[A Case of Malignant Lymphoma Undergoing HAI Treatment for Multiple Liver Metastases of Carcinoid That Appeared about Nine Years after Resection of Rectal Carcinoid with Liver Metastases].

The present case pertained to a 70-year-old woman. The fecal occult blood test was positive. Colonoscopyrevealed rectal cancer. She underwent the first operation of low anterior resection. Pathological diagnosis was carcinoid, se, ly2, v0, n1. Approximately2 months later, multiple liver metastases were found. Because of strong enhancement at angiography, transarterial chemoembolization(TACE)was selected. After 3 rounds of TACE, we operated the residual liver metastasis approximately1 year and 7 months after the first operation. However, approximately8 years and 9 months after the first operation, multiple liver metastases were found again. Hepatic arterial infusion(HAI)was chosen because tumors showed weak en- hancement on CT. First, we tried high-dose HAI(5-FU 1 g/dayat 1-3 and 5-7, amount: 6 g/week), and liver metastases was almost in CR. However, extrahepatic metastasis was found on PET-CT. Because of rapid growth, we operated the growing lymph node. Pathological diagnosis was diffuse large-cell type B-cell malignant lymphoma. Thus, we extended the interval of HAI(weekly, biweekly, and monthly)and simultaneously4 courses of R-THP-COP(R: rituximab, THP: pirarubicin, C: cyclophosphamide, O: vincristine, P: prednisolone)therapyfor malignant lymphoma was administered. She is now an outpatient. Liver metastases continue to be in CR at approximately1 year and the IL-2R value is almost within normal range.

Small-Scale Panel Comprising Diverse Gene Family Targets To Evaluate Compound Promiscuity.

Despite the recent advances in the life sciences and the remarkable investment in drug discovery research, the success rate of small-molecule drug development remains low. Safety is the second most influential factor of drug attrition in clinical studies; thus, the selection of compounds with fewer toxicity concerns is crucial to increase the success rate of drug discovery. Compounds that promiscuously bind to multiple targets are likely to cause unexpected pharmacological activity that may lead to adverse effects. Therefore, avoiding such compounds during early research stages would contribute to identifying compounds with a higher chance of success in the clinic. To evaluate the interaction profile against a wide variety of targets, we constructed a small-scale promiscuity panel (PP) consisting of eight targets (ROCK1, PDE4D2, GR, PPARγ, 5-HT2B, adenosine A3, M1, and GABAA) that were selected from diverse gene families. The validity of this panel was confirmed by comparison with the promiscuity index evaluated from larger-scale panels. Analysis of data from the PP revealed that both lipophilicity and basicity are likely to increase promiscuity, while the molecular weight does not significantly contribute. Additionally, the promiscuity assessed using our PP correlated with the occurrence of both in vitro cytotoxicity and in vivo toxicity, suggesting that the PP is useful to identify compounds with fewer toxicity concerns. In summary, this small-scale and cost-effective PP can contribute to the identification of safer compounds that would lead to a reduction in drug attrition due to safety issues.

Relationship of MATE1 Inhibition and Cytotoxicity in Nephrotoxicity: Application for Safety Evaluation in Early Drug Discovery.

Accumulation of toxic endogenous and/or exogenous substances can trigger tissue injury. Multidrug and toxin extrusion proteins (MATEs) are transporters at renal proximal tubules involved in the secretion of hydrophilic substances into urine. Multidrug and toxin extrusion protein inhibition can lead to nephrotoxicity via accumulation of toxic substances; however, case studies demonstrating causality are rare, except for drug-drug interaction studies. To explore the involvement of MATE inhibition in nephrotoxicity, MATE1 inhibition, cytotoxicity, and mitochondrial toxicity (MT) of 38 in-house compounds that showed toxicity were assessed in in vivo safety evaluations using rats, dogs, and monkeys and compared considering unbound exposures at minimal steady-state concentration (C24h,u) between nephrotoxicity positive and negative compounds. Logarithmic-corrected means of C24h,u normalized by MATE1 IC50 or cytotoxicity EC50 (C24h,u/IC50 and C24h,u/EC50) were higher for nephrotoxic compounds. An exposure cutoff of C24h,u/IC50 > 0.01 filtered nephrotoxicity with a 54% positive predictive value. Of 7 cases filtered with this cutoff, all the cases showed pathological changes at renal proximal tubules expressing MATE1. Furthermore, all cases with > 0.01 reliable exposure for MATE1 inhibition and cytotoxicity exhibited nephrotoxicity. Although compounds potent for MATE1 inhibition and cytotoxicity without and with MT (potentials of 10, 30, and 40 µM, respectively) were correctly classified as nephrotoxic by evaluation of in vitro potency alone, without considering exposures, these results suggest that MATE1 inhibition potency and cytotoxicity can be used to assess nephrotoxicity, especially at proximal tubules, and could be used for safety assessment in early drug discovery.

