Acquired Coagulation Factor V Inhibitor That Was Successfully Treated with Oral Corticosteroid Therapy.

Acquired coagulation factor V (FV) inhibitors are rare disorders in which antibodies against FV develop under various conditions. We herein report the case of a 71-year-old woman with FV inhibitor during radiochemotherapy for pancreatic cancer. Multiple purpuras suddenly appeared on her bilateral upper limbs with prolonged coagulation data (APTT 97.3 seconds). The FV activity was less than 3% and the FV inhibitor was positive (1.7 B.U./mL). Oral prednisolone induced a rapid normalization of the coagulation data and FV activity and a rapid disappearance of FV inhibitor within 7 days. Early diagnosis and treatment may therefore be important in cases of FV inhibitor.

A Possible, Non-Invasive Method of Measuring Dynamic Lung Compliance in Patients with Interstitial Lung Disease Using Photoplethysmography.

BACKGROUND: Measuring lung compliance is useful for evaluating progression of interstitial lung disease (ILD), because reduced lung compliance due to fibrosis progression is the main cause of decreased vital capacity. However, because insertion of a balloon into the esophagus is invasive, lung compliance is rarely measured. A recently developed method uses fingertip photoplethysmography to estimate intrathoracic pressure. This method non-invasively measures lung dynamic compliance (Cdyn) by simultaneously measuring tidal volume. We evaluated the efficacy of this method in assessing ILD. METHODS: This single-center, cross-sectional, observational study evaluated the efficacy of this method in patients with ILD and healthy controls. The primary outcome was estimated Cdyn (eCdyn), as determined with this method. We also evaluated baseline characteristics that are potential confounding factors for eCdyn. RESULTS: Median eCdyn was significantly lower in the ILD group (n = 14) than in the control group (n = 49) (0.122 vs. 0.183; P = 0.011). In univariate regression analysis, eCdyn was significantly correlated with height, weight, forced vital capacity, forced expiratory volume in 1 second, diffusing capacity for carbon monoxide, and usual interstitial pneumonia. In multivariate regression analysis, weight (ß = 0.49, P = 0.011) and usual interstitial pneumonia (ß = 0.52, P = 0.007) were significantly correlated with eCdyn. CONCLUSIONS: Using photoplethysmography, we noted a significant reduction in Cdyn in patients with ILD. This novel non-invasive method is a promising tool for evaluating fibrosis progression in ILD.

Sorafenib exposure and its correlation with response and safety in advanced hepatocellular carcinoma: results from an observational retrospective study.

PURPOSE: Severe adverse events frequently occur in patients treated with sorafenib, whereas some patients have suboptimal response to sorafenib. We aimed to evaluate the association of sorafenib-induced toxicities and clinical outcomes with the pharmacokinetics of sorafenib in patients with hepatocellular carcinoma (HCC). METHODS: This was a retrospective, observational study in which 26 HCC patients who had been treated with sorafenib were enrolled between September 2010 and March 2015. The association between trough sorafenib concentration and occurrence of grade ≥ 3 toxicities was evaluated. In addition, we estimated the association of trough sorafenib concentration with overall survival (OS). RESULTS: The median sorafenib concentration was 2.91 µg/mL (range 0.74-8.8 µg/mL). Based on the receiver operating characteristic curve, the threshold value of the trough sorafenib concentration for predicting grade ≥ 3 toxicities and responder (complete response or partial response at best response, or stable disease for ≥ 3 months) was 3.45 µg/mL [area under the curve (AUC) 0.74, 95% confidence interval (CI) 0.54-0.93; p <0.05] and 1.40 µg/mL (AUC 0.97, 95% CI 0.97-1.00; p <0.05), respectively. OS of patients with sorafenib 1.40-3.45 µg/mL had a tendency to be longer than those of patients administered < 1.40 µg/mL and ≥ 3.45 µg/mL [median 17.8 months (1.40-3.45 µg/mL) vs. 5.3 months (< 1.40 µg/mL) and 9.5 months (≥ 3.45 µg/mL)]. CONCLUSIONS: From results of this study, we proposed that the target range of sorafenib may be a trough concentration of 1.40-3.45 µg/mL in patients with HCC.

