A 78-year-old man underwent laparoscopy-assisted total gastrectomy for gastric cancer (pT3N0M0). Multiple port sites were used, including a 10 mm port for a videoscope at the umbilical point and three other working ports. During the six-month follow-up evaluation, a 2 cm enhancing mass confined to the muscle layer was found 12 mm from the right lower quadrant port site, suggesting a metastatic or desmoid tumor. Follow-up computed tomography imaging two months later showed that the mass had increased in size to 3.5 cm. We confirmed that there was no intra-abdominal metastasis by diagnostic laparoscopy and then performed a wide resection of the recurrent mass. The histologic findings revealed poorly differentiated adenocarcinoma, suggesting a metastatic mass from the stomach cancer. The postoperative course was uneventful, and the patient completed adjuvant chemotherapy with TS-1 (tegafur, gimeracil, and oteracil potassium). There was no evidence of tumor recurrence during the 50-month follow-up period.
Adenocarcinoma ; Aged ; Chemotherapy, Adjuvant ; Fibromatosis, Aggressive ; Follow-Up Studies ; Gastrectomy* ; Humans ; Laparoscopy ; Metastasectomy* ; Neoplasm Metastasis ; Oxonic Acid ; Recurrence ; Stomach Neoplasms*

PURPOSE: To report two cases of lacrimal drainage obstruction associated with the anticancer drug S-1 (tegafur, gimeracil, oteracil ; TS-1(R), Taiho Pharmaceutical, Japan). CASE SUMMARY: (Case 1) A 34-year-old male who had previously undergone a total gastrectomy for treatment of gastric cancer visited with epiphora in both eyes that had developed 6 months after S-1 treatment. On examination, a right canalicular obstruction and left punctal and nasolacrimal partial obstruction were noted. Endoscopic dacrycystorhinostomy with lacrimal trephinization was done in the right eye and punctoplasty with punctal membrane removal and silicone tube intubation were performed in the left eye and the epiphora were successfully treated. (Case 2) A 60-year-old male who was treated with S-1 for gastric cancer presented with tearing in both eyes that had developed 2 months after S-1 treatment. Ophthalmic examinations revealed a right nasolacrimal partial obstruction in the right eye and lacrimal sac obstruction in the left. Silicone intubations were performed on both sides and the epiphora were successfully treated. CONCLUSIONS: Lacrimal drainage obstructions may develop after S-1 treatment. Therefore, ophthalmologic evaluations should be performed in patients treated with S-1 to detect lacrimal drainage obstruction.
Adult ; Drainage ; Eye ; Gastrectomy ; Humans ; Intubation ; Lacrimal Apparatus Diseases ; Male ; Membranes ; Middle Aged ; Oxonic Acid ; Pyridines ; Silicones ; Stomach Neoplasms ; Tears

OBJECTIVEWe tested whether melamine nephrotoxicity was exacerbated by urate (a typical component of renal stones in humans) in rats with hyperuricemiainduced by the uricase inhibitor, potassium oxonate (Oxo).

METHODSRats were exposed to melamine or Oxo alone or combinations of melamine (200-400 mg/kg) and Oxo (200-600 mg/kg) for 3 consecutive days. Kidney injury was evaluated by renal biochemical functions, histomorphology, and lipid peroxidation. Kidney crystals were analyzed for their composition.

RESULTSNephrotoxicity was minimal in animals administered melamine or Oxo alone, but it was demonstrable in animals administered at least 800 mg/kg of the two compounds combined. All rats in the 400+600 (melamine+Oxo) and 400+400 mg/kg groups and 4 out of 6 in the 200+600 mg/kg group died within 3 days; no rat died in the 200+400 or 200+200 mg/kg group. Dose-dependent renal damage resembling clinical findings in affected patients was observed in rats administered the two compounds. Crystal composition determination revealed the existence of melamine and uric acid in the affected kidneys, resembling human stones.

CONCLUSIONOur findings suggest that uric acid plays a key role in melamine-related kidney injury in humans. Future studies should consider uric acid together with melamine when examining adverse effects in humans.

