Longitudinal Outcomes of COVID-19-Associated Collapsing Glomerulopathy and Other Podocytopathies.

BACKGROUND: The long-term outcome of COVID-19-associated collapsing glomerulopathy is unknown. METHODS: We retrospectively identified 76 native kidney biopsies from patients with history of COVID-19 between March 2020 and April 2021. Presenting and outcome data were obtained for all 23 patients with collapsing glomerulopathy and for seven patients with noncollapsing podocytopathies. We performed APOL1 genotyping by Sanger sequencing, immunostaining for spike and nucleocapsid proteins, and in situ hybridization for SARS-CoV-2. RESULTS: The 23 patients with COVID-19-associated collapsing glomerulopathy were median age 57 years (range, 35-72), included 16 men, and were predominantly (91%) Black. Severity of COVID-19 was mild or moderate in most (77%) patients. All but one patient presented with AKI, 17 had nephrotic-range proteinuria, and six had nephrotic syndrome. Fourteen (61%) patients required dialysis at presentation. Among 17 patients genotyped, 16 (94%) were high-risk APOL1. Among 22 (96%) patients with median follow-up at 155 days (range, 30-412), 11 (50%) received treatment for COVID-19, and eight (36%) received glucocorticoid therapy for podocytopathy. At follow-up, 19 (86%) patients were alive, and 15 (68%) were dialysis free, including seven of 14 who initially required dialysis. The dialysis-free patients included 64% (seven of 11) of those treated for COVID-19 and 75% (six of eight) of those treated with glucocorticoids for podocytopathy. Overall, 36% achieved partial remission of proteinuria, 32% had no remission, and 32% reached combined end points of ESKD or death. Viral infection of the kidney was not detected. CONCLUSIONS: Half of 14 patients with COVID-19-associated collapsing glomerulopathy requiring dialysis achieved dialysis independence, but the long-term prognosis of residual proteinuric CKD remains guarded, indicating a need for more effective therapy.

Association between PD-L1 expression and initial brain metastasis in patients with non-small cell lung cancer and its clinical implications.

BACKGROUND: Brain metastases frequently occur in patients with non-small cell lung cancer (NSCLC) resulting in a poor prognosis. Here, we investigated the association between PD-L1 expression and brain metastasis in patients with NSCLC and its clinical significance. METHODS: A total of 270 patients diagnosed with metastatic NSCLC who underwent PD-L1 testing on their tumor tissue between January 2017 and March 2019 were retrospectively reviewed. The VENTANA PD-L1 (SP263) assay was used, and positive PD-L1 expression was defined as staining in ≥1% of tumor cells. RESULTS: Positive PD-L1 expression was observed in 181 (67.0%) patients, and 74 (27.4%) patients had brain metastasis at diagnosis. Synchronous brain metastases were more frequently observed in PD-L1-positive compared with PD-L1-negative patients (31.5% vs. 19.1%, p = 0.045). Multiple logistic regression analysis identified positive PD-L1 expression (odds ratio [OR]: 2.24, p = 0.012) as an independent factor associated with synchronous brain metastasis, along with the histological subtype of nonsquamous cell carcinoma (OR: 2.84, p = 0.003). However, the incidence of central nervous system (CNS) progression was not associated with PD-L1 positivity, with a two-year cumulative CNS progression rate of 26.3% and 28.4% in PD-L1-positive and PD-L1-negative patients, respectively (log rank p = 0.944). Furthermore, positive PD-L1 expression did not affect CNS progression or overall survival in patients with synchronous brain metastasis (long rank p = 0.513 and 0.592, respectively). CONCLUSIONS: Initial brain metastases are common in NSCLC patients with positive PD-L1 expression. Further studies are necessary to understand the relationship between early brain metastasis and cancer immunity.

Possible Role of CRF-Hcrt Interaction in the Infralimbic Cortex in the Emergence and Maintenance of Compulsive Alcohol-Seeking Behavior.

