Peripheral nerve regeneration following scaffold-free conduit transplant of autologous dermal fibroblasts: a non-randomised safety and feasibility trial.

BACKGROUND: The use of Bio 3D nerve conduits is a promising approach for peripheral nerve reconstruction. This study aimed to assess their safety in three patients with peripheral nerve defects in their hands. METHODS: We describe a single institution, non-blinded, non-randomised control trial conducted at Kyoto University Hospital. Eligibility criteria included severed peripheral nerve injuries or a defect in the region distal to the wrist joint not caused by a congenital anomaly; a defect with a length of ≤20 mm in a nerve with a diameter ≤2 mm; failed results of sensory functional tests; ability to register in the protocol within 6 months from the day of injury; refusal of artificial nerve or autologous nerve transplantation; age 20-60 years; and willingness to participate and provide informed written consent. Six weeks before transplantation, skin was harvested, dermal fibroblasts were isolated and expanded, and Bio 3D nerve conduits were created using a Bio 3D printer. Bio 3D nerve conduits were transplanted into the patients' nerve defects. The safety of Bio 3D nerve conduits in patients with a peripheral nerve injury in the distal part of the wrist joint were assessed over a 48-week period after transplantation. RESULTS: No adverse events related to the use of Bio 3D nerve conduits were observed in any patient, and all three patients completed the trial. CONCLUSIONS: Bio 3D nerve conduits were successfully used for clinical nerve reconstruction without adverse events and are a possible treatment option for peripheral nerve injuries.

Physical injuries often result in damage to nerves, for example, in the hands. Replacement of the nerve with nerves removed from elsewhere in the patient's body is often the suggested treatment when the nerve is unable to repair itself. As an alternative to remove healthy nerve from elsewhere in the body, we used an adapted printer to create an artificial nerve equivalent from skin cells obtained from the patient's skin. We reconstructed the nerves of three individual with nerve defects in their hands, and we found that the function of the nerve improved, and the people did not experience negative consequences. This approach could be used widely to repair damaged nerves.

A Clinically Applicable Prediction Model to Improve T Cell Collection in Chimeric Antigen Receptor T Cell Therapy.

As chimeric antigen receptor (CAR) T cell therapy targeting CD19 has shown favorable outcomes in patients with relapsed or refractory (r/r) mature B cell lymphomas and B cell acute lymphoblastic leukemia (B-ALL), an increasing number of patients are waiting to receive these treatments. Optimized protocols for T cell collection by lymphapheresis for chimeric antigen receptor (CAR) T cell therapy are urgently needed to provide CAR T cell therapy for patients with refractory and progressive disease and/or a low number of lymphocytes owing to prior chemotherapy. The predicted efficiency of CD3+ cell collection in apheresis can guide protocols for apheresis, but a clinically applicable model to produce reliable estimates has not yet been established. In this study, we prospectively analyzed 108 lymphapheresis procedures for tisagenlecleucel therapy at 2 centers. The apheresis procedures included 20 procedures in patients with B cell acute lymphoblastic leukemia and 88 procedures in patients with diffuse large B cell lymphoma, with a median age at apheresis of 58 years (range, 1 to 71 years). After lymphapheresis with a median processing blood volume of 10 L (range, 3 to 16 L), a median of 3.2 × 109 CD3+ cells (range, .1 to 15.0 × 109 cells) were harvested. Collection efficiency 2 (CE2) for CD3+ cells was highly variable (median, 59.3%; range, 11.0% to 199.8%). Multivariate analyses revealed that lower hemoglobin levels, higher circulating CD3+ cell counts, and higher platelet counts before apheresis significantly decreased apheresis CE2. Based on multivariate analyses, we developed a novel formula that estimates CE2 from precollection parameters with high accuracy (r = .56; P < .01), which also suggests the necessary processing blood volume. Our strategy for lymphapheresis should help reduce collection failure, as well as achieve efficient utilization of medical resources in clinical practice, thereby allowing delivery of CAR T cell therapy to more patients in a timely manner.

