Efficacy and Safety of Conversion Therapy by Intraperitoneal and Intravenous Paclitaxel Plus Oral S-1 in Gastric Cancer Patients With Peritoneal Metastasis: A Prospective Phase II Study.

Background: Neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) has shown promising results in gastric cancer (GC) with peritoneal metastasis. However, clinical practice experience of NIPS is still lacking in China. In this study, we investigate the efficacy and safety of NIPS in Chinese patients. Methods: Eligible patients received NIPS every 3 weeks. Gastrectomy was performed for patients who met the criteria of conversion surgery. The primary end point was 1-year overall survival (OS) rate. Secondary end points were the response rate, toxic effects, conversion surgery outcomes and median survival time (MST). Results: Sixty-seven patients were enrolled. The primary endpoint was achieved with 1-year OS rate reached 67.2% (95% CI, 56.8%-79.4%). Conversion surgery was performed in 42 patients (62.9%), and R0 resection was achieved in 23 patients (54.8%) with the MST of 31.3 months (95% CI, 24.3-38.3). And the MST was 19.3 months (95% CI, 16.4-22.2) for all patients. Toxicity and surgical complications were well-tolerated. Moreover, sex, R0 resection, pathological nodal stage and tumor regression grade (TRG) were independent prognostic factors for patients who underwent conversion surgery. Conclusion: The NIPS is effective and safe in treating GC patients with peritoneal metastasis. Male patients, patients who underwent R0 resection, patients with ypN0-1 or TRG 1 after conversion surgery are more likely to benefit from the NIPS. Clinical Trial Registration: http://www.chictr.org.cn/, identifier https://clinicaltrials.gov/ ().

Drug-Drug Interactions and Disease Status Are Associated With Irinotecan-Induced Hepatotoxicity: A Cross-Sectional Study in Shanghai.

Irinotecan-induced hepatotoxicity can cause severe clinical complications in patients; however, the underlying mechanism and factors affecting hepatotoxicity have rarely been investigated. In this cross-sectional study, we screened all clinical, demographic, medication, and genetic variables among 126 patients receiving irinotecan and explored potential associations with the incidence and time to onset of irinotecan-induced hepatotoxicity. Approximately 38.9% of the patients suffered from hepatotoxicity after irinotecan administration. The presence of cardiovascular diseases increases the incidence of hepatotoxicity ≈2.9-fold and doubles the hazard of time to hepatotoxicity. Patients with liver metastasis had a >4-fold higher risk of hepatotoxicity and a 3.5-fold increased hazard of time to hepatotoxicity compared to those without liver metastasis. Patients who took cytochrome P450 (CYP) 3A inducers had a 4.4-fold increased incidence of hepatotoxicity, and furthermore, concomitant use of platinum-based antineoplastics revealed 4.2 times the hazard of time to hepatotoxicity compared to those receiving antimetabolites. The cumulative dose of irinotecan (5-9 cycles) increased hepatotoxicity by 8.5 times. However, the genotypes and phenotypes of UGT1A1*28/*6 failed to be predictive factors of hepatotoxicity. The findings of this study suggest that irinotecan-induced hepatotoxicity is not directly associated with genetic variables but is mostly related to concomitant use of CYP3A4 inducers and platinum, as well as the presence of liver metastasis and cardiovascular disease. Thus, close monitoring of liver function is recommended, especially in patients with liver impairment or using CYP3A inducers and platinum antineoplastic drugs, which may be the best way to prevent hepatotoxicity.

Gene-Gene Interactions of Gemcitabine Metabolizing-Enzyme Genes hCNT3 and WEE1 for Preventing Severe Gemcitabine-Induced Hematological Toxicity.