Alcohol use disorder (AUD) is a chronic, relapsing disorder that is characterized by the compulsive use of alcohol despite numerous health, social, and economic consequences. Initially, the use of alcohol is driven by positive reinforcement. Over time, however, alcohol use can take on a compulsive quality that is driven by the desire to avoid the negative consequences of abstinence, including negative affect and heightened stress/anxiety. This transition from positive reinforcement- to negative reinforcement-driven consumption involves the corticotropin-releasing factor (CRF) system, although mounting evidence now suggests that the CRF system interacts with other neural systems to ultimately produce behaviors that are symptomatic of compulsive alcohol use, such as the hypocretin (Hcrt) system. Hypocretins are produced exclusively in the hypothalamus, but Hcrt neurons project widely throughout the brain and reach regions that perform regulatory functions for numerous behavioral and physiological responses-including the infralimbic cortex (IL) of the medial prefrontal cortex (mPFC). Although the entire mPFC undergoes neuroadaptive changes following prolonged alcohol exposure, the IL appears to undergo more robust changes compared with other mPFC substructures. Evidence to date suggests that the IL is likely involved in EtOH-seeking behavior, but ambiguities with respect to the specific role of the IL in this regard make it difficult to draw definitive conclusions. Furthermore, the manner in which CRF interacts with Hcrt in this region as it pertains to alcohol-seeking behavior is largely unknown, although immunohistochemical and electrophysiological experiments have shown that CRF and Hcrt directly interact in the mPFC, suggesting that the interaction between CRF and Hcrt in the IL may be critically important for the development and subsequent maintenance of compulsive alcohol seeking. This review aims to consolidate recent literature regarding the role of the IL in alcohol-seeking behavior and to discuss evidence that supports a functional interaction between Hcrt and CRF in the IL.

Reduced ethanol self-administration in rats produced by the introduction of a high value non-drug alternative reinforcer.

Previous studies have shown that providing rats with a non-drug alternative in a choice situation can reduce ethanol taking in rats. There is also evidence that brief experience with non-drug reinforcers can reduce the reinforcing effects of drugs like cocaine, even when those non-drug alternatives are not pitted against the drug in a choice procedure. The goal of the present experiment was to determine whether experience with sucrose - a high value non-drug reinforcer in rats - in a non-choice situation would reduce ethanol's reinforcing effects, as measured within a behavioral economic framework. In a first phase, separate groups of rats worked on fixed-ratio schedules for ethanol, sucrose, or ethanol plus sucrose (during separate components within a session). In a second phase, all rats worked for ethanol and sucrose during alternating components. The introduction of sucrose components in the second phase to the group that previously only had experience with ethanol caused a significant decrease in ethanol self-administration. There was also a significant interaction whereby the effect of phase on the elasticity of demand for ethanol differed between the group that only had ethanol and the group that had ethanol plus sucrose in the first phase. These results indicate that a high value non-drug alternative reinforcer can reduce ethanol's reinforcing effects even when that alternative is not available at the time when ethanol is available. These findings suggest that treatments aiming to increase exposure to non-alcohol sources of reinforcement might be beneficial in reducing alcohol drinking.

The effect of economy type on demand and preference for cocaine and saccharin in rats.

BACKGROUND: Economy type is an important determinant of reinforcer value. This study investigated the effect of open and closed economies on demand and preference for cocaine and saccharin in rats. METHODS: In the first phase, rats were trained to lever press for cocaine infusions or saccharin. The number of presses required for each reinforcer increased across sessions. Cocaine and saccharin economy type was manipulated over groups by varying post-session availability of these reinforcers. One group of rats had three hours' post-session access to unlimited cocaine (open economy). A second group had three hours' post-session access to unlimited saccharin. A third group had no post-session access to either reinforcer (closed economy). In a second phase, rats in the three conditions could make mutually exclusive choices for cocaine or saccharin. RESULTS: Post-session access to saccharin caused saccharin demand to become more elastic. Post-session access to cocaine had no effect on demand for cocaine but made demand for saccharin more elastic. Results from the choice phase generally paralleled those from the demand phase, the main finding being that post-session saccharin access caused an increase in cocaine preference. CONCLUSIONS: These results show that manipulating economy type can affect cocaine and non-drug reinforcers differently. Opening the saccharin economy decreased saccharin's value. Opening the cocaine economy did not decrease cocaine's value, but instead led to a devaluation of saccharin. These results suggest that cocaine choice may be determined not only by the reinforcers immediately available, but also by those reinforcers' broader contexts of availability.

