Mogamulizumab Treatment Prior to Allogeneic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-versus-Host Disease.

Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development.

Comparison of graft-versus-host disease-free, relapse-free survival according to a variety of graft sources: antithymocyte globulin and single cord blood provide favorable outcomes in some subgroups.

Graft-versus-host disease-free relapse-free survival, which is defined as the absence of grade III-IV acute graft-versus-host disease, systemically treated chronic graft-versus-host disease, relapse, and death, is a novel, meaningful composite end point for clinical trials. To characterize risk factors and differences in graft-versus-host disease-free relapse-free survival according to a variety of graft sources, we analyzed 23,302 patients with hematologic malignancy that had a first allogeneic transplantation from 2000 through 2013 using the Japanese national transplant registry database. The 1-year graft-versus-host disease-free relapse-free survival rate was 41% in all patients. The rate was higher after bone marrow transplantation than after peripheral blood stem cell transplantation due to the lower risks of III-IV acute and chronic graft-versus-host disease. The rate was highest after HLA-matched sibling bone marrow transplantation. The rate after single cord blood transplantation was comparable to that after HLA-matched unrelated bone marrow transplantation among patients aged 20 years or under, and was comparable or better than other alternative graft sources among patients aged 21 years or over, due to the low risk of chronic graft-versus-host disease. Other factors associated with better graft-versus-host disease-free relapse-free survival include female patients, antithymocyte globulin prophylaxis (for standard-risk disease), recent years of transplantation, sex combinations other than from a female donor to a male patient, the absence of prior autologous transplantation, myeloablative conditioning, negative cytomegalovirus serostatus, and tacrolimus-based prophylaxis. These results provide important information to guide the choice of graft sources and are benchmarks for future graft-versus-host disease prophylaxis studies.

Significance of monitoring trough plasma concentration levels for invasive fungal infection prophylaxis with itraconazole oral solution in patients with hematological malignancies: a prospective study.

In this prospective study, we examined the prophylactic effect of itraconazole oral solution (ITCZ-OS) against invasive fungal disease in hematologic malignancy patients. The participants were 36 patients, at least 16 years of age, with hematologic malignancies treated at our hospital. ITCZ-OS 200 mg/day was administered orally twice a day with a target trough plasma concentration of 350 ng/ml. If the patient did not achieve the target trough plasma concentration, the dose was increased. The success rate of achieving the target trough plasma concentration of ITCZ with a dose of 200 mg/day was 63.9%. During the observation period, 2 patients (5.6%) were diagnosed with possible invasive fungal disease according to the EORTC/MSG 2008 criteria. Adverse events were observed in 2 patients (5.6%). The results showed administration of ITCZ-OS while monitoring ITCZ trough plasma concentrations to be effective for preventing invasive fungal disease, and no serious adverse events occurred. Since predicting trough levels in response to ITCZ administrations is difficult, its measurement is necessary to maintain the prophylactic effect of ITCZ.

[Efficacy and safety of TS-1 monotherapy for advanced/metastatic breast cancer - an observational study by the Kumamoto Breast Cancer Cooperative Group(KBCCG)].

TS-1, an oral fluoropyrimidine, is known to be effective for the treatment of various carcinomas including advanced/metastatic breast cancer.The Kumamoto Breast Cancer Cooperative Group(KBCCG)conducted an observational study, wherein, the efficacy and safety of TS-1 monotherapy was analyzed in 35 patients with recurrent or metastatic breast cancer.The median time to cancer progression was 3.7 months, overall response rate was 12%, and clinical benefit rate was 32%. Adverse events were observed in 27 patients(77%), and adverse events of Grade >3 were observed in 7 patients(20%). The rate of treatment-related Grade 3 and 4 adverse events increased, and was associated with poor levels of creatinine clearance(Ccr)ie <60mL/min.This study suggests that TS-1 monotherapy can potentially be used as a salvage treatment for advanced/metastatic breast cancer owing to its safety and efficacy.Measuring the level of Ccr before TS-1 therapy should be considered to avoid severe adverse events.

