[A Case of Long-Term Survival without Recurrence after Completion of Immunotherapy Due to Response of Third- Line Nivolumab for Liver Metastasis Recurrence of Esophagogastric Junction Cancer].

The patient was a 66-year-old man with dysphagia. He underwent total gastrectomy and trans-hiatal abdominal esophagectomy with lymph node dissection, including the inferior mediastinum, for esophagogastric junction cancer. The postoperative pathological examination revealed poorly differentiated adenocarcinoma T4aN2, Stage ⅢA, HER2 negative, and postoperative adjuvant therapy S-1 oral administration was started. Four months after surgery, computed tomography (CT)showed recurrent liver and para-aortic lymph node metastases. First-line XELOX therapy and second-line weekly PTX therapy resulted in PD, and nivolumab administration was started as third-line. The evaluation was PR and CR at 3 and 6 months, respectively. At the same time, he developed acute cholangitis and underwent open lithotripsy drainage. Postoperatively, treatment was terminated according to the patient's wishes. To date, it has been 5 years since the first operation and 3 and a half years since remission with nivolumab, and no recurrence has been observed. There is little evidence regarding the timing of conversion or treatment discontinuation for successful cases of immunotherapy in the salvage line for gastric cancer.

[A Patient with AFP-Producing Gastric Cancer and Stenosis Who Regained Oral Intake Capabilities after T-DXd Treatment].

We present the case of a 55-year-old man with HER2-positive, AFP-producing gastric cancer and multiple liver metastases. The patient consequently underwent 7 courses of SOX plus trastuzumab therapy, 3 courses of weekly PTX plus ramucirumab therapy, and 3 courses of nivolumab therapy, all of which resulted in PD. Obstruction due to tumor growth became noticeable 9 months after the start of the first treatment. Subsequently, the patient experienced malnutrition and systemic edema due to impaired oral intake. However, subsequent trastuzumab deruxtecan(T-DXd)therapy induced remarkable tumor shrinkage. Furthermore, oral intake became possible, and edema started subsiding. Thus, we report the course of a patient with AFP-producing gastric cancer and stenosis who regained oral intake capabilities after T-DXd treatment.

Dienogest is a selective progesterone receptor agonist in transactivation analysis with potent oral endometrial activity due to its efficient pharmacokinetic profile.

Dienogest was introduced as an oral progestin. Yet its strong oral potency on endometrial activity is not clearly explained. To circumvent this situation, steroid hormone receptor profiling using transactivation assay and endometrial activity test in rabbits were carried out with determination of plasma drug concentration. Agonistic/antagonistic activity on human progesterone receptor (PR), androgen receptor (AR), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), estrogen receptor alpha (ERalpha), or estrogen receptor beta (ERbeta) were determined. Dienogest activate PR (EC50=3.4 or 10.5 nmol/l) with antagonistic activity on AR (EC50=420.6 or 775.0 nmol/l) but not agonistic nor antagonistic action on GR, MR (3000 nmol/l). Dienogest activate neither ERalpha nor ERbeta (3000 nmol/l). Progesterone activated PR with antagonistic activity on AR and on MR. Dydrogesterone showed a similar profile to progesterone. Norethisterone activated PR, AR, and ERalpha. Medroxyprogesterone acetate activated PR, AR, and GR. Danazol activated PR and AR. Collectively, dienogest has a good specificity to PR compared with the other drugs. By oral treatment, dienogest showed the strongest endometrial activity (ED50=0.0042 mg/kg) in McPhail test among other progestins (ED50 values for MPA, DYG, NES were 0.074, 1.9, >0.05 mg/kg, respectively). Dienogest showed higher plasma concentrations than those of the other progestins with higher doses. The estimated plasma concentration of dienogest at ED50 (3.66 nmol/l) was close to its EC50 value to activate PR. Thus, the stronger oral activity of dienogest could be explained simply by its in vitro potency on PR and its oral pharmacokinetic profile.

Evaluation of the hepatic blood flow increase in the cases with liver metastasis and prediction of patent cases of liver metastasis using dynamic CT.

BACKGROUND/AIMS: This study aimed to measure hepatic blood flow increase in cases with liver metastasis and to diagnose minimal metastasis which cannot be visualized by imaging modalities. METHODOLOGY: The evaluation of hepatic arterial flow increase was performed quantitatively by newly devised index ELR (early-late-ratio) using dynamic computed tomographic (CT) scanning with contrast media. RESULTS: The ratio of the cases with liver metastasis was significantly higher than that of normal liver control. It was revealed that the ratio was correlated with microvessel proliferation in the liver around the metastasis by examination of surgical specimen. Moreover, the patent group which proved to have metastasis within 6 months also had a significant higher ELR value. CONCLUSIONS: ELR not only was useful to evaluate hepatic blood flow increase in the cases with liver metastasis but also could be applied to predict the patent group with micrometastasis.

Employment of the human estrogen receptor beta ligand-binding domain and co-activator SRC1 nuclear receptor-binding domain for the construction of a yeast two-hybrid detection system for endocrine disrupters.

To screen a wide variety of chemicals for endocrine disrupters, and to develop an effective microbial degradation system for them, a good system is needed for the rapid and accurate evaluation of the endocrine-disrupting activities of suspected chemicals and their degradation products. We constructed two-hybrid systems that co-express the Gal4p DNA binding domain/ligand-binding domain of human estrogen receptor (hER) alpha or beta and the Gal4p transactivation domain/nuclear receptor-binding domain of co-activator SRC1, TIF2, or AIB1 in Saccharomyces cerevisiae with a chromosome-integrated lacZ reporter gene under the control of Gal4p-binding sites. We found that the combination of the hERbeta ligand-binding domain and SRC1 nuclear receptor-binding domain was most effective for the xenoestrogen-dependent induction of reporter activity. The extent of transcriptional activation by known xenoestrogens and phytoestrogens was found to correlate well with their estrogenic activities as measured by the previous system with rat ERalpha. This system detects estrogenic activity in some chemicals that have not been suspected of being positive. We also applied this assay system to test the microbial degradation products of gamma-hexachlorocyclohexane (gamma-HCH) by Sphingomonas paucimobilis. Among the gamma-HCH metabolites, 2,5-dichlorohydroquinone and chlorohydroquinone had estrogenic activities similar to the original chemical, while hydroquinone, a later stage metabolite, showed no activity, suggesting the necessity of evaluating intermediate metabolites in microbial degradation systems.

Yeast two-hybrid detection systems that are highly sensitive to a certain kind of endocrine disruptors.

We tested the effects of several combinations of bait and fish components of the yeast two-hybrid detection system for estrogenic activity. A combination of the full-length human estrogen receptor alpha with the nuclear receptor-binding domain of co-activator steroid receptor co-activator-1 (SRC-1) or transcriptional intermediate factor-2 (TIF-2) was most effective for estrogen-dependent induction of the chromosome-integrated UAS(GAL)-CYC1(p)-lacZ reporter construct among the two-hybrid systems so far tested.