Fibrosing Cholestatic Hepatitis Developing within One Month after Living Donor Liver Transplantation for Chronic Hepatitis C-related Cirrhosis: A Case Report

Fibrosing cholestatic hepatitis (FCH) is a life-threatening consequence of hepatitis C virus (HCV) infection occurring in a small minority of liver transplantation (LT) recipients. We herein report a case of early-onset FCH after living donor LT in a 47-year-old woman with HCV-related cirrhosis. The patient underwent balloon-occluded retrograde transvenous obliteration of a splenorenal shunt to treat an impaired portal flow on the sixth postoperative day (POD 6) and a bypass operation for hepatic artery thrombosis on POD 12. Thereafter, the serum bilirubin levels increased gradually; however, computed tomography revealed no evidence of biliary stricture. The serum HCV-RNA level on POD 27 was >7.8 log IU/mL. Histopathology of a needle graft biopsy performed on POD 28 revealed FCH with extensive portal fibrosis accompanied by mild inflammation, hepatocyte ballooning, and ductular proliferation with cholestasis. The patient received combination therapy with pegylated interferon, ribavirin, and double-filtration plasmapheresis for the treatment of early-onset FCH. Both the recipient and the donor carried the major genotype single nucleotide polymorphism (TT) at rs8099917 near the interleukin-28B gene. Furthermore, the HCV genotype was treatment-sensitive 2a. Nonetheless, the recipient died of hepatic failure on POD 211. Thus far, few cases of FCH occurring within 1 month after LT have been reported. In addition, the early onset of FCH may be an adverse prognostic factor.     

Donors' Quality of Life Evaluated by Short Form-36 Analysis After Living Donor Liver Transplantation in a Single-Center Experience

Background and Purpose

The purpose of this study was to compare the quality of life of donors using the Short Form 36 (SF-36) analysis between the left and right graft periods of living donor liver transplantation.

Patients and Methods

In the left graft period (July 1991 to July 2003), 68 donors were eligible for analysis and 76 were eligible in the right graft period (August 2003 to October 2010). Nine right lobe grafts were included in the left graft period, and 52 right lobe grafts were included in the right graft period. We investigated the risks of donation and evaluated the following: blood loss, operation time, postoperative liver function, and duration of hospitalization. We also assessed quality of life in donors, who were mailed a structured questionnaire and the SF-36.

Results

Ten of the 68 donors in the left graft period and 12 of the 76 in the right graft period had postoperative complications. Most postoperative complications were treated without surgical procedures. There was no donor death in our series. Forty-eight donors in the left graft period and 36 in the right graft period responded to our investigation. Compared with published Japanese norms in SF-36, our donors scored similar or higher than the general population in both groups. Two donors in the left graft period and one in the right graft period regretted their decisions to donate. All donors returned to normalcy.

Conclusions

These results suggested that the donors' quality of life was guaranteed in terms of the SF-36 investigation regardless of the donation period in our series.     

Successful treatment of unresectable recurrent cutaneous squamous cell carcinoma of the scalp with meningeal invasion with nivolumab monotherapy

Although the number of cutaneous squamous cell carcinoma (cSCC) cases is increasing, the effectiveness of systemic therapy for the treatment of advanced cSCC is limited. Since cSCC possesses a high tumor mutation burden (TMB) compared to other cancer species, and since high TMB correlated with increased neoantigens and the efficacy of anti‐PD1 antibodies (Abs) in various cancers, cSCC could be a target for anti‐PD1 Abs monotherapy. In this report, we describe a case of unresectable recurrent cSCC of the scalp with meningeal invasion, but highly expressed programmed death‐ligand 1 (PD‐L1), treated with nivolumab monotherapy.     