Two cases of benign hepatic nodules caused by sinusoidal dilatation with different hemodynamics.

We describe two cases of benign nodules caused by sinusoidal dilatation with different hemodynamic statuses. Case 1 was a 50-year-old woman with a 1-cm nodule that showed a low density in the arterial phase of computed tomography. Pathologically, there were no atypical cells with sinusoidal dilatation, and immunostaining was negative for CD34. We speculated that sinusoidal dilatation was caused by congestion due to loss of frequency of the central vein. In contrast, case 2 was a 50-year-old woman with a 1.5-cm nodule that was highly stained in the arterial phase of computed tomography. Although she had a sinusoidal dilatation similar to that in case 1, immunostaining was positive for CD34. Sinusoidal dilatation was thought to be caused by hyperperfusion of arterial blood. Moreover, CD34 may be potentially useful for the differentiation of the hemodynamic status.

Interval between hepatocellular carcinoma treatment and interferon-free direct-acting antiviral agents against hepatitis C is necessary to suppress tumor recurrence.

Interferon (IFN) has been identified to suppress carcinogenesis when used for treating hepatitis C virus (HCV) infections. Treatment with IFN-free direct-acting antiviral agents (DAAs) is an acceptable alternative, even in elderly patients or patients who have been treated for hepatocellular carcinoma (HCC), because it has a lower incidence of side effects and higher sustained virological response (SVR) rate compared with IFN treatment. However, the suppression of carcinogenesis by DAAs is unclear. In the present study, 19 patients who underwent DAA treatment following treatment for HCC between January 2015 and March 2017 were retrospectively investigated. The clinical data were compared between 9 patients with HCC recurrence following DAA treatment (recurrence group) and 10 patients without HCC recurrence (no-recurrence group). The 1-year cumulative recurrence rate of HCC following SVR was as high as 50.2%. Age and sex did not significantly differ between the two groups, and the average number of HCC treatments prior to DAA treatment was also not significantly different between the recurrence and no-recurrence groups (3.2 and 2.2, respectively). The median interval between the final HCC treatment and the commencement of DAA treatment was 88 days in the recurrence group, which was significantly less compared with 790 days in the no-recurrence group (P=0.018). An interval of 120 days or more from final HCC treatment to the commencement of DAA treatment was a significant independent factor of no HCC recurrence following DAA treatment (P=0.028). A high HCC recurrence rate was identified following DAA treatment in patients with a history of HCC treatment. Therefore, there should be at least a 4-month interval from the final HCC treatment to the commencement of DAA treatment to ensure no HCC recurrence.

[Cases of Three Patients with Gastric Cancer and Metastasis to the Skeletal Muscle].

Metastasis to the skeletal muscle from gastric cancer is relatively rare. We report cases of 3 patients undergoing chemotherapy for gastric cancer with metastasis to the skeletal muscle. Case 1: A man in his 70s was diagnosed with advanced gastric cancer (cT4N3M1P0, stage IV), with metastasis to the lung, brain, lymph node, and iliopsoas muscle. Case 2: A man in his 60s was diagnosed with advanced gastric cancer (cT3N3M1P0, stage IV), with metastasis to the brain, lung, lymph node, and iliopsoas muscle. Case 3: A man in his 50s was diagnosed with advanced gastric cancer (cT4N3M1P0, stage IV), with metastasis to the urinary duct, lymph node, back muscle, and iliopsoas muscle. All 3 patients died within 7-8 months after the diagnosis due to progressive disease despite chemotherapy. The prognosis of these 3 patients was significantly poorer than that of patients in our hospital with metastasis not involving the skeletal muscle (p<0.01). Accordingly, metastasis to the skeletal muscle may be an adverse prognostic factor in gastric cancer.

