Intermittent Hypoxic Therapy Inhibits Allogenic Bone-Graft Resorption by Inhibition of Osteoclastogenesis in a Mouse Model

Systemic Intermittent Hypoxic Therapy (IHT) relies on the adaptive response to hypoxic stress. We investigated allogenic bone-graft resorption in the lumbar spine in 48 mice. The mice were exposed to IHT for 1 week before surgery or 1 week after surgery and compared with controls after 1 and 4 weeks. Complete graft resorption was observed in 33–36% of the animals in the control group, but none in the preoperative IHT group. Increased bone-graft volume was demonstrated by micro-computed tomography in the preoperative IHT group after 1 week (p = 0.03) while a non-significant difference was observed after 4 weeks (p = 0.12). There were no significant differences in the postoperative IHT group. Increased concentration of immune cells was localized in the graft area, and more positive tartrate-resistant acid phosphatase (TRAP) staining was found in controls compared with IHT allogenic bone grafts. Systemic IHT resulted in a significant increase of the major osteoclast inhibitor osteoprotegerin as well as osteogenic and angiogenic regulators Tgfbr3, Fst3l, Wisp1, and Vegfd. Inflammatory cytokines and receptor activator of nuclear factor kappa-B ligand (RANKL) stimulators IL-6, IL-17a, IL-17f, and IL-23r increased after 1 and 4 weeks, and serum RANKL expression remained constant while Ccl3 and Ccl5 decreased. We conclude that the adaptive response to IHT activates numerous pathways leading to inhibition of osteoclastic activity and inhibition of allogenic bone-graft resorption.

ADULT SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS – A CASE SERIES

Hemophagocytic lymphohistiocytosis is a hyper-inammatory condition that is either Familial (Primary) or Secondary to autoimmune diseases , infection, malignancy or other triggers.It is a cytokine storm syndrome where there inefcient antigen removal that leads to sustained cytokine release.It is a rare phenomenon occuring in adults that has got a specic trigger which is less documented and have a good response to steroids where as Familial form is a childhood disease due to genetic defects, both of which are life threatening and may need Allogenic bone marrow transplant. Macrophage activation syndrome is also a subtype of this entity that occurs in the treatment phase of SLE and Still's disease.We describe here 8 cases of secondary HLH, their primary triggers and treatment response.

Allogeneic bone marrow transplantation possibly induces a localized type of porokeratosis

A 15-year-old girl underwent allogenic bone marrow transplantation for neuroblastoma. A few years later, she noticed a round lesion on her left buttock. Since the lesion had been asymptomatic and never grown, more than 20 years had passed before she saw a local doctor to consult about it. Although the lesion was suspected to be tinea corporis, no fungi were found on microscopic examination. Subsequently, administered topical corticosteroids were not effective. She was referred to our hospital for further evaluation, and a skin biopsy confirmed the diagnosis of porokeratosis. There was a possibility that chemotherapy, total body radiation, or immunosuppressive therapy associated with allogeneic bone marrow transplantation was involved in the development of porokeratosis. Numerous cases of acquired porokeratosis in immunocompromised status have been observed; as for those after allogenic bone marrow transplantation, 12 cases have been reported in the English literature, 4 of which had only one or a few lesions on a limited area of body surface. Our case was relatively uncommon in that the lesion was solitary and comparatively large. In a localized type of porokeratosis, it was suggested that a malignant skin tumor developed earlier than in other types. Careful follow-up for malignant transformation is especially required.

Myasthenia gravis as a rare complication of graft-versus-host disease following allogenic bone marrow transplantation

The article's abstract is not available.

Early Cytomegalovirus Reactivation after Allogenic Bone Marrow Transplantation Is Associated with the Loss of Recipient-Derived Humoral Immunity and Is Reduced By IL-6 Inhibition

