Impaired response of granulocyte-committed progenitor cells to stem cell factor and granulocyte colony-stimulating factor in human cyclic neutropenia

 Although cyclic neutropenia (CN) has been the subject of extensive studies due to its striking clinical picture, the abnormality of hematopoietic progenitor cells in patients with CN has been poorly defined. We studied the sensitivity of progenitor cells of a CN patient to colony-stimulating factors (CSF) including G-CSF, interleukin-3 (IL-3), and stem cell factor (SCF). Peripheral blood progenitor cells of the patient required a significantly higher dose of G-CSF to give rise to colonies than those of normal controls. While the presence of SCF enhanced the number of G-CSF-induced colonies regardless of the concentration of G-CSF in normal controls, this synergistic effect of SCF was limited to the high concentration of G-CSF in the patient, indicating that the abnormality in hematopoiesis in CN involved more immature progenitor cells responsive to SCF. Received: July 30, 1998 / Accepted: November 12, 1998     

Expansion and activation of minor histocompatibility antigen HY-specific T cells associated with graft-versus-leukemia response

The immune system of females is capable of recognizing and reacting against the male-specific minor histocompatibility antigen (mHA), HY. Thus, cytotoxic T-lymphocytes (CTLs) recognizing this antigen may be useful in eradicating leukemic cells of a male patient if they can be generated in vivo or in vitro from a human leukocyte antigen (HLA)-identical female donor. The HLA-A*0201-restricted HY antigen, FIDSYICQV, is a male-specific mHA. Using HLA-A2/HY peptide tetrameric complexes, we reveal a close association between the emergence of HY peptide-specific CD8(+) T cells in peripheral blood and molecular remission of relapsed BCR/ABL(+) chronic myelogenous leukemia in lymphoid blast crisis in a patient who underwent female-to-male transplantation. Assessment of intracellular cytokine levels identified T cells that produce interferon-gamma in response to the HY peptide during the presence of HY tetramer-positive T cells. These results indicate that transplant with allogeneic HY-specific CTLs has therapeutic potential for relapsed leukemia, and that expansion of such T cells may be involved in the development of a graft-versus-leukemia response against lymphoblastic leukemia cells.     

Statins and Angiotensin‐Converting Enzyme Inhibitors are Associated with Reduced Mortality and Morbidity in Chronic Liver Disease

Liver fibrosis is a common response to many chronic liver diseases. The aim of our study was to explore whether pharmacotherapy for concurrent diseases affects overall mortality, liver‐related mortality and liver‐related morbidity in patients with chronic liver disease. We performed a register‐based cohort study of all patients with a first‐time diagnosis of chronic liver disease between 2005 and 2012 in Sweden (n = 70 546). Data from the Patient Register, the Prescribed Drug Register and the Death Certificate Register were linked . We studied whether the use of statins, angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers and antibiotics affected the risk of total mortality, liver‐specific mortality and morbidity. We found a reduction in mortality risk for statin users (n = 11,245) with hazard ratios from 0.57 (95% CI: 0.32–0.99) for patients with autoimmune hepatitis to 0.84 (95% CI: 0.75–0.95) for patients with alcoholic liver disease. There was a significantly reduced liver‐related mortality for patients with alcoholic liver disease who used angiotensin‐converting enzyme inhibitors, 0.85 (95% CI: 0.65–0.96). There were increased overall mortality risks for antibiotic users (n = 44,572), with hazard ratios up to 1.67 (95% CI, 1.55–1.80) for viral hepatitis. Statin use was associated with decreased risks of liver‐specific mortality and morbidity, and reduced total mortality foremost among patients with alcoholic liver disease. Angiotensin ‐converting enzyme inhibitors was associated with reduced liver‐related mortality among patients with alcoholic liver disease.     

Brain uptake and safety of Flutemetamol F 18 injection in Japanese subjects with probable Alzheimer’s disease,subjects with amnestic mild cognitive impairment and healthy volunteers

Objective

This Phase 2 study assessed the performance of positron emission tomography (PET) brain images made with Flutemetamol F 18 Injection in detecting β-amyloid neuritic plaques in Japanese subjects.

Methods

Seventy subjects (25 with probable Alzheimer’s disease (pAD), 20 with amnestic mild cognitive impairment (aMCI), and 25 cognitively normal healthy volunteers[HVs]) underwent PET brain imaging after intravenous Flutemetamol F 18 Injection (185 MBq). Images were interpreted as normal or abnormal for neuritic plaque density by each of five non-Japanese and five Japanese readers who were blinded to clinical data. The primary efficacy analysis (based on HV and pAD data) was the agreement of the non-Japanese readers’ image interpretations with the clinical diagnosis, resulting in estimates of positive percent agreement (PPA; based on AD subjects; similar to sensitivity) and negative percent agreement (NPA; based on HVs; similar to specificity). Secondary analyses included PPA and NPA for the Japanese readers; inter-reader agreement (IRA); intra-reader reproducibility (IRR); quantitative image interpretations (standardized uptake value ratios [SUVRs]) by diagnostic subgroup; test–retest variability in five pAD subjects; and safety.