[Two Year Recurrence Free Survival after Resection of Cutaneous Metastasis from Pancreatic Cancer - A Case Report].

The patient was a 73-year-old woman who underwent distalpancreatectomy for pancreas tailcancer (T3, N0, M0, stage III ). Hepatic arterialinfusion(HAI)using high-dose 5-fluorouracil(5-FU)(6,000mg/week)was performed 35 days after curative resection to prevent liver metastases. Although chemotherapy with gemcitabine(GEM)was administered for 2 weeks, the patient was aware of a nodule(1 cm in diameter)on the right lower quadrant of the abdomen. Resection of the cutaneous mass was performed and histological findings revealed metastatic adenocarcinoma from the pancreas cancer. Six courses of chemotherapy with GEM were administered as adjuvant therapy. Two years after the treatment with GEM, neurological symptoms appeared, and computed tomography(CT)and magnetic resonance imaging(MRI)revealed a solitary metastatic thalamus tumor(2 cm in diameter). After stereotactic radiotherapy, the patient was transferred to a different hospitalfor physicaltherapy. Herein, we report on a case of 2 year recurrence free survivalafter the resection of a cutaneous metastasis from pancreatic cancer.

[Pre-Operative Treatment with Transcatheter Arterial Chemoembolization (TACE) and Hepatic Arterial Infusion (HAI) for Liver Metastasis from Gastric Cancer--A Case Report].

The patient was an 83-year-old man who underwent distal gastrectomy for gastric cancer (T3, N1, M0, P0, M0, stage ⅡB) at a different hospital from ours. A metastatic lesion was detected in the liver 5 months after gastrectomy. Although chemotherapy with S-1 or bi-weekly CPT-11 was administered for 6 months, the liver tumor increased in size. The patient was referred to our hospital for treatment of the liver metastasis. Abdominal-computed tomography (CT) and magnetic resonance imaging (MRI) revealed a solitary metastatic liver tumor (9 cm in diameter: S7/S6/S8) with a hypervascular tumor stain. Transcatheter arterial chemoembolization (TACE) using degradable starch microspheres (DSM) plus mitomycin C, and hepatic arterial infusion (HAI) using high-dose 5-fluorouracil (5-FU) (6,000 mg/week), were performed 54 days before curative resection of the liver (S6+S7+S8+S5b/c). Histological findings revealed metastatic adenocarcinoma with a tumor thrombus in the posterior branch of the portal vein. The patient was treated with 2 courses of adjuvant chemotherapy with paclitaxel. No recurrence was observed 8 months after hepatectomy. This case suggests that combined treatment with TACE/HAI as a multimodal treatment might be effective in the management of hypervascular liver metastasis from gastric cancer.

Biomimetic one-pot preparation of a black tea polyphenol theasinensin A from epigallocatechin gallate by treatment with copper(II) chloride and ascorbic acid.

Chromatographic separation of black tea polyphenols is too difficult to supply sufficient quantities of pure compounds for biological experiments. Thus, facile methods to prepare black tea constituents were desired. Treatment of epigallocatechin gallate with copper(II) chloride efficiently afforded an unstable quinone dimer, dehydrotheasinensin A, and subsequent treatment with ascorbic acid stereoselectively yielded theasinensin A. The latter is a dimer with an R-biphenyl bond, one of the major polyphenols found in black tea. The method is simpler and more effective than enzymatic preparation.