Cancer-related cognitive impairment (CRCI) is often related to chemotherapy. Increased chronic inflammation is believed to play a key role in the development of CRCI related to chemotherapy but ...studies assessing this hypothesis specifically in patients receiving chemotherapy are rare.
We assessed several cognitive domains using the Cambridge Neuropsychological Test Automated Battery (CANTAB) in twenty-two breast cancer patients currently receiving chemotherapy. We also measured inflammatory cytokine and receptor (MCP-1, TNF-α, sTNFRI, sTNFRII) concentrations in patient sera using Luminex assays. These concentrations were log-transformed to obtain a normal distribution. Associations between log-transformed cytokines and cognition were evaluated using Pearson correlations and linear regression, taking into account relevant covariates.
Increased concentrations of sTNFRI and sTNFRII were associated with poorer performance on the CANTAB Delayed Matching to Sample (DMS, tests visual memory). Increasing sTNFRI levels were negatively correlated with DMS percent correct (r=−0.47, p=0.029) and DMS percent correct after a 12 second (s) delay (r=−0.65, p=0.001). Increasing levels of sTNFRII negatively correlated with DMS percent correct after 12s delay (r=−0.57, p=0.006). After controlling for relevant demographic (i.e. age, education) and clinical variables (i.e. disease stage, regimen type), we found that increased sTNFRI remained significantly related to decline on the DMS at the 12s delay (p=0.018).
This preliminary study shows a significant association between higher sTNFRI and lower scores on the short-term visual memory delayed match to sample test in breast cancer patients receiving chemotherapy, supporting the hypothesis that sTNFRI is involved in CRCI.
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•First study to examine association between inflammation and CRCI during chemotherapy treatment.•Assessed TNF-α, IL-6, IL-8, sTNFR1, sTNFR2, and IL6R in relation to multiple cognitive domains.•Increasing sTNFRI concentrations are associated with worse short-term visual memory.•This association remained after adjustment for age, education, stage, & anthracycline exposure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The most challenging issue for breast cancer (BC) patients is metastasis to other organs because current therapies do not prevent or eliminate metastatic BC. Here, we show that SM-164, a small ...molecule inhibitor, which degrades inhibitor of apoptosis proteins (IAPs), eliminated early-stage metastases and reduced progression of advanced BC metastasis from MDA-MB-231 BC cells in bones and lungs of nude mice. Mechanistically, SM-164-induced BC cell death is TNFα-dependent, with TNFα produced by IL-4-polarized macrophages triggering MDA-MB-231 cell apoptosis in combination with SM-164. SM-164 also inhibited expression of RANKL, which mediates interactions between metastatic BC and host microenvironment cells and induces osteoclast-mediated osteolysis. SM-164 did not kill adriamycin-resistant BC cells, while adriamycin inhibited SM-164-resistant BC cell growth, similar to parental cells. We conclude that SM-164 is a promising therapeutic agent for early stage bone and lung metastasis from triple-negative breast cancer that should be given prior to conventional chemotherapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Hepcidin is the principal iron-regulatory hormone and a pathogenic factor in anemia of inflammation. Patients with multiple myeloma (MM) frequently present with anemia. We showed that MM patients had ...increased serum hepcidin, which inversely correlated with hemoglobin, suggesting that hepcidin contributes to MM-related anemia. Searching for hepcidin-inducing cytokines in MM, we quantified the stimulation of hepcidin promoter-luciferase activity in HuH7 cells by MM sera. MM sera activated the hepcidin promoter significantly more than did normal sera. We then examined the role of bone morphogenetic proteins (BMPs) and interleukin-6 (IL-6), the major transcriptional regulators of hepcidin. Mutations in both BMP-responsive elements abrogated the activation dramatically, while mutations in the IL-6–responsive signal transducer and activator of transcription 3-binding site (STAT3-BS) had only a minor effect. Cotreatment with anti–BMP-2/4 or noggin-Fc blocked the promoter induction with all MM sera, anti–IL-6 blocked it with a minority of sera, whereas anti–BMP-4, -6, or -9 antibodies had no effect. BMP-2–immunodepleted MM sera had decreased promoter stimulatory capacity, and BMP-2 concentrations in MM sera were significantly higher than in normal sera. Our results demonstrate that BMP-2 is a major mediator of the hepcidin stimulatory activity of MM sera.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Now that severe combined immune deficiency (SCID) has been added to newborn screening panels in all 50 states in the U.S., there is a need to develop and disseminate well-designed educational ...materials to parents who need information to make informed decisions about treatment and care for identified infants. SCID Compass was designed to address this gap. We summarize the results of two needs assessment activities for parents-a journey mapping exercise and online survey-which will inform the development of a website and new resources.