Heroin and saccharin demand and preference in rats.

BACKGROUND: Several recent studies have investigated the choice between heroin and a non-drug alternative reinforcer in rats. A common finding in these studies is that there are large individual differences in preference, with some rats preferring heroin and some preferring the non-drug alternative. The primary goal of the present study was to determine whether individual differences in how heroin or saccharin is valued, based on demand analysis, predicts choice. METHODS: Rats lever-pressed for heroin infusions and saccharin reinforcers on fixed-ratio schedules. The essential value of each reinforcer was obtained from resulting demand curves. Rats were then trained on a mutually exclusive choice procedure where pressing one lever resulted in heroin and pressing another resulted in saccharin. After seven sessions of increased access to heroin or saccharin, rats were reexposed to the demand and choice procedures. RESULTS: Demand for heroin was more elastic than demand for saccharin (i.e., heroin had lower essential value than saccharin). When allowed to choose, most rats preferred saccharin. The essential value of heroin, but not saccharin, predicted preference. The essential value of both heroin and saccharin increased following a week of increased access to heroin, but similar saccharin exposure had no effect on essential value. Preference was unchanged after increased access to either reinforcer. CONCLUSION: Heroin-preferring rats differed from saccharin-preferring rats in how they valued heroin, but not saccharin. To the extent that choice models addiction-related behavior, these results suggest that overvaluation of opioids specifically, rather than undervaluation of non-drug alternatives, could identify susceptible individuals.

Essential values of cocaine and non-drug alternatives predict the choice between them.

This study investigated the relationship between reinforcer value and choice between cocaine and two non-drug alternative reinforcers in rats. The essential value (EV, a behavioral economic measure based on elasticity of demand) of intravenous cocaine and food (Experiment 1) or saccharin (Experiment 2) was determined in the first phase of each experiment. Food had higher EV than cocaine, whereas the EVs of cocaine and saccharin did not differ. In the second phase of each experiment, rats were allowed to make mutually exclusive choices between cocaine and the non-drug alternative reinforcer. The main findings were that the EV of cocaine was a positive predictor of cocaine preference and the EV of food or saccharin was a negative predictor of cocaine preference. An analysis of within-session patterns of choice behavior revealed sequential dependencies, whereby rats were more likely to choose cocaine on a particular trial after having chosen the non-drug alternative on previous trials. When the time between choices was increased, these sequential dependencies disappeared. The results of these experiments are consistent with the suggestion that addiction-like behavior involves both overvaluation of drug reinforcers and undervaluation of non-drug reinforcers.

A test of stress, cues, and re-exposure to large wins as potential reinstaters of suboptimal decision making in rats.

The present experiment investigated potential reinstaters of suboptimal economic decision making in rats. Rats were first trained on a version of the rat Gambling Task under conditions designed to promote choice of a suboptimal option that occasionally resulted in large "wins" (four sucrose pellets). In a second phase, preference for this economically suboptimal option was reduced by substantially increasing the probability of punishment when this option was chosen. Then, three events were tested for their ability to reinstate choice of the suboptimal option. A brief period of re-exposure to a high frequency of large wins significantly increased choice of the suboptimal option. The pharmacological stressor yohimbine did not reinstate suboptimal choice, but did increase impulsive action as indexed by premature responding. Presentation of cues previously associated with large wins did not alter behavior. Results suggest reinstaters of suboptimal choice may differ from reinstaters of extinguished drug- and food-seeking behavior.

Timing in a variable interval procedure: evidence for a memory singularity.