MHC class I-related chain B gene polymorphism is associated with virological response to pegylated interferon plus ribavirin therapy in patients with chronic hepatitis C infection.

The outcome of antiviral therapy is associated with viral and host factors. In the present study, the association between MHC class I-related chain B (MICB) genotypes and therapeutic response to pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy was investigated in hepatitis C virus (HCV)-infected patients. In total, 107 patients with chronic HCV infection (74 with HCV serotype 1 and 33 with serotype 2) were enrolled. Genotyping of MICB single-nucleotide polymorphism (SNP) rs3828913 and interleukin-28B (IL28B) SNP rs8099917 was performed using TaqMan® SNP genotyping assays. The genotype distribution of the MICB alleles was: CC, 79.4%; CA, 17.8%; and AA, 2.8%. Sustained virological response (SVR) was achieved by 55.1% (59/107) of the HCV patients. The SVR rate of patients with MICB major (CC) alleles was 62.3% and this rate was significantly higher than that of the patients with MICB minor (CA and AA) alleles (27.2%) (P=0.0068). A multivariate logistic model showed that the MICB major genotype was an independent factor contributing to SVR (OR, 4.47; 95% CI, 1.46-13.70; P=0.009). In addition, the MICB genotype was identified as the sole independent factor contributing to SVR and non-virological response in HCV serotype 1 patients with the IL28B major genotype. In HCV serotype 2 patients, the MICB genotype was the sole significant factor contributing to SVR (OR, 30.68; 95% CI, 2.72-346.3; P=0.006). In conclusion, the MICB genotype is a strong predictive factor for virological response to PEG-IFN/RBV therapy in HCV patients.

Polymorphisms of the Niemann-Pick C1-like 1 gene in a Japanese population.

The Niemann-Pick C1 like 1 (NPC1L1) protein is a polytopic transmembrane protein responsible for dietary cholesterol absorption. Genetic variation in the NPC1L1 gene affects cholesterol absorption and serum cholesterol levels. However, NCP1L1 genotypes have not previously been invesigated. In this study, genotyping of the NPC1L1 gene was examined in healthy individuals as well as patients with hepatitis C virus (HCV) and inflammatory bowel disease (IBD). A total of 541 individuals were enrolled in the study, including 80 patients with HCV hepatitis, 205 with ulcerative colitis (UC) and 127 with Crohn's disease (CD). Genotyping was performed using TaqMan® SNP assays. Minor allelic frequencies of the 17345C>G (rs2072183) and 19031G>A (rs4720470) SNPs were found to be 0.40 and 0.30, respectively. No significant differences were detected in serum HCV levels in the 1735C>G or 19031G>A SNPs. The 1735C>G SNPs were not associated with total cholesterol (TC) levels in the healthy controls and/or HCV patients. However, statistically significant associations between the 1735GG variant and TC levels were detected in CD patients, with 1735GG carriers having the highest TC levels compared to the 1735CC and 1735CG carriers (P=0.048). Similar trends were noted in UC patients, but did not reach statistical significance (P= 0.19). The 19031G>A SNPs were not associated with TC levels in the healthy controls or patients. This study showed the allelic and genotypic distribution of 1735C>G and 19031G>ASNPs of the NPC1L1 gene in a large number of subjects. The NPC1L1 1735GG variant may therefore be favorable for CD accompanied with malnutrition.

Interleukin-28B genotypes determine response to pegylated-interferon plus ribavirin therapy in patients with hepatitis C virus infection.