We conducted in-depth interviews with seven parents of children with SCID identified through newborn screening. Participants were asked to complete a journey map to describe key timepoints related to SCID, starting at diagnosis through present day. This qualitative information informed an online survey that was completed by 76 parents who had a child with SCID. All participants were from the United States.
Analysis of journey maps revealed five distinct stages that parents experience: (1) Diagnosis, (2) Pre-Treatment, (3) Treatment, (4) Post-Treatment, and (5) The New Normal. At each stage, parents described unique emotions, challenges, contextual factors that can make a difference in their experience, and information and resource needs. Survey results indicated the highest-rated information needs for parents were understanding available treatment options and what to expect across the SCID lifespan. Emotional support needs included dealing with uncertainty about child's future and additional opportunities to connect with other families. Parents preferred receiving new materials from their healthcare provider or other families, and preferred materials in print, from social media, or online. Several differences were found among subgroups of parents, including those whose child had been identified through newborn screening as well as those considered medically underserved.
Findings about unmet parent needs and informational preferences will serve as the foundation for creating a suite of resources for those who have a child with SCID. The materials will be tailored to specific stages of the journey. By using a family-centered approach, we will help to ensure that the materials designed and developed as part of SCID Compass will be understandable, comprehensive, and useful.
Protracted inhibition of osteoblast (OB) differentiation characterizes multiple myeloma (MM) bone disease and persists even when patients are in long-term remission. However, the underlying ...pathophysiology for this prolonged OB suppression is unknown. Therefore, we developed a mouse MM model in which the bone marrow stromal cells (BMSCs) remained unresponsive to OB differentiation signals after removal of MM cells. We found that BMSCs from both MM-bearing mice and MM patients had increased levels of the transcriptional repressor Gfi1 compared with controls and that Gfi1 was a novel transcriptional repressor of the critical OB transcription factor Runx2. Trichostatin-A blocked the effects of Gfi1, suggesting that it induces epigenetic changes in the Runx2 promoter. MM-BMSC cell-cell contact was not required for MM cells to increase Gfi1 and repress Runx2 levels in MC-4 before OBs or naive primary BMSCs, and Gfi1 induction was blocked by anti–TNF-α and anti–IL-7 antibodies. Importantly, BMSCs isolated from Gfi1−/− mice were significantly resistant to MM-induced OB suppression. Strikingly, siRNA knockdown of Gfi1 in BMSCs from MM patients significantly restored expression of Runx2 and OB differentiation markers. Thus, Gfi1 may have an important role in prolonged MM-induced OB suppression and provide a new therapeutic target for MM bone disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Severe combined immunodeficiency (SCID) is T cell development disorders in the immune system and can be detected at birth. As of December 2018, all 53 newborn screening (NBS) programs within the ...United States and associated territories offer universal screening for SCID. The Association of Public Health Laboratories (APHL), along with the Immune Deficiency Foundation (IDF), surveyed public health NBS system laboratory and follow-up coordinators regarding their NBS program's screening methodologies and targets, protocols for stakeholder notifications, and long-term follow-up practices. This report explores the variation that exists across NBS practices, revealing needs for efficiencies and educational resources across the NBS system to ensure the best outcomes for newborns.
Purpose: Hepcidin is a liver-produced peptide implicated in the anemia of inflammation. Because interleukin (IL)-6 is a potent inducer
of hepcidin expression and its levels are elevated in multiple ...myeloma, we studied the role of hepcidin in the anemia of multiple
myeloma.
