In vivo construction of liver tissue by implantation of a hepatic non‐parenchymal/adipose‐derived stem cell sheet

Subcutaneous hepatocyte sheet implantation is an attractive therapeutic option for various liver diseases. However, this technique is limited by the availability of hepatocytes. Thus, the use of hepatic non‐parenchymal cells (NPCs) containing small hepatocytes, which have the ability to proliferate more rapidly than mature hepatocytes, for transplantation has been suggested. The aim of our study was to construct liver tissue subcutaneously in rats by implanting NPC sheets co‐cultivated with adipose‐derived stem cells (ADSCs), which produce certain angiogenic factors. We crafted NPC‐ADSC sheets on temperature‐responsive culture dishes. NPCs formed functioning bile canaliculi and stored glycogen. In addition, their ability to produce albumin was not inferior to that of hepatocytes. Albumin production increased over time when co‐cultivated with ADSCs. We then implanted the co‐cultivated cell sheets subcutaneously. The co‐cultivated sheets retained glycogen, formed bile canaliculi, showed signs of vascularization and survived subcutaneously without pre‐vascularization. These results suggest that NPCs can be a viable option in cell therapy for liver diseases. This technique using co‐cultivated cell sheets may be useful in the field of regenerative medicine. Copyright © 2017 John Wiley & Sons, Ltd.     

Poor Blood Pressure and Urinary Albumin Excretion Responses to Home Blood Pressure-Based Antihypertensive Therapy in Depressive Hypertensive Patients

J Clin Hypertens (Greenwich). There has been no report comparing the changes in home blood pressure (HBP) and target organ damage between depressive and nondepressive hypertensives receiving antihypertensive therapy based on HBP monitoring. This study was a multicenter prospective study conducted by 7 doctors at 2 institutions. The authors prospectively studied 42 hypertensive patients with home systolic blood pressure >135 mm Hg. Participants were divided into a depression group (Beck Depression Inventory score >10; n=21) and a nondepression group (Beck Depression Inventory score <9, matched for HBP level; n=21). The authors performed antihypertensive therapy to reduce home systolic blood pressure to below 135 mm Hg and, 6 months later, evaluated the urinary albumin/creatinine ratio (UACR). Although patients in the depression group tended to require the addition of a greater number of medications than those in the nondepression group (2.3±1.0 vs 1.7±1.0 drugs, P<.05), HBP was reduced similarly in both groups at 6 months (depression group: 150±17/78±11 mm Hg to 139±11/73±8 mm Hg, P<.001; nondepression group: 150±11/76±9 mm Hg to 135±9/70±8 mm Hg, P<.01). The reduction of UACR was smaller in the depression group than in the nondepression group (2.4 vs 10.1 mg/gCr, P<.05). Depressive hypertensive patients required a larger number of antihypertensive drugs to control HBP, and showed a smaller reduction in UACR than nondepressive hypertensives.     

Monitoring of therapeutic efficacy in a patient with RS3PE syndrome by serologic variables and radiographic methods

We describe a typical case of a patient with remitting seronegative symmetrical synovitis and pitting edema (RS₃PE) syndrome. He underwent a successful clinical course monitored by serologic variables and radiographic methods. Serum levels of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), matrix metalloproteinase-3 and serum amyloid A were remarkably elevated. Accumulation of inflammatory cells into the multiple joints was found by gallium-67 scintigraphy. Multiple and symmetrical tenosynovitis with hypervascularity in the presence of subcutaneous edema of the hands and feet were determined by magnetic resonance imaging (MRI) and ultrasonography. These serologic and radiographic abnormalities immediately improved after treatment with a low-dose steroid. Our present case supports a previous observation that synovial tissue is a major inflammatory source of RS₃PE syndrome. IL-6 (and VEGF), probably produced from the synovial tissues, are considered to be essential factors in the development of RS₃PE syndrome.     