Rats were trained in either a 30 s peak-interval procedure, or a 15-45 s variable interval peak procedure with a uniform distribution (Exp 1) or a ramping probability distribution (Exp 2). Rats in all groups showed peak shaped response functions centered around 30 s, with the uniform group having an earlier and broader peak response function and rats in the ramping group having a later peak function as compared to the single duration group. The changes in these mean functions, as well as the statistics from single trial analyses, can be better captured by a model of timing in which memory is represented by a single, average, delay to reinforcement compared to one in which all durations are stored as a distribution, such as the complete memory model of Scalar Expectancy Theory or a simple associative model. This article is part of a Special Issue entitled: Associative and Temporal Learning.

Population-based incidence and burden of childhood intussusception in Jeonbuk Province, South Korea.

OBJECTIVES: The aim of this study was to describe the clinical characteristics of childhood intussusception and to estimate the incidence rate of intussusception before the introduction of rotavirus vaccines in Korea. METHODS: Demographic, clinical, diagnostic, treatment, and outcome data for patients aged <5 years who were diagnosed with intussusception in Jeonbuk Province, South Korea from January 2000 through December 2002, were retrospectively collected using a standardized data collection instrument. RESULTS: During the 3-year period, 408 patients were diagnosed with intussusception; 82.8% of children were aged <24 months. Predominant signs and symptoms were vomiting (64.5%), bloody stool (43.9%), and abdominal pain/irritability (41.9%). The combination of ultrasound and barium or air enema was the most frequently used diagnostic approach (38.7%). Three hundred and thirteen patients (76.7%) were treated by radiologic reduction, 88 (21.6%) patients were treated by surgical intervention, and the remaining seven patients had no treatment. The mean annual incidence rate of intussusception in Jeonbuk Province was 236/100,000 among children aged <2 years and 106/100,000 among children aged <5 years. CONCLUSIONS: This retrospective study provides a background incidence rate of childhood intussusception in Korean children before the introduction of the rotavirus vaccine.

Genetic and pathologic changes associated with lymphovascular invasion of colorectal adenocarcinoma.

Lymphovascular invasion (LVI) is a biological manifestation of aggressive behavior in colorectal cancer. This study sought to identify and examine the association between genetic and pathologic alterations implicated in this invasive tumor progression. We consecutively recruited 81 and 79 colorectal cancer patients with and without LVI, respectively. Biological changes were evaluated by clinicopathological parameters together with CEA and E-cadherin expressions using immune staining. Allelic loss or MSI was examined using 10 microsatellite markers on chromosomes 10, 16, 18, and TGFbetaRII, possibly associated with colorectal cancer. The germline mutation of BMPR1A and SMAD4 was also sought. Tumor stage and lymph node metastasis were significantly greater in patients with LVI tumor than without it (P < 0.001). Decreased CEA expression was closely correlated with allelic loss or MSI at D16S421, D18S46, and D18S474 (P = 0.004-0.047). Allelic loss at D10S14 was specific to LVI tumors (P = 0.007). Using multivariate analysis, allelic loss at D18S46 significantly correlated with histological differentiation (P = 0.02). In addition, allelic loss and MSI at D18S474, histological differentiation, and expression of CEA and E-cadherin were closely associated with the progression of LVI (P = 0.005-0.049). However, no germline mutation in BMPR1A or SMAD4 was detected in all patients regardless of LVI status. In summary, in a subset of colorectal cancers, histological differentiation and expression of CEA or E-cadherin appear to determine aggressive behavior such as LVI. These changes are closely associated with chromosomal alterations at 10q22-23, 16q22 and 18q21, which carry several tumor suppressor genes.

Epidemiological profile of rotavirus infection in the Republic of Korea: results from prospective surveillance in the Jeongeub District, 1 July 2002 through 30 June 2004.