Background: Interleukin-6 (IL-6) promotes the differentiation of pathogenic T cells and represents a dominant pathway of cytokine-dysregulation and graft-versus-host disease (GVHD). Cytomegalovirus (CMV) reactivation is a common and life-threatening infectious complication following allogenic bone marrow transplantation (BMT). The role of T cell immunity is long-established, and our group recently demonstrated that CMV strain-specific immunoglobulins (Ig) are critical in preventing CMV reactivation in preclinical models (Martins JP et al, Science 2019). Methods and Results: In a phase I/II clinical trial (Kennedy GA et al, Lancet Onc. 2014), we observed unexpectedly low rates of CMV reactivation following IL-6 receptor (IL-6R) blockade with tocilizumab (TCZ) compared to historical control (8/35 vs 20/43, P < 0.05). We used our preclinical models of murine CMV (MCMV) reactivation to pursue the mechanisms. We transplanted bone marrow (BM) and T cells from naïve B6 donors into CMV-latently infected B6D2F1 recipients and monitored MCMV reactivation. Ablation of IL-6R in donor T cells (using B6 CD4 cre x IL-6R fl/fl transgenic mice; IL-6R -/-) significantly reduced MCMV reactivation 5 weeks after BMT, as measured by plasma viremia and infectious viral loads in the liver (Fig 1A). Next, we examined the contribution of donor T and B cells to the suppression of MCMV reactivation by IL-6R inhibition. At 2 - 3 weeks after BMT and prior to MCMV reactivation, cytokine (IFNɣ/TNF) secretion from CD4 + T cells (in response to MCMV infected DC) was not detectable; MCMV m38 tetramer + CD8 T cells were present at very low frequencies (< 0.1% of CD8 T cells) which were not altered by IL-6R ablation. The frequency of CXCR-5 +PD-1 + T FH cells was comparable or lower in IL-6R -/- vs wild-type (WT) T cells after BMT. Transplant of BM from B6.μMT mice (unable to generate mature B cells and plasma cells) did not increase MCMV viremia (Fig 1B), excluding a role for donor B cells. Thus, early MCMV reactivation in the presence of IL-6 is independent of MCMV-specific T cells and donor B cells. To study the effects of IL-6 on recipient-derived humoral immunity we quantified MCMV-specific IgG in plasma after BMT and found that levels were significantly higher in recipients of IL-6R -/- T cells (Fig 1C). Furthermore, MCMV-IgG levels in plasma correlated with MCMV viremia (r = - 0.72, P < 0.0001) and viral loads in liver (r = - 0.68, P < 0.0001). MCMV-IgG2a, which can only be generated by B6D2F1 recipients, was significantly higher in recipients of IL-6R -/- T cells, confirming that differences in humoral responses were of recipient-origin. To define relevant mechanisms, we examined the kinetics of IgG after BMT by monitoring the loss of murine IgG (transferred on day 0) in plasma (Fig 1D). Recipients of IL-6R -/- T cells showed significantly slower loss of IgG than recipients of WT T cells, with or without GVHD prophylaxis with cyclosporine (CSA). Thus, ablation of IL-6 signaling in donor T cells is associated with reduced loss of recipient IgG and protection from MCMV reactivation, an outcome which seems independent of the effects of IL-6 on GVHD. We correlated our findings with data from a recent randomized, placebo-controlled, double-blind phase III clinical trial of TCZ administration on Day -1 of BMT (Kennedy GA et al, Blood 2021). TCZ reduced CMV reactivation in at risk seropositive BMT recipients of volunteer unrelated donor grafts regardless of acute GVHD (all at risk recipients, TCZ vs. control: 12/26 vs 21/28, P = 0.03; at risk without grade 2-4 GVHD, TCZ vs control: 6/18 vs 9/13, P = 0.03). TCZ did not alter the frequency of B cells or the frequency and function of HCMV-specific CD8 + T cells, quantified by HCMV-pMHC tetramer-staining and HCMV peptide-specific cytokine (IFNγ/TNF) secretion. In contrast, levels of HCMV-specific IgG at day +30 in HCMV-seropositive recipients were significantly higher in the TCZ versus control group (Fig 1E). Consistent with our preclinical studies, the level of HCMV-IgG significantly and inversely correlated with early HCMV reactivation (within 35 days) after transplant. Conclusion: These data confirm the importance of recipient-derived humoral immunity in controlling early CMV reactivation in clinical BMT recipients. Critically, we demonstrate the ability of IL-6R blockade to maintain protective humoral responses until effective donor-derived adaptive immunity can be generated. Figure 1 Figure 1. Disclosures Boeckh: Merck: Consultancy, Research Funding; SymBio Pharmaceuticals: Consultancy; Helocyte: Consultancy; Evrys Bio: Consultancy; Moderna: Consultancy; Gilead: Consultancy, Research Funding; AlloVir: Consultancy; GSK: Consultancy. Hill: Generon corporation: Consultancy; NapaJun Pharma: Consultancy; Compass Therapeutics: Research Funding; Syndax Pharmaceuticals: Research Funding; Applied Molecular Transport: Research Funding; iTeos Therapeutics: Consultancy, Research Funding; Roche: Research Funding; Neoleukin Therapeutics: Consultancy.

A Novel Screw Drive for Allogenic Headless Position Screws for Use in Osteosynthesis—A Finite-Element Analysis

Due to their osteoconductive properties, allogenic bone screws made of human cortical bone have advantages regarding rehabilitation compared to other materials such as stainless steel or titanium. Since conventional screw drives like hexagonal or hexalobular drives are difficult to manufacture in headless allogenic screws, an easy-to-manufacture screw drive is needed. In this paper, we present a simple drive for headless allogenic bone screws that allows the screw to be fully inserted. Since the screw drive is completely internal, no threads are removed. In order to prove the mechanical strength, we performed simulations of the new drive using the Finite-Element method (FEM), validated the simulations with a prototype screw, tested the novel screw drive experimentally and compared the simulations with conventional drives. The validation with the prototype showed that our simulations provided valid results. Furthermore, the simulations of the new screw drive showed good performance in terms of mechanical strength in allogenic screws compared to conventional screw drives. The presented screw drive is simple and easy to manufacture and is therefore suitable for headless allogenic bone screws where conventional drives are difficult to manufacture.

Bilateral parotid gland enlargement as a presenting manifestation of relapsed pediatric acute myeloid leukemia

Parotid gland involvement is a rare presentation of Acute Myeloid Leukemia (AML). We report a 10-year-old girl of acute myelomonocytic leukemia with normal cytogenetics and positivity for inversion 16, who after completion of first consolidation of the BFM 2004 AML protocol, presented with bilateral parotid gland enlargement. Bone marrow examination was suggestive of a relapse. Fine needle aspiration of the parotid gland showed presence of myeloblasts. Patient was given FLAG-IDA chemotherapy, with which the parotid swellings rapidly regressed and she achieved a remission and was planned for allogenic bone marrow transplantation. Acute myelomonocytic and monoblastic leukemias are known to be associated with tissue infiltration. However, exocrine gland involvement such as parotid enlargement is rare and is associated with a poor prognosis as was seen in our patient who despite having inversion 16 positivity had poor disease outcome. Keywords: acute myeloid leukemia; parotid gland enlargement; granulocytic sarcoma.