We recently reported that the interleukin (IL)-28B major genotype is a predictor of early suppression of the hepatitis C virus (HCV) at 12 weeks in response to pegylated interferon (PEG-IFN) plus ribavirin (RBV) therapy. The present study investigated the relationship between IL-28 genotypes and the virological response to PEG-IFN/RBV therapy at 24 and 48 weeks. Genotypes of the IL-28B rs8099917 T>G single nucleotide polymorphism were determined in 177 patients with HCV infection. Among them, 56 patients with HCV1 infection were treated with PEG-IFN/RBV. The frequency of the IL-28B major allele (TT) was 73.8% in patients with HCV serotype 1 and 86.3% in patients with HCV serotype 2. The rate of HCV-RNA positivity was significantly lower at 48 weeks in patients with the IL-28B major allele compared to patients with the IL-28B minor allele (TG or GG). The rate of HCV-RNA positivity at 24 weeks tended to be lower in patients with the IL-28B major allele, but there was no statistical significance (P=0.059). The sustained virological response (SVR) rate was 45.9% in patients with the IL-28B major allele, but 13.3% in patients with the IL-28B minor allele. The SVR correlated with the IL-28B major allele (OR=7.13, P=0.010), early virological response (OR=33.3, P=0.008), HCV-RNA ≤ 6.3 log IU/ml (OR=81.2, P=0.009) and γ-GTP ≤ 47 IU/l (OR=49.4, P=0.027). The IL-28B genotype is a significant pre-treatment predictor of the response to PEG-IFN/RBV therapy at 48 weeks in patients with HCV infection.

Polymorphism of the inosine triphosphate pyrophosphatase gene predicts ribavirin-induced anemia in chronic hepatitis C patients.

Ribavirin (RBV)-induced anemia is a serious side effect of pegylated interferon (PEG-IFN) plus RBV therapy which is the standard care most effective for hepatitis C virus (HCV) infection. In the present study, we investigated the association of inosine triphosphate pyrophosphatase (ITPA) genotypes with RBV-induced hemoglobin (Hb) reduction in HCV patients treated with PEG-IFN/RBV therapy. The genotypes of the ITPA rs1127354 single nucleotide polymorphism were determined in 179 patients with HCV infection. Among them, 52 patients were treated with PEG-IFN/RBV. The frequency of the ITPA major allele (CC) was 76.3% and that of the minor allele (CA and AA) was 23.7%. A rapid decrease in Hb levels during the initial 4 weeks was observed in patients with the ITPA major allele (CC), but not in patients with the ITPA minor allele (C/A and AA). Hb levels at 4 weeks were significantly lower in patients with the ITPA major allele than the levels in patients with the minor allele. Out of the 41 patients, 6 (14.6%) with ITPA major allele had Hb levels <10 g/dl and 11 patients (26.8%) had a decline in Hb of >3 g/dl. None of the patients with the ITPA minor allele had such data. There were no significant differences in virological responses of HCV-RNA between patients with the ITPA major allele and those with the minor allele. In conclusion, the ITPA genotypes may be a useful marker for prediction of RBV-induced anemia.

A new isoform of interleukin-32 suppresses IL-8 mRNA expression in the intestinal epithelial cell line HT-29.

Interleukin (IL)-32 plays a role in the pathophysiology of inflammatory bowel disease (IBD). We isolated a new isoform of the IL-32 transcript in the process of cloning the full-length IL-32 gene from human colonic subepithelial myofibroblasts (SEMFs). The expression of mRNA in the samples was assessed by RT-PCR and real-time PCR analyses. The PCR products from the IL-32 genes were ligated into the expression vector pIRESneo2. The new isoform of the IL-32 transcript (336 nucleotides) completely lacked exon 4 of the IL-32γ gene, and was 60 bp shorter than IL-32α. TNF-α induced the mRNA expression of the new IL-32 isoform in a dose- and time-dependent manner. Stable transfection of this new isoform significantly decreased TNF-α-induced IL-8 mRNA expression in HT-29 cells, but the expression of the IL-32α gene had no effect. The mRNA expression of this new isoform was significantly elevated in the inflamed mucosa of IBD patients. A new isoform of the IL-32 transcript may play an anti-inflammatory role in the inflamed mucosa of IBD.

