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Despite the promising efficacy of atezolizumab plus bevacizumab (atezo/bev), some patients with unresectable hepatocellular carcinoma (HCC) experience disease progression. This retrospective study, which included 154 patients, aimed to evaluate predictors of treatment efficacy of atezo/bev for unresectable HCC. Factors associated with treatment response were examined, focusing on tumor markers. In the high-alpha-fetoprotein (AFP) group (baseline AFP ≥ 20 ng/mL), a decrease in AFP level > 30% was an independent predictor of objective response (odds ratio, 5.517; p = 0.0032). In the low-AFP group (baseline AFP < 20 ng/mL), baseline des-gamma-carboxy prothrombin (DCP) level < 40 mAU/mL was an independent predictor of objective response (odds ratio, 3.978; p = 0.0206). The independent predictors of early progressive disease were an increase in AFP level ≥ 30% at 3 weeks (odds ratio, 4.077; p = 0.0264) and the presence of extrahepatic spread (odds ratio, 3.682; p = 0.0337) in the high-AFP group and up-to-seven criteria, OUT (odds ratio, 15.756; p = 0.0257) in the low-AFP group. In atezo/bev therapy, focusing on early AFP changes, baseline DCP, and tumor burden of up-to-seven criteria are useful in predicting response to treatment.

Recent success of systemic therapeutic agents, including combination immunotherapy, could promote a change in the treatment strategy in patients with advanced hepatocellular carcinoma (HCC). Although hepatic arterial infusion chemotherapy (HAIC) is a treatment option for advanced HCC in Japan, it is not recommended by other guidelines. We discuss the clinical benefits of HAIC compared to sorafenib. The clinical benefits of HAIC are as follows: (1) even a patient with Child–Pugh B HCC (7 or 8 points) is a candidate for HAIC (2) Child–Pugh scores barely decline with the use of HAIC compared with sorafenib (3) HAIC is highly effective in patients with vascular invasion compared with sorafenib; and (4) survival in patients receiving HAIC may not be associated with skeletal muscle volume. In contrast, the disadvantages are problems related with the reservoir system. HAIC has clinical benefits in a subpopulation of patients without extrahepatic metastasis with Child–Pugh A HCC and vascular invasion (especially primary branch invasion or main portal vein invasion) or with Child–Pugh B HCC.

There are limited reports regarding early predictors of objective response (OR) in patients with hepatocellular carcinoma (HCC) treated with lenvatinib. This retrospective study including 70 patients aimed to investigate the efficacy of hepatic biochemical markers. Changes in tumor marker (alpha-fetoprotein (AFP)/des-gamma-carboxy prothrombin (DCP)) levels and albumin&ndash, bilirubin (ALBI) score between the baseline value and that estimated one month after treatment were evaluated. We identified several predictors of OR, including changes in tumor marker levels. The OR rate calculated using modified Response Evaluation Criteria in Solid Tumor (mRECIST) was 41.4%. Response was defined as a reduction in AFP and DCP levels of &ge, 40% from baseline. OR was significantly associated with AFP response, but not with DCP. Predictors of OR were evaluated in two groups (high-AFP group: baseline AFP &ge, 10 ng/mL, low-AFP group: remaining patients). A multivariate analysis identified AFP response (odds ratio, 51.389, p = 0.001) and ALBI score (odds ratio, 6.866, p = 0.039) as independent predictors of OR in the high-AFP and low-AFP groups, respectively. Changes in the ALBI score indicated deterioration in both responders and non-responders, with a significant difference in non-responders (p = 0.003). AFP response, baseline ALBI score, and change in the ALBI score were early predictors of OR in patients with HCC undergoing lenvatinib treatment.

Previous studies have reported prognostic factors for hepatocellular carcinoma (HCC) patients receiving lenvatinib, however, no studies have evaluated the effects of both handgrip strength and skeletal muscle mass on the clinical outcomes. Therefore, this retrospective study investigated the individual effect of handgrip strength, skeletal muscle mass, and sarcopenia on clinical outcomes of 53 HCC patients treated with lenvatinib. Before receiving lenvatinib, handgrip strength and skeletal muscle index (SMI) were measured. Low handgrip strength and muscle depletion were defined as &lt, 26 and &lt, 18 kg and SMI &lt, 42 and SMI &lt, 38 cm2/m2 in men and women, respectively. Sarcopenia was defined as having low handgrip strength and muscle depletion. Multivariate analysis identified modified albumin&ndash, bilirubin grade 1&ndash, 2a (p = 0.010), Barcelona Clinic Liver Cancer stage A&ndash, B (p = 0.011), and absence of low handgrip strength (p = 0.015) as favorable prognostic factors for survival. Furthermore, sarcopenia was an independent significant prognostic factor for survival. Time to treatment failure was associated with handgrip strength and sarcopenia. Our findings suggest that handgrip strength may be a useful marker of clinical outcomes in HCC patients treated with lenvatinib.