Development of a quantitative prediction model for peripheral blood stem cell collection yield in the plerixafor era.

BACKGROUND AIMS: Predicting autologous peripheral blood stem cell (PBSC) collection yield before leukapheresis is important for optimizing PBSC mobilization and autologous stem cell transplantation (ASCT) for treating hematological malignancies. Although guidelines for plerixafor usage based on peripheral blood CD34+ (PB-CD34+) cell count are available, their predictive performance in the real world remains unclear. METHODS: This study retrospectively analyzed 55 mobilization procedures for patients with non-Hodgkin lymphoma or multiple myeloma and developed a novel quantitative prediction model for CD34+ cell collection yield that incorporated four clinical parameters available the day before leukapheresis; namely, PB-CD34+ cell count the day before apheresis (day -1 PB-CD34+), number of prior chemotherapy regimens, disease status at apheresis and mobilization protocol. RESULTS: The effects of PB-CD34+ cell counts on CD34+ cell collection yield varied widely per patient characteristics, and plerixafor usage was recommended in patients with poorly controlled disease or those with a history of heavy pre-treatments even with abundant day -1 PB-CD34+ cell count. This model suggested a more proactive use of plerixafor than that recommended by the guidelines for patients with poor pre-collection condition or those with a higher target number of CD34+ cells. Further, the authors analyzed the clinical outcomes of ASCT and found that plerixafor use for stem cell mobilization did not affect short- or long-term outcomes after ASCT. CONCLUSIONS: Although external validations are necessary, the results can be beneficial for establishing more effective and safer mobilization strategies.

Teriparatide with Octacalcium Phosphate Collagen Composite Stimulates Osteogenic Factors.

Octacalcium phosphate and collagen composite (OCPcol) promotes osteogenic differentiation and angiogenesis, thereby enhancing bone regeneration. Although a newly developed freeze-dried composite of OCPcol and teriparatide (OCPcolTPTD) reinforced bone regeneration more than OCPcol, the mechanism of bone regeneration remains unresolved. In this study, disks containing OCPcolTPTD, OCPcol, or ß-tricalcium phosphate (ß-TCP) col were inserted into rodents with calvarial bone defects, before euthanasia 4 weeks later. Immunohistochemical and histochemical analyses were performed on bone samples to evaluate bone matrix development, angiogenesis, and osteoclast and osteoblast localization. In the OCPcolTPTD and OCPcol groups, bone regeneration was observed at the surface of calvarial dura mater and around acidophilic granular cells with abundant collagenous fiber-containing cells. Furthermore, the newly formed bone in the OCPcolTPTD group showed a larger total area and individual separated area than the other groups. Various osteogenic proteins were detected in the regenerated bone and peri-bone tissues by histochemistry and immunohistochemistry. Although the expression of several osteogenic biomarkers in the OCPcolTPTD group after 4 weeks of implantation was significantly lower than that in the OCPcol group, new bone formation by OCPcolTPTD in the center of the defect, where bone regeneration is difficult, tended to be superior to that by OCPcol. These results suggest that OCPcolTPTD enhanced bone regeneration more evenly and homogenously than OCPcol. Impact statement Our study suggests that octacalcium phosphate and collagen (OCPcol) together with a TPTD enhances bone regeneration in rodents with calvarial bone defects. Furthermore, we believe that composite of OCPcol and teriparatide (OCPcolTPTD) could be developed into novel clinical technique for the regeneration or repair of bone.

[Clinical experience of leukapheresis for CD19 CAR-T cell therapy].