Utility of an upright-type 11-gauge stereotactic vacuum-assisted biopsy device （Mammotome@） for the diagnosis of breast microcalcifications

Objective： The aim of this study was to evaluate the utility of an upright-type 11-gauge stereotactic vacuum-assisted biopsy device （Mammotome@） for the diagnosis of breast microcalcifications Methods： Between May 2001 and October 2005, 154 biopsies in 152 patients with microcalcifications were performed using the upright-type 11-gauge stereotactic vacuum-assisted biopsy device. Patients in whom this biopsy was diagnosed as carcinoma or a borderline lesion, had a subsequent surgical excision of the lesion. Histopathological and radiological features of the two specimens were then compared with each other. Results： Microcalcification was identified on specimen mammograms and microscopic slides in 97.4% of cases. Of 154 Mammotome biopsies 98 （63.6%） were benign, 51 （33.1%） were malignant, 3 （1.9%） showed atypical hyperplasia, and 2 （1.3%） were indeterminate, respectively. Of the 48 cases that received surgical excision, 6 of 36 ductal carcinomas in situ （16.7%） upstaged to invasive ductal carcinoma and 1 of 2 atypical ductal hyperplasias was upstaged to ductal carcinoma in situ. The positive predictive value of the 11-gauge Mammotome for the diagnosis of invasion in breast cancer was 100%. Linear calcification and pleomorphic calcification linear/segmental distribution was reliable indications of malignancy. The mean follow-up time of the benign lesions was 22 months, and without evidence of lesion growth. Complications included vasovagal reactions （6.3%）, bleeding （0.6%） and hematoma （2.6%）. Conclusion： The upright stereotactic 11-gauge Mammotome procedure is an effective and reliable method for the diagnosis of breast microcalcifications. It has minimal side effects. For lesions diagnosed as ADH or DCIS with the 11-gauge Mammotome, subsequent surgical excision should be performed.     

X-irradiation and ageing as reflected in the accumulation and insolubilization of collagen

Male mice received 300 R of whole body X-irradiation 4 times at 6,43, 45 and 48 weeks of age. Skin collagen was divided into 2 fractions, neutral salt soluble and insoluble collagens, by prolonged extraction of the minced skin with 1 M NaCl.

The ratio of insoluble collagen to neutral salt soluble collagen was increased significantly by a total of 1200 R of whole body irradiation at 3 and 21 weeks after the last irradiation, though single 300 R did not cause any significant increase at 8 weeks after the irradiation.

Not only tissue concentration but also total contents of collagen in entire lung, heart and kidney constantly increased with ageing.

X-irradiation caused no significant elevation in the concentration or the total content of collagen in any of the three organs or the skin throughout the experimental pe period of 14 weeks to 65 weeks of age.     

Diversified expression patterns of autotaxin,a gene for phospholipid‐generating enzyme during mouse and chicken development

Autotaxin (ATX), or nucleotide pyrophosphatase‐phosphodiesterase 2, is a secreted lysophospholipase D that generates bioactive phospholipids that act on G protein–coupled receptors. Here we show the expression patterns of the ATX gene in mouse and chicken embryos. ATX has a dynamic spatial and temporal expression pattern in both species and the expression domains during neural development are quite distinct from each other. Murine ATX (mATX) is expressed immediately rostral to the midbrain‐hindbrain boundary, whereas chicken ATX (cATX) is expressed in the diencephalon and later in the parencephalon‐synencephalon boundary. In the neural tube, cATX is expressed in the alar plate in contrast to mATX in the floor plate. ATX is also expressed in the hindbrain and various organ primordia such as face anlagen and skin appendages of the mouse and chicken. These results suggest conserved and non‐conserved roles for ATX during neural development and organogenesis in these species. Developmental Dynamics 236:1134–1143, 2007. © 2007 Wiley‐Liss, Inc.     

Histopathological subclassification of triple negative breast cancer using prognostic scoring system: five variables as candidates

We attempted to subclassify triple negative breast cancer (TNBC) cases into subgroups according to clinical outcome or prognosis of TNBC patients using archival specimens. We analyzed 102 Japanese cases of invasive TNBC who underwent surgery between January 1998 and December 2007. The clinicopathological factors and clinical information were retrospectively retrieved from reviewing the charts of the patients. Immunohistochemical staining was performed for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor 1 (EGFR1), CK5/6, CK14, Ki-67, and CD31 for microvessel density (MVD). Median follow-up time of the patients was 68.5 months. Multivariable analysis demonstrated that pathologic node status was the most significantly associated with relapse-free survival (RFS) and breast cancer-specific survival (BCSS) of these patients. Pathological tumor size, basal-like type, Ki-67 labeling index (LI) and MVD were also independently associated with RFS and BCSS. Based on these results, we devised the risk score system reflecting hazard ratios of these prognostic factors above. With this system, TNBC patients in this study were classified into three subgroups (low-risk group: score 0–3, intermediate-risk group: score 4–7 and high-risk group: score 8–10). The significant difference of RFS and BCSS was detected among these three different subgroups of the patients (p < 0.05). We propose the risk score system, which incorporated pathologic nodal status, size of the primary tumor, the presence or absence of basal-like features, Ki-67 LI, and MVD in order to predict postoperative clinical course of the Japanese TNBC patients.     