Most patients experience severe hematological toxicity during treatment with gemcitabine; thus, preventing such toxicity would improve the treatment effects and patient quality of life. We analyzed 13 polymorphisms in the transporters, metabolizing enzymes, targets, and genes involved in DNA damage and the folate pathway among 132 patients treated with gemcitabine and studied their association with the severity of the hematological toxicities. Single-locus analysis showed that the single-nucleotide polymorphisms (SNPs) RRM1 rs12806698 and rs11031918 and DCTD rs7663494 were significantly associated with severe neutropenia, hENT1 rs760370 and hCNT3 rs7867504 and rs4877831 were associated with severe leukopenia, CDA rs2072671, DCTD rs7663494, and WEE1 rs3910384 were associated with severe anemia, and MTHFR rs1801133 was associated with severe thrombocytopenia after stringent Bonferroni correction (P < .0038). The gene-gene interaction analysis identified the overall best models, including a 2-way interaction model (hCNT3 rs7867504 and dCK rs12648166) for severe leukopenia (P = .0022) and a 3-locus model (CDA rs207671, DCTD rs7663494, and WEE1 rs3910384) for severe anemia with a strong synergistic effect (P = .0001). The association with hematological toxicity was further strengthened by the results of a haplotype analysis, in which the homozygous genotype combination of rs3910384 CC, rs2072671 AA, rs12648166 GG, rs7867504 CC, and rs7663494 TT conferred high genetic susceptibility to severe thrombocytopenia. Our results suggest that the gene-gene interaction of gemcitabine metabolic pathway genes and WEE1 contributes to susceptibility to gemcitabine-induced hematological toxicity. Moreover, we propose a promising data-mining analysis approach (generalized multifactor dimensionality reduction) to detect and characterize gene-gene interactions.

Relationship between UGT1A1*6/*28 polymorphisms and severe toxicities in Chinese patients with pancreatic or biliary tract cancer treated with irinotecan-containing regimens.

PURPOSE: The aim of this retrospective study was to investigate the relationship between UGT1A1 polymorphisms and toxicities in Chinese patients with pancreatic or biliary tract cancer receiving irinotecan-containing regimens as the second- or third-line chemotherapy. PATIENTS AND METHODS: A total of 36 patients with unresectable pancreatic cancer and 12 patients with unresectable biliary tract cancer were included. Approximately 33 patients were treated with FOLFIRI regimen, a chemotherapy regimen, where FOL stands for folinic acid, F for fluorouracil, and IRI for irinotecan (irinotecan 180 mg/m(2) at day 1, CF 200 mg/m(2) at day 1-2, 5-FU 400 mg/m(2) at day 1-2, followed by continuous infusion of 5-FU 600 mg/m(2) for 22 hours at day 1-2, every 2 weeks). The other 15 patients were treated with irinotecan monotherapy (180 mg/m(2), every 2 weeks). UGT1A1*6/*28 polymorphisms were detected by direct sequencing. RESULTS: The frequencies of GG, GA, AA genotypes for UGT1A1*6 were 70.8% (n=34), 25.0% (n=12), and 4.2% (n=2), respectively. And those of TA6/TA6, TA6/TA7, TA7/TA7 for UGT1A1*28 were 79.2% (n=38), 18.8% (n=9), and 2.0% (n=1), respectively. A total of 22 patients (45.8%) had grade III-IV neutropenia, and six patients (12.5%) experienced grade III-IV diarrhea. The incidence of grade III-IV neutropenia in patients with UGT1A1*6 GA or AA genotype was 71.4%, which was significantly higher than that with GG genotype (35.3%, P=0.022). No relationship was found between grade III-IV neutropenia and UGT1A1*28 polymorphism. The statistical analysis between grade III-IV diarrhea and UGT1A1*6/*28 polymorphisms was not conducted in view of the limited number of patients. CONCLUSION: In Chinese patients with pancreatic or biliary tract cancer administered irinotecan-containing regimens, those with UGT1A1*6 variant may have a high risk of severe neutropenia.

[Evaluation of preoperative radiotherapy or chemoradiotherapy in sphincter preservation for locally advanced middle-low rectal cancer].

