Prediction of human serum concentration-time profiles of therapeutic monoclonal antibodies using common marmosets (Callithrix jacchus): Initial assessment with canakinumab, adalimumab, and bevacizumab.

1. Cynomolgus monkeys and human FcRn transgenic mice are generally used for pharmacokinetic predictions of therapeutic monoclonal antibodies (mAbs). In the present study, the application of the common marmoset, a small nonhuman primate, as a potential animal model for prediction was evaluated for the first time.2. Canakinumab, adalimumab, and bevacizumab, which exhibited linear pharmacokinetics in humans, were selected as the model compounds. Marmoset pharmacokinetic data were reportedly available only for canakinumab, and those for adalimumab and bevacizumab were acquired in-house.3. Four pharmacokinetic parameters for a two-compartment model (i.e., clearance and volume of distribution in the central and peripheral compartments) in marmosets were extrapolated to the values in humans with allometric scaling using the average exponents of the three mAbs. As a result, the observed human serum concentration-time curves of the three mAbs following intravenous administration and those of canakinumab and adalimumab following subcutaneous injections (with an assumed absorption rate constant and bioavailability) were reasonably predicted.4. Although further prediction studies using a sufficient number of other mAbs are necessary to evaluate the versatility of this model, the findings indicate that marmosets can be an alternative to preceding animals for human pharmacokinetic predictions of therapeutic mAbs.

Positive predictive value of the clinical diagnosis of T1a-epithelial/lamina propria esophageal cancer depends on lesion size.

OBJECTIVES: Endoscopic resection (ER) is a minimally invasive treatment for esophageal squamous cell carcinoma (ESCC). However, stricture may develop after ER for widespread lesions. Application of ER is justified if these cancers are pathological T1a-epithelial/lamina propria (pEP/LPM) cancers that can be cured by ER. We conducted a study to clarify the association between pathological invasion depth and lesion size or circumference in clinical (c) EP/LPM cancers. METHODS: From our database, we identified patients diagnosed with cEP/LPM ESCC via endoscopic examination who underwent endoscopic or surgical tumor resection. The accuracy of the cEP/LPM ESCC diagnosis was determined by histologically diagnosing cancer invasion depth as a reference standard. RESULTS: Between January 2015 and December 2019, 1271 cancer patients were diagnosed with cEP/LPM ESCC, of which 1195 (94.0%) were correctly diagnosed with pEP/LPM cancer. The positive predictive value (PPV) classified according to lesion sizes of ≤25, 26-49, and ≥50 mm was 95.8% (981/1024 lesions), 89.7% (191/213 lesions), and 67.6% (23/34 lesions), respectively. PPV according to the circumferential extent of <3/4, ≥3/4, and <1, and whole was 94.6% (1164/1230 lesions), 75.0% (24/32 lesions), and 77.8% (7/9 lesions), respectively. In multivariate analysis, the PPV of cEP/LPM ESCC was significantly associated with lesion size (P < 0.001) and male sex. CONCLUSIONS: Between January 2015 and December 2019, 1271 cancer patients were diagnosed with cEP/LPM ESCC, of which 1195 (94.0%) were correctly diagnosed with pEP/LPM cancer. The PPV of cEP/LPM ESCC was related to lesion size. Treatment should be determined considering the high risk of cancer invasion into the muscularis mucosa or deeper in cEP/LPM cancers with a lesion size of ≥50 mm.

Regulation of Organic Anion Transporting Polypeptide 2B1 Expression by MicroRNA in the Human Liver.

