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Atezolizumab; Isatuximab; Solid tumors Atezolizumab; Isatuximab; Tumores sólidos Atezolizumab; Isatuximab; Tumors sòlids Background The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Patients and methods Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon’s two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Results Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Conclusions Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients. This work was sponsored by Sanofi (no grant number).

This case–control study was aimed to assess the effect of genetic variants of tumor necrosis factor (TNF) α−308 and lymphotoxin (LT) α+252 on development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Their gene–gene interaction was also investigated. We enrolled 200 pairs of age- and sex-matched patients with cirrhotic HBV-HCC and unrelated patients with HBV-cirrhosis alone. Polymorphisms of TNFα −308 and LTα +252 were genotyped. Synergy index was used to calculate interaction between the variant genotypes. The results indicated that the frequency distribution of the variant genotypes ( TNFα −308 G/A and LTα +252 G/G) in patients with HCC were significantly higher than those in patients with cirrhosis alone. Multivariate analysis indicated that TNFα −308 G/A (odds ratio [OR], 2.34) and LTα +252 G/G (OR, 2.04) were independent risk factors for HCC. By the clinical characteristics of study population, multivariate analysis demonstrated that independent factors associated with harboring the variant genotypes included cirrhosis with Child-Pugh C (OR = 6.47 in cases and OR = 11.56 in controls) and thrombocytopenia (OR = 8.86 in cases and OR = 7.74 in controls). Calculation of synergy index (SI) indicated that there are additive interaction between TNFα −308 G/A and LTα +252 G/G on risk of HCC (SI = 1.29). In conclusion: There are independent and additive interactions between TNFα −308 G/A and LTα +252 G/G on risk for HBV-HCC. They correlated with advanced hepatic fibrosis and severe liver damage, which might contribute to a higher risk for HCC.

Objective To explore the characteristics of individuals with mental disorders suspected of road traffic offences and to find their differences from normal offenders, in order to regulate mental disorder patients' driving activities and prevent road traffic offences. Methods One hundred and twenty-three cases of forensic psychiatry testimony of individuals suspected of road traffic offences between 2014 and 2019 from the West China Forensic Center of Sichuan Province were collected. Fisher exact probability test was used to compare the differences between offenders with mental disorders and without mental disorders in terms of demographic characteristics, criminological characteristics, psychiatric characteristics and criminal responsibilities. Results There was no statistical significance in the differences of demographic characteristics, vehicles and kinds of alcohol between the two groups （123例涉嫌道路交通犯罪的司法精神病学鉴定案例分析.目的 探究精神障碍者涉嫌道路交通犯罪的特点及其与正常人群的差异，为规范精神障碍者的驾驶活动及预防其违法犯罪提供帮助。 方法 选取四川华西法医学鉴定中心2014—2019年涉嫌道路交通犯罪的司法精神病学鉴定案例共123例，采用Fisher确切概率法比较精神障碍组与无精神病组在人口学特征、犯罪学特征、精神病学特征及刑事责任能力等方面的差异。 结果 两组在人口学特征、交通工具及饮酒类别上差异无统计学意义（司法精神病学；事故，交通；驾驶能力；精神障碍；刑事责任能力；案例分析.

This case–control study aimed to assess the interactive effect between polymorphisms of lymphotoxin (LT) α +252 and habitual substance use on risk of hepatocellular carcinoma (HCC). We enrolled 150 pairs of sex- and age-matched HCC patients and unrelated healthy controls. LTα genotypes were detected with polymerase-chain reaction and restrictive fragment length polymorphisms. Information about habits of substance use was obtained through personal interview. Multivariate analysis indicated that LTα +252 G/G genotypes [odds ratio (OR) = 3.36], Hepatitis B surface antigen (OR = 16.68), antibodies to hepatitis C virus (OR = 34.88) and having at least two habits of substance use (OR = 2.50) were independent risk factors for HCC. There were additive interactions among LTα +252 G/G genotype, chronic viral hepatitis, and habit of each substance use. In conclusion: There are independent and additive interactions between LTα +252 G/G genotype, chronic viral hepatitis, and habits of substance use on risk of HCC.