Patients with dermatomyositis positive for anti-aminoacyl tRNA synthetase (ARS) antibodies, also known as antisynthetase syndrome (ASS), frequently present with mechanic's hand and interstitial lung disease (ILD). We first screened the antibody profiles of 59 patients with dermatomyositis, and then examined the cutaneous, muscular and pulmonary manifestations characteristic for patients with ASS. The anti-ARS antibodies Jo-1, PL-7, PL-12, EJ and KS, along with antibodies to TIF1-γ, MDA5 and Mi-2, were examined. Among the 59 patients, 20, 21, 15 and three patients were classified into the ASS, non-ASS, myositis-specific antibody-negative and unknown groups, respectively. Five of 16 patients (31%) with ASS had six relatives with a history of collagen diseases, within the second degree of relationship, including two cases of dermatomyositis (vs the non-ASS group, P = 0.018). Patients with ASS more frequently presented with fever and arthralgia, and had elevated levels of C-reactive protein. Nine of the 11 finger lesions (82%) clinically diagnosed as mechanic's hands showed a psoriasiform tissue reaction. ILD was observed in 19 of 20 patients (95%) with ASS, and eight of 21 patients (38%) in the non-ASS group, in which six patients possessed anti-MDA5 antibody. Patients with ASS showed higher serum levels of muscle enzymes, and four of 12 patients (33%) had fasciitis-dominant myopathy, while only one of 11 patients (9%) in the non-ASS group had fasciitis-dominant myopathy. Patients with ASS often present with a psoriasiform tissue reaction in the hand lesions and fasciitis-dominant myopathy, and the relatives of those with ASS are at high risk for collagen diseases.

症例は52歳男性. 1999年著明な黄疸, 肝機能障害にて入院しB型肝炎ウイルスキャリアよりの劇症肝炎と診断された. 入院後血漿交換, 血液濾過透析などのアフェレーシス, およびステロイドの大量療法により救命に成功した. しかし, 治療終了後, ステロイドの免疫抑制によりB型肝炎ウイルスが増殖し, これによる肝炎の再燃が認められた. 肝炎の改善にはウイルス量を減らす必要があると考えB型肝炎ウイルスに対する新たな抗ウイルス薬として認可されたラミブジンを投与したところ, ウイルス量は著減し肝機能も改善がみられた. 劇症肝炎は予後が極めて不良で救命率は30%前後に過ぎないため治療的アフェレーシス, 免疫抑制療法による救命が最優先される. 救命後, 免疫抑制剤によるウイルス増殖に起因した肝炎の再燃が問題となるが, ラミブジンはこの肝炎の再燃に極めて有効であった.

火山灰土壌で覆われ,農耕地としての土地利用の割合が高い3つの小流域での浮流土砂の特徴を明らかにした.流域の表層地質の透水性が高いことから,流出率は小さいが,火山灰土壌は軽くまた固結が弱いことや凍結土壌により融雪時期に地表流が発生し,浮流土砂量が多く観測される.浮流土砂量は,既報されている流量(Q)と浮遊土砂量(Qs)の経験式,Qs=(4×10-8～6×10-6)Q2より3～4桁ほどオーダーが高い.また,融雪期では,降雨期より流水中の懸濁物質の濃度が高いことが特徴的である.浮流土砂の粒度分布をみると,農地の土壌と類似し,農地を土砂の生成起源と考えられる.浮流土砂は粒径0.1mm以下の細かいシルトを多く含み,wash loadとして流下するものが多く,河川での沈砂はわずかと考えられる.すなわち,農地から河川へ流入する前に土砂流出抑止対策を行うことが効果的である.