Abductor recovery after muscle-sparing periacetabular osteotomy using a lateral approach.

To decrease hip abductor dysfunction after periacetabular osteotomy using a lateral/trochanteric approach, we aimed to modify transposition osteotomy of the acetabulum (TOA) to not cut the greater trochanter and abductor-iliac crest detachment. We subsequently compared abductor muscle strength recovery between TOAs with [conventional TOA (C-TOA)] and without [modified TOA (M-TOA)] trochanteric osteotomy. C-TOA and M-TOA were performed in 27 and 34 hips, respectively. Hip abduction, flexion and knee extension muscle strength were measured preoperatively and at 3, 5, 10, 24 and 52 weeks postoperatively. The muscle strength ratio of the affected and contralateral lower limbs was compared between the C-TOA and M-TOA groups. Neither the mean Merle d'Aubigné-Postel score at the final follow-up nor the postoperative center-edge angle showed significant differences between the M-TOA and C-TOA groups (15.7 versus 16.4 points; P = 0.25 and 38.5° versus P = 0.62 and 39.8°, respectively). The mean muscle strength ratios of hip abduction at 5, 12 and 24 weeks postoperatively were significantly higher in the M-TOA group than in the C-TOA group (0.62 versus 0.39, 0.76 versus 0.59 and 0.94 versus 0.70; P = 0.03, 0.04 and 0.01, respectively). There were no significant differences between groups at Postoperative Week 52 (P = 0.36). Discomfort at the greater trochanter was observed in 18 hips (66.7%) in the C-TOA group but only in 4 hips (11.2%) in the M-TOA group. In conclusion, M-TOA is less invasive than C-TOA and allows an earlier recovery of abductor muscle strength without significant correction loss.

A Novel Hematopoietic Progenitor Cell Mobilization Regimen Comprising Bortezomib, G-CSF, and Preemptive Plerixafor for Multiple Myeloma.

Adequate hematopoietic progenitor cell collection is critical for autologous peripheral blood stem cell transplantation. Conventionally, patients with multiple myeloma are treated with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) or G-CSF alone to mobilize their peripheral blood stem cells. However, some patients exhibit insufficient stem cell recruitment in response to these regimens. Recently, plerixafor has been approved for coverage by insurance in Japan. Combination treatment with plerixafor and G-CSF is now a standard procedure. In addition, treatment with bortezomib and G-CSF results in efficient stem cell recruitment. On the basis of the results from mouse studies, we hypothesized that combination treatment with bortezomib ensures efficient mobilization and mediates in vivo purging of malignant cells. Therefore, we administered a regimen of bortezomib, G-CSF, and preemptive plerixafor to 10 patients with multiple myeloma, and analyzed its efficacy and safety. The median patient age was 68 years. We collected CD34-positive cells (median: 4.9×106/kg) in a single session of apheresis from all patients. We observed no obvious myeloma cell contamination in the collected product or serious toxicity during treatment and collection. After collection, we performed autologous peripheral blood stem cell transplantation and confirmed engraftment in all patients (median: day 10). We found that the regimen is safe and reliably facilitated the collection of sufficient autologous peripheral blood stem cells by apheresis from all patients in a single day. Despite the small patient group size, we conclude that the regimen is promising for safe and efficient collection of peripheral blood stem cells for autologous transplantation in patients with multiple myeloma.

[A patient with gastric cancer complicated with multiple spinal bone metastases showing a complete remission to combination of S-1 and CDDP].