Summary Background Peginterferon-α–based therapy frequently leads to neutropenia. It remains unclear whether neutropenia is associated with bacterial infection in chronic hepatitis C (CHC). Aim To evaluate the risk of bacterial infection and neutropenia in patients with CHC treated with peginterferon-α/ribavirin. Methods In all, 207 patients with CHC with (group A, n = 30) and without (group B, n = 177) baseline neutropenia were treated with peginterferon-α/ribavirin. Results Group A had significantly higher rates of moderate (

To evaluate the diagnostic application of serum insulin-like growth factor-II (IGF-II) and alpha-fetoprotein (AFP) levels in hepatocellular carcinoma (HCC), IGF-II and AFP were determined in 100 cirrhotic patients with HCC, 100 sex- and age-matched patients with cirrhosis alone and 50 healthy controls. The results indicated that IGF-II and AFP levels in patients with HCC were higher than in those with cirrhosis alone (p = 0.0001). There is an inverse correlation between IGF-II and (log)AFP (r = -0.410, p = 0.0001) in patients with HCC. Multivariate analysis indicated that IGF-II and AFP were closely associated, in a dose-related fashion, with the presence of HCC. Receiver operating characteristic curves were used to determine the optimal cutoff values of IGF-II (4.5 mg/g prealbumin) and AFP (100 ng/ml), respectively. Both IGF-II and AFP show a high specificity and positive likelihood ratio. The sensitivity was 42.0% for IGF-II and 73.0% for AFP. Determination of both markers in parallel significantly increased the diagnostic accuracy (96.5%) and sensitivity (97.9%), with a high specificity (95.1%) and positive likelihood ratio (19.9). In conclusion, IGF-II and AFP may be used as complementary tumor markers to discriminate HCC from cirrhosis.

In 1979, a mass poisoning of more than 2000 people occurred in central Taiwan due to consumption of rice-bran oil contaminated with PCBs and their heat-degraded byproducts. The incident was later referred to as Yucheng (oil disease). Serum samples from 56 women with the 1979 exposure were collected in February 1992 and analyzed for their contaminant content using sample enrichment and isotope dilution mass spectrometry. In most of the samples, levels of PCDFs and PCBs were detectable, and the median values of 2,3,4,7,8-PCDFs and 1,2,3,4,7,8-PCDFs were 1,030 and 2,220 ng/kg serum lipid, respectively. The median level of the total PCBs on a whole weight basis was 8,730 ng/kg. The PCB/PCDF concentrations in Yucheng women 14 years after the toxic exposure were still one to two orders of magnitude higher than controls. Concentrations of PCB levels in 1992 were positively correlated with the 1980-1981 measured PCB levels in these women and both PCBs and PCDFs were negatively correlated with the total duration when these women breast fed their children between 1979 and 1992. It is concluded that serum levels of congener-specific PCBs/PCDFs in exposed women are good indicators of previous exposure and may provide important information for more reliable estimation of dose-response relationship.

This case–control study aimed to evaluate the diagnostic application of urinary transforming growth factor (TGF) α and serum α-fetoprotein (AFP) in hepatocellular carcinoma (HCC). TGFα and AFP were determined in 90 pairs of age- and gender-matched patients with cirrhotic HCC and patients with cirrhosis alone and 60 healthy controls. The results indicated that TGFα and AFP levels in patients with HCC were higher than in those with cirrhosis alone or healthy controls (each P = 0.0001). Multivariate analysis indicated that TGFα (odds ratio (OR) 1.03, 95 % confidence interval (CI) 1.05–1.16) and AFP (OR 1.03, 95 % CI 1.01–1.06) were closely associated, in a dose-related fashion, with the development of HCC. The optimal cutoff values, determined with the receiver operating characteristic (ROC) curves, were 29 μg/g creatinine for TGFα and 100 ng/ml for AFP, respectively. The areas under ROC curve (AUC) were 0.74 for TGFα and 0.78 for AFP, respectively. Both biomarkers showed the same sensitivity (52.2 %), high specificity, high positive predictive value, and moderate positive likelihood ratio. Determination of both markers in parallel significantly increased the AUC (0.91) and diagnostic accuracy (92.2 %), with a high sensitivity (86.7 %), specificity (97.8 %), positive predictive value (PPV; 97.5 %), and moderate positive likelihood ratio (PLR; 39.4). Among 31 cirrhotic HCC with AFP ≤ 20 ng/ml, the calculated AUC for TGFα was 0.79, with a sensitivity of 64.5 %, specificity of 96.7 %, PPV of 87.0 %, and PLR of 19.5. In conclusion, urinary TGFα and serum AFP are complementary tumor markers for detection of HCC with low AFP production.