To facilitate future decisions regarding the usefulness of rotavirus vaccines in the Republic of Korea, active surveillance was conducted in a network of clinics, emergency departments, and hospitals serving Jeongeub District, Korea. Children with diarrhea underwent standard clinical evaluations, and stool specimens were collected to test for the presence of rotavirus. Parents were interviewed to collect demographic and family information. From 1 July 2002 through 30 June 2004, a total of 4106 children, representing 1 (50%) of every 2 children <5 years old in the study population, were evaluated for rotavirus diarrhea. Of the 2232 stool specimens obtained throughout the year, 460 (20.6%) were rotavirus positive; however, the monthly prevalence of rotavirus infection peaked at 49.5% in February 2004. Of the 460 rotavirus-positive stool specimens, 366 were obtained from children who visited outpatient clinics, and 94 were obtained from children who were hospitalized. By extrapolating the proportion of rotavirus-positive patients to all children with diarrhea in the surveillance system, we calculate that 882 children in Jeongeub District had rotavirus infection (which would predict that there would be 702 associated clinic visits and 180 hospitalizations). Genotyping of rotavirus strains showed that 39% of strains were type G9P[8], 24% were type G1P[8], 17% were type G3P[8], and 13% were type G2P[4]. The incidence of rotavirus diarrhea peaked at age 13-24 months, and 94% of cases occurred during the first 3 years of life. The annual incidence of all rotavirus disease-associated outcomes was 56.9 cases/1000 children <5 years old (95% confidence interval [CI], 51.9-62.2 cases/1000 children <5 years old). The incidence of rotavirus disease-associated hospitalizations was 11.6 cases/1000 children <5 years old (95% CI, 9.5-14.2 cases/1000 children <5 years old). In Korea, diarrhea is common during childhood, and the incidence of diarrhea due to rotavirus infection suggests that improved programs for the prevention and control of both rotavirus diarrhea and diarrhea due to other causes are needed.

Experimental radioimmunoguided surgery for peritoneal metastases of gastric cancer using anticarcinoembryonic antigen-specific T84.66 F(ab')2.

PURPOSE: In gastric cancer, peritoneal dissemination is the most frequent cause of the noncurative resection and recurrence after curative resection. We therefore evaluated the feasibility of radioimmunoguided surgery (RIGS) in the treatment of peritoneal metastases of gastric cancer and the use of anti-CEA-specific T84.66 F(ab')2 as an efficient immune agent. METHODS: Two human gastric cancer cell lines, MKN45 and RF48, were intraperitoneally xenografted into nude mice, which were later injected with 125I-labeled T84.66 F(ab')2. Peritoneal tumors were localized by RIGS 5 days after antibody injection. The minimum number of cells detected by a gamma probe was assayed by in vitro tumor cell localization. RESULTS: We observed 37 peritoneal metastases: 8 invisible (long diameter, <1 mm), 6 small (1- < 5 mm), and 23 large (> or =5 mm) tumors. The accuracy, sensitivity and specificity of RIGS in detecting peritoneal metastasis were 82% (69/84), 76% (28/37), and 87% (41/47), respectively. RIGS accuracy did not differ with respect to tumor diameter. Mean labeling indices over minimal and maximal normal counts were 6.1+/-1.2 (mean +/- SEM) and 4.7+/-1, respectively. Mean scores of CEA immunostaining and silver grains in tumors were significantly higher than those in the nontumor-bearing peritoneum (P < 0.001). There was a close correlation among radioactivity, immunostaining and microautoradiography (P < 0.001-0.005). We observed six false-positive and nine false-negatives which may have been due to high blood background and negative radioimmune reactivity, respectively. CONCLUSIONS: 125I-labeled T84.66 F(ab')2 efficiently targeted peritoneally disseminated gastric cancer cells, suggesting that RIGS using this immune agent may accurately detect occult peritoneal metastases in patients with gastric cancer.

Correlation between hMLH1/hMSH2 and p53 protein expression in sporadic colorectal cancer.