Organic anion transporting polypeptide 2B1 (OATP2B1, SLCO2B1) is an uptake transporter expressed in several tissues, including the liver, intestine, brain, kidney, and skeletal muscle. Hepatocyte nuclear factor 4 alpha (HNF4α) is known as an important transcriptional factor of OATP2B1 in the liver. It has been reported that there are large interindividual differences in OATP2B1 mRNA and protein expressions in human livers. The mechanism causing the interindividual differences in OATP2B1 expression is still unclear. MicroRNAs (miRNAs) control gene expression by leading translational repression and/or degradation of the target mRNA. There is no significant correlation between OATP2B1 mRNA and protein expression, suggesting that post-transcriptional regulating mechanisms, such as miRNAs, play an important role in the interindividual differences in OATP2B1 expression. In this study, we hypothesized that certain miRNAs cause the interindividual differences in OATP2B1 expression in the human liver. In silico analysis showed that miR-24 was a candidate miRNA regulating OATP2B1 expression. It has been reported that miR-24 degrades HNF4α mRNA expression. We revealed that the miR-24 expression level was negatively correlated with OATP2B1 mRNA, protein, and HNF4α mRNA expression levels in human livers. Transfection by the miR-24 precursor decreased the luciferase activity in the transfected cells with the vector containing the OATP2B1 3' untranslated region (3'UTR) or SLCO2B1 promoter region. In HepaRG cells, miR-24 decreased the OATP2B1 and HNF4α expression levels. These results suggest that miR-24 represses not only the translation of OATP2B1 but also the transcription of OATP2B1 by HNF4α mRNA degradation.

High incidence of lung cancer death after curative endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma.

BACKGROUND AND AIM: Following treatment of superficial esophageal squamous cell carcinoma (ESCC), surveillance for a second primary malignancy (SPM) is necessary. However, detailed evidence regarding the timing and prognosis of SPMs is insufficient. We aimed to clarify the details of SPMs and their effects on patient outcomes. METHODS: This retrospective, multicenter study involved 11 hospitals. Patients with superficial ESCC curatively resected using endoscopic submucosal dissection between May 2005 and December 2012, were included in this study. RESULTS: The 5-year survival rate of 187 patients was 92.6% during a median follow-up duration of 96.8 months. Thirty-one patients died, 14 of whom died of SPMs. Compared to patients with SPMs detectable by esophagogastroduodenoscopy (EGD), patients with SPMs detectable only by modalities other than EGD had a significantly higher mortality rate (p < 0.001). Patients with second primary lung cancer (LC) had a high mortality rate (56.3%). Univariate and multivariate analyses showed that multiple Lugol-voiding lesions (LVLs) tended to be associated with SPMs (p = 0.077, hazard ratio [HR] 4.43, 95% confidence interval [CI]: 0.91-6.50), and metachronous ESCC was an independent risk factor for the incidence of second primary LC (p = 0.037, HR 3.51, 95% CI: 1.08-11.41). CONCLUSIONS: SPMs that cannot be detected by EGD, such as LC, must be considered after the curative resection of ESCC. We suggest strict screening by both EGD and computed tomography for patients with multiple LVLs or metachronous ESCC to detect SPMs in their early stages.

Characterization of enzyme-crosslinked albumin hydrogel for cell encapsulation.

Albumin is an attractive component for the development of biomaterials applied as biomedical implants, including drug carriers and tissue engineering scaffolds, because of its high biocompatibility and low immunogenicity. Additionally, albumin-based gelators facilitate cross-linking reactions under mild conditions, which maintains the high viability of encapsulated living cells. In this study, we synthesized albumin derivatives to undergo gelation under physiological conditions via the peroxidase-catalyzed formation of cross-links. Albumin was modified with phenolic hydroxyl groups (Alb-Ph-OH) using carbodiimide chemistry, and the effect of degree of substitution on gelation was investigated. Various properties of the Alb-Ph-OH hydrogels, namely the gelation time, swelling ratio, pore size, storage modulus, and enzymatic degradability, were easily controlled by adjusting the degree of substitution and the polymer concentration. Moreover, the viability of cells encapsulated within the Alb-Ph-OH hydrogel was high. These results demonstrate the potential applicability of Alb-Ph-OH hydrogels as cell-encapsulating materials for biomedical applications, including tissue engineering.