To perform chimeric antigen receptor T (CAR-T) cell therapy in heavily pretreated patients with progressive disease and depleted lymphocytes, an optimized leukapheresis protocol must be established. To probe the effects of patient-related parameters on the collection efficiency of CD3+ cells, we retrospectively analyzed patients with relapsed/refractory diffuse large B-cell lymphoma who underwent leukapheresis for tisagenlecleucel at two centers. A total of 51 patients were analyzed, with a median age at apheresis of 59 years, and precollection hemoglobin levels, CD3+ cell counts, and platelet counts of 9.2 g/dl, 574/µl, and 15.8×104/µl, respectively. A median of 3.0×109 (0.7-8.4) CD3+ cells were harvested with 8.7 (4.0-15.7) l apheresis volume. The collection efficiency 2 (CE2) for CD3+ cells was 61.0% (21.0-127.3). One-day apheresis was sufficient to obtain the designated cell numbers in all cases. Lower hemoglobin levels, higher CD3+ cell counts, and higher platelet counts before apheresis were significantly associated with lower CE2 for CD3+ cells. These results suggest a need to increase the apheresis volume in anemic, lymphocyte- or platelet-rich patients due to an expected low CE2. Erythrocyte transfusions before or during apheresis may be a reasonable option for patients with anemia.

Segmental Bone Reconstruction by Octacalcium Phosphate Collagen Composites with Teriparatide.

Octacalcium phosphate and collagen composite (OCPcol) demonstrated superior bone regeneration and has been commercialized recently in Japan. Teriparatide (TPTD) is a bioactive recombinant form of parathyroid hormone that is approved for osteoporosis treatment. Because mandibular bone reconstruction after segmental resection is a key clinical problem, it was examined whether single-dose local administration of OCPcol with TPTD can affect recovery after this procedure. OCPcol was prepared, and a commercially available hydroxyapatite and collagen composite (HAPcol) was used as a control. A 15 mm length segmental bone defect was made in the mandibular region of male beagle dogs. The experimental animals were divided in four groups. OCPcol treated with TPTD (OCPcol + TPTD), OCPcol, HAPcol treated with TPTD (HAPcol + TPTD), or HAPcol was implanted into the defect. The radiopaque areas of the implanted site were measured and statistically analyzed, and histological examination was performed after 6 months. The value of radiopaque area in total region of OCPcol + TPTD was highest (90.8 ± 7.3 mm2), followed in order by OCPcol (49.3 ± 21.8 mm2), HAPcol + TPTD (10.6 ± 2.3 mm2), and HAPcol (6.4 ± 2.3 mm2), and that of OCPcol + TPTD was significantly higher than that of HAPcol + TPTD or HAPcol. All segmented mandibles of OCPcol + TPTD and a part of those of OCPcol were bridged with newly formed bone, whereas no bone bridges were observed in HAPcol + TPTD or HAPcol. These results suggested that OCPcol treated with TPTD enabled bone reconstruction after segmental mandibular resection more than other three groups.

An analysis of oral microbial flora by T-RFLP in patients undergoing hematopoietic stem cell transplantation.

Even though the hematopoietic stem cell transplantation (HSCT) procedure has been improved, oral mucositis (OM) is still a severe complication of the conditioning regimen. We investigated the association between OM severity and the alteration of oral bacterial flora using 16S rRNA gene-based terminal restriction fragment length polymorphism (T-RFLP) analysis in 19 consecutive patients undergoing HSCT. Oral samples were collected at pre-transplantation, at the peak of mucositis and post-engraftment. T-RFLP profiles for each timepoint were constructed into an X-Y matrix, and the distances between timepoints were calculated. Patients with severe and moderate OM had larger changes in their oral bacterial flora from before HSCT to peak of mucositis than controls (p = 0.031 and 0.016, respectively). Moreover, severe mucositis was significantly associated with an extended period of fever until engraftment, high maximum C-reactive protein levels, and prolonged periods of opioid treatment and intravenous hyper-alimentation. These findings suggest that mucositis severity is associated with the magnitude of change in the oral bacterial flora. This novel finding may help advance strategies for the prevention or treatment of OM after HSCT.

Octacalcium phosphate collagen composite (OCP/Col) enhance bone regeneration in a rat model of skull defect with dural defect.

