-induced sarcomas do not depend on absence of FN. Temporary FN repression during early preneoplasia is associated with certain phenotypic cell characteristics.