The patient was a 66-year-old man. Total gastrectomy was performed due to Borrmann V type moderately differentiated adenocarcinoma of the middle part of the stomach. The final diagnosis was UM 7x6 cm, sT3, sN1, sH0, sP0, sM0, sCY0, sStage IIIA, PM (-), DM (-), D2+alpha, Cur B, ly2, v2. Because CEA had increased slowly from ten months after the operation, it was judged a possibly partial relapse. Twice-administered CDDP 80 mg/body and S-1 80 mg on the eighth day served to decrease CEA. He was hospitalized again due to fracture of the spine, though he left the hospital once. The patient was diagnosed by MRI inspection of the vertebrae thoracicae and the lumbar vertebra as multiple spinal bone metastases. After CDDP 60 mg/body of day 8 was administered twice at S-1 80 mg/day, CEA became normal. Osteolytic changes of the spinal bone disappeared. The 24 months from February 2004 to January 2006 passed without additional treatment. His CEA value tended to rise within the normal range in February 2006. After that, the CEA level increased with a 4-week cycle of 2 weeks of S-1 40-80 mg alternating with a two-week rest.

Does hip center location affect the recovery of abductor moment after total hip arthroplasty?

BACKGROUND: In total hip arthroplasty (THA), placing the cup in an anatomic position is not always possible in case of deformities related to developmental dysplasia of the hip (DDH). Thus far, the influence of a hip center on the abductor moment after THA has not been clearly elucidated. Therefore, we performed a retrospective study to assess (1) how abductor muscle moment recovers postoperatively in THA and (2) whether acetabular cup position affects the recovery of abductor moment. HYPOTHESIS: A high hip center affects the recovery of abductor moment of a dysplastic hip after THA. PATIENTS AND METHODS: We evaluated 100 patients, who underwent unilateral primary THA, at 12 months postoperatively. The study included 86 women and 14 men, with a mean age of 65.5±9.9 years (range, 40 to 86 years). Patients with secondary osteoarthritis due to DDH were included (Crowe 1: 76; Crowe 2: 15, Crowe 3:9, and Crowe 4: none). A cementless straight stem was implanted in all hips. Hip abductor moment was measured using a belt-stabilized hand-held dynamometer. The ratio of moment of the affected side to that of the contralateral side was calculated as moment ratio. The horizontal and vertical centers of rotation (H-COR and V-COR) (with respect to the inter teardrop line) and vertical shift (V-shift) (difference in V-COR between the affected hip and the contralateral normal hip) were determined. RESULTS: At 6 and 12 months postoperatively, the abductor moment ratios were 95.1 and 94.7%, respectively. Significant negative correlation was observed between the postoperative abductor moment ratio and V-COR at 6 months postoperatively (r=-0.2436, p=0.0238). Significant delay in the recovery of abductor moment ratio was observed in the groups with higher hip center (V-shift>15mm) (odds ratio=12.7; 95% CI: 2.11-232.1, p=0.0034) at 6 months postoperatively, which was fully recovered at 12 months postoperatively. DISCUSSION: Superior placement of a hip center, more than 15mm above the true hip center, delayed the recovery of abductor muscle moment after THA. LEVEL OF EVIDENCE: III, retrospective comparative study.

The Confirmation of Safety for the Intensified Conditioning Regimens: A Retrospective Study of Allogeneic Hematopoietic Stem Cell Transplantation for Non-Remission Hematological Malignant Diseases.

Background: The prognosis of allogeneic hematopoietic stem cell transplantation (HSCT) for non-remission hematological malignant diseases is usually unfavorable. The most uncontrollable factor is residual disease or relapse. To overcome this problem, intensified conditioning regimens- sequential and/or additional chemotherapy to the standard regimen- could be effective. However, increasing the intensity of conditioning might also lead to more complications. Materials and Methods: We retrospectively analyzed 81 patients with non-remission disease who received allogeneic HSCT in our institution between 2007 and 2011. Results: 55.6% in 36 myeloablative conditioning patients and 46.7% in 45 reduced-intensity conditioning patients received intensified conditioning. The 5-year probability of overall survival was 35.0% and 17.1% in the standard and intensified group, respectively (p=0.027). Relapse mortality was 30% in the standard regimen group and 36.6% in the intensified regimen group (p=0.54). Transplant-related mortality (TRM) at 30 and 100 days was 5%, 17.1% (p=0.086) and 27.5%, 34.2% (p=0.52) in the standard and intensified group, respectively. There was no difference in TRM between the 2 groups at 30 days and 100 days. Conclusion: The results of the study confirm the safety of the intensified conditioning regimen. Meanwhile, it could be considered as one of the few methods available to reduce the tumor burden before HSCT for refractory malignant diseases.