Serum amyloid A is a useful marker to evaluate the disease activity of Takayasu’s arteritis

Takayasu’s arteritis (TA) is a rare large vessel vasculitis that is difficult to diagnose in the early stages. Therefore, it is also very difficult to manage and prevent irreversible vascular damage in TA. A 19-year-old female patient with back pain was examined using [¹⁸F]-FDG-PET to detect the source of inflammation. Specific accumulation of [¹⁸F]-FDG was observed in the thoracic and abdominal aorta, leading to the diagnosis of TA. Corticosteroid treatment resulted in clinical remission. However, the serum amyloid A (SAA) levels remained elevated. A follow-up scan showed residual uptake of [¹⁸F]-FDG in the thoracic aorta suggesting subclinical vascular inflammation. Methotrexate was combined with the corticosteroid, and the elevated levels of SAA became normalized. The present case suggests that monitoring serum levels of SAA and [¹⁸F]-FDG-PET could help clinicians to make adequate treatment adjustments in TA patients.     

Reversal of dialysis-dependent renal failure in patients with advanced multiple myeloma: single institutional experiences over 8 years

Acute renal failure in patients with multiple myeloma (MM) requiring dialysis is a serious complication and is associated with extremely poor survival. In addition, its treatment included high-dose dexamethasone and/or thalidomide-containing regimens on the reversibility of renal function, which has not been adequately evaluated previously. We studied the impact on the reversibility of high-dose dexamethasone and/or thalidomide-containing regimen in 12 newly diagnosed MM patients (median 74 years, range; 63–85 years) who required dialysis at Kameda General Hospital from 2001 to 2008. There were seven light chain only myelomas, three IgD myelomas, and two IgG myelomas. Ten patients initially received high-dose dexamethasone-based treatment and two received thalidomide-based treatment, with modifications. Complete (CR) and partial responses (PR) were obtained in three and five patients, respectively. Dialysis independency was achieved in all eight patients (67%) who achieved better than PR, with a median duration of 2.0 months. Six of the ten patients who received high-dose dexamethasone-containing regimen and all of the two patients received thalidomide-containing regimen became dialysis-independent. A high concentration of serum-free light chain was detected in all patients examined, before the start of anti-myeloma treatment, and this was associated with the presence of advanced renal failure. Improved renal function was preceded by a significant decrease in serum-free light chain in patients who achieved dialysis independence. These results suggest that dialysis-dependent renal failure is reversible by dexamethasone- or thalidomide-based treatments in most patients with MM, even if the patient is in advanced age, and that serum-free light chain monitoring might be useful for predicting improvements in renal function.     

Strong CD8+ T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma

Aim

We investigated whether tumor-specific CD8⁺ T-cell responses affect tumor-free survival as well as the relationship between CD8⁺ T-cell responses against tumor-associated antigens (TAAs) and the clinical course after tumor treatment in patients with hepatocellular carcinoma (HCC).

Methods

Twenty patients with HCC that were treated by radiofrequency ablation or trans-catheter chemo-embolization (TACE) and in whom HCC was undetectable by ultrasonography, CT, and/or MRI 1 month after treatment were enrolled in the study. Before and after treatment for HCC, analyses of TAA (glypican-3, NY-ESO-1, and MAGE-1)-specific CD8⁺ T-cell responses were evaluated with an interferon-γ enzyme-linked immunospot (ELISpot) assay using peripheral CD8⁺ T-cells, monocytes, and 104 types of 20-mer synthetic peptide overlapping by 10 residues and spanning the entirety of the 3 TAAs.

Results

Sixteen out of 20 patients (80%) showed a positive response (≥10 TAA-specific cells/10⁵ CD8⁺ T-cells) before or after treatment. When we performed univariate analysis of prognostic factors for the tumor-free period in the 20 patients, platelet count, prothrombin time, and the number of TAA-specific CD8⁺ T-cells after treatment were significant factors (P = 0.027, 0.030, and 0.004, respectively). In multivariate analysis, the magnitude of the TAA-specific CD8⁺ T-cell response (≥40 TAA-specific cells/10⁵ CD8⁺ T-cells) was the only significant prognostic factor for a prolonged tumor-free interval (hazard ratio 0.342, P = 0.022).

