Underestimated caregiver burden by cancer patients and its association with quality of life, depression and anxiety among caregivers.

This study examined how patients with cancer estimate caregiver burden (CB) and the association between their underestimation of CB and their caregivers' self-ratings of their quality of life (CQOLC-K; Korean version of the Caregiver Quality of Life Index-Cancer), depression and anxiety (Korean version of the Hospital Anxiety and Depression Scale). Participants consisted of 990 patient-caregiver dyads recruited from a nationwide cross-sectional survey conducted in South Korea. Medical baseline data were retrieved from the hospital information systems of the participating centres. The patients with cancer who underestimated CB ranged from 18.62% (for physical CB) to 23.33% (for social CB). They had less advanced cancer, a lower income, were the caregiver's spouse, reported higher levels of family avoidance of communication about cancer, and had female caregivers. The patients' underestimation of CB was significantly related to lower CQoL and higher levels of caregiver depression and anxiety. The current study provides empirical evidence for the link between the underestimation of CB by patients with cancer and compromised caregiving experiences of cancer caregivers. Open family communication about cancer was discussed as one of several practical strategies for decreasing patients' underestimation of CB.

The effect of overweight/obesity on cognitive function in euthymic individuals with bipolar disorder.

BACKGROUND: Persistent impairment in cognitive function has been described in euthymic individuals with bipolar disorder. Collective work indicates that obesity is associated with reduced cognitive function in otherwise healthy individuals. This sub-group post-hoc analysis preliminarily explores and examines the association between overweight/obesity and cognitive function in euthymic individuals with bipolar disorder. METHODS: Euthymic adults with DSM-IV-TR-defined bipolar I or II disorder were enrolled. Subjects included in this post-hoc analysis (n=67) were divided into two groups (normal weight, body mass index [BMI] of 18.5-24.9 kg/m2; overweight/obese, BMI ≥ 25.0 kg/m2). Demographic and clinical information were obtained at screening. At baseline, study participants completed a comprehensive cognitive battery to assess premorbid IQ, verbal learning and memory, attention and psychomotor processing speed, executive function, general intellectual abilities, recollection and habit memory, as well as self-perceptions of cognitive failures. RESULTS: BMI was negatively correlated with attention and psychomotor processing speed as measured by the Digit Symbol Substitution Test (P<0.01). Overweight and obese bipolar individuals had a significantly lower score on the verbal fluency test when compared to normal weight subjects (P<0.05). For all other measures of cognitive function, non-significant trends suggesting a negative association with BMI were observed, with the exception of measures of executive function (i.e., trail making test B) and recollection memory (i.e., process-dissociation task). CONCLUSION: Notwithstanding the post-hoc methodology and relatively small sample size, the results of this study suggest a possible negative effect of overweight/obesity on cognitive function in euthymic individuals with bipolar disorder. Taken together, these data provide the impetus for more rigorous evaluation of the mediational role of overweight/obesity (and other medical co-morbidity) on cognitive function in psychiatric populations.

Clinical heterogeneity of extranodal NK/T-cell lymphoma, nasal type: a national survey of the Korean Cancer Study Group.

BACKGROUND: This national survey was undertaken to propose the classification of extranodal natural killer (NK)/T-cell lymphoma (NTCL) subtypes and to clarify a clinical heterogeneity. PATIENTS AND METHODS: Two hundred and eighty patients newly diagnosed as NTCL were enrolled from 22 Korean medical centers. Two subsets were compared: one involving the upper aerodigestive tract (UAT) and another involving the non-upper aerodigestive tract (NUAT) region, which comprises the skin, gastrointestinal tract, and liver or soft tissues. Clinical prognostic factors, survival outcomes, and independent predictors for survival were compared between each subset. RESULTS: NUAT-NTCL (59 patients) had significantly higher proportions of disseminated disease, aggressive biologic features, and unfavorable host reactions compared with UAT-NTCL (221 patients). NUAT-NTCL had shortened 5-year overall survival (OS) (22% versus 41%, P = 0.001). Ann Arbor staging, the International Prognostic Index, and the NTCL prognostic index failed to predict the OS of NUAT-NTCL, but did predict the OS in UAT-NTCL. Independent predictors for OS by multivariate analyses differed between each subset. In the NUAT subset, extranodal sites and regional nodes predicted the OS, while Ann Arbor staging, age, performance status, and lactate dehydrogenase level predicted the OS in the UAT subset. CONCLUSION: NUAT-NTCL may represent a distinctive disease entity in terms of clinical factors, independent predictors, and survival outcomes.