OBJECTIVE: To investigate the effect of preoperative radiotherapy or chemoradiotherapy on the sphincter preservation and local tumor control as well as survival for the patient with locally advanced middle-low rectal cancer. METHODS: 121 locally advanced middle-low rectal cancer patients were treated with preoperative radiotherapy or chemoradiotherapy followed by surgery after rest of 4 to 6 weeks. 103 of these patients who underwent radical surgery were finally included in this study. The irradiation regimen was: 40 Gy/4 - 5 weeks, whereas 57 of these 103 patients received concurrent chemotherapy of 5-Fu or Xeloda. Sphincter-preserving surgery was performed in 59 patients and abdominoperineal resection in 44 patients. The survival was estimated by Kaplan-Meier model, and the differences between groups were compared using Log rank test. Multivariate analysis was performed by Cox's model. RESULTS: Ten patients (9.7%) achieved a complete pathological response (pCR) to preoperative radiotherapy or chemoradiotherapy. The sphincter preservation rate was 57.3%. The 3-year overall survival (OS) and disease free survival (DFS) was 66.3% and 59.5%, respectively. Univariate analysis showed that pCR and postoperative pTNM stage were prognostic factors affecting survival, whereas, only pTNM stage was an independent prognostic factor (P = 0.003) by multivariate analysis. CONCLUSION: Neoadjuvant preoperative radiotherapy and chemoradiotherapy is effective in local tumor control and improving survival for locally advanced middle-low rectal cancer, which can raise the rate of sphincter-preserving surgery, and achieve comparable result to abdominoperineal resection.

[In vitro chemo-sensitivity MTT assay guided intraperitoneal chemotherapy for malignant ascites].

OBJECTIVE: To evaluate the feasibility and efficacy of intraperitoneal chemotherapy for malignant ascites caused by different types of abdominal cancers guided by chemo-sensitivity methyl tetrojolium coloremetric (MTT) assay in vitro. METHODS: Cancer cells in the malignant ascites were collected for MTT assay to determine the chemo-sensitivity. The drug producing the highest or the second highest inhibition rate was selected for intraperitoneal chemotherapy. The correlation between the results of MTT assay and the response of malignant ascites, the clinical features, Karnofsky performance score (KPS) and prognosis were analyzed. RESULTS: MTT assay indicated that Taxotere (TXT) and Hydroxycamptothecin (HCPT) were the most effective to cancer cells in malignant ascites, and HCPT was mostly frequently used for intraperitoneal chemotherapy (56.9%). Twenty-four patients showed response by intraperitoneal chemotherapy (complete response: 7; partial response: 17) with a slightly significant correlation between the results of MTT assay and response of malignant ascites (P = 0. 014). The KPS of the responders was improved significantly (P < 0.001), and the response of malignant ascites to intraperitoneal chemotherapy was demostrated as an independent prognostic factor by multi-variate analysis in this series. CONCLUSION: In vitro chemo-sensitivity MTT assay guided intraperitoneal chemotherapy for malignant ascites is simple, effective and safe, which can improve the KPS and prognosis of the responders.

[A clinical analysis of 9 cases of Gitelman syndrome].

OBJECTIVE: To analyze the clinical characteristics of Gitelman syndrome. METHODS: Clinical data of 9 cases of Gitelman syndrome seen in the past 25 years in Chinese PLA General Hospital were analyzed retrospectively. RESULTS: The age of onset of Gitelman syndrome was 14 - 33 years. Main symptoms included weakness, tetany, polydipsia, polyuria, nocturia and paralysis. All patients had normal blood pressure. The biochemical tests showed hypokalemic alkalosis (9/9), hypocalciuria and hypomagnesaemia (9/9), low urine Ca/Cr ratio (<0.2, 5/5) and hyperreninemia (9/9). Renal pathological examination showed juxtaglomerular apparatus hyperplasia (2/2). All the patients' symptoms were relieved after treatment with potassium and magnesium supplementation or with combined spironolactone and indomethacin. However, serum potassium and magnesium levels were still lower than normal range (8/9); only one patient's serum potassium recovered to normal level. CONCLUSION: When clinical features such as weakness, hypokalemic alkalosis with normotension were encountered, Gitelman syndrome should be suspected. Serum magnesium as well as urine magnesium and calcium should be measured for confirmation of diagnosis. The treatment of choice included potassium and magnesium supplementation, or combination with anti-aldosterone medications, prostaglandin inhibitors and angiotensin-converting enzyme inhibitor. Generally, these patients have good prognosis.