In 2003, we started autologous bone marrow cell infusion (ABMi) therapy for treating liver cirrhosis. ABMi therapy uses 400 mL of autologous bone marrow obtained under general anesthesia and infused mononuclear cells from the peripheral vein. The clinical study expanded and we treated liver cirrhosis induced by HCV and HBV infection and alcohol consumption. We found that the ABMi therapy was effective for cirrhosis patients and now we are treating patients with combined HIV and HCV infection and with metabolic syndrome-induced liver cirrhosis. Currently, to substantiate our findings that liver cirrhosis can be successfully treated by the ABMi therapy, we are conducting randomized multicenter clinical studies designated "Advanced medical technology B" for HCV-related liver cirrhosis in Japan. On the basis of our clinical study, we developed a proof-of-concept showing that infusion of bone marrow cells (BMCs) improved liver fibrosis and sequentially activated proliferation of hepatic progenitor cells and hepatocytes, further promoting restoration of liver functions. To treat patients with severe forms of liver cirrhosis, we continued translational research to develop less invasive therapies by using mesenchymal stem cells derived from bone marrow. We obtained a small quantity of BMCs under local anesthesia and expanded them into mesenchymal stem cells that will then be used for treating cirrhosis. In this review, we present our strategy to apply the results of our laboratory research to clinical studies. Copyright © 2014, Mary Ann Liebert, Inc.

血液透析 (HD) 患者の腎性貧血の機序を解明するため, HD導入期から全くrHuEPOの投与を必要としない症例および一時rHuEPOが投与されていたが, 貧血改善後投与中止例で, ともにヘマトクリット値 (Ht) が30%以上に維持されている患者を非投与群 (14例) とし, rHuEPO週3回HD後静注により5か月の観察期間中Htが30%以上に維持されている患者を投与群 (14例) として, 両群の比較検討を行った. その結果, 非投与群の赤血球 (RBC), ヘモグロブリン (Hb), Ht, 総鉄結合能 (TIBC), 不飽和鉄結合能 (UIBC), およびトランスフェリンは投与群に比して有意に高値を, フェリチンは有意に低値を示した. 非投与群では, フェリチンとトランスフェリンの間, フェリチンとHtの間にそれぞれ有意な負の相関を, トランスフェリンとHtの間に有意な正の相関を認めた. トランスフェリンは, HD患者の栄養状態および貧血の評価として重要である.

Defensins are widely distributed and broad-spectrum antimicrobial peptides with activities against bacteria, fungi, and enveloped viruses. Defensins have been isolated from granules of neutrophils from humans, rabbits, rats, and guinea pigs. They have also been found in lung macrophages as well as in Paneth cells of the human, rabbit, and mouse small intestine. The human β-defensin-2 was recently isolated from human skin. In this study, we detected the expression of mRNA for the defensin cryptdin in BALB/c mouse skin by means of reverse transcriptase PCR amplification. Expression was also detected in dispase-separated epidermis and cultured keratinocytes, but expression was not detected in fibroblasts. The expression of cryptdin mRNA was found to begin on embryonic day 17.5. As determined with specific primers, the cDNA sequence cloned from the skin was found to be identical to that previously reported for cryptdin-5. cDNA derived from cultured keratinocytes demonstrated the sequences of the cryptdin-6 and cryptdin-1 isoforms. In situ hybridization analysis showed that the mRNA of cryptdin was expressed in the suprabasal keratinocytes of the skin in embryonic and neonatal days and then shifted to the hair bulbs in the skin of adult mice.

Prolidase deficiency is an autosomal recessive inherited disease characterized clinically by frequent infections, mental retardation, and various skin lesions. Fundamental treatments for these manifestations have not been established. We performed adenovirus-mediated gene transfer of human prolidase cDNA into fibroblasts from patients with prolidase deficiency. Infection with the adenovirus vector carrying human prolidase cDNA increased prolidase activity in fibroblasts up to approximately 7.5 times of that of normal control fibroblasts. This indicates the feasibility of adenovirus-mediated gene therapy to treat patients with prolidase deficiency in the future.