Response to high-dose intravenous immune globulin as a valuable factor predicting the effect of splenectomy in chronic idiopathic thrombocytopenic purpura patients.

This study was conducted to verify whether the response to high-dose intravenous immune globulin (IVIG) was related to the effect of splenectomy in chronic idiopathic thrombocytopenic purpura (ITP) patients. A total of 79 patients over 16 years of age were enrolled in this study. The response to the treatment was classified on the basis of the platelet count as no response (NR, <50 x 10(9)/l), incomplete response (IR, (50-150) x 10(9)/l), and complete response (CR, >150 x 10(9)/l). The response was evaluated after the infusion of high-dose IVIG, within 2 weeks after splenectomy (immediate response), and during a follow-up period of more than 6 months after splenectomy (sustained response), respectively. 58 patients (73.4%) showed responses (CR or IR) to high-dose IVIG. After splenectomy, immediate responses were observed in 73 patients (92%). The response to high-dose IVIG had no relationship with the immediate response to splenectomy (P = 0.333). A follow-up evaluation was possible with 58 patients; 6 patients with NR in immediate responses did not show any response during the follow-up period, and 17 patients relapsed within 6 months after immediate responses, so 35 patients (60.3%) had sustained responses. Responders to IVIG had significantly higher sustained response rates to splenectomy than non-responders (62% vs. 38%, P = 0.001). These results indicate that the response to high-dose IVIG could be a valuable factor predicting the sustained response to splenectomy in chronic ITP patients.

Technetium-99m MDP bone scintigraphic findings of hypercalcemia in accelerated phase of chronic myelogenous leukemia.

Hypercalcemia in accelerated phase of chronic myelogenous leukemia (CML) is very rare. Its pathogenesis is considered humoral hypercalcemia of malignancies mediated by parathyroid hormone-related protein (PTHrP). In severe hypercalcemia, calcifications in kidneys, skin, vessels, heart, and stomach may occur. Our two cases were admitted because of severe hypercalcemia in accelerated phase of CML. On Tc-99m methylene diphosphonate (MDP) bone scintigraphies, a marked tracer accumulation was seen in the lung, heart, stomach and kidney. We report increased tracer accumulation of multiple organs on Tc-99m MDP bone scintigraphy in two rare hypercalcemic patients with CML.

Cytokines secreted by lymphokine-activated killer cells induce endogenous nitric oxide synthesis and apoptosis in DLD-1 colon cancer cells.

IL-2-activated killer lymphocytes (LAK cells) secrete inflammatory cytokines such as interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNFalpha) that can induce nitric oxide (NO) synthesis. We evaluated whether LAK cells could activate NO synthesis in human cancer cells. LAK cells and their culture supernatants induced NO synthesis in DLD-1 colon cancer cells in a dose-dependent manner. NO synthesis was inhibited completely by blocking antibodies to IFN-gamma, demonstrating a key role for this LAK cell cytokine in regulating NO synthesis. The addition of TNFalpha antibodies resulted in partial inhibition. Induction of iNOS mRNA and protein expression in DLD-1 cells was detected. Endogenous NO production inhibited DLD-1 cell proliferation and induced apoptosis, processes that were inhibitable by the NO synthase inhibitor N(G)-monomethyl-l-arginine. Our study has identified a novel, non-contact-dependent LAK cell cytotoxic mechanism: induction of growth inhibition and programmed cell death due to endogenous NO synthesis in susceptible human cancer cells.

Interaction of two classes of ADP-ribose transfer reactions in immune signaling.