Cranial bone defects are a major issue in the field of neurosurgery, and improper management of such defects can cause cosmetic issues as well as more serious infections and inflammation. Several strategies exist to manage these defects clinically, but most rely on synthetic materials that are prone to complications; thus, a bone regenerative approach would be superior. We tested a material (octacalcium phosphate collagen composite [OCP/Col]) that is known to enhance bone regeneration in a skull defect model in rats. Using a critical-sized rat skull defect model, OCP/Col was implanted in rats with an intact dura or with a partial defect of the dura. The results were compared with those in a no-treatment group over the course of 12 weeks using computed tomographic and histological analysis. OCP/Col enhanced bone regeneration, regardless of whether there was a defect of the dura. OCP/Col can be used to treat skull defects, even when the dura is injured or removed surgically, via bone regeneration with enhanced resorption of OCP/Col, thus limiting the risk of infection greatly.

Clinical study of octacalcium phosphate and collagen composite in oral and maxillofacial surgery.

Octacalcium phosphate and its collagen composite have been recognized as bone substitute materials possessing osteoconductivity and biodegradation properties. We evaluated the effectiveness of octacalcium phosphate and its collagen composite used for bone augmentation in major oral and maxillofacial surgeries in a clinical trial. Octacalcium phosphate and its collagen composite were used in cases of sinus floor elevation in 1- and 2-stage, socket preservation, cyst, and alveolar cleft procedures. A total of 60 patients were evaluated for effectiveness after the implantation of octacalcium phosphate and its collagen composite. Although sinus floor elevation in 1-stage, cyst, and alveolar cleft cases met the criteria for the judgment of success, sinus floor elevation in 2-stage and socket preservation groups did not meet the criteria in the initial evaluation. However, an additional evaluation for reconfirmation revealed the effectiveness of octacalcium phosphate and its collagen composite in those groups, and all evaluation results ultimately indicated the success of this clinical trial. Therefore, this clinical trial suggested that application of octacalcium phosphate and its collagen composite for oral and maxillofacial surgery was safe and effective and that octacalcium phosphate and its collagen composite could be a bone substitute candidate instead of autologous bone.

Octacalcium phosphate collagen composite stimulates the expression and activity of osteogenic factors to promote bone regeneration.

OBJECTIVE: This study investigated the bone regenerative properties of an octacalcium phosphate collagen composite (OCP/Col) in a rat calvarial bone defect model. DESIGN: An OCP/Col or ß-tricalcium phosphate (ß-TCP)/Col disk was implanted into the critical-sized calvarial defects and fixed 2 or 4 weeks later. The radiopacity of defects was examined after disk implantation by the radiographic examination and micro-computed tomography (µ-CT). Immunohistochemical and histochemical analyses were carried out to assess the bone matrix maturation, neovascularization, and osteoclast and osteoblast distribution in the neonatal bone. RESULTS: Radiographic and µ-CT examination of the area of implanted OCP/Col indicated the newly formed bone and no difference from those of the original bone. Osteopontin, osteocalcin, Runt-related transcription factor 2, type 1 collagen, vascular endothelial growth factor, and alkaline phosphatase or tartrate-resistant acid phosphatase in the newly formed calvarial bone and the surrounding connective tissue were detected by immunohistochemistry and histochemistry. Biomarker expression was not significantly elevated at the defect site; the area of which was calculated by dividing the distance from the healthy bone margin or calvarium and dura mater surface. There was no difference in the expression of these biomarkers in the OCP/Col group at 2 and 4 weeks after surgery. In addition, the expression levels of all markers were higher in the OCP/Col group than in the ß-TCP/Col group at 2 and 4 weeks after surgery. CONCLUSIONS: The OCP/Col as a bone regeneration material not only exhibits osteoconductive activity that is dependent on residual healthy bone tissue, but also has osteoinductive capacity, which promotes angiogenesis and osteogenic cell invasion from host tissue into the bone defect.

Successful granulocyte apheresis using medium molecular weight hydroxyethyl starch.