BACKGROUND/AIMS: The aim of this study was to analyze expression of hMLH1 and hMSH2 mismatch repair proteins in terms of p53 protein expression and clinicopathological parameters in sporadic colorectal cancer. METHODOLOGY: Four hundred and two cases of curative colorectal surgery for primary colorectal cancer were included in this study (patients with a familial history of colorectal cancer and familial adenomatous polyposis were not included). Clinicopathological parameters were reviewed retrospectively. HMLH1, hMSH2 and p53 protein expression in tumor tissue sections was determined using immunohistochemical staining with specific monoclonal antibodies. RESULTS: Of the 402 cases, immunohistochemical analysis showed 35 (8.7%) had loss of expression of hMLH1, 19 (4.7%) had loss of expression of hMSH2, and three cases (0.7%) had loss of expression of both proteins. Multivariate analysis showed that early age of onset (p=0.023), right side dominance (p<0.001) and poorly differentiated or mucinous cell type (p<0.001) were associated with loss of expression of hMLH1 or hMSH2. Loss of expression of hMLH1 or hMSH2 correlated with low p53 expression (p<0.001). In terms of clinicopathological parameters, p53 expression was associated only with hMLH1 or hMSH2 expression. CONCLUSIONS: Colorectal cancers not expressing hMLH1 or hMSH2 may have distinct features from those expressing these mismatch repair proteins. p53 expression appears to be implicated in a compensatory pathway with mismatch repair proteins.

Characterization of mutator phenotype in familial colorectal cancer patients not fulfilling amsterdam criteria.

PURPOSE: Although the mutator phenotype, including genetic and epigenetic alterations of the mismatch repair (MMR) system, seems to be pronounced in familial colorectal cancer, there have been few integrative studies comprising the entire mutator pathway. This study was done to identify the entire mutator pathway determining risk factors in patients with familial colorectal cancer not fulfilling the Amsterdam criteria. EXPERIMENTAL DESIGN: We consecutively recruited 134 colorectal cancer patients with a family history of accompanying cancers. Patients with hereditary nonpolyposis colorectal cancer meeting the Amsterdam criteria, familial adenomatous polyposis, or those receiving preoperative radiotherapy were excluded. Mutator phenotype was assessed by assaying microsatellite instability (MSI) at 24 markers, hMLH1-promoter methylation, mutations at MMR genes (hMLH1, hMSH2, hMSH6, and hPMS2), and immune staining of MMR proteins (hMLH1, hMSH2, hMSH6, hPMS1, and hPMS2). RESULTS: Of the 208 cancers in first-degree and/or second-degree relatives of patients, colorectal and gastric cancers (81%) were most common. Of the 134 proband colorectal cancers, 23 (17%) were MSI in high level, and 32 (24%) were MSI in low level. MMR alterations, including known polymorphism and splicing substitution, were identified in eight patients (6%). Twenty-eight tumors with mutator phenotype were further identified by hMLH1-promoter methylation and/or loss of MMR protein expression. In 51 tumors (38%), mutator phenotype was associated with right-sided colon cancer (P < 0.001) and younger age at onset (P=0.032), but the number of patients with a mutator phenotype did not differ with respect to inheritance patterns of accompanying cancers, either successive or horizontal transmission (P=0.815). Familial impact value, which differentially associated the degree of relatives with all accompanying cancers, effectively discriminated MSI in high level from microsatellite stable/MSI in low level tumors. CONCLUSION: Familial colorectal cancer may be associated with multiple occurrences of colorectal or accompanying cancers inherited by dominant or recessive transmission. MMR gene mutations, however, are less associated with mutator phenotype in familial colorectal cancer.

Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients.

