MicroRNA‐375‐3p enhances chemosensitivity to 5‐fluorouracil by targeting thymidylate synthase in colorectal cancer

Resistance to chemotherapy is a major challenge for the treatment of patients with colorectal cancer (CRC). Previous studies have found that microRNAs (miRNAs) play key roles in drug resistance; however, the role of miRNA‐373‐3p (miR‐375‐3p) in CRC remains unclear. The current study aimed to explore the potential function of miR‐375‐3p in 5‐fluorouracil (5‐FU) resistance. MicroRNA‐375‐3p was found to be widely downregulated in human CRC cell lines and tissues and to promote the sensitivity of CRC cells to 5‐FU by inducing colon cancer cell apoptosis and cycle arrest and by inhibiting cell growth, migration, and invasion in vitro. Thymidylate synthase (TYMS) was found to be a direct target of miR‐375‐3p, and TYMS knockdown exerted similar effects as miR‐375‐3p overexpression on the CRC cellular response to 5‐FU. Lipid‐coated calcium carbonate nanoparticles (NPs) were designed to cotransport 5‐FU and miR‐375‐3p into cells efficiently and rapidly and to release the drugs in a weakly acidic tumor microenvironment. The therapeutic effect of combined miR‐375 + 5‐FU/NPs was significantly higher than that of the individual treatments in mouse s.c. xenografts derived from HCT116 cells. Our results suggest that restoring miR‐375‐3p levels could be a future novel therapeutic strategy to enhance chemosensitivity to 5‐FU.     

多西他赛联合氟尿嘧啶、顺铂方案与多西他赛联合氟尿嘧啶、洛铂方案治疗胃癌的疗效比较

目的:比较多西他赛联合氟尿嘧啶、顺铂方案与多西他赛联合氟尿嘧啶、洛铂方案治疗晚期不可手术胃癌患者的疗效和不良反应。方法:回顾性分析2015年2月至2018年6月126例晚期不可手术的胃癌患者。洛铂组55例:多西他赛+氟尿嘧啶+洛铂，顺铂组71例:多西他赛+氟尿嘧啶+顺铂。洛铂组和顺铂组均21天为一个疗程，连续治疗四个疗程。结果:洛铂组患者客观有效率为50.91%，顺铂组为35.21%，差异无统计学意义（P＞0.05）。洛铂组患者疾病控制率达到83.64%，顺铂组为67.61%，差异有统计学意义（P＜0.05）。洛铂组患者在恶心、呕吐、白细胞减少和四肢麻木方面发生率明显低于顺铂组，差异有统计学意义（P＜0.05）。洛铂组患者血小板减少发生率高于顺铂组，差异有统计学意义（P＜0.05）。洛铂组患者严重不良反应的发生率为21.82%，顺铂组为39.44%，差异具有统计学意义（P＜0.05）。结论:将多西他赛联合氟尿嘧啶、顺铂方案中的顺铂以洛铂替代，取得了更好的疾病控制率，而患者的不良反应更轻，严重不良反应的发生率也更低，值得临床进一步研究。     

Early administration of pegfilgrastim for esophageal cancer treated with docetaxel,cisplatin, and fluorouracil: A phase II study

Preoperative or induction chemotherapy with docetaxel, cisplatin, plus 5‐fluorouracil (DCF) is a promising regimen for advanced esophageal cancer. However, the DCF regimen is associated with a high risk of severe neutropenia or febrile neutropenia (FN). However, the current guidelines fail to recommend an optimal dosing schedule of pegfilgrastim along with the DCF regimen to prevent FN. In the present study, we assessed the efficacy and safety of giving pegfilgrastim early on day 3 during DCF therapy for esophageal cancer. In this single‐arm phase II study, patients with squamous cell carcinoma of the esophagus were recruited. They were treated with the DCF therapy on days 1‐5, with pegfilgrastim given on day 3. Primary endpoint was the occurrence of grade 4 neutropenia. Secondary endpoints included the incidence of FN, grade 3 neutropenia, dose delays/reductions, antitumor effect, and safety. Between July 2016 and December 2018, 23 patients were enrolled. The incidence of grade 4 neutropenia was 8.7% (95% confidence interval 1.1%‐28.0%). No patient experienced FN. Of the 19 patients who received two cycles of DCF, one required a dose reduction/treatment delay due to hematological toxicity in the second treatment cycle. No serious adverse events, considered relevant to pegfilgrastim, were observed. This is the first prospective study that showed an efficacious dosing schedule of pegfilgrastim for preventing hematological toxicity during DCF therapy. The results might be generalized to other similar regimens where continuous infusions of 5‐fluorouracil are used.     

Keratoacanthoma centrifugum marginatum after photodynamic therapy with good response to oral retinoids and topical 5‐fluorouracil

Keratoacanthoma centrifugum marginatum (KCM) is a rare variant of keratoacanthoma (KA), characterized by progressive peripheral growth, and usually devoid of deep invasion. Different systemic (oral retinoids) or topical treatments have been reported, but there is not a well‐defined therapeutic protocol. We report the case of a KCM developing after photodynamic therapy (PDT) on the right leg of a 64‐year‐old woman. It was treated successfully with oral acitretin combined with topical 5‐Fluorouracil + salicylic acid for 5 months. This is the first case of KCM developing after PDT and successfully treated with oral retinoid combined with topical treatment.     

