Giant cell arteritis (GCA) is a chronic immune-mediated disease of medium-to-large sized arteries that affects older adults. GCA manifests with arthritis and occlusive symptoms of headaches, stroke or vision loss. Macrophages and T-helper lymphocytes infiltrate the vascular wall and produce a pro-inflammatory response that lead to vessel damage and ischemia. To date, there is no GCA biomarker that can monitor disease activity and guide therapeutic response. Folate receptor beta (FRB) is a glycosylphosphatidylinositol protein that is anchored on cell membranes and normally expressed in the myelomonocytic lineage and in the majority of myeloid leukemia cells as well as in tumor and rheumatoid synovial macrophages, where its expression correlates with disease severity. The ability of FRB to bind folate compounds, folic acid-conjugates and antifolate drugs has made it a druggable target in cancer and inflammatory disease research. This report describes the histopathologic and immunohistochemical methods used to assess expression and distribution of FRB in relation to GCAimmunopathology. Formalin-fixed and paraffin-embedded temporal artery biopsies from GCA and normal controls were stained with Hematoxylin and Eosin to review tissue histology and identify pathognomonic features.Immunohistochemistry was used to detect FRB, CD68 and CD3 expression. A microscopic analysis was performed to quantify the number of positively stained cells on 10 selected high-power-field sections and their respective locations in the arterial wall. Lymphohistiocytic (LH) inflammation accompanied by intimal hyperplasia and disrupted elastic lamina was seen in GCA with none found in controls. The LH infiltrate was composed of approximately 60% lymphocytes and 40% macrophages. FRB expression was restricted to macrophages, comprising 31% of the total CD68+ macrophage population and localized to the media and adventitia. No FRB was seen in controls. This protocol demonstrated a distinct numerical and spatial pattern of the FRB macrophage relative to the vascular immune microenvironment in GCA.
BACKGROUND: Radiation therapy (RT) is a treatment modality traditionally used in patients with multiple myeloma (MM), but little is known regarding the role and effectiveness of RT in the era of novel agents, i.e, immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). METHODS: We retrospectively reviewed data from 449 consecutive MM patients seen at our institute in 2010-12 to assess indications for RT as well as its effectiveness. Pain response was scored similarly to RTOG 0631 and used the numerical rating pain scale (NRPS). RESULTS: Among 442 evaluable patients, 149 (34%) patients and 262 sites received RT. The most common indication for RT was palliation of bone pain (n=109, 42%), followed by prevention/treatment of pathological fractures (n=73, 28%), spinal cord compression (n=26, 10%), and involvement of vital organs/extramedullary disease (n=25, 10%). Of the 55 patients evaluable for pain relief, complete and partial responses were obtained in 76.4% and 7.2% respectively. Prior RT did not significantly decrease the median number of peripheral blood stem cells collected for autologous transplant, even when prior RT was given to both the spine and pelvis. Inadequacy of stem cell collection for autologous stem cell transplant (ASCT) was not significantly different and it occurred in 9% and 15% of patients receiving no RT and spine/pelvic RT, respectively. None of the 3 cases of therapy-induced AML/MDS occurred in the RT group. CONCLUSIONS: Despite the introduction of novel effective agents in the treatment of MM, RT remains a major therapeutic component for the management in 34% of patients, and it effectively provides pain relief while not interfering with successful peripheral blood stem cell collection for ASCT.
Hypoxia-inducible factor 1 (HIF-1) is a major mediator of tumor physiology, and its activation is correlated with tumor progression, metastasis, and therapeutic resistance. HIF-1 is activated in a broad range of solid tumors due to intratumoral hypoxia or genetic alterations that enhance its expression or inhibit its degradation. As a result, decreasing HIF-1α expression represents an attractive strategy to sensitize hypoxic tumors to anticancer therapies. Here, we show that cyclin-dependent kinase 1 (CDK1) regulates the expression of HIF-1α, independent of its known regulators. Overexpression of CDK1 and/or cyclin B1 is sufficient to stabilize HIF-1α under normoxic conditions, whereas inhibition of CDK1 enhances the proteasomal degradation of HIF-1α, reducing its half-life and steady-state levels. In vitro kinase assays reveal that CDK1 directly phosphorylates HIF-1α at a previously unidentified regulatory site, Ser668. HIF-1α is stabilized under normoxic conditions during G 2/M phase via CDK1-mediated phosphorylation of Ser668. A phospho-mimetic construct of HIF-1α at Ser668 (S668E) is significantly more stable under both normoxic and hypoxic conditions, resulting in enhanced transcription of HIF-1 target genes and increased tumor cell invasion and migration. Importantly, HIF-1α (S668E) displays increased tumor angiogenesis, proliferation, and tumor growth in vivo compared with wild-type HIF-1α. Thus, we have identified a novel link between CDK1 and HIF-1α that provides a potential molecular explanation for the elevated HIF-1 activity observed in primary and metastatic tumors, independent of hypoxia, and offers a molecular rationale for the clinical translation of CDK inhibitors for use in tumors with constitutively active HIF-1.