Animals ; Disease Models, Animal ; Hyperuricemia ; chemically induced ; complications ; Kidney Diseases ; chemically induced ; Lipid Peroxidation ; drug effects ; Male ; Oxonic Acid ; Rats, Wistar ; Triazines ; toxicity

OBJECTIVEThis study was to investigate the molecular biomarkers of apoptosis induced by BH3 mimetic S1 in human primary AML cells.

METHODSMononuclear cells were isolated from 27 newly diagnosed AML samples. Apoptosis was analyzed by flow cytometry. IC(50) value of S1 on these samples was determined by XTT assay. The expression level of BCL-2 family members and phosphorylated BCL-2 were assessed by Western blot with subsequent semi-quantitatively densitometric analysis. XTT assay was performed to determine the cell viability of the combined use of S1 and MEK/ERK inhibitor PD98059. The interactions between BCL-2 and pro-apoptosis proteins were tested by co-immunoprecipitation.

RESULTSThe flow-cytometry detection showed that S1 induced the apoptosis of primary AML cells. Based on the responses, 27 primary samples could be classified into three groups: (1) a sensitive group (12 of 27 cases) with IC(50)<14 µmol/L, (2) an intermediate group (8 of 27 cases) with IC(50) of 14-30 µmol/L and (3) a resistant group (7 of 27 cases) with IC(50)>30 µmol/L. The ratio of pBCL-2/(BCL-2+MCL-1) showed a good linear correlation with the IC(50) values. (R(2) = 0.71, P < 0.0001). PD98059 suppressed BCL-2 phosphorylation. When PD98059 suppressed BCL-2 phosphorylation, the apoptotic rate of drug-resistant cells induced by S1 increased from 9.8% to 64.5% (combination index, CI = 0.4), accompanied by more dissociation of BCL-2 heterodimers.

CONCLUSIONThe combination of S1 with PD98059 decrease pBCL-2 level of AML patients and inhibits of the anti-apoptotic function of BCL-2 through enhancing the dissociation of BCL-2 heterodimers.

Antimetabolites, Antineoplastic ; Apoptosis ; Cell Line, Tumor ; Drug Combinations ; Humans ; Leukemia, Myeloid, Acute ; Molecular Mimicry ; Oxonic Acid ; Phosphorylation ; Proto-Oncogene Proteins c-bcl-2 ; Tegafur

S-1, a novel oral fluoropyrimidine, is an effective therapeutic agent for gastric cancer. Herein, we report a case with locally advanced gastric cancer that achieved a curative resection after S-1 monotherapy as neoadjuvant treatment. A 68-year-old man was diagnosed with gastric cancer and massive lymphadenopathy involving the perigastric, celiac axis and splenic hilum. His clinical stage was cT3N2H0P0M0. Considering his relatively poor performance (ECOG 2, severe weight loss) and advanced age, we started the patient on S-1 monotherapy at a dose of 35 mg/m2 bid for 4 consecutive weeks followed by a 2-week rest. Follow-up study after 4 treatment cycles revealed disappearance of the lymphadenopathy of the perigastric and celiac axis with diminished extension of the stomach mass. The patient had a partial response (PR) with a 72% tumor reduction, according to the Response Evaluation Criteria in Solid Tumors (RECIST). His performance status was improved to an ECOG 1 and he gained 7 kg. A curative (R0) resection was achieved with a radical total gastrectomy and D2 dissection. The pathological stage was pT3N2M0, stage IIIB. In conclusion, S-1 neoadjuvant chemotherapy aided in the treatment of gastric cancer in this patient.
Adenocarcinoma/*drug therapy/pathology/surgery ; Aged ; Antimetabolites, Antineoplastic/administration & dosage/*therapeutic use ; Drug Combinations ; Gastrectomy ; Humans ; Male ; *Neoadjuvant Therapy ; Neoplasm Staging ; Oxonic Acid/administration & dosage/*therapeutic use ; Stomach Neoplasms/*drug therapy/pathology/surgery ; Tegafur/administration & dosage/*therapeutic use