Pharmacokinetic study of the oral fluorouracil antitumor agent S‐1 in patients with impaired renal function

Although dose reduction of S‐1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5‐fluorouracil, 5‐chloro‐2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S‐1 in patients with renal impairment. We classified patients receiving S‐1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S‐1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m²), 10 patients in cohort 2 (eGFR = 50‐79 mL/min/1.73 m²), 10 patients in cohort 3 (eGFR = 30‐49 mL/min/1.73 m²), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m²). Those in cohorts 3 and 4 treated with an adjusted dose of S‐1 showed a similar area under the curve for 5‐fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S‐1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S‐1 in patients with impaired renal function using eGFR is appropriate and safe.     

Hepatic Artery Infusion Chemotherapy Using Fluorouracil,Leucovorin, and Oxaliplatin versus Transarterial Chemoembolization as Initial Treatment for Locally Advanced Hepatocellular Carcinoma: A Propensity Score–Matching Analysis

PurposeTo compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with a modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) regimen with that of transarterial chemoembolization as a locoregional treatment for patients with locally advanced hepatocellular carcinoma (HCC).MethodsThis retrospective study included adult patients with locally advanced HCC who received first-line treatment with either HAIC-mFOLFOX or conventional transarterial chemoembolization monotherapy from January 2015 to December 2016. The outcomes, including tumor response rates, evaluated via imaging assessment using the modified response evaluation criteria in solid tumors; overall survival; progression-free survival; and safety, were compared. The propensity score–matching methodology was used to reduce the influence of confounding factors on the outcomes.ResultsThe study included 131 patients with locally advanced HCC who underwent transarterial chemoembolization and 101 who received HAIC-mFOLFOX as initial treatment. After propensity score matching (n = 67 in each group), patients who received HAIC-mFOLFOX had a higher objective response rate (43.3% vs 13.4%, P = .001), longer median overall survival (13.9 vs 6.0 months, P < .001), and longer median progression-free survival (6.4 vs 2.8 months, P = .001) than those who underwent transarterial chemoembolization. The survival benefit with HAIC-mFOLFOX was strengthened in patients with HCC with vascular invasion (hazard ratio: 0.379; 95% confidence interval: 0.237–0.607). HAIC-mFOLFOX was associated with lower incidences of severe adverse events (8.9% vs 22.9%) and liver toxicity than transarterial chemoembolization.ConclusionsCompared with transarterial chemoembolization, HAIC-mFOLFOX is a potentially safer and more effective locoregional therapy for patients with locally advanced HCC.     

A comparative study of the effectiveness of cisplatin and 5‐fluorouracil on cutaneous squamous human carcinoma cell line: Potential chemotherapy alternative to surgery

Surgery as treatment for local invasive cutaneous squamous cell carcinoma (cSCC) is not always feasible due to the age and/or the health status of patients. Thus, the investigation of new strategies to improve the quality of life of them is required. The aim of this work is to investigate two chemotherapy agents individually on cSCC cells with the purpose to provide a better understanding of the effectiveness underlying each one. The cisplatin effectiveness is compared at different times with that observed for the 5‐fluorouracil treatment. The effectiveness of both was assessed by using flow cytometry to determine the survival cell ratio, and QBlue test to study the cell recovery ability after treatments. A significant increase in the number of apoptotic cells, especially 48 hours after treatments, has been detected. Despite this, cisplatin arises as the most promising agent for the treatment of local invasive cutaneous squamous cell carcinoma due to the fact that a lower concentration and time are required to observe a higher effectiveness on cells with respect to the 5‐fluorouracil. An optimal cisplatin‐based chemotherapy might provide a better outcome for patients affected by a local invasive cSCC rather than surgery.     

S-1 monotherapy as second line chemotherapy in advanced gastric cancer patients previously treated with cisplatin/infusional fluorouracil

The treatment choice of advanced gastric carcinoma after failure from first-line therapy is quite limited. To evaluate the efficacy and toxicity of S-1 monotherapy in patients with advanced gastric cancer after failure of first line cisplatin and fluorouracil combination (CF). S-1 monotherapy as a second line treatment was given to the patients who had failed to CF combination in SC-101 study. The efficacy and toxicity of S-1 monotherapy were evaluated exploratory. The results indicated that forty-one patients received S-1 as a second line therapy after disease progression. The overall response rate and disease control rate were 14.6% and 41.5%, respectively. The median progression free survival (PFS) was 5.1 months (ange: 2.9~6.2 month). The median overall survival time was 6.4 months. The survival rates at 6 month and 1 year were 56% and 7.3%, respectively. Grade 3/4 adverse events were uncommonly occurred, including anemia (2.4%), neutropenia (2.4%), thrombocytopenia (4.9%) and rash (2.4%). There were no unexpected or life-threatening toxicities. Only one patient experienced dose reduction due to grade 3 rash. In conclusion, S-1 monotherapy provided a mild response rate and overall survival, and a favorable toxicity profile in the second line setting after the first line failure to cisplatin and fluorouracil combination.     

经颞浅动脉灌注氟尿嘧啶和卡铂治疗舌癌

目的探讨术前联合应用氟尿嘧啶、卡铂诱导化疗治疗舌癌的临床效果。方法20例舌癌患者经颞浅动脉插管连续顺序灌注氟尿嘧啶和卡铂,比较化疗前、后原发肿瘤灶的大小,并记录化疗的主要不良反应。结果完全缓解(CR)18例(90%),部分缓解(PR)2例(10%),总有效率(CR+PR)100%;不良反应轻微。结论经颞浅动脉插管灌注氟尿嘧啶和卡铂是治疗舌癌的一种有效方法,不良反应发生率低且轻。