The Role of the Carnitine/Organic Cation Transporter Novel 2 in the Clinical Outcome of Patients With Locally Advanced Esophageal Carcinoma Treated With Oxaliplatin

2021 ◽  
Vol 12 ◽  
Dongfeng Sun ◽  
Qingfa Chen ◽  
Zhibo Gai ◽  
Fengxia Zhang ◽  
Xiaoqing Yang ◽  

Esophageal cancer is the ninth most common malignancy worldwide, ranking sixth in mortality. Platinum-based chemotherapy is commonly used for treating locally advanced esophageal cancer, yet it is ineffective in a large portion of patients. There is a need for reliable molecular markers with direct clinical application for a prospective selection of patients who can benefit from chemotherapy and patients in whom toxicity is likely to outweigh the benefit. The cytotoxic activity of platinum derivatives largely depends on the uptake and accumulation into cells, primarily by organic cation transporters (OCTs). The aim of the study was to investigate the impact of OCT expression on the clinical outcome of patients with esophageal cancer treated with oxaliplatin. Twenty patients with esophageal squamous cell carcinoma (SCC) were prospectively enrolled and surgical specimens used for screening OCT expression level by western blotting and/or immunostaining, and for culture of cancer cells. Sixty-seven patients with SCC who received oxaliplatin and for whom follow-up was available were retrospectively assessed for organic cation/carnitine transporter 2 (OCTN2) expression by real time RT-PCR and immunostaining. OCTN2 staining was also performed in 22 esophageal adenocarcinomas. OCTN2 function in patient-derived cancer cells was evaluated by assessing L-carnitine uptake and sensitivity to oxaliplatin. The impact of OCTN2 on oxaliplatin activity was also assessed in HEK293 cells overexpressing OCTN2. OCTN2 expression was higher in tumor than in normal tissues. In patient-derived cancer cells and HEK293 cells, the expression of OCTN2 sensitized to oxaliplatin. Patients treated with oxaliplatin who had high OCTN2 level in the tumor tissue had a reduced risk of recurrence and a longer survival time than those with low expression of OCTN2 in tumor tissue. In conclusion, OCTN2 is expressed in esophageal cancer and it is likely to contribute to the accumulation and cytotoxic activity of oxaliplatin in patients with esophageal carcinoma treated with oxaliplatin.

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15559-e15559
G. M. Videtic ◽  
H. M. Macley ◽  
C. Reddy ◽  
D. J. Adelstein ◽  
T. W. Rice ◽  

e15559 Background: To assess the value of the primary tumor's SUVmax (PT-SUVmax) from the staging FDG-PET as a predictor of clinical and pathologic outcomes in patients undergoing trimodality therapy for locally advanced esophageal cancer. Methods: A retrospective chart review was conducted on patients with T3/4 and/or node positive esophageal carcinoma treated at the Cleveland Clinic between 7/1/03 and 5/31/06. All patients were managed with an institutional regimen consisting of preoperative radiotherapy [30 Gy @ 1.5 Gy twice daily over two weeks] with concurrent cisplatin and 5-fluorouracil during the first week. Following resection, an identical postoperative course of concurrent chemoradiotherapy (CRT) was delivered. Pretreatment patient and tumor characteristics including PT-SUVmax were analyzed with respect to response and survival. Results: 141 patients completed preoperative CRT: 125 (88.7%) were male, median age was 60 years, 73.8% had adenocarcinoma, 79.4% had N1 disease, 81.6% underwent surgery and 63.8% completed the full regimen. Median follow-up was 17.2 months [range 0.7–75.1]. Median PT-SUVmax was 9.43 [range 0 to 47.7]. Increasing clinical stage was associated with increasing PT-SUVmaxs: for cT2 vs. cT3 and cN0 vs. cN1, PT-SUVmax cutoffs were 8 (p=0.03) and 11 (p=0.02), respectively. Median (MST) and 5-year overall survivals were 20.7 months and 27.4%, respectively. A PT-SUVmax of < vs. > 7 was a significant predictor for T downstaging (p=0.0502) and N downstaging (p=0.0467). A PT-SUVmax cutoff of 7.6 was associated with a significant difference in MST, at 29.1 and 13.0 months for PT-SUVmax< 7.6 and >7.6, respectively (p=0.0158, HR=1.82, 95%CI=1.19–2.94). On multivariate analysis, PT-SUVmax was the only significant factor associated with survival (p=0.0.314, HR=1.71, 95%CI=1.05–2.79). Conclusions: The pretreatment SUVmax of a primary esophageal cancer appears to correlate with clinical stage, pathologic response to therapy and survival. This finding could play a role in the design of clinical trials and in adapting treatment strategies. No significant financial relationships to disclose.