[Angioimmunoblastic T-cell lymphoma accompanied by pure red cell aplasia].

A 71-year-old woman was admitted in December 2002 because of lymphadenopathy, hepatosplenomegaly and pleural effusion. She had severe anemia with hemoglobin 5.9 g/dl and a reticulocyte count of 1% per hundred. Direct/indirect Coombs tests and anti-double stranded DNA antibody were positive, her serum CH50 level was reduced and an increase in serum LDH isoenzyme 3 was observed. Bone marrow aspiration showed an almost total absence of erythroblasts and no pathological cell proliferation. The diagnosis of angioimmunoblastic T-cell lymphoma (AILT) was made based on the lymph node histological findings. Proliferation of arborizing small vessels with hyperplastic endothelium and infiltration of atypical T-lymphocytes were observed. After combination chemotherapy (THP-COP), remission was achieved in both the pure red cell aplasia (PRCA) and AILT. Remission was also accompanied by normalization of the Coombs tests, suggesting that autoimmune mechanisms in AILT may contribute to the development of PRCA.

[Remission induction of refractory diffuse large B-cell lymphoma with allogeneic peripheral blood stem cell transplantation followed by interferon-alpha and donor lymphocyte infusion].

Graft-versus-lymphoma (GVL) effect has been described in patients with malignant lymphoma after allogeneic stem cell transplantation (alloSCT). The effect of interferon-alpha (IFN-alpha) on the GVL effect still remains unclear. Here we report on a 29-year-old woman with refractory diffuse large B-cell lymphoma (DLBL). Her clinical findings included multiple masses in the liver, stomach, bilateral kidneys, thyroid, vertebral bones and a bulky mediastinal mass. Since the patient did not respond to various combination chemotherapies and further developed superior vena cava syndrome, allogeneic peripheral blood stem cell transplantation (PBSCT) from a HLA-identical brother was carried out after a myeloablative TBI/CY-based conditioning regimen. DLIs have been also performed every 4 weeks since day +14. As a result, the lymphoma masses showed a partial response. In order to enhance the GVL effect, IFN-alpha was further given at a maximum of 3 MU four times per week. Although the patient only experienced graft-versus-host disease of the skin (grade II) even after both DLIs and IFN, complete clinical remission was observed. 200 days after transplantation, the patient is still disease-free and in good condition. This report suggests the curative potential of IFN-alpha combined with DLI after allogeneic SCT in refractory DLBL.

Nab-paclitaxel for the treatment of breast cancer: efficacy, safety, and approval.

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel formulation of paclitaxel that does not require solvents such as polyoxyethylated castor oil and ethanol. Use of these solvents has been associated with toxic response, including hypersensitivity reactions and prolonged sensory neuropathy, as well as a negative impact in relation to the therapeutic index of paclitaxel. nab-paclitaxel displays greater antitumor activity and less toxicity than solvent-base paclitaxel. In a phase I trial of single nab-paclitaxel, the maximum tolerated dose was 300 mg/m(2) with the dose limiting toxicities being sensory neuropathy, stomatitis, and superficial keratopathy. In the metastatic setting, a pivotal comparative randomized phase III study demonstrated that nab-paclitaxel (at 260 mg/m(2) over 30 minutes infusion without premedication every 3 weeks) mediated a superior objective response rate and prolonged time to progression compared with solvent-based paclitaxel (at 175 mg/m(2) over a 3-hour injection with standard premedication). The nab-paclitaxel-treated group showed a higher incidence of sensory neuropathy than the solvent-based paclitaxel group. However, these adverse side effects rapidly resolved after interruption of treatment and dose reduction. Weekly administration of nabpaclitaxel was also more active and displayed less toxicity compared with 100 mg/m(2) docetaxel given triweekly. Nab-paclitaxel has already been approved in 42 countries for the treatment of metastatic breast cancer previously treated with anthracycline, based on confirmation of the efficacy and manageable toxicity in the metastatic setting. This review summarizes the most relevant knowledge on nab-paclitaxel for treating breast cancer in terms of clinical usefulness including efficacy and safety of this new agent.