The long-term benefits of interferon-based therapy on preventing cirrhosis at non-cirrhotic stage in chronic hepatitis C patients are not fully clarified.To evaluate the effectiveness of interferon-based therapy regarding to cirrhosis prevention in non-cirrhotic chronic hepatitis C patients.A total of 1386 biopsy-proven, non-cirrhotic chronic hepatitis C patients (892 received interferon-based therapy and 494 untreated) were enrolled.Fifty-six untreated and 51 treated (24 sustained virologic responders and 27 non-responders) patients developed cirrhosis during a mean follow-up period of 5.0 (1-16) and 5.1 (1-15.3) years, respectively. The annual incidences of cirrhosis in untreated and treated groups were 2.26 and 1.11% (non-responders: 1.99%, sustained responders: 0.74%), respectively. The 15-year cumulative incidence of cirrhosis was significantly lower in treated (9.9%) than untreated patients (39.8%, P = 0.0008, log-rank test). The 14.5-year cumulative incidence of cirrhosis was significantly lower in sustained responders (4.8%) compared with non-responders (21.6%, P = 0.0007) and untreated patients (36.6%, P0.0001). The difference was not significant between non-responders and untreated controls. Cox proportional hazards regression showed sustained virologic responders and younger age were independent negative factors for cirrhosis development.A sustained virologic response secondary to IFN-based therapy could reduce cirrhosis development in chronic hepatitis C patients.

To determine the hepatitis C virus (HCV) genotype distribution in Taiwan and to clarify the relationship between genotype and the pathogenesis of HCV infection, 1,164 subjects positive for serum HCV antibodies and HCV RNA from three HCV hyperendemic areas (Masago, Tzukuan, and Taoyuan) and a tertiary referral center in Taiwan were studied during 1995-1997. HCV genotypes and viral loads were determined using Okamoto's method and branched DNA assay, respectively. Genotype 1b was the most prevalent in Tzukuan (61.9%), Taoyuan (76.9%), and the referral center (47.0%). By contrast, genotype 2a was the major HCV type in Masago (63.5%). Prevalence of genotype 1b positively and that of genotype 2a negatively correlated to age, regardless of study populations (P0.01). Based on multivariate analysis, the significant factors associated with the presence of cirrhosis, with or without hepatocellular carcinoma, in chronic hepatitis C patients were genotype 1b and age. In conclusion, these results underline that independent HCV outbreaks continue in HCV hyperendemic areas in Taiwan, concomitant with a changing relative prevalence of HCV genotypes in relation to age. Both the correlation of genotype 1b with age (cohort effect) and intrinsic properties of HCV genotypes are probably responsible for the association between genotype and the pathogenesis of HCV infection.

TT virus (TTV) is a newly isolated DNA virus from the serum of a patient with posttransfusion hepatitis of unknown etiology in 1997. To evaluate the clinical and molecular characteristics of TT virus (TTV) in a hepatitis C virus (HCV) and B (HBV) hyperendemic area (Masago), 200 residents were enrolled in the study. The sera were tested for alanine aminotransferase (ALT), HCV RNA and GB virus C/Hepatitis G virus (HGV) RNA, TTV DNA, HBsAg, anti-HCV and antibodies to HGV E2-protein (anti-E2). TTV DNA was positive in 99 of the 200 sera with a prevalence rate of 49.5%. The prevalence of HBsAg, anti-HCV, HCV RNA, HGV RNA, anti-E2 and HGV exposure (defined as positive for serum HGV RNA and/or anti-E2) was 38.9%, 69.5%, 64.5%, 17.0%, 25.5% and 39.5%, respectively. Neither clinical nor virological factors were associated with TTV viremia. The rate of ALT abnormality was significantly elevated in HCV RNA-positive (34.9%) than -negative (7.0%) residents (p0.001). HCV viremia was the only factor significantly associated with ALT elevation by multiple logistic regression (odds ratio: 6.96; 95% C.I.: 2.60-18.7). We concluded that in this HCV/HBV hyperendemic area, the prevalence of TTV DNA was high. No significant clinical factor was observed to be associated with TTV infection. TTV infection is not related to abnormal ALT levels and ALT abnormality was mainly attributable to HCV but not TTV, HBV or HGV infection.

This paper presents a SAS macro for a simulation study of comparing a new variant of hot-deck imputation with mean imputation for missing values, in which a simple algorithm proposed by Bebbington (Applied Statistics, 1975) for carrying out simple random sampling without replacement was employed to draw repeated random samples efficiently. A simulated example of drawing repeated random samples from a regional survey of obesity in school children was used to demonstrate the SAS macro.