The genotypic consequences of numerous single-nucleotide variants in human mismatch repair genes are mostly undetermined. We examined 27 reported single-nucleotide variants, rarely or ambiguously verified in a population-based study, to identify single-nucleotide polymorphisms (SNPs), haplotypes, and the genotype-phenotype association in Korean populations of 330 healthy individuals, 107 sporadic colorectal cancer patients, and 107 of their first-degree relatives. Real-time PCR 5'-nuclease assays (TaqMan) MGB assay) were used to determine 24 single-nucleotide variants, and restriction fragment length polymorphism (RFLP) assays were used to determine 3 variants. Of these 27 variants, 4 (hMSH2 gIVS12-6, hMLH1 655, hMLH1 1151, and hMSH2 1168, in descending order) were identified as SNPs occurring in 4.5 to 53.1% of healthy individuals, with polymorphism levels of 0.023-0.3 (mean, 0.092). East Asian populations had an ethnic predilection for the hMLH1 1151 SNP. The genotype distribution for all four SNPs showed no association with sporadic colorectal cancer. Twenty-three variants were not identified in the Korean population, suggesting that fifteen of these variants are colorectal cancer-related mutations and eight are SNPs. Two haplotype patterns existed exclusively, but with rare frequency, in sporadic colorectal cancer patients. The hMLH1 655 allele was closely correlated with hMLH1 protein expression (P = 0.02), but none of the four SNPs was associated with clinicopathologic variables. Among the 27 single nucleotide variants of mismatch repair genes, 12 were suggestive of nonfunctional SNPs and 15 may be colorectal cancer-related mutations. Further verification in other ethnic groups may provide the genotypic and phenotypic significance of single nucleotide variants found in mismatch repair genes.

Efficient targeting of gastric cancer cells using radiolabeled anti-carcinoembryonic antigen-specific T84.66 fragments in experimental radioimmunoguided surgery.

BACKGROUND: Radioimmunoguided surgery (RIGS) appears as an efficient tool for accurate tumor detection up to the level of micrometastases by detecting radiolabeled antibody-bound tumor cells during operation. Anti-CEA-specific T84.66 fragments were examined as to whether they efficiently detected gastric cancer cells in experimental RIGS. T84.66, anti-CEA-specific antibody, has widely been used as an immune carrier in the preclinical and clinical trials of radioimmunotherapy and radioimmunoscintiscan. MATERIALS AND METHODS: Fifty-one tumors from two human gastric carcinoma cell lines with profuse (MKN45) and low (RF48) CEA expression were successfully implanted subcutaneously in the backs of 32 nude mice. Tumors were localized after 125I-labeled T84.66 F(ab')2 and Fab' injection. RESULTS: The radioactivity of F(ab')2-pretreated mice was greater than that of Fab'-pretreated in all organs and tumors (p<0.001-0.035). Localization indices of the tumor in various organs revealed 7.4 to 32.5 in F(ab')2-pretreated and 1 to 7.1 in Fab'-pretreated mice. Silver grains and immune staining were predominantly distributed in tumor cells regardless of fragment types and cell lines. There was no false-negative evaluation of tumor in F(ab')2-pretreated mice. Sensitivity and specificity of tumor localization by RIGS were the highest in the F(ab')2-pretreated mice (95% for MKN45- and 82% for RF46-xenografted mice) and the least in the Fab'-pretreated mice (66% for MKN45- and 67% for RF46-xenografted mice). In all organs, three quarters of the false-positive evaluations occurred from silver grains as radioimmune complex or dissociated nuclides in the circulation that can be eliminated with time. CONCLUSION: Anti-CEA-specific T84.66 fragments achieved a great affinity and avidity with accurate localization of gastric carcinoma in experimental RIGS.

Geno- and pheno-typic characterization in ten patients with double-primary gastric and colorectal adenocarcinomas.