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4531-4531
G. Crehange ◽  
F. Bonnetain ◽  
S. Seng ◽  
T. N'guyen ◽  
X. Mirabel ◽  

4531 Background: The FFCD 9102 trial demonstrated that CRT is an alternative to CRT+S for responding patients. We investigated the type of PP in the follow-up (FU) period, according to the RT scheme: protracted (P-RT) vs. split course (SC-RT). Methods: Resectable T3 N0–1 M0 thoracic esophageal carcinoma were included. First sequence : 2 cycles of cisplatin and 5-FU (day (d)1 - d22) combined with RT. Two schemes of RT were allowed: P-RT (46 Gy / 4.5 weeks (w), 2 Gy / f) or SC-RT (2 one-week courses of 15 Gy, 3 Gy / f). For CRT, the same chemotherapy was given on d43, d64 and d92 combined with 20 Gy / 2w (P-RT) or 15 Gy / 1w (SC-RT). Responding patients after the first sequence were randomized between CRT and CRT+S. The impact of SC-RT vs. P-RT on PP in the FU period was explored using a Mann-Whitney test. Results: From February 1993 to December 2000, 451 pts were registered and 446 were eligible. P-RT: 161 pts, SC-RT: 285 pts. After a median FU of 47.4 months, 2-year overall survival and local relapse-free survival were for P-RT vs. SC-RT: 37.1% vs. 30.5% (p = 0.25) and 76.7% vs. 56.8% (p = 0.002), respectively. P-RT vs. SC-RT: mean length of hospital stay: 48 d vs. 60.5 d (p= 0.0003). Mean number of dilatation sessions: 0.56 vs. 0.66 (p= 0.43). Mean number of stents: 0.21 vs. 0.34 (p= 0.03). Mean number of any PP: 1.01 vs. 1.50 (p= 0.001). Mean dysphagia grade: 2.99 vs. 3.12 (p= 0.21). In the CRT+S-group, P-RT vs. SC-RT: mean length of hospital stay 55.0d vs. 68.7d (p =0.051). Mean number of dilatation sessions: 0.74 vs. 0.74 (p= 0.77). Mean number of stents: 0.09 vs. 0.18 (p= 0.44). Mean number of PP: 1.00 vs. 1.37 (p= 0.054). In the CRT-group, P-RT vs. SC-RT, mean length of hospital stay: 42.6d vs 54.0d (p= 0.053). Mean number of dilatation sessions : 0.38 vs. 0.67 (p= 0.12). Mean number of stents: 0.31 vs. 0.50 (p= 0.03). Mean number of PP: 0.83 vs. 1.86 (p= 0.0005). Conclusions: Stents, rate of PP and length of hospital stay were significantly increased with SC-RT. Dysphagia score was similar between SC-RT and P-RT at last FU. No significant financial relationships to disclose.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 99-99 ◽  
Abigail Berman Milby ◽  
Andrzej Pawel Wojcieszynski ◽  
Smith Apisarnthanarax ◽  
James M. Metz ◽  
John Peter Plastaras