CD38 is a bifunctional ectoenzyme predominantly expressed on hematopoietic cells where its expression correlates with differentiation and proliferation. The two enzyme activities displayed by CD38 are an ADP-ribosyl cyclase and a cyclic adenosine diphosphate ribose (cADPR) hydrolase that catalyzes the synthesis and hydrolysis of cADPR. T lymphocytes can be induced to express CD38 when activated with antibodies against specific antigen receptors. If the activated T cells are then exposed with NAD, cell death by apoptosis occurs. During the exposure of activated T cells to NAD, the CD38 is modified by ecto-mono-ADP-ribosyltransferases (ecto-mono-ADPRTs) specific for cysteine and arginine residues. Arginine-ADP-ribosylation results in inactivation of both cyclase and hydrolase activities of CD38, whereas cysteine-ADP-ribosylation results only in the inhibition of the hydrolase activity. The arginine-ADP-ribosylation causes a decrease in intracellular cADPR and a subsequent decrease in Ca(2+) influx, resulting in apoptosis of the activated T cells. Our results suggest that the interaction of two classes of ecto-ADP-ribose transfer enzymes plays an important role in immune regulation by the selective induction of apoptosis in activated T cells and that cADPR mediated signaling is essential for the survival of activated T cells.

Receptor-mediated activation of murine peritoneal macrophages by antithrombin III acts as a costimulatory signal for nitric oxide synthesis.

We evaluated the effect of antithrombin III (ATIII), a serine protease inhibitor (SERPIN), on induction of nitric oxide (NO) synthesis in murine peritoneal macrophages. Incubation of macrophages with ATIII plus interferon-gamma (IFN-gamma) but not ATIII alone induced nitrite accumulation (a metabolite of NO) in a dose-dependent manner. Expression of the inducible nitric oxide synthase isoform was confirmed by Western blot. NO synthesis was inhibited by NG-monomethyl-l-arginine, by complexing ATIII with thrombin or by rabbit anti-human ATIII antiserum. Addition of polymyxin B to macrophage cultures failed to inhibit ATIII/IFN-gamma-induced NO synthesis, excluding lipopolysaccharide contamination. 125I-ATIII bound to macrophages in a dose-dependent, specific, and saturable manner, with a Km of approximately 7.1 nM. Our results demonstrate that ATIII, but not ATIII/thrombin complex, acts to costimulate macrophage activation and NO synthesis via a novel receptor mediated mechanism, which may indicate a role for SERPINs in macrophage activation.

Nitric oxide exposure inhibits induction of lymphokine-activated killer cells by inducing precursor apoptosis.

Nitric oxide synthesis is strongly induced during IL-2 treatment of mice and humans. While this free radical can act as an antitumor mechanism by inhibiting cellular respiration and DNA synthesis in cancer cells, immunosuppressive effects have also been suggested. We evaluated the effects of NO exposure on the induction of murine lymphokine-activated killer (LAK) cells from splenocytes by IL-2 (6000 IU/ml). When splenocytes were exposed to pure NO gas for 30 min prior to the addition of IL-2, complete abrogation of LAK cell cytotoxicity was observed. In contrast, cytolytic activity of already activated LAK cells was only minimally affected by NO exposure. NO exposure markedly depressed cellular proliferation in response to concanavalin A or IL-2. Immunostaining of LAK cell cultures following NO exposure revealed a marked decrease in CD8+, and peanut lectin (PNA+)/CD56+ subsets (48 and 69%). Dual staining of LAK cells for DNA strand breaks and either PNA or CD8+ identified the induction of programmed cell death in these subsets 12-24 h following NO exposure. These experiments demonstrate that NO has the capacity to inhibit LAK cell induction by inducing apoptosis of cytolytic lymphocyte precursors.

Differences in immunophenotyping of mucosal lymphocytes between ulcerative colitis and Crohn's disease.

OBJECTIVES: Immunologic studies have characterized the numbers and types of inflammatory cells in diseased inflammatory bowel disease (IBD) mucosa but have yielded conflicting results regarding intestinal lymphocytes activation in IBD. We investigated the levels of lymphocytes subsets, interleukin-2 receptor, transferrin receptor, and T cell receptors in mainly isolated lamina propria lymphocytes. Including intraepithelial lymphocytes of normal colonic mucosa or IBD (ulcerative colitis and Crohn's disease) mucosa to understand the pathogenesis of IBD. We have results from this study. RESULTS: 1) In comparing ulcerative colitis with control, IL-2R (p < 0.05), TR (p < 0.01), and CD3/HLA-DR (< 0.05) showed a significant increase. 2) In comparing Crohn's disease with control, CD3 (P < 0.05), TCR alpha/beta (p < 0.01) and TCR gamma/delta (p < 0.05) showed a significant decrease. 3) In comparing Crohn's disease with ulcerative colitis, CD19 (p < 0.01), TR (p < 0.01), TCR alpha/beta (p < 0.01) and TCR gamma/delta (p < 0.05) showed a significant decrease. CONCLUSION: From these results, there are increased T cell markers, IL-2R, TR, and CD3/HLA-DR in UC, but differently, decreased CD3, TCR alpha/beta and TCR gamma/delta in CD compared with control. In addition, definitive differences in lymphocytes markers, CD19, TR, TCR alpha/beta and TCR gamma/delta, which are higher in UC than in CD, may elucidate the different immunopathogenesis between UC and CD.