In the analysis of complex survey data such as stratified multi-stage cluster samples, ignoring the design effects such as clustering and stratification usually will lead to erroneous conclusions. In this paper, we will demonstrate the consequences in the estimation of means and proportions by two examples from a stratified two-stage cluster sample. A brief review of methodology will be presented, and some suggestions on computational issues will be provided.

In 1979, a mass poisoning involving some 2,000 persons occurred in central Taiwan from cooking oil contaminated by polychlorinated biphenyls (PCBs) and their heat-degraded byproducts, including polychlorinated dibenzofurans (PCDFs). The responsible health department registered cases for clinical purposes between 1979 and 1983. The exposed persons are referred to as the "yucheng" (oil disease) cohort. PCBs and PCDFs are toxic chemicals widely dispersed in the environment and in human tissue, which persist long after exposure. The consequences of exposure to these agents are not well understood. We traced the cohort through December 31, 1991, and compared overall and cause-specific mortality of 1,837 "yucheng" subjects with age, gender, and calendar time-specific mortality rates for the Taiwan general population. Eighty-three deaths were identified from 23,404 observed person-years. Even though the overall standardized mortality ratio (SMR) was 0.8 (95% confidence interval (CI) 0.7-1.0), there was a substantial elevation in the mortality rate for chronic liver disease and cirrhosis (10 deaths, SMR = 2.7, 95% CI = 1.3-4.9). Mortality from malignant neoplasms and other causes was not significantly different from that of the Taiwan population. PCB/PCDF exposure appears to promote the development of severe liver disease, perhaps in combination with known risk factors such as infection with hepatitis B virus. Further follow-up of this young cohort is necessary to see if the consequences include hepatic cancer.

To investigate the genotype distribution of hepatitis C virus (HCV) in southern Taiwan, the sera from 56 patients with chronic HCV infection were studied. Twenty-nine patients were men and 27 were women. Age ranged from 22 to 65 years (mean, 47.3 +/- 11.4). Eighteen of them had chronic persistent hepatitis, 27 had chronic active hepatitis, and 11 had liver cirrhosis. HCV RNA was detected by reverse transcription-nested polymerase chain reaction using primers derived from the 5'-noncoding region. The genotypes of HCV were determined by amplification of the core region with the type-specific primers as described by Okamoto et al.. All sera were positive for HCV RNA. The prevalence rates of genotypes were as follows: 1b/II, 44.6%(25/56); 2a/III, 41.1%(23/56); 2b/IV, 3.6%(2/56); mixed 1b/I + 2a/III, 5.4%(3/56): mixed 1b/II + 2b/IV, 1.8%(1/56) and type unclassified 3.6%(2/56). The distribution of genotypes was not related to the patients' age, sex, and histological changes. Nevertheless, patients having past history of blood transfusion had a significantly higher rate of HCV type 2a/III infection (72.2% versus 34.2%, p.05, chi-square test). We concluded that both of the HCV genotypes 1 b/II and 2a/III are predominant types in southern Taiwan and regional HCV genotype distribution may differ even within this island. Selective transmission of specific genotypes may pass along different infectious routes.

Interferon alpha (IFN-alpha) has been indicated to be dramatically effective in some but not all patients with chronic hepatitis C virus (HCV) infection. We investigated prospectively 27 patients of chronic hepatitis C, 12 females and 15 males, treated with IFN-alpha for a better regimen of the therapy and for any effective predictor of response to the treatment. All patients were treated with 3 to 6 million units (MU) of recombinant IFN-alpha 2b (n = 15) or lymphoblastoid IFN-alpha (n = 12) given 3 times weekly for 12 to 36 weeks. Patients with normal alanine aminotransferase (ALT) value during therapy, who sustained this response throughout 6 months follow-up after treatment was completed, were grouped into the complete responders. Patients with normal ALT value during therapy but who relapsed after treatment completed, were grouped as partial responders. Non-responders were defined as patients without normal ALT value during therapy. The rates of complete response, partial response, and non-response were 29.6%, 40.8%, and 29.6%, respectively. The degree of response to IFN-alpha therapy was not related to age, sex, type of IFN-alpha, history of blood transfusion, the state of liver pathology, or pretreatment level of ALT value. The complete responsive rate to IFN-alpha was higher in patients treated with total dose above 215 MU [38.1% (8/21) vs. 0% (0/6), p = 0.06], in patients treated for at least 24 weeks [40% (8/20) vs. 0% (0/7), p0.05], and in patients with non-genotype 1b/II HCV infection [40% (8/20) vs. 0% (0/7), p0.05]. We concluded that IFN-alpha was effective in the treatment of chronic HCV infection, particularly in those other than HCV genotype 1b/II. A high-dose, and long-duration regimen may be recommended for better response of chronic hepatitis C to IFN-alpha therapy.