Novel hybrid mesh surgery combines sacrocolpopexy with transvaginal mesh placement for pelvic organ prolapse

Mesh surgeries, such as sacrocolpopexy and transvaginal mesh surgery, are commonly used to treat pelvic organ prolapse. Although mesh surgeries have a high success rate, they are unsuitable for some patients. For a patient with pelvic organ prolapse and highly calcified multiple fibroids, we performed hybrid sacrocolpopexy combined with transvaginal mesh surgery with a method modified for the patient's condition. Three months after surgery, the results were highly satisfactory. This approach is simple, secure, and versatile for patients who are not good candidates for conventional mesh surgeries. This novel hybrid mesh surgery is an option for treating various types of pelvic organ prolapse.     

Mechanistic Effects of Long-Term Ultraviolet B Irradiation Induce Epidermal and Dermal Changes in Human Skin Xenografts

UVB irradiation has been reported to induce photoaging and suppress systemic immune function that could lead to photocarcinogenesis. However, because of the paucity of an UVB-induced photodamaged skin model, precise and temporal mechanism(s) underlying the deleterious effects of long-term UVB exposure on human skin have yet to be delineated. In this study, we established a model using human skin xenografted onto severe combined immunodeficient mice, which were subsequently challenged by repeated UVB irradiation for 6 weeks. Three-dimensional optical image analysis of skin replicas and noninvasive biophysical measurements illustrated a significant increase in skin surface roughness, similar to premature photoaging, and a significant loss of skin elasticity after long-term UVB exposure. Resembling authentically aged skin, UVB-exposed samples exhibited significant increases in epithelial keratins (K6, K16, K17), elastins, and matrix metalloproteinases (MMP-1, MMP-9, MMP-12) as well as degradation of collagens (I, IV, VII). The UVB-induced deterioration of fibrous keratin intermediate filaments was also observed in the stratum corneum. Additionally, similarities in gene expression patterns between our model and chronologically aged skin substantiated the plausible relationship between photodamage and chronological age. Furthermore, severe skin photodamage was observed when neutralizing antibodies against TIMP-1, an endogenous inhibitor of MMPs, were administered during the UVB exposure regimen. Taken together, these findings suggest that our skin xenograft model recapitulates premature photoaged skin and provides a comprehensive tool with which to assess the deleterious effects of UVB irradiation.Morphological changes in the skin, such as wrinkling and sagging, are often found in photoaged skin caused by chronic UV irradiation.^1,2,3 Skin photodamage is physiologically correlated with several alterations including the increase and disorganization of elastic fibers and the reduction of collagens in the dermal extracellular matrix^{4,5,6,7,8,9,10,11} and the increase of keratin contents and the deterioration of keratin intermediate filaments (KIFs) in the epidermis.^12,13,14Elastic fibers are age-dependent-decreasing dermal extracellular matrix that respond primarily to the fibrous mechanism controlling cutaneous elasticity.^4,5,15,16 The accumulation of dystrophic elastotic material in the reticular dermis, referred to as solar elastosis, is commonly observed in photoaged skin.^17,18,19 Reported in both in vivo and in vitro, UVB irradiation induces tropoelastin gene and protein expression in fibroblasts and keratinocytes, resulting in an aberrant accumulation of dermal elastic fibers and elastin content.^5,8,10,11,20 On the other hand, it has been reported that the degeneration of these fibers in chronologically and/or photoaged skin stems from an increase in matrix metalloproteinase-12 (MMP-12) and/or elastase, an elastin-degrading enzyme that is produced and secreted by dermal fibroblasts.^21,22,23,24 To date, the mechanisms underlying the alteration of elastin fibers in photoaged skin including their production, accumulation, and degradation are not fully understood.As the main constituent of the dermal matrix, collagen fibers are responsible in regulating the mechanical properties of the skin (ie, skin resilience and skin elasticity). In photoaged skin, the concomitant reductions of collagen I and III occur as procollagen synthesis subsides and the existed dermal collagen degrades because of the disproportionate expression of MMP-1.