Objective To investigate the clinical effects and safety of bevacizumab combined with S-1 as the second-line treatment of recurrent and/or metastatic esophageal cancer after chemoradiation. Methods Patients with recurrent or metastatic esophageal cancer after chemoradiation were treated with bevacizumab and S-1. Bevacizumab was used by intravenous infusion, 7.5mg/kg body weight on day 1; S-1 was used by oral at 80mg/m·d on day 1-14, 21 days as a cycle of treatment and repeated until either pro- gressive disease or intolerable toxicity occurred. Chest CT were performed and RECIST 1.1 was used for response evaluation. Kaplan-Meier method was used for survival analysis. Side effects were recorded and analyzed. Results Totally 78 patients were enrolled in the study, including 67 squamous cell carcinoma and 11 adenocarcinoma histologically. The overall response (CR+PR) rate was 22.4% (17/76) and disease control (CR+PR+SD) rate was 61.8% (47/76) respectively. The median follow-up time was 20 months (range from 9 to 44 months). The median progression-free survival (PFS) was 4.9 months (95% CI 4.4-5.5) and the median overall survival (OS) was 8.1 months (95% CI 7.6-9.2). The median PFS and OS of patients with metastasis diseases were 6.2 months (95% CI 3.3 to 6.3) and 8.5 months (95% CI 5.8 to 11.2), where PFS was longer than that of patients with local regional recurrence (median 5.0 months, 95% CI 3.0 to 5.5, P=0.017) and OS was longer than that of patients with regional disease and metastasis (median 8.0 months, 95% CI 4.6 to 9.5, P=0.010). The common adverse effects were mild to moderate neutropenia (84.2%), grade I-II hand and foot syndrome (51.3%), grade I-II nausea (48.7%), mild epistaxis (30.1%) and mild vomiting (14.5%). Esophageal bleeding occurred in 7.9% of patients. One patient (1.3%) died from massive bleeding which was caused by esophageal perforation. Conclusion Bevacizumab combined with S-1 was effective and safe for esophageal cancer patients who had recurrent or metastatic diseases after chemoradiation.
Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Bevacizumab ; administration & dosage ; adverse effects ; Drug Combinations ; Esophageal Neoplasms ; drug therapy ; mortality ; pathology ; Female ; Humans ; Male ; Middle Aged ; Oxonic Acid ; administration & dosage ; adverse effects ; Tegafur ; administration & dosage ; adverse effects

OBJECTIVETo explore the effect of hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) on the postoperative metastatic rate and survival rate of advanced gastric cancer (AGC).

METHODSIn HIIC group, patients received HIIC (mitomycin C 30 mg and cisplatin 100 mg were added into 2000 ml distilled water, heated to 42 approximately 45 degrees C, perfused to abdominal cavity for 30 min and then sucked) and intravenous chemotherapy after operation (5- FU 10 approximately 15 mg/kg, mitomycin C 0.1 approximately 0.15 mg/kg, adriamycin 0.5 approximately 1 mg/kg i.v drip, once a week for 2 approximately 3 weeks). In control group, patients received intravenous chemotherapy only. The postoperative metastatic rate and survival rate (1- , 3- and 5- year) of patients were compared between 92 cases of AGC undergone HIIC and 120 cases of AGC without HIIC (control group).

RESULTSThe peritoneal recurrence rates after operations occurred within two years were 14.1% and 37.5% in HIIC group and control group respectively (P < 0.01). The 1- , 3- , and 5- year survival rates in HIIC group were 98.9%, 68.5%, and 52.2% and in control group 95.0%, 56.7% and 37.5% respectively. The 3- , and 5- year survival rates were significantly different between the two the groups (P < 0.05).

CONCLUSIONHIIC can kill isolated intraperitoneal cancer cells, reduce peritoneal recurrence rate after operations, raise significantly survival rate of patient, and improve the prognosis of AGC.

Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Chemotherapy, Cancer, Regional Perfusion ; Cisplatin ; administration & dosage ; Female ; Humans ; Hyperthermia, Induced ; Injections, Intraperitoneal ; Intraoperative Period ; Male ; Middle Aged ; Mitomycin ; administration & dosage ; Oxonic Acid ; administration & dosage ; Stomach Neoplasms ; therapy ; Young Adult