Summary Background. Cytotoxic T lymphocytes (CTLs) have been recognized as an important effector cell in Behçet disease (BD). Granulysin is a cytolytic granule protein expressed by CTLs and natural killer cells. Aim. To evaluate the involvement of granulysin-producing T cells in the pathogenesis of BD. Methods. Using immunohistochemistry, lymphocyte subsets expressing granulysin were investigated in mucocutaneous lesions of BD. Serum granulysin levels were assayed by ELISA. Results. Granulysin-positive cells were seen in specimens from oral ulcers, genital ulcers and acne-like eruptions, but not erythema nodosum-like lesions. Both CD4+ and CD8+ T cells expressed granulysin. Serum granulysin levels did not correlate with disease activity in BD. Conclusion. Immune reactions mediated by granulysin-positive CTLs may play an important role in the pathogenesis of acne-like eruptions, oral ulcers and genital ulcers in BD.

Prolidase deficiency is an autosomal recessive disorder with highly variable symptoms, including mental retardation, skin lesions, and abnormalities of collagenous tissues. In Japanese female siblings with polypeptide negative prolidase deficiency, and with different degrees of severity of skin lesions, we noted an abnormal mRNA with skipping of 192 bp sequence corresponding to exon 14 in lymphoblastoid cells taken from these patients. Transfection and expression analyses using the mutant prolidase cDNA revealed that a mutant protein translated from the abnormal mRNA had an Mr of 49,000 and was enzymatically inactive. A 774-bp deletion, including exon 14 was noted in the prolidase gene. The deletion had termini within short, direct repeats ranging in size of 7 bp (CCACCCT). The "slipped mispairing" mechanism may predominate in the generation of the deletion at this locus. This mutation caused a 192-bp in-frame deletion of prolidase mRNA and was inherited from the consanguineous parents. The same mutation caused a different degree of clinical phenotype of prolidase deficiency in this family, therefore factor(s) not related to the PEPD gene product also contribute to development of the clinical symptoms. Identification of mutations in the PEPD gene from subjects with prolidase deficiency provides further insight into the physiological role and structure-function relationship of this biologically important enzyme.

Objectives To determine the pathogenic association of latent Epstein-Barr virus (EBV) infections with both typical hydroa vacciniforme (HV) and severe HV-like eruptions, and to survey the complications and outcomes of patients. Design Case series. Patients Twenty-nine patients with HV or severe HV-like eruptions. Interventions In situ hybridization and immunostaining of biopsy specimens; extraction of DNA samples from cutaneous lesions and/or peripheral blood mononuclear cells for EBV DNA assay. Main Outcome Measures Clinicopathologic manifestations, hematologic findings, complications, and outcomes; presence of latent EBV infection. Results T cells positive for EBV-encoded small nuclear RNA (EBER) were detected, to various degrees, in cutaneous infiltrates in 28 (97%) of 29 patients, including all 6 patients with definite HV with a positive phototest reaction, 11 of 12 patients with probable HV without evidence of photosensitivity, and all 11 patients with severe HV associated with systemic symptoms. In addition to EBER-positive T cells, many cytotoxic T lymphocytes expressing T-cell intracellular antigen 1 and granzyme B were present in the cutaneous lesions. Natural killer (NK) cells were absent or at a background level. The UV-induced cutaneous lesions showed histopathologic findings consistent with those of HV, containing many EBER-positive cells. Although no hematologic abnormalities were found in the definite and probable HV groups, the amounts of EBV DNA were increased in the peripheral blood mononuclear cells. By contrast, the severe HV group had markedly increased levels of EBV DNA associated with NK-cell lymphocytosis, and complications including chronic active EBV infection, hypersensitivity to mosquito bites, and hemophagocytic syndrome. Five patients with severe disease died of EBV-associated NK/T-cell lymphomas or hemophagocytic syndrome 2 to 14 years after onset. Conclusion Both typical and severe HV are included within the spectrum of cutaneous disorders mediated by EBV-infected T cells, and the severe HV group may have overt EBV-associated NK/T-cell lymphoproliferative disorders with a frequently fatal outcome.