Granulocyte transfusion (GTX) is a therapeutic option for severe bacterial or fungal infection in patients with sustained neutropenia after chemotherapy or stem cell transplantation. However, high molecular weight hydroxyethyl starch (HES), which has been used for selective sedimentation of red blood cells during apheresis, is not easily available in many countries including Japan. In this study, we evaluated the efficiency of granulocyte collection using medium molecular weight HES (130 kDa) in combination with the Spectra Optia apheresis system. Apheresis was performed for 2 consecutive days from seven donors and the mean total neutrophil yield from the first and second apheresis was 5.27 ± 3.10 × 1010 and 2.91 ± 2.92 × 1010, respectively. Infusion of concentrates from the first apheresis resulted in a significant neutrophil count increase and concentrates from the second apheresis were enough for maintenance of the neutrophil counts in all the recipients. Although the number of cases is limited, our results clearly show that sufficient number of granulocytes can be harvested by using medium molecular weight HES and this strategy is a safe and effective clinical practice in countries where high molecular weight HES is not available.

Primary CNS post-transplant lymphoproliferative disorder following haploidentical HSCT using post-transplant high-dose cyclophosphamide.

Neurological complications after hematopoietic stem cell transplantation (HSCT) are frequently life-threatening, and their clinical management can be highly challenging. In the case of central nervous system lesions post-HSCT, a definitive diagnosis is often difficult to reach because many different causative and contributing conditions may be present, including bacterial, fungal, or viral infections; original disease relapse; and post-transplant lymphoproliferative disorder (PTLD). Here, we report a case of a 32-year-old male patient with Philadelphia chromosomepositive acute lymphoid leukemia who underwent three HSCTs and was then diagnosed with primary central nervous system (PCNS) PTLD by brain biopsy. The third HSCT was a haplo-identical peripheral blood stem cell transplantation from his mother, with post-transplant high-dose cyclophosphamide and tacrolimus used as graft-versus-host disease prophylaxis. Four months after the HSCT, multiple small ring lesions were detected in the parabasal ganglia of the patient's brain during magnetic resonance imaging. A lesion biopsy indicated Epstein-Barr virus (EBV)-positive, diffuse large B-cell lymphoma. Because the patient had no evidence of systemic lymphadenopathy, we diagnosed him with PCNS-PTLD. There was no EBV DNA in this patient's cerebrospinal fluid. The diagnosis of PCNS-PTLD by EBV DNA polymerase chain reaction is difficult and highlights the importance of a brain biopsy to diagnose PCNS-PTLD, especially in cases showing no EBV DNA in the cerebrospinal fluid. Although a rare condition, it is essential to locate and analyze cases of PCNS-PTLD after HSCT to establish the optimal strategy for treatment or prophylaxis.

Correction to: Dysplastic features seen in a patient with acute myeloid leukemia harboring the KMT2A-TET1 fusion gene.

In the original publication of the article, the title was incorrectly published as "Dysplastic features seen in a patient with acute myeloid leukemia harboring the KTM2A-TET1 fusion gene". The correct title should be "Dysplastic features seen in a patient with acute myeloid leukemia harboring the KMT2A-TET1 fusion gene".

Bone regeneration by freeze-dried composite of octacalcium phosphate collagen and teriparatide.

OBJECTIVE: Octacalcium phosphate (OCP) and collagen (col) composite (OCPcol) demonstrated superior bone regeneration properties, and its commercialization appears to be forthcoming. As a practical medical material for new combination products, we developed a freeze-dried composite with OCPcol and teriparatide (TPTD) (OCPcolTPTDf), and investigated its bone regenerative properties. MATERIALS AND METHODS: A disk of OCPcol was made by mixing OCP granules and atelocollagen for medical use. Then, OCPcolTPTDf was prepared by impregnation of the OCPcol disk with 1.0 or 0.1 µg of TPTD solution (OCPcolTPTDf 1.0 and OCPcolTPTDf 0.1, respectively) followed by lyophilization. In vitro release profiles of TPTD from OCPcolTPTDf were determined using an enzyme-linked immunosorbent assay. Implantation of OCPcolTPTDf or OCPcol was carried out for a rat critical-sized calvarial defect. And five defects in each group were collected after 12 weeks of implantation. RESULTS: The retention-release profiles of TPTD from OCPcolTPTDf supported a higher degree of retention of TPTD. Radiographic, histological, and histomorphometric examinations indicated that regenerated bone was filled in most of the defects of the OCPcolTPTDf. Additionally, the OCPcolTPTDf groups showed significantly enhanced bone regeneration compared with the OCPcol group. CONCLUSIONS: These results suggested that this newly developed bone regenerative composite could be a practical medical material.