Objective: To explore the safety and efficacy of oxaliplatin plus capecitabine (CapeOX) or oxaliplatin plus S-1 (SOX) regimen neoadjuvant chemotherapy in the treatment of advanced gastric cancer. Methods: A retrospective cohort study was performed. Clinical data of patients diagnosed as advanced gastric cancer undergoing CapeOX/SOX neoadjuvant chemotherapy and standard laparoscopic radical operation for gastric cancer in Ruijin Hospital of Shanghai Jiaotong University School of Medicine from April 2016 to April 2019 were retrospectively collected. Inclusion criteria were as follows: (1) age≥18 years; (2) gastric adenocarcinoma was confirmed by histopathology and the clinical stage was T3-4aN+M0; (3) tumor could be resectable; (4) preoperative neoadjuvant chemotherapy was CapeOX or SOX regimen without radiotherapy or other regimen chemotherapy; (5) no other concurrent malignant tumor; (6) the Eastern Cooperative Oncology Group (ECOG) score ≤ 1; (7) no bone marrow suppression; (8) normal liver and kidney function. Exclusion criteria were as follows: (1) patients with recurrent gastric cancer; (2) patients receiving emergency surgery due to tumor perforation, bleeding, obstruction, etc.; (3) allergy to oxaliplatin, S-1, capecitabine or any drug excipients; (4) diagnosed with coronary heart disease, cardiomyopathy, or the New York Heart Association class III or IV; (5) pregnant or lactating women. A total of 118 patients were enrolled as the neoadjuvant chemotherapy group, and 379 patients with locally advanced gastric cancer who received surgery combined with postoperative adjuvant chemotherapy over the same period simultaneously were included as the adjuvant chemotherapy group. After propensity score matching was performed including gender, age, ECOG score, tumor site, clinical stage, chemotherapy regimen and other factors by 1:1 ratio, there were 40 cases in each group. The differences between the two groups in general conditions, efficacy of neoadjuvant chemotherapy, intraoperative conditions, postoperative conditions, histopathological results, chemotherapy-related adverse events, and survival status were compared and analyzed. Results: Comparison of baseline demographics between the two groups showed no statistically significant difference (all P>0.05). In the neoadjuvant chemotherapy group, 5.0% (2/40) of patients achieved clinical complete response, 57.5% (23/40) achieved partial response, 32.5% (13/40) remained stable disease, and 5.0% (2/40) had disease progression before surgery. Objective response rate was 62.5% (25/40), and disease control rate was 95.0% (38/40). There were no statistically significant differences between neoadjuvant chemotherapy group and adjuvant chemotherapy group in terms of operation time, intraoperative blood loss, number of lymph node harvested, length of postoperative hospital stay, and postoperative mortality and morbidity (all P>0.05). Postoperative complications were well managed with conservative treatment. No Clavien-Dindo IV or V complications were observed in both groups. Pathological results showed that the proportion of patients with pathological stage T1 in the neoadjuvant chemotherapy group was significantly higher than that in the adjuvant chemotherapy group [27.5% (11/40) vs. 5.0% (2/40)], while the proportion of patients with pathological stage T3 was significantly lower than that in the adjuvant chemotherapy group [20.0% (8/40) vs. 45.0% (18/40)], with statistically significant difference (χ(2)=15.432, P=0.001). In the neoadjuvant chemotherapy group, there were 4 cases of tumor regression grade 0, 8 cases of grade 1, 16 cases of grade 2, and 12 cases of grade 3. The pathological complete response rate was 10% (4/40), the overall pathological response rate was 70.0% (28/40). There was no statistically significant difference in the incidence of chemotherapy-related adverse events between neoadjuvant chemotherapy group and adjuvant chemotherapy group [40% (16/40) vs. 37.5% (15/40), P>0.05). There were no statistically significant differences in OS (43 months vs. 40 months) and 3-year OS rate (66.1% vs. 59.8%) between neoadjuvant chemotherapy group and adjuvant chemotherapy group (P=0.428). The disease-free survival (DFS) and 3-year DFS rates of the neoadjuvant chemotherapy group were significantly superior to those of the adjuvant chemotherapy group (36 months vs. 28 months, 51.4% vs. 35.8%, P=0.048). Conclusion: CapeOX or SOX regimen neoadjuvant chemotherapy is a safe, effective and feasible treatment mode for advanced gastric cancer without increasing surgical risk and can improve the DFS of patients.
Adenocarcinoma/surgery* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Capecitabine/administration & dosage* ; Chemotherapy, Adjuvant ; Drug Combinations ; Humans ; Neoadjuvant Therapy ; Oxaliplatin/administration & dosage* ; Oxonic Acid/administration & dosage* ; Radiotherapy ; Retrospective Studies ; Stomach Neoplasms/surgery* ; Tegafur/administration & dosage* ; Treatment Outcome