Effects of nitric oxide (NO) synthesis inhibition on antitumor responses during interleukin-2 (IL-2) treatment of mice.

OBJECTIVES: To evaluate if L-arginine: NO pathway is activated in tumor tissues during IL-2 therapy and to evaluate whether IL-2 induced NO synthesis represents an antitumor effector mechanism or an inhibitory factor against therapeutic effects of IL-2. METHODS: Four groups [untreated control, NG-monomethyl-L-arginine (MLA) therapy only, IL-2 therapy only, IL-2/MLA therapy groups] of BALB/c mice were injected intraperitoneally with 2 x 10(8) Meth A tumor cells on day 0. MLA was administered subcutaneously with Alzet continuous infusion pumps on day 2. IL-2 therapy (180,000 IU s.c. every 12h for 5 days) was started on day 3. NO production within ascites tumors was assessed by measuring nitrite concentrations in cultures of ascites cells harvested on day 8. Survival and the rate of body weight increment of the mice were measured to evaluate therapeutic responses. Daily urinary nitrate excretion was monitored to demonstrate the effectiveness of MLA in inhibiting NO synthesis. RESULTS: Nitrite production in supernatants of Meth A ascites cell cultures was 63 +/- 14 microM in IL-2 treated mice and 3.2 +/- 1.5 microM in untreated controls (p < 0.001). MLA prevented the IL-2 therapy induced increase in nitrite production. IL-2 therapy did not decrease the rate of body weight increment and marginally prolonged mean survival to 18.2 days, compared to 16.6 days in control mice (p = 0.255). MLA administration decreased the rate of body weight increment and prolonged mean survival of IL-2 treated mice (21.8 days, p = 0.001 versus IL-2 alone). Interestingly, the MLA treatment increased the rate of body weight increment and diminished the survival of control mice to 11.6 days (p = 0.003). MLA administration via Alzet continuous infusion pumps achieved approximately 60% suppression of urinary nitrate excretion by control mice. Subcutaneous IL-2 treatment strongly induced nitric oxide synthesis (up to 3.5 mumoles of urinary nitrate/ mouse/day). MLA also effectively suppressed IL-2 induced NO production. CONCLUSION: L-arginine: NO pathway can be activated in malignant ascites by IL-2 therapy and NO synthesis functions as an inhibitory mechanism against IL-2 induced anti-tumor effects.

Nitric oxide synthesis contributes to IL-2-induced antitumor responses against intraperitoneal Meth A tumor.

IL-2 therapy is a potent inductive stimulus for nitric oxide (NO.) synthesis in mice and humans. It is not yet clear whether NO. can contribute to IL-2-induced therapeutic responses. The murine skin cancer Meth A is relatively resistant to lymphokine-activated killer (LAK) cell killing, allowing evaluation of the role of IL-2-induced NO. synthesis in vivo, without contribution by LAK cells. Subcutaneous IL-2 treatment of mice bearing i.p. Meth A tumor increased nitrite production by cells derived from ascites (63 +/- 14 microM vs 3.2 +/- 1.5 microM in untreated controls). N omega-monomethyl-L-arginine (MLA), NO. synthase inhibitor, prevented this increase. NO. production correlated in an inverse fashion with tumor cell proliferation in vitro. Evidence for IL-2-induced heme nitrosylation was demonstrated in tumor cells by electron paramagnetic resonance spectroscopy. By immunomagnetic depletion experiments, macrophages were implicated as a major source of NO. synthesis. Cytologic and flow-cytometric evaluation revealed that IL-2 treatment resulted in enhanced lymphocyte and macrophage recruitment into malignant ascites, and decreases in tumor cell recovery. MLA administration further increased host cell recovery. Subcutaneous IL-2 therapy increased urinary nitrate excretion up to eightfold in mice, and appeared to produce a significant survival advantage that was prevented by MLA administration.