To elucidate the status of serum hepatitis B virus (HBV) DNA in HBsAg-positive hepatocellular carcinoma (HCC), 100 type B chronic liver disease (CLD) patients and 19 HCC patients were studied. The positive rate of serum HBV DNA in HBeAg-positive CLD patients was significantly higher than that in HBeAg-negative CLD patients, and the correlation between the presence of serum HBV DNA and patients' age showed a negative trend. In contrast, the positive rates of serum HBV DNA in HCC patients were not related to the status of HBeAg and age, and the positive rate of serum HBV DNA in HBeAg-negative HCC patients was significantly higher than that in HBeAg-negative CLD patients. Nevertheless, the serum concentrations of HBV DNA in HCC patients were significantly lower than those in CLD patients. These results suggest that replication of HBV in HCC patients might differ from that in CLD patients, and that persistent low-level HBV replication might be related to the presence of HCC.

Necrotizing fasciitis is a rare and rapid progression soft tissue infection. The only identifiable feature is tissue necrosis along a single fascia plane. Because the skin is initially spared, it is difficult for early recognition prior to extensive tissue destruction. Ultrasonography was used for early diagnosis of this infection in five cases. All 5 patients presented with severe cellulitis. Under the suspicion of necrotizing fasciitis, ultrasonography was performed before surgical debridement. Tissue biopsy was done for histological confirmation of the diagnosis. Three patients were proven to have necrotizing fasciitis and two cellulitis only. The ultrasonographic findings of necrotizing fasciitis included: 1) irregularity of the fascia; 2) abnormal fluid collections along the fascia plane; and 3) diffuse thickening of the fascia when compared with the control site in the normal limb. However, in severe infectious cellulitis, the above mentioned findings were not observed. Our results indicate the usefulness of the ultrasonography for early diagnosis of necrotizing fasciitis.

Neutrophils (PMN) from 20 patients with atopic disease (atopy), the parents of 8 of the patients and 10 normal controls were studied by light-microscopic cytochemistry. The results revealed that myeloperoxidase (MPO) and acid phosphatase (ACP) activities in PMN in all cases significantly decreased and alkaline phosphatase activity was normal. Parents or parent of 7 of those patients had PMN enzyme deficiency similar to that of the patients. The results indicated that a primary combined and partial deficiency of MPO and ACP in PMN azurophilic granule existed in atopy. It is postulated that the deficiency led to reduction of PMN bactericidal power and delay of bactericidal action. Foreign bodies which were partially degraded could possess antigenic property. This is believed to be the important cytobiological mechanism of the tendency toward infections and formation of sensitive antigen in atopy.

The neutrophils in 2 patients with atopic disease were studied. Ultrastructurally, a number of abnormal azurophilic granules (AG) with low electron-density (Case 1) and secondary lysosomes with "myelinoid membranes" figures (Case 2) were found. Myeloperoxidase (MPO) and acid phosphatase activity were detected by light cytochemical techniques, and showed significantly low values. The deficiency of MPO and abnormal distribution of AG were also demonstrated by electron microscopic cytochemical technique. The neutrophils from the parents revealed changes similar to the patients. This study suggests that since genetic partial deficiency of neutrophil AG enzymes existed, the phagocytosed substances were only partially degraded, leading to accumulation of substances with antigenicity, and became trigger event of atopic disease.

To investigate the effect of obesity at diagnosis on prognosis of renal cell carcinoma, 360 renal cell carcinoma patients newly diagnosed at 29 hospitals in Oklahoma between January 1, 1981 and December 31, 1984 were followed through December 31, 1987. The Cox proportional-hazard model was used to estimate the hazard ratio, adjusting for other potentially prognostic factors. Both the disease-free interval and the overall survival were longer in patients who were obese (greater than or equal to 120% standard body mass index) at diagnosis. The adjusted-hazard ratio for disease recurrence between obese and nonobese patients was 0.43 (95% confidence interval [CI], 0.19 to 0.98). The obese patients had an adjusted death hazard rate 0.68 times that of the nonobese patients (95% CI, 0.38 to 1.22). Although obesity was reported to increase the risk for renal cell carcinoma, prognosis was no worse and may be better among obese patients with the disease.