99 Background: Radiation (RT) is considered an integral component of trimodality therapy for locally-advanced esophageal carcinoma to improve locoregional control and potentially survival. However, the long-term risk of cardiopulmonary mortality (CPM) is not well-understood in this population. Methods: Patients age 20-85 with esophageal carcinoma with T3, T4 or node positive (N+) disease who underwent esophagectomy were identified within 17 Surveillance, Epidemiology, and End Results registries from 1988-2006. Patients with metastatic disease or <6 mo follow up were excluded. CPM was calculated for patients receiving vs not receiving RT and compared by the Kaplan-Meier method. The log-rank test was used for univariate associations and Cox proportional hazards model was used for multivariate analysis (MVA). Results: A total of 4,079 patients met the defined selection criteria of whom 2,408 were treated with RT, and 1,671 were not. Median age was 62.2 yrs (22-84) and follow-up was 22 mos (6-248). There was no significant difference in CPM in patients who received RT versus those who did not (p=0.8). At 10 yr, the majority of deaths were from esophageal cancer (73 with vs 78% without RT) compared to CPM (13.7 with vs 11.6% without RT). On univariate analysis ( table ), age <60, diagnosis era, and histology were significant independent predictors of CPM. On MVA, age <60 (HR 0.36) and diagnosis era (0.63 for 1994-2000 and 0.55 for 2000-2006) remained statistically significant for CPM. Conclusions: RT for esophageal cancer is not associated with an increased long-term risk of CPM in the overall population. Older age and earlier diagnosis era predict for CPM. Although survival in esophageal cancer is dominated by cancer deaths, advances in RT are still needed to prevent excess treatment-related mortality. [Table: see text]

2018 ◽  
Vol 2018 ◽  
pp. 1-5
Rui Wang ◽  
Hongfei Cai ◽  
Yang Li ◽  
Caiwen Chen ◽  
Youbin Cui

Objective. Preoperative nutritional status of patients is closely associated with their recovery after the surgery. This study aims to ascertain the impact exerted by the nutritional risk screening on clinical outcome of patients with esophageal cancer. Methods. 160 patients with esophageal cancer aged over 60, having got therapy at the First Hospital of Jilin University from Jun 2016 to Feb 2017 were evaluated by adopting the NRS2002. 80 cases of patients got active therapy of nutritional support, and the other patients not supported nutritionally were selected as the control group. The comparison was drawn between two groups in serum albumin, serum immunoglobulin, postoperative complications, hospitalization, and hospitalization expenses. Results. For all the patients, in 3 and 7 days after the surgery, the serum albumin in the nutritionally supported group outstripped that in group without nutritional support (P<0.05) regardless of the nutritional risk. For the patients in the risk of nutrition, the IgA in the nutritionally supported group outstripped that of group without nutritional support (P<0.05) in 3 and 7 days before the surgery, and the serum IgG outstripped that of the group without nutritional support in 1 and 3 days before the surgery (P<0.05). In terms of the patients in the risk of nutrition, the average hospitalization of nutritionally supported group was shorter (P<0.05), and the average hospitalization expenses were lower compared with those of the group without nutritional support. And for the patients in no risk, the hospitalization expenses of supported group surmounted those of group without nutritional support (P<0.05), whereas the average hospitalization took on no statistic difference (P>0.05). Conclusion. For the patients in the risk of nutrition, preoperative nutritional support can facilitate the nutritional status and immunization-relative result after surgery, which shall also decrease the average hospitalization and hospitalization cost.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 93-93
Erika Ruiz-Garcia ◽  
Alicia Lopez-Yañez ◽  
German Caderillo-Ruiz ◽  
Connie Zuratzi Deneken ◽  
Consuelo Diaz ◽  

93 Background: Fluoropyrimidines as 5-fluorouracil (5-FU) and its prodrug capecitabine are chemotherapeutic drugs commonly used in the treatment of gastrointestinal cancer. Patients with deficiency of dihydropyrimidine dehydrogenase enzyme (DPD), which interfere with the pyrimidine metabolism, could be at risk toxicity (mild, severe or lethal) because 80-90% of the administered 5-FU is catabolized by DPD. Methods: Retrospectively, we analyzed the initial paraffin embedded tissue block of 72 Mexican patients with locally advanced esophageal cancer, DPD activity was evaluated through the detection of the seven most relevant DPYD SNPs (IVS14 + 1G>A; 85T>C/85T>T; 2657G>A; 2921A>T; 1679T>G; 2846A>T; and 496A>G). Results: We found that 20.83% (15/72) of our patients had three different polymorphisms: 9.72% (7/72) were positive for SNP 496A>G in heterozygous patients and 4.16% (3/72) in homozygous patients; 4.16% (3/72) were positive for SNP 2657G>A in heterozygous patients; 2.77% (2/72) were positive for SNPs 85T>C and 85T>T in heterozygous patients. The rest of patients 79.10% (57/72) were negative to these SNPs. Conclusions: This is the first study in Mexican population, determining DPYD SNPs. We found that frequency of SNP 85T>C and 85T>T is similar as Oriental race (2-3%), but contrast with Caucasians (0.19%). The SNP 2657G>A whose allelic frequency is unknown, in Mexicans is about 4%; meanwhile, for SNP 496A>G which Caucasian prevalence was reported 0.8%, in our Mexican sample was very high (14%). None of our patients even those with toxicity grade 3-4, were positive to the SNP associated to high toxicity (IVS14 + 1G>A). Because of this heterogeneity, know we are sequencing the complete gen.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15501-e15501
Jingping Yu