Experimental Design: Urinary hepcidin and serum levels of IL-6, ferritin, C-reactive protein, tumor necrosis factor-α, and IL-1β were studied
in newly diagnosed myeloma patients. In vitro hepcidin induction assay was assessed by real-time PCR assay.
Results: Pretreatment urinary hepcidin levels in 44 patients with stage III multiple myeloma were 3-fold greater than normal controls.
In the subset of multiple myeloma patients without renal insufficiency ( n = 27), a marked inverse correlation was seen between hemoglobin at diagnosis and urinary hepcidin level ( P = 0.014) strongly supporting a causal relationship between up-regulated hepcidin expression and anemia. The urinary hepcidin
also significantly ( P < 0.05) correlated with serum ferritin and C-reactive protein, whereas its correlation with serum IL-6 levels was of borderline
significance ( P = 0.06). Sera from 14 multiple myeloma patients, with known elevated urinary hepcidin, significantly induced hepcidin mRNA
in the Hep3B cells, whereas normal sera had no effect. For 10 patients, the ability of anti-IL-6 and anti-IL-6 receptor antibodies
to prevent the serum-induced hepcidin RNA was tested. In 6 of these patients, hepcidin induction was abrogated by the anti-IL-6
antibodies, but in the other 4 patients, the neutralizing antibodies had no effect.
Conclusions: These results indicate hepcidin is up-regulated in multiple myeloma patients by both IL-6-dependent and IL-6-independent
mechanisms and may play a role in the anemia of multiple myeloma.
Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome of immune system dysregulation characterized by the phagocytosis of various cells by histiocytes in the bone marrow. ...HLH can present in one of the two ways: primary HLH, which is caused by mutations in genes essential to T and NK-cell function, and secondary HLH, typically caused by Epstein–Barr virus (EBV) infection or malignancy. Because of the rapid progression and high mortality of this disease, prompt diagnosis is essential to good outcomes. Here, we report the 2-month clinical course of a patient who presented with altered mental status and recurrent fever of unknown origin. Initially, he did not meet diagnostic criteria for HLH and had a negative bone marrow biopsy; however, he eventually progressed to full-blown HLH secondary to occult Hodgkin lymphoma. This case is unusual for the slow and smoldering course of the patient’s disease and highlights the importance of aggressively searching for potential malignancies to ensure the initiation of definitive therapy as soon as possible.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Introduction
Cancer treatment-induced bone loss (CTIBL) is a long-term side effect of breast cancer therapy. Both calcitriol and weight-bearing exercise improve bone metabolism for osteoporotic ...patients, but are unproven in a breast cancer population. We used a novel high-dose calcitriol regimen with an individualized exercise intervention to improve bone metabolism in breast cancer survivors.
Methods
We accrued 41 subjects to this open label, 2 × 2 factorial, randomized feasibility trial. Breast cancer survivors were randomized to receive the following: (1) calcitriol (45 micrograms/week), (2) individualized exercise with progressive walking and resistance training, (3) both, or (4) a daily multivitamin (control condition) for 12 weeks. Primary outcomes included changes in biomarkers of bone formation, bone resorption, and the bone remodeling index, a composite measure of bone formation and resorption. Safety measures included clinical and biochemical adverse events. A main effect analysis was used for these endpoints.
Results
Hypercalcemia was limited to three grade I cases with no grade ≥ 2 cases. Among exercisers, 100% engaged in the prescribed aerobic training and 44.4% engaged in the prescribed resistance training. Calcitriol significantly improved bone formation (Cohen’s d = 0.64;
p
< 0.01), resulting in a non-significant increase in the bone remodeling index (Cohen’s d = 0.21;
p
= 31). Exercise failed to improve any of the bone biomarkers.
Conclusions
Both calcitriol and exercise were shown to be feasible and well tolerated. Calcitriol significantly improved bone formation, resulting in a net increase of bone metabolism. Compliance with the exercise intervention was sub-optimal, which may have led to a lack of effect of exercise on bone metabolism.
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