A strong and positive correlation exists between chronic disease and affective disorders, but the biological mechanisms underlying this relationship are not known. Here we show that rats with mammary cancer exhibit depression-and anxiety-like behaviors in the absence of overt sickness behaviors. The production of proinflammatory cytokines, known to induce depressive-like behaviors, was elevated in the periphery and in the hippocampus of rats with tumors compared with controls. In tumor-bearing rats, circulating corticosterone, which inhibits cytokine signaling, was suppressed following a stressor, and gene expression of hippocampal glucocorticoid receptors was elevated. The results establish that tumors alone are sufficient to trigger changes in emotional behaviors. Dampened glucocorticoid responses to stressors may exacerbate the deleterious effects of tumor-induced cytokines on affective states.cancer ͉ depression ͉ HPA ͉ hippocampus P hysical and psychological health share a bidirectional relationship (1-4). Individuals suffering from major peripheral illnesses (e.g., cancer, cardiovascular disease, AIDS, etc.) are at greater risk for depression and anxiety disorders relative to the healthy population (5-7). For example, mood disorders are reported in up to 60% of breast cancer patients (8-10). Co-morbid depression is associated with decreased cancer survivorship (11) and increased treatment noncompliance (12); therefore, understanding the mechanisms underlying cancer-associated depression is of profound clinical significance. Despite the strong association between cancer and mood disorders, the respective contributions of: (i) subjective disease awareness, (ii) toxic side-effects of chemotherapy, and (iii) direct biological effects of tumors in the pathogenesis of cancerassociated affective disorders have remained largely unexamined and undifferentiated (13)(14)(15).Tumor cells secrete cytokines and chemokines locally (16,17). Proinflammatory cytokines (primarily IL-1, IL-6, and TNF␣) induce depressive-like behavior (e.g., anhedonia, anorexia, lethargy) (18) via humoral and neural signaling from the periphery to the brain (19). The overwhelming majority of data relating peripheral proinflammatory cytokine production to alterations in behavior and affective states are generated using acute bacterial infection models (18, 19), not chronic disease models. Information on the effects of tumors or tumor-induced cytokines on behavior, on the other hand, is limited to the study of cancer-induced anorexia or cachexia (20). Thus, the hypothesis that tumor-derived cytokines contribute to cancer-induced depression has never been examined.Cytokine signaling can be regulated by neuroendocrine activity, principally through the production of glucocorticoids (21). Corticosterone suppresses the synthesis and actions of proinflammatory cytokines and can thereby inhibit the effects of proinflammatory cytokines on depressive-like behaviors (22-25). Because glucocorticoid production changes during progression of chronic disease ...
Cancer, in addition to many other chronic diseases, is associated with serious and problematic behavioral symptoms, including cognitive impairments. In humans, various factors likely contribute to cancer-associated cognitive deficits including disease awareness and chemotherapy; however, the endogenous biological factors arising from tumor development may also play a causal role. In the present study, rats with mammary tumors exhibited impaired spatial reference memory on a radial arm maze and amnesia for familiar objects in an object recognition memory test. In contrast, their performance in the Morris water maze and in fear conditioning tests was comparable to that of controls. These select cognitive impairments were accompanied by elevations in hippocampal interleukin-1β mRNA expression, but were not associated with decreases in hippocampal brainderived neurotrophic factor gene expression. Together the results indicate that peripheral tumors alone are sufficient to induce increases in hippocampal cytokine expression and select deficits in hippocampal-dependent memory tasks.