Results

PPA was 92% for all non-Japanese readers and ranged from 88 to 92% for the Japanese readers. NPA ranged from 96 to 100% for both the non-Japanese readers and the Japanese readers. The majority image interpretations (the interpretations made independently by ≥3 of 5 readers) resulted in PPA values of 92 and 92% and NPA values of 100 and 96% for the non-Japanese and Japanese readers, respectively. IRA and IRR were strong. Composite SUVR values (mean of multiple regional values) allowed clear differentiation between pAD subjects and HVs. Test–retest variability ranged from 1.14 to 2.27%, and test–retest agreement of the blinded visual interpretations was 100% for all readers. Flutemetamol F 18 Injection was generally well tolerated.

Conclusions

The detection of brain neuritic plaques in Japanese subjects using [¹⁸F]Flutemetamol PET images gave results highly consistent with clinical diagnosis, with non-Japanese and Japanese readers giving similar results. Inter-reader agreement and intra-reader reproducibility were high for both sets of readers. Visual delineation of abnormal and normal scans was corroborated by quantitative assessment, with low test–retest variability.

Trial registration

Clinicaltrials.gov registration number NCT02813070.

     

Percutaneous fluoroscopically guided <Emphasis Type="Italic">n</Emphasis>-butyl cyanoacrylate (NBCA) injection for iatrogenic femoral arterial pseudoaneurysm under temporary balloon occlusion of arterial blood flow

Purpose  

To evaluate the safety and efficacy of n-butyl cyanoacrylate (NBCA) injection under fluoroscopy for iatrogenic femoral artery pseudoaneurysms under temporary balloon occlusion.     

Hemobilia immediately after transcatheter arterial chemoembolization using drug‐eluting beads for hepatocellular carcinoma with intrahepatic bile duct invasion

Transcatheter arterial chemoembolization (TACE) is used as a palliative treatment for unresectable hepatocellular carcinoma (HCC) worldwide. Recently, a novel drug delivery–embolic agent, the drug‐eluting bead (DEB), was introduced for TACE. There are a few reports of tumor hemorrhage after TACE using DEB (DEB‐TACE) for HCC. However, there have not been any reports of hemobilia immediately after DEB‐TACE for HCC with intrahepatic bile duct invasion. Here, the first such case is reported. A 71‐year‐old woman was admitted to our hospital to undergo DEB‐TACE for multiple HCCs with worsening left intrahepatic bile duct dilatation. She was diagnosed with HCC that extensively invaded the left hepatic duct. After DEB‐TACE through the left hepatic artery, a hepatic arteriogram showed extra flow of the contrast agent to the left hepatic and common bile ducts. Therefore, transcatheter arterial embolization (TAE) of the responsible vessel was carried out using coils, and no extra flow of the contrast agent was identified. The patient was discharged 14 days after TAE without deterioration of liver function. Although hemobilia immediately after DEB‐TACE is rare, there may be increased potential for hemobilia when DEB‐TACE is carried out for HCC with extensive bile duct invasion. We suggest that DEB‐TACE may be contraindicated for such cases.     

Serum concentration of L‐kynurenine predicts the clinical outcome of patients with diffuse large B‐cell lymphoma treated with R‐CHOP

Purpose: Introduction of rituximab has largely improved the prognosis of patients with diffuse large B‐cell lymphoma(DLBCL). Such change in therapeutic outcome necessitates the identification of additional prognostic factors to conventional indexes that have been validated for CHOP without rituximab. Indoleamine 2,3‐dioxygenase (IDO) exerts intense immunomodulatory effects because of enzymatic activities that catalyze the breakdown of the essential amino acid L‐tryptophan. The activity of IDO can be estimated by measuring the serum concentration of L ‐kynurenine. Here, we investigated the role of L ‐kynurenine as a prognostic marker in R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) therapy. Experimental design: Data from 73 consecutive patients treated with eight cycles of R‐CHOP or R‐THP (tetrahydropyranyl adriamycin)‐COP between December 2002 and March 2007 were analyzed. L ‐kynurenine concentrations in serum samples obtained at admission were measured by high‐performance liquid chromatography. Results: The median serum L ‐kynurenine level was 1.575 μm (range 0.537–9.588). The complete response (CR) rates of patients with L ‐kynurenine <1.5 and ≥1.5 μm were 83% and 61%, respectively (P < 0.05). The three‐yr overall survival (OS) rates for patients with L ‐kynurenine <1.5 and ≥1.5 μm were 89% and 58%, respectively (P < 0.005). In addition, higher age, poor performance status, elevated serum lactate dehydrogenase, and unfavorable as well as revised International Prognosis Index were significantly worse factors for CR rate and OS. Multivariate analyses revealed only L ‐kynurenine as an independent prognostic factor for OS. Conclusions: Serum L ‐kynurenine might be a novel prognostic factor to determine the treatment outcome of DLBCL with the R‐CHOP regimen.     

Orbital T-cell lymphoma in a multiple myeloma patient

PURPOSE: To report an 82-year-old woman with multiple myeloma who developed an orbital T-cell lymphoma concomitantly. METHODS: The patient presented with left upper eyelid swelling. Magnetic resonance imaging demonstrated an orbital mass compressing the eyeball. The mass was excised for diagnostic purposes and orbital decompression. RESULTS: Histopathologic and immunohistochemical evaluation identified the mass as a T-cell lymphoma. The disease progressed rapidly despite chemotherapy. CONCLUSIONS: Orbital T-cell lymphoma is rare and we are unaware of previous reports of orbital T-cell lymphoma in patients with multiple myeloma.