Boring biopsy with rapid on-site evaluation for gastric gastrointestinal stromal tumor: A pilot study.

One of 4 patients (25%) and 2 of 3 patients (67%) were correctly diagnosed by conventional and hot boring biopsies, respectively. The median procedure time of conventional and hot boring biopsies was 21 (range, 13-33) and 17 (range, 16-23) min, respectively. Rapid on-site evaluation was performed totally 12 times in 7 patients. The positive and negative predictive values of rapid on-site evaluation for gastrointestinal stromal tumor were 0.5 (0.12-0.88) and 1.0 (0.42-1.00), respectively.

Utility of an artificial intelligence system for classification of esophageal lesions when simulating its clinical use.

Previous reports have shown favorable performance of artificial intelligence (AI) systems for diagnosing esophageal squamous cell carcinoma (ESCC) compared with endoscopists. However, these findings don't reflect performance in clinical situations, as endoscopists classify lesions based on both magnified and non-magnified videos, while AI systems often use only a few magnified narrow band imaging (NBI) still images. We evaluated the performance of the AI system in simulated clinical situations. We used 25,048 images from 1433 superficial ESCC and 4746 images from 410 noncancerous esophagi to construct our AI system. For the validation dataset, we took NBI videos of suspected superficial ESCCs. The AI system diagnosis used one magnified still image taken from each video, while 19 endoscopists used whole videos. We used 147 videos and still images including 83 superficial ESCC and 64 non-ESCC lesions. The accuracy, sensitivity and specificity for the classification of ESCC were, respectively, 80.9% [95% CI 73.6-87.0], 85.5% [76.1-92.3], and 75.0% [62.6-85.0] for the AI system and 69.2% [66.4-72.1], 67.5% [61.4-73.6], and 71.5% [61.9-81.0] for the endoscopists. The AI system correctly classified all ESCCs invading the muscularis mucosa or submucosa and 96.8% of lesions ≥ 20 mm, whereas even the experts diagnosed some of them as non-ESCCs. Our AI system showed higher accuracy for classifying ESCC and non-ESCC than endoscopists. It may provide valuable diagnostic support to endoscopists.

Clinical features of superficial esophagus squamous cell carcinoma according to alcohol-degrading enzyme ADH1B and ALDH2 genotypes.

BACKGROUND: Inactivated alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are related to esophageal carcinogenesis. We aimed to clarify the clinical features associated with the alcohol-degrading enzyme genotypes, ADH1B and ALDH2. We also investigated the risk factors for metachronous esophageal squamous cell carcinoma (ESCC) and head and neck SCC (HNSCC). METHODS: We conducted a single-center, retrospective study including patients with ESCC treated by endoscopic resection. Patients were recruited between October 2020 and September 2021. Buccal mucosal swabs were obtained from them to analyze the genetic polymorphisms affecting ADH (ADH1B) and ALDH (ALDH2) activity. Patients were categorized into three groups: both inactivated = double-inactivated group; inactivated ADH1B or ALDH2 = single-inactivated group; and both activated = activated group. RESULTS: Among the 297 enrolled patients, patients in the double-inactivated group were significantly younger (P < 0.001) and 60% of them were ≤ 50 years old. This group also had more ESCCs located in the upper esophagus (P < 0.001) and more simultaneous multiple ESCCs (P = 0.044). More than half of the patients had multiple Lugol-voiding lesions (LVLs) (P < 0.001) and heavy alcohol consumers (P = 0.012). Metachronous ESCC and HNSCC were more common in the double-inactivated group (P < 0.001, P = 0.001). Multivariate analysis identified located in the upper esophagus, multiple LVLs and history of HNSCC as risk factors for metachronous ESCC. CONCLUSIONS: Activation patterns of alcohol-metabolizing enzymes were related to age at ESCC onset, lesion location, and metachronous ESCC and HNSCC. Different approaches to the prophylaxis and treatment of esophageal cancer should be considered, depending on the enzyme activity pattern.