Summary Background Herpetic vesicles caused by herpes simplex virus and varicella zoster virus, and hydroa vacciniforme (HV) are characterized by umbilicated vesicule formation. Objectives To understand the histogenesis of umbilicated vesicles in herpetic vesicles and HV, we demonstrated the presence of the virus-associated molecules in the lesions, and the pathogenic role of cytotoxic T-lymphocyte (CTL) immune responses. Methods Phenotyping of infiltrating cells was carried out in biopsy specimens from herpes simplex, varicella, herpes zoster and HV, and compared with nonviral contact dermatitis. Viral antigens and Epstein–Barr virus-encoded small nuclear RNA (EBER) were detected by immunostaining and by in situ hybridization, respectively. Infiltrating CTLs expressing granzyme B and granulysin were determined by double immunostaining using confocal laser scanning microscopy. Results In all herpetic vesicles, the corresponding viral antigens were observed in the cytopathic keratinocytes, and infiltration of lymphoid cells was present in the upper dermis and around the vessels. In all HV lesions studied, EBER+ T cells made up 5–10% of the dermal infiltrates and the dermal infiltrates contained almost no CD56 cells. CTLs expressing granzyme B and granulysin were present in both herpetic and HV lesions, in which they made up 10–30% of the total dermal infiltrates, whereas they comprised less than 5% of the infiltrates of biopsy specimens from nonviral contact dermatitis. Confocal laser microscopic examination demonstrated that both CD4+ and CD8+ T cells expressed granzyme B and granulysin. Conclusions CD4+ and/or CD8+ CTLs reactive to the virus-infected cells might be responsible for the histogenesis of herpetic and HV lesions characterized by umbilicated vesicles.

Defensins are cationic antimicrobial peptides with a broad spectrum. Recently human beta-defensin 2 (hBD-2) has been isolated from psoriatic skin; however, its exact localization and fate have not been fully understood. We studied the distribution pattern of hBD-2 in skin tissues of psoriasis and other inflammatory skin diseases. In the upper spinous and granular layer of psoriasis vulgaris hBD-2 was present in the cytoplasm. In the horny layer the positive signals were in a basket-weave pattern, indicating possible accumulation of hBD-2 in the intercellular space. The similar pattern of hBD-2 distribution was observed in the lesions of nummular eczema and atopic dermatitis. hBD-2 was not detected in the section of normal elbow and knee skin. When isolated psoriatic scales were stained, hBD-2 was detected in a wrapping paper-like distribution pattern surrounding the corneocytes. In horny layer of psoriatic skin hBD-2 was closely associated or colocalized with elafin, which is known to be in extracellular space, as demonstrated by double staining. Western blot analysis using cultured human keratinocytes detected hBD-2 with an expected size in the conditioned medium and in the cell lysates when stimulated with 5% FCS or IL-alpha. These results indicate that hBD-2 was synthesized and remained in cytoplasm in the upper spinous and granular layer, and then secreted into intercellular space in the horny layer. This dynamic change in hBD-2 distribution in epidermis is certainly relevant to function as an innate host defense mechanism against invading micro-organisms.

We examined the antibacterial action of several tannins on plasma coagulation by Staphylococcus aureus and the effect of conventional chemotherapy combined with tannic acid below the MIC. Coagulation was inhibited in plasma containing tannic acid (100 mg/L), gallic acid (5000 mg/L), ellagic acid (5000 mg/L), (-)-epicatechin (1500 mg/L), (-)-epicatechin gallate (500 mg/L) or (-)-epigallocatechin gallate (200 mg/L) after incubation for 24 h. All tannins inhibited coagulation at a concentration below the MIC. The MICs of oxacillin and cefdinir for S. aureus were reduced to < or = 0.06 mg/L in Mueller-Hinton agar plates with tannic acid (100 mg/L) at a concentration below the MIC. The antistaphylococcal activity of tannic acid was reduced in plates with 10% rabbit blood, but not in those with 10% rabbit plasma. Membranous structures formed in a culture medium containing equal proportions of plasma and tryptic soy broth after incubation for 24 h. The colony counts of S. aureus in membranous structures in the medium containing oxacillin (40 mg/L) and tannic acid (100 mg/L) were c. 10-fold lower than those in medium containing oxacillin (40 mg/L) alone (P < 0.01). Tannic acid merits further investigation as a possible adjuvant agent against S. aureus skin infections treated with beta-lactam antibiotics.

Dyskeratosis congenita (DKC) is an inherited disease characterized by the triad of mucosal leukoplakia, abnormal skin pigmentation and nail dystrophy, and it usually appears between the ages of 5 and 10 yr. Reports show that 19.5% of DKC patients have short stature (1). A major complication of DKC is progressive development of pancytopenia and there is also an increased incidence of malignancies. The X-linked form accounts for the majority of cases and is caused by mutations in the DKC1 gene. We report a 9 yr old boy, who presented with the triad of DKC, a mutation in the DKC1 gene and short stature, who was treated with human recombinant growth hormone (hGH). This is the first report of a DKC patient treated with hGH.