Interleukin-28B polymorphisms are associated with an early viral response in patients receiving hepatitis C therapy.

Prediction of the efficacy of pegylated interferon (PEG-IFN) plus ribavirin (RBV) therapy against hepatitis C (HCV) infection is valuable for determining its applications. This study investigated the relationship between the early response of HCV to PEG-IFN/RBV therapy and the inter-leukin (IL)-28B genetic polymorphism in patients with HCV infection. The genotypes of IL-28B rs8099917 T>G single nucleotide polymorphism were determined in 144 patients with HCV infection. Among them, 59 were treated with PEG-IFN/RBV. The frequency of IL-28B TT homozygosity was 75.2% in patients with HCV serotype 1 and 84.6% in patients with serotype 2. Multivariate analysis showed that IL-28B TT homozygosity (P=0.014) and the platelets number (P=0.030) was associated with the early suppression of HCV-RNA at 12 weeks after the start of PEG-IFN/RBV therapy. The IL-28B polymorphism was a significant pre-treatment predictor of the response to PEG-IFN/RBV therapy in patients with HCV infection.

Accuracy of genotyping using the TaqMan PCR assay for single nucleotide polymorphisms responsible for thiopurine sensitivity in Japanese patients with inflammatory bowel disease.

Thiopurine drugs are the most common drugs used to maintain clinical remission in inflammatory bowel disease (IBD). Three single-nucleotide polymorphisms (SNPs), TPMT A719G (rs1142345), inosine triphosphate pyrophosphatase (ITPase) C94A (rs1127354) and multidrug resistance protein 4 MRP4 G2269A (rs3765534), have been reported to account for heightened sensitivity to thiopurine drugs in the Japanese population. We investigated the usefulness of the TaqMan(®) PCR assay (Applied Biosystems) for the rapid detection of these SNPs to improve the safety of thiopurine therapy. We enrolled 44 healthy volunteers and 235 IBD patients. Genotyping of the SNPs was performed using Custom TaqMan SNP genotyping assays, direct sequencing and PCR-RFLP. Genotyping for MRP4 G2269A by the TaqMan PCR assay was successfully achieved in all samples. Comparison with our previous data using direct sequencing indicated one discordant result, and re-sequencing showed that the TaqMan PCR assay was correct. The overall accuracy of the TaqMan assay for MRP4 G2269A was 100%. The TaqMan PCR genotyping for TPMT A719G and ITPase C94A was successfully performed in all samples. The results of TPMT A719G by the TaqMan assay were identical with those of PCR-RFLP. In ITPase C94A, a comparison of the TaqMan assay and PCR-RFLP yielded 12 discordant results, and direct sequencing showed that the TaqMan PCR assay was correct. The allelic frequency determined by the TaqMan assay was 0.145 for MRP4 G2269A, 0.009 for TPMT A719G and 0.121 for ITPase C94A, respectively. In conclusion, the TaqMan(®) PCR assay is useful for genotyping of SNPs responsible for thiopurine sensitivity in Japanese IBD patients.

Acute cytomegalovirus infection superimposed on corticosteroid-naïve ulcerative colitis.

Most cases of cytomegalovirus (CMV) colitis that develop in patients with inflammatory bowel disease (IBD) are caused by a reactivation of a latent virus; acute CMV infections are rare. Treatment with immunosuppressive agents further increases the infection risk. Here, we present a 32-year-old man with acute CMV-mononucleosis and colitis, superimposed on corticosteroid-naïve ulcerative colitis (UC). The diagnosis was confirmed by a viral-like prodrome, positive CMV antigenemia (C7-HRP), a positive CMV IgM titer, the presence of atypical lymphocytes, mild transaminase elevation, and immunohistological detection of CMV positive cells in his colonic mucosa. Gancyclovir was intravenously administered, and all symptoms were improved.