Background: The Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Consortium and Children's Oncology Group (COG) have recently adopted a modified UK ALLR3 (R3) re-induction regimen as a chemotherapy backbone to test novel agents in multiply relapsed pediatric acute lymphoblastic leukemia (ALL). A detailed toxicity profile of this platform has not previously been published, nor have data using this regimen beyond 1st relapse. Such baseline data with this backbone would be helpful in the design, conduct and assessment of future clinical trials of R3 in combination with novel agents. Methods: This was a multi-institutional, retrospective study to investigate adverse events (AEs) and outcome following R3 re-induction chemotherapy (vincristine, mitoxantrone, dexamethasone, and asparaginase) in pediatric relapsed/refractory (R/R) ALL. The objectives of the study were to: 1) establish baseline treatment related AEs during re-induction block 1; and 2) analyze the complete remission (CR) rate and minimal residual disease (MRD) status at the end of re-induction. Patients were identified using medical records from 5 pediatric oncology centers. The study was approved by IRBs at all sites. Data about diagnosis, relapse, prior therapy, AEs, and response to R3 block 1 were extracted from medical records and de-identified. AEs were graded according to the NCI CTCAE v4.0. Results: 59 patients were included in the study (Table 1). The median number of prior treatment attempts in multiply relapsed patients was 2.5 (range 2-4). Grade ≥ 3 infection was reported in 54/59 patients (92%) and 41 (76%) of these had an infectious source identified by culture, biopsy, and/or imaging. Poly-microbial infection was detected in 18 patients. Bacterial infections occurred most frequently, followed by viral and fungal infections (Table 2). The only grade 5 event in re-induction was due to sepsis. 9 patients (15%) were admitted to the intensive care unit (ICU) due to infection. The most common site of infection was blood, followed by gastrointestinal (GI) and pulmonary. Other grade ≥ 3 non-hematologic toxicities were metabolic derangements (39%), GI (22%), and pain (8%). There was no difference in the grade > 3 toxicities between 1st relapsed vs. multiply relapsed patients. 36 patients were discharged home prior to neutrophil count recovery. Among these patients, 92% (33/36) had hospital readmission, 7 (19%) required ICU care, and 10 (28%) required chemotherapy modification. In contrast, only 9% (2/23) of patients who remained hospitalized until count recovery received ICU care or had chemotherapy modifications. The median duration from the start of block 1 to block 2 was 39 days (range 28-115 days). 53 patients achieved CR after block 1; 5 had refractory disease; and 1 died of septic shock prior to disease evaluation. Conclusion: Our study confirmed that R3 block 1 is a highly active re-induction chemotherapy regimen for children with R/R ALL. However, it was associated with very high risk of life-threatening infections. Toxicity reported from this study should be used as a reference for future combination clinical trials using R3 as a backbone in pediatric R/R ALL. Hospitalization until blood count recovery may reduce the need for ICU care and chemotherapy modification. Table 1. Patient Characteristics and Response All Patients 1st Relapse > 2nd Relapse N 59 43 16 Median Age (yrs) 7 (0.4 – 19) 7 (0.4 – 19) 6.5 (2 – 15) Gender Male 41 (69%) 30 (70%) 11 (69%) Female 18 (31%) 13 (30%) 5 (31%) Site of Relapse Isolated BM 32 (54%) 22 (51%) 10 (63%) Isolated EM 15 (25%) 11 (26%) 4 (25%) Combined 12 (20%) 10 (23%) 2 (13%) Induction Death 1 (2%) 1 (2%) 0 Response Data CR/CRi 53 (90%) 41 (95%) 12 (75%) MRD - 30 (59%)* 23 (59%)* 7 (58%) MRD + 21 (41%) 16 (41%) 5 (42%) Refractory Disease 5 (8%) 1 (2%) 4 (25%) Subsequent HSCT Yes 24 (41%) 14 (33%) 10 (63%) No 35 (59%) 29 (67%) 6 (38%) BM = bone marrow; EM = extra medullary; CRi = CR with incomplete blood count recovery; HSCT = hematopoietic stem cell transplant *MRD was not performed in 2 patients. Table 2. Organism identified Biopsy/Culture confirmed or Suspected Infection by Imaging* 65 Bacterial Infection 44 (68%) Gram + 18 Gram - 19 Other 7 Fungal Infection 11 (17%) Biopsy/Culture confirmed 7 Suspected by CT/MRI 4 Viral Infection 10 (15%) Parasite 1 *Eighteen patients had > 1 organism identified Disclosures No relevant conflicts of interest to declare.
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