Cystic Squamous Cell Carcinoma of the Thyroid A Possible New Subgroup of Intrathyroidal Epithelial Thymoma.

In the thyroid gland, both squamous cell carcinoma and intrathyroidal epithelial thymoma are rare tumors with squamous features, but their prognoses differ; the former is usually fatal, and the latter is favorable. We describe a 38-yr-old female patient with a cystic tumor diagnosed cytologically as squamous cell carcinoma, who was treated with subtotal thyroidectomy. The tumor was located intrathyroidally in the middle third of the left lobe, and no invasion to the surrounding tissues was found. Histologic examination disclosed a cyst lined by epithelial cells with squamous cell differentiation. The tumor cells had ill-defined cell borders and large nuclei with prominent nucleoli. Invasion of the tumor capsule, a few mitoses, and infiltration of lymphocytes in the tumor periphery were noted, but neither necrosis nor metastasis to lymph nodes was observed. The patient has been free from recurrence for 3 yr after thyroid lobectomy. We propose that this type of cystic intrathyroidal squamous cell carcinoma may represent a cystic variant of intrathyroidal epithelial thymoma.

Immunoreactive Characteristics and Classification of Hyperparathyroidism.

Hyperparathyroidism is caused mainly by three different conditions: namely, secondary hyperplasia, primary hyperplasia, and adenoma with only a few cases due to carcinomas. Histological distinction among these diseases is still difficult. In an attempt to characterize the three conditions, 17 cases from patients with hyperparathyroidism and 12 with normal glands were investigated immunohistochemically using antibodies against PTH, PTHrP, Ki-67 (MIB-1), and chromogranin A. The normal glands showed a diffuse staining pattern for PTH, and focal staining for PTHrP and for chromogranin A. Secondary hyperplasia demonstrated either focal, diffuse, or mixed staining in one gland with the three antibodies. For the primary hyperplasias and adenomas, the cases could be divided into two groups. The first group (group I), including 1 case of primary hyperplasia and 3 cases of adenoma, showed a homogeneous staining pattern with all three antibodies. A heterogeneous staining pattern similar to secondary hyperplasia was found in the other 8 cases that formed the second group (group II). There were five types of cytologic staining patterns after immunostaining. In secondary hyperplasia and group II, several patterns appeared simultaneously. On the contrary, only one pattern was found in group I. The proliferative index (P1) from Ki-67 staining of group I was also significantly higher than in group II. A lower P1 was observed in the normal glands. The present results indicate that different immunohistochemical characteristics exist in primary hyperplasias and in adenomas.

Immunolocalization of Parathyroid Hormone in Human Parathyroid Glands with Special References to Microwave Antigen Retrieval.

The subcellular localization of parathyroid hormone (PTH) in the normal human parathyroid glands with particular reference to microwave antigen retrieval was investigated using peroxidase-labeled PTH antibody, immunohistochemical, and immunoelectron microscopic methods. The results revealed that PTH granules existed mainly as pro-PTH on the trans side of Golgi and in the regions adjacent to Golgi apparatus. Only a small proportion of secretory granules were stored near the plasma membrane. Microwave irradiation was essential for the immunodetection of PTH. As the irradiative time extended from 1 to 30 min, the staining intensity increased, and the subcellular preservation decreased. Microwave irradiation for 15 mm (with the sections in citrate buffer) with a power output of 500 W is the most ideal for PTH antigen retrieval, as well as for subcellular preservation.