Conclusions

Our results suggest that strong TAA-specific CD8⁺ T-cell responses suppress the recurrence of HCC. Immunotherapy to induce TAA-specific cytotoxic T lymphocytes by means such as the use of peptide vaccines should be considered for clinical application in patients with HCC after local therapy.     

Existence of pyogenic spondylitis in Modic type 1 change without other signs of infection: 2-year follow-up

The relationship of Modic change to pain and inflammation remains to be unclear. Recently, some authors have reported that Modic type 1 signals are closely related to infection. However, if the patients do not have severe back pain, fever, or an abnormal blood profile, it is difficult to distinguish between common Modic change and infection. The purpose of this study was to examine the prevalence of pyogenic spondylitis in patients who showed Modic type 1 change without other signs of infection. Seventy-one patients with Modic type 1 change were evaluated (average age 55, 32 males and 39 females). X-ray and magnetic resonance imaging (MRI) were performed to investigate low-back pain and leg pain. Body temperature was measured and blood analysis (including white blood cell count and level of C-reactive protein) was conducted for all patents. All 71 patients with Modic type 1 change, but without other signs of infection were followed for 2 years. Low-back pain, X-ray, and blood analyses were performed every 3 months; and MRI was performed every year. Severe low-back pain or abnormal signs developed in four patients during the follow-up. Pyogenic spondylitis was diagnosed in three patients by symptoms, blood results, and imaging, and confirmed by biopsy. Two of the three patients were diabetic. A total of 4.2% of patients with Modic type 1 change, but without other signs of infection were diagnosed as having pyogenic spondylitis during the 2-year follow-up, therefore, it is important to consider this before treating Modic type 1 change.     

Primary sensory neurons with dichotomizing axons projecting to the facet joint and the low back muscle in rats

Background

Clinically, the origin of low back pain is unknown. The pain may originate from the lumbar muscles directly, or it may be referred pain from the spine. Dorsal root ganglion (DRG) neurons with dichotomizing axons have been reported in several species and are thought to be related to referred pain. However, these neurons, which have dichotomizing axons to the lumbar facet joints and to the lumbar muscle, have not been fully investigated.

Methods

Two neurotracers — 1,1′-dioctadecyl-3,3,3′,3′- tetramethyl-indocarbocyanine perchlorate (DiI) and fluorogold (FG) — were used in the present double-labeling study. DiI crystals were placed in the right L5/6 facet joint, and FG was applied to right multifidus muscles at the L5 level in 10 rats. Two weeks later, bilateral DRGs from L1 through L6 were harvested, sectioned, and observed under a fluorescence microscope.

Results

DiI-labeled DRG neurons innervating the L5/6 facet joint (5.17% of the total DRG neurons) were distributed from L1 to L6. FG-labeled DRG neurons innervating the lower back muscle (15.9% of the total) were also distributed from L1 to L6. Double-labeled DRG neurons were found from L1 to L6. The ratio of total double-labeled/total DiI-labeled DRG neurons was 17% and that of total double-labeled/total FG-labeled DRG neurons was 7%. Approximately 17% of all DRG neurons innervating the facet joints had other axons that extended to the lower back muscle.

Conclusions

This finding provides a possible neuroanatomical explanation for referred low back muscle pain from the lower facet joints.     

Surgical treatment of patients with stenosis of the central airway due to tracheal tumours

This study retrospectively evaluated bronchoscopic and surgical treatments for patients with central airway stenosis due to tracheal tumours. Seven patients treated by resection and reconstruction of the trachea for tracheal tumours between 1994 and 2008 were retrospectively reviewed. The most common histological finding was thyroid carcinoma (n = 3), followed by adenoid cystic carcinoma (n = 2), a metastatic thyroid tumour (n = 1), and a benign granular cell tumour (n = 1). Three of the patients required preoperative laser treatment (Nd:YAG) for recanalization. Five patients underwent end-to-end anastomosis for reconstruction. There was no postoperative mortality or morbidity such as anastomotic insufficiency of the reconstructed trachea. Three patients with a microscopic residual tumour required postoperative external radiotherapy. Surgical resection of malignant tracheal tumours is recommended not only for curative purposes, but also for reduction of the risk of smothering.