BACKGROUND AND AIMS: Although a number of double-primary gastric and colorectal cancers have been known to correlate with the mutator pathway, a possible association with known hereditary cancers regarding geno-pathogenesis has rarely been investigated. This study was intended to identify a possible association of hereditary cancers and the implications of the mutator or tumor-suppressor pathway in double-primary gastric and colorectal cancers. MATERIALS AND METHODS: Fresh colorectal tissues and lymphocytes from ten patients with double-primary gastric and colorectal cancers were obtained consecutively. The mutator pathway was evaluated by detecting hMSH2 and hMLH1 mutations, microsatellite instability (MSI) using 12 microsatellite markers, and hMLH1 promoter region methylation. Protein expressions of hMSH2, hMLH1, APC, E-cadherin, and beta-catenin were identified by immune staining. RESULTS: There was no pathogenic mutation in any introns or exons of hMSH2, hMLH1 or CDH1, and in exons 3, 5, 6, and 15 of CTNNB1. Either MSI or methylator phenotype was found in five gastric cancers and in four colorectal cancers. No patients met the Amsterdam criteria of hereditary nonpolyposis colorectal cancer (HNPCC) or its equivalent of hereditary gastric cancer. Two patients with gastric cancers among their first-degree relatives showed no E-cadherin expression. The two of the three patients with rectal cancers among their first-degree relatives showed mutator phenotype either in the gastric or in the colorectal cancer. A subset of double-primary gastric and colorectal cancers may thereby be categorized as variant forms of hereditary gastric or colorectal cancer. Both cytoplasmic and nuclear beta-catenins were expressed in all gastric and colorectal cancers. Among the gastric and colorectal cancers with either MSI or methylator phenotype, four of five gastric cancers showed both APC and E-cadherin expression, whereas one of four colorectal cancers showed them. CONCLUSION: This may suggest that the mutator pathway and the aberrant tumor suppressor pathway of the APC-E-cadherin may be cooperative or separately activated in the geno-pathogenesis of double-primary gastric and colorectal cancers.

An 18-month follow-up study on the influence of smoking on blood antioxidant status of teenage girls in comparison with adult male smokers in Korea.

OBJECTIVES: The influence of cigarette smoking on blood antioxidant status in teenage girls with a history of short-term smoking was followed over 18 mo. METHODS: Data obtained from female senior high school students (ages 14 to 18 y) in Korea were compared with data obtained from adult male smokers (ages 36 to 51 y) with a long history of smoking and living in the same geographic areas as the teenage subjects. A smoker was a person who had smoked at least three cigarettes a day for at least 1 y for teenagers (n = 35) or at least 10 cigarettes a day for at least 13 y for adults (n = 20). Serum, urine, and anthropometric data were obtained from teenagers every 6 mo over an 18-mo period. Samples were collected once from adults. Data were analyzed by Student's t test and Fisher's protected least significant difference test for comparing smokers and non-smokers and for analyzing period effects in each group. RESULTS: Serum nicotine and cotinine concentrations were higher in smokers than in non-smokers. Blood pressures were higher in teenage (at 0 and 12 mo) and adult smokers than in non-smokers. Extracellular superoxide dismutase activities and concentrations of serum vitamin C and folate were lower in smokers in the teenage (at 0, 12, or 18 mo) and adult groups. Serum ceruloplasmin activities and thiobarbituric acid-reactive substance production were not influenced by smoking. In adults, serum copper concentrations were higher in smokers than in non-smokers. This parameter for teenagers did not change consistently throughout the study. CONCLUSIONS: Similar to adults, cigarette smoking by teenagers has a negative effect on oxidant defense systems.

[Prognostic factors of stage II rectal cancer].

BACKGROUND/AIMS: We aimed to verify the prognostic factors of stage II rectal cancer and the effect of radiation therapy on the survival and local recurrence rate. METHODS: This study was undertaken in 202 patients who underwent curative resection of rectal cancer and confirmed to be stage II between July 1989 and December 1996. Univariate and multivariate (Cox's model) analyses of survival were employed to identify prognostic factors. Statistical significance was assigned by p value of <0.05. RESULTS: Overall recurrence occurred in 32 patients. Four patterns of recurrence were observed: hematogenous recurrence in 17 patients, local recurrence in 11, peritoneal seeding in two and simultaneous hematogenous and local recurrence in two cases. Overall 5-year survival rate was 85.6% and 5 year disease free survival rate was 82.8%. There was no significant difference in local recurrence rate and survival according to radiation therapy or location of cancer. In multivariate analysis, the number of harvested lymph node was only a prognostic factor. CONCLUSIONS: The number of harvested lymph nodes has prognostic value in stage II rectal cancer. Postoperative radiation therapy should be considered for stage II rectal cancer with poor prognostic factors although radiation did not decrease local recurrence rate in present study.