Efficacy of Octacalcium Phosphate Collagen Composite for Titanium Dental Implants in Dogs.

BACKGROUND: Previous studies showed that octacalcium (OCP) collagen composite (OCP/Col) can be used to repair human jaw bone defects without any associated abnormalities. The present study investigated whether OCP/Col could be applied to dental implant treatment using a dog tooth extraction socket model. METHODS: The premolars of dogs were extracted; each extraction socket was extended, and titanium dental implants were placed in each socket. OCP/Col was inserted in the space around a titanium dental implant. Autologous bone was used to fill the other sockets, while the untreated socket (i.e., no bone substitute material) served as a control. Three months after the operation, these specimens were analyzed for the osseointegration of each bone substitute material with the surface of the titanium dental implant. RESULTS: In histomorphometric analyses, the peri-implant bone areas (BA%) and bone-implant contact (BIC%) were measured. There was no difference in BA% or BIC% between OCP/Col and autologous bone. CONCLUSION: These results suggested that OCP/Col could be used for implant treatment as a bone substitute.

Single-dose local administration of teriparatide with a octacalcium phosphate collagen composite enhances bone regeneration in a rodent critical-sized calvarial defect.

Octacalcium phosphate and collagen composite (OCP/Col) achieves stable bone regeneration without cell transplantation in preclinical studies. Recently, a sponsor-initiated clinical trial was conducted to commercialize the material. The present study investigated bone regeneration by OCP/Col with the single local administration of teriparatide (parathyroid hormone 1-34; TPTD). OCP/Col was prepared by mixing sieved granules of OCP and atelocollagen for medical use and a disk was molded. After the creation of a rodent critical-sized calvarial defect, OCP/Col or OCP/Col with dripped TPTD solution (1.0 or 0.1 µg; OCP/Col/TPTDd1.0 or OCP/Col/TPTDd0.1) was implanted into the defect. Six defects in each group were fixed 12 weeks after implantation. Radiographic examinations indicated that radiopaque figures in defects treated with OCP/Col with TPTD (OCP/Col/TPTDd) occupied a wider range than those treated with OCP/Col. Histological results demonstrated that most of the defect in OCP/Col/TPTDd was filled with newly formed bone. A histomorphometrical examination indicated that the percentage of newly formed bone was significantly higher in the defects of OCP/Col/TPTDd 1.0 (53.6 ± 4.3%) and OCP/Col/TPTDd 0.1 (52.2 ± 7.4%) than in those of OCP/Col (40.1 ± 8.4%), whereas no significant differences were observed between OCP/Col/TPTDd1.0 and OCP/Col/TPTDd0.1. These results suggest that OCP/Col with the single local administration of TPTD enhances bone regeneration in a rodent calvarial critical-sized bone defect. © 2017 The Authors Journal of Biomedical Materials Research Part B: Applied Biomaterials Published by Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1851-1857, 2018.

Antioxidant role of autophagy in maintaining the integrity of glomerular capillaries.