Abstract Chimerism testing by short tandem repeats (STRs) is used to monitor engraftment after allogeneic hematopoietic stem cell transplantation (HSCT). Generally, STR alleles are stable and transferred from parent to child or from donor to recipient. However, 3 cases did not follow this norm. Additional work-up with help from forensic literature solved these mysteries. In case 1, the patient received HSCT from his son. The son shared STR alleles in 22/23 loci except Penta E, which was explained by repeat expansion in the son. In case 2, the patient had been in remission for 14 years after HSCT for lymphoma and developed repeat expansion in CSF1PO in granulocytes. In case 3, a pre-HSCT patient demonstrated 3 alleles, with 2 peaks taller than the third, in the FGA locus (chromosome 4). A combination of a triallelic variant and leukemia-associated trisomy 4 explained the finding. STR number variants are rare and clinically inconsequential but can overlap malignancy-associated, clinically significant changes.
7071 Background: Allogeneic stem cell transplant (SCT) is the only potentially curative treatment for intermediate and high-risk myelofibrosis (MF). The use of Ruxolitinib (Rux) in the pre-SCT setting has demonstrated significant improvements in constitutional symptoms and splenomegaly. However, the optimal time of starting Rux and the effects of post-SCT Rux maintenance are still unclear. Methods: We analyzed outcomes of patients diagnosed with MF at our center who never received Rux (Cohort A), received only pre-SCT Rux (Cohort B), and received post-SCT Rux (Cohort C) between 6/2012 and 6/2017. Results: This study analyzed 16 patients, 11 male and 5 female, with median age of 59 years (range 47-72) at the time of SCT. The MF scores ranged from 2 to 3 (WHO Grade) at diagnosis. All patients had constitutional symptoms and splenomegaly at diagnosis except 1 who had prior splenectomy. There were 3 patients in cohort A, 9 patients in cohort B, and 4 patients in cohort C (3 patients received both pre- and post-SCT Rux; 1 received only post-SCT Rux). The median duration of Rux pre-SCT was 8 months (5-20); the mean duration of Rux post-SCT was 20 months (4-32). A JAK2V617F mutation was detected in all patients in cohort A, 7 patients in cohort B, and 3 patients in cohort C. All patients received reduced intensity conditioning regimen. The median time (days) for neutrophil engraftment (ANC>500) was 17 (13-18) in group A, 15 (0-74) in group B, and 12.5 (12-16) in group C. The median time (days) to transfusion independence was 148 (118-1140), 72 (11-105), and 24.5 (13-101) for patients in cohorts A, B, and C respectively. CMV/EBV viremia was detected in 8 patients before day 100, 3 of them in cohort A. Grade II-III acute GVHD was seen in all patients in cohort A and 4 patients in cohort B, but none in cohort C. The median spleen size reduction post-SCT was 17% in cohort A, 11% in cohort B, and 32% in cohort C. At the time of last follow up, an overall response was seen in 4 patients in cohort B, 2 with CR. All patients in cohort C achieved a CR and are alive. No one in group A achieved a remission. Conclusions: In this pilot study, patients treated with Rux pre- and post-SCT showed better outcomes and fairly good tolerability. Further studies on a larger patient population are warranted.
Graduate medical education programs typically set up call under the assumption that residents will have similar experiences. The terms black cloud and white cloud have frequently been used to describe residents with more difficult (black) or less difficult (white) call experiences. This study followed residents in the department of head and neck surgery during call to determine whether certain residents have a significantly different call experience than the norm. It is a prospective observational study conducted over 16 months in a tertiary care center with a resident training program in otolaryngology. Resident call data on total pages, consults, and operative interventions were examined, as well as subjective survey data about sleep and perceived difficulty of resident call. Analysis showed no significant difference in call activity (pages, consults, operative interventions) among residents. However, data from the resident call surveys revealed perceived disparities in call difficulty that were significant. Two residents were clearly labeled as black clouds compared to the rest. These residents did not have the highest average number of pages, consults, or operative interventions. This study suggests that factors affecting call perception are outside the objective, absolute workload. These results may be used to improve resident education on sleep training and nighttime patient management in the field of otolaryngology and may influence otolaryngology residency programs.
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