^25,26,27,28 The reduction of collagens VII and IV at the dermo-epidermal junction has been also reported in the pronounced wrinkling skin.²⁹ In hairless mouse, repetitive UVB exposure has been reported to escalate the degradation of collagens VII and IV by up-regulating MMP-2 and MMP-9 expression.^30,31In addition to the alterations in the dermal compartment, the changes in several epithelial keratins have been well documented in photoaged skin. In healthy skin, keratins compose up to 85% of a fully differentiated keratinocyte and orderly form the epithelial-specific intermediate filament composed of acidic type I (K9 to K20)-basic type II (K1 to K8) coiled-coil heterodimer in healthy skin.^{32,33,34,35,36,37} The existence of keratin fibers strengthening the viscoelastic properties in the stratum corneum (SC) provides a semi-impermeable membrane that is tough and resilient.^38,39,40,41 In hairless mice, a repeated low-dose UV exposure has been reported to deteriorate KIFs and induce the expression of epithelial keratins (K1, K5, and K10), resulting in the loss of skin elasticity and eventually initiating wrinkled skin, consistent with previous reports demonstrating no causal relationship between wrinkle formation and dermal changes.^{12,13,14,42,43}Many studies of skin photoaging have been conducted using animal models and human skin substitute. The results may be misleading because of inferior architecture, such as the relative thin epidermal layer and compromised barrier function.⁴⁴ The use of actual human skin or human skin xenografts to study skin photoaging is more appropriate.^45,46,47 The reversible hyperproliferation and differentiation of human epidermis after acute UVB exposure has been successfully demonstrated using human skin grafted onto congenitally athymic nude mice.⁴⁸ Although the lack of inflammatory cells, T and B cells, in athymic and severe combined immunodeficient (SCID) mice allows the implantation of human skin without rejection, it may pose a problematic interpretation of immune function and UV response. A result from a clinical study suggested that T lymphocytes are involved in collagen degradation by the activation of MMP-1.⁴⁹ To date, the detail mechanisms of premature photoaging because of long-term UVB exposure on actual human skin had not been assessed. Therefore, it is of particular interest to establish a chimeric model with human skin xenograft on SCID mice to examine the mechanism(s) of photodamaged skin after long-term UVB irradiation. Here we report for the first time that repeated UVB irradiation in combination with the repetitive motion of the human skin xenograft represents a photodamaged skin model reflecting the documented changes in both the epidermis and the dermis. In addition, we also suggest new insights for the involvement of K6 and its partners in this process.     

Plasma extravasation induced by dietary supplemented histamine in histamine-free mice

Histidine decarboxylase (HDC) synthesizes endogenous histamine from histidine in mammals. To evaluate the role of histamine in skin allergic reaction, we used HDC gene knockout mice lacking histamine. No plasma extravasation reaction was observed in HDC-/- mice after passive cutaneous anaphylaxis (PCA) test. Compound 48/80, a mast cell granule depletor, produced plasma extravasation inHDC+/+ mice but no extravasation in HDC-/- mice. Interestingly, orally administered histamine was distributed in the skin in HDC-/- mice and in these histamine-supplemented mice the plasma extravasation reaction was observed after the injection of compound 48/80 and the PCA test. Cultured bone marrow-derived mast cells of HDC-/- mice took up histamine from the histamine-supplemented medium into the secretory granules. The absorbed histamine was released in response to the same antigen and antibody combination used as in PCA test. In contrast to the immediate-type response, the delayed-type hypersensitive response, observed as a thickening of the ear skin after trinitrochlorobenzene challenge (following sensitization), showed no differences between HDC+/+ and HDC-/- mice. Therefore, among the allergic skin reactions, histamine is revealed to be an important mediator especially for the plasma extravasation in an immediate-type allergy model.