In this study, SD rats were orally administrated with oteracil potassium (300 mg . kg-1 . d-1 ) to prepare the hyperuricemia model, and divided into normal, model, Allopurinol, LE high dosage, middle dosage and low dose (200, 100, 50 mg . kg-1 . d-1) groups. The rats were orally administrated with test drugs 1 hour later after being orally administrated with Oteracil potassium. After 7 days, serum uric acid, serum creatinine, uric acid and expression of relevant transporters in kidney were tested to study the regulatory effect of leonurus extracts on serum uric acid, renal function and relevant transporters in kidney of rats with hyperuricemia. Compared with the model group, the leonurus extract group could significantly down-regulate serum uric acid and creatinine levels of rats with hyperuricemia, and increase the urine uric acid level. Meanwhile, leonurus extracts could notably down-regulate the mRNA expressions of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9), up-regulate the mRNA expressions of organic cation transportanter (OCT) and Carnitine transporter (OCTN) and promote the excretion of uric acid of kidney.
Allopurinol ; pharmacology ; Animals ; Blood Urea Nitrogen ; Creatinine ; blood ; Disease Models, Animal ; Down-Regulation ; Gene Expression Regulation ; drug effects ; Hyperuricemia ; blood ; drug therapy ; Kidney ; drug effects ; Leonurus ; chemistry ; Male ; Organic Anion Transporters ; genetics ; Oxonic Acid ; administration & dosage ; Plant Extracts ; isolation & purification ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Specific Pathogen-Free Organisms ; Up-Regulation ; Uric Acid ; blood

The study is to investigate the pharmacokinetics of S-1 capsule (tegafur, gimeracil and potassium oxonate capsule) in patients with advanced gastric cancer after single and multiple oral administration. Twelve patients with advanced gastric cancer were recruited to the study. The dose of S-1 for each patient was determined according to his/her body surface area (BSA). The dose for single administration was 60 mg every subject. The dose for multiple administration for one subject was as follows: 100 mg x d(-1) or 120 mg x d(-1), 28-days consecutive oral administration. The pharmacokinetic parameters of tegafur, 5-fluorouracil, gimeracil, potassium oxonate and uracil after single oral administration were as follows: (2,207 +/- 545), (220.0 +/- 68.2), (374.9 +/- 103.0), (110.5 +/- 100.8) and (831.1 +/- 199.9) ng x mL(-1) for Cmax; (11.8 +/- 3.8), (4.4 +/- 3.3), (7.8 +/- 5.1), (3.1 +/- 0.9) and (8.8 +/- 4.1) h for t1/2, respectively. After six days oral administration, the average steady state plasma concentrations (Cav) of tegafur, 5-fluorouracil, gimeracil, potassium oxonate and uracil were (2,425 +/- 1,172), (73.88 +/- 18.88), (162.6 +/- 70.8), (36.89 +/- 29.35) and (435.3 +/- 141.0) ng x mL(-1), respectively, and the degree of fluctuation (DF) were (1.0 +/- 0.2), (2.5 +/- 0.4), (3.1 +/- 0.8), (2.4 +/- 0.8) and (1.5 +/- 0.3), respectively. The cumulative urine excretion percentage of tegafur, 5-fluorouracil, gimeracil and potassium oxonate in urine within 48 h were (4.2 +/- 2.8) %, (4.7 +/- 1.6) %, (18.5 +/- 6.0) % and (1.7 +/- 1.2) %, repectively, after single oral administration of S-1. The results exhibited that tegafur had some drug accumulation observed, and gimeracil, potassium oxonate, 5-fluorouracil and uracil had no drug accumulation observed.
Administration, Oral ; Adult ; Aged ; Antimetabolites, Antineoplastic ; pharmacokinetics ; Capsules ; Drug Combinations ; Female ; Fluorouracil ; blood ; urine ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Oxonic Acid ; blood ; pharmacokinetics ; urine ; Pyridines ; blood ; urine ; Stomach Neoplasms ; blood ; metabolism ; pathology ; urine ; Tegafur ; blood ; pharmacokinetics ; urine ; Uracil ; blood ; urine