Autophagy is a lysosomal degradation system by which cytosolic materials and damaged organelles are broken down into basic components. To explore the physiological role of autophagy in glomerular endothelial cells (GEnCs), we compared the autophagic flux among cells in the kidney under starvation. Inhibition of autophagy by chloroquine administration significantly increased the number of autophagosomes or autolysosomes in GEnCs and proximal tubular cells, but not in podocytes, suggesting that the GEnCs exhibit substantial autophagic activity. Next, we analyzed endothelial and hematopoietic cell-specific atg5-deficient mice (atg5-conditional KO [cKO] mice). Glomeruli of 4-wk-old atg5-cKO mice exhibited slightly distended capillary loops accompanied by an accumulation of reactive oxygen species (ROS). Glomeruli of 8-wk-old atg5-cKO mice showed a lobular pattern with thickening of the capillary loops and mesangial matrix expansion; however, the vasculature of other organs was preserved. The atg5-cKO mice died by 12 wk of age, presumably due to pancytopenia resulting from the defect in their hematopoietic lineages. Therefore, we subjected 4-wk atg5-cKO mice to irradiation followed by bone marrow transplantation from normal littermates. Transplanted mice recapitulated the glomerular phenotypes of the atg5-cKO mice with no obvious histological changes in other organs. Twelve-mo-old transplanted mice developed mesangiolysis and glomerulosclerosis with significant deterioration of kidney function. Administration of N-acetyl-l-cysteine, a ROS scavenger, to atg5-cKO mice rescued the glomerular phenotypes. These data suggest that endothelial autophagy protects glomeruli from oxidative stress and maintains the integrity of glomerular capillaries. Enhancing endothelial autophagy may provide a novel therapeutic approach to minimizing glomerular diseases.

Influence of electron beam irradiation doses on bone regeneration by octacalcium phosphate collagen composites.

An octacalcium phosphate and collagen composite (OCP/Col) achieved efficient bone regeneration with excellent resorbability. After the confirmation of its safety and efficacy in preclinical animal studies, the present study investigated the influence of electron beam irradiation doses on bone regeneration by OCP/Col in order to secure its commercialization. OCP/Col was prepared as previously described and the packed OCP/Col was sterilized using different doses of electron beam irradiation. A standardized defect, 9 mm in diameter, was made in the rat calvarium. A disk of OCP/Col (diameter 9 mm, thickness 1.5 mm) sterilized using different doses of electron beam irradiation was then implanted into the defect. Five defects in each group were treated and fixed 4, 12 and 24 weeks after implantation. Specimens were decalcified and stained with haematoxylin and eosin. In a histomorphometrical analysis, the percentage of newly formed bone in the defect (n-Bone%) was calculated. In OCP/Col 15 kGy, newly formed bone was enhanced and present throughout the defect with the resorption of OCP/Col. Furthermore, vigorous bone remodelling and bone maturation were observed. In OCP/Col 40 kGy, newly formed bone was not as prominent as that with OCP/Col 15 kGy. A histomorphometrical analysis using Student's t-test at 24 weeks revealed that the n-Bone% of OCP/Col 15 kGy (65.9 ± 7.14%) was significantly higher than that of OCP/Col 40 kGy (38.0 ± 10.2%). These results suggest that different electron beam irradiation doses influence bone regeneration by OCP/Col.

Successful treatment with low-dose nivolumab in refractory Hodgkin lymphoma after allogeneic stem cell transplantation.

Previous studies have reported that an antibody that blocks programmed cell death 1 (PD-1) has therapeutic activity in patients with refractory/relapsed Hodgkin lymphoma (HL). However, the safety and efficacy of these agents in the post-allogeneic stem cell transplantation (allo-SCT) setting are not well known. Here, we describe a patient who was diagnosed as classical HL and treated with five regimens of chemotherapies with autologous SCT. Complete remission (CR) was not achieved following this initial treatment, so we performed allo-SCT from an HLA-matched sibling donor. Since his disease progressed at day 403 after allo-SCT, we decided to use nivolumab in the treatment of his refractory disease. To prevent the worsening of his chronic graft-versus-host disease (GVHD), we reduced the initial dose and frequency of nivolumab compared with the previous report. After four courses of 0.5 mg/kg of nivolumab every three weeks, FDG-PET imaging showed partial response (PR) to the treatment, a remarkable result. However, since the escalated dose of 2 mg/kg resulted in worsening of dyspnea and skin sclerosis, we initiated systemic administration of prednisolone and reduced nivolumab to 1 mg/kg. At the time of this report, his HL is in stable PR with three weekly administration of nivolumab and steroid controlled mild chronic GVHD.