e15501 Background: To investigate the effects of apatinib on esophageal cancer cells in vitro and xenograft models, and discuss the mechanisms of its actions. Methods: Used various assays to measure the different biological processes of esophageal cancer cells: used MTT assay to measure the proliferation rate; used transwell assay to determine the migration capacity and used colony formation assay to assess the clone formation rate. The effect of apatinib on cell cycle and apoptosis was analyzed by flow cytometry. The expression levels of VEGF and VEGFR2 were measured by qRT-PCR. The concentration of VEGF in the supernatant of cancer cell was assessed by ELISA. The expression levels of MEK, ERK, p-MEK, p-ERK, STAT3, p-STAT3, CHK2 and CDC2 after VEGF stimulation were detected by western blot. We also established human esophageal squamous carcinoma xenograft model in nude mice. The mice were randomly divided into healthy control group, low dose group (250mg) and high dose group (500mg), with 6 mice in each group. The tumor growth rate of each group was calculated, and the expression levels of VEGF and VEGFR2 in tumor tissues were detected by immunohistochemistry. Results: Apatinib inhibited the proliferation of esophageal cancer cell in a time-dependent (P < 0.05) and concentration-dependent (P < 0.05) manner; it also inhibited the cell migration capacity (P < 0.05) and colony formation rate (P < 0. 05). In addition, apatinib induced apoptosis in esophageal cancer cells and increased the proportion of cells in G2 / M phase (P < 0.05). The mRNA levels of VEGF (P < 0.05) and VEGFR2 (P < 0.05) and the protein levels of VEGF (P < 0.05) were also suppressed by apatinib. Western blot showed that apatinib could down-regulate the expression of p-MEK, p-ERK, STAT3, p-STAT3, CHK2 and CDC2 (P < 0.05). The inhibition rates of apatinib in esophageal carcinoma xenograft model was 29.25% and 19.96% for 250mg and 500mg drug treatment groups. Compared with healthy control group, the VEGF levels in drug treatment groups were not significantly different (P > 0.05), but the VEGFR2 levels were significantly decreased (P < 0.05). Conclusions: Apatinib can induce apoptosis of esophageal cancer cell KYSE-150 and ECA-109, and inhibit the cell proliferation, migration and colony formation. Moreover, apatinib can inhibit the tumor growth in esophageal carcinoma xenograft models. This inhibitory action of apatinib is related to the alterations in VEGF-related pathways such as Ras / Raf / MEK / ERK and JAK2 / STAT3 pathways.

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4568-4568
W. M. Eisterer ◽  
A. De Vries ◽  
B. Spechtenhauser ◽  
D. Kendler ◽  
A. Königsrainer ◽  

4568 Background: Surgery is the standard treatment for patients with resectable esophageal carcinoma, but 5-year survival rates rarely exceed 20%. Neoadjuvant chemoradiotherapy (CRT) may lead to downstaging of the tumor and thus improve the possibility of complete oncologic resection. Docetaxel (Dx) showed considerable activity in combination with hyperfractionated radiotherapy and only moderate toxicity. We evaluated a triple neoadjuvant regime including Dx in patients with locally advanced esophageal adenocarcinoma (AC) or squamos cell carcinoma (SCC). Methods: 24 patients (pts) with AC (n=8) or SCC (n=16) medically fit, no prior therapy, ECOG-performance status = 2 were included. Pts received 2 cycles of cisplatin (Cis) 15mg/ms2 d1–5, 5-fluorouracil (5-FU) 750mg/m2 continuous infusion (CI) d1–5, and Dx 75mg/m2 d1 repeated every 29 days followed by radiotherapy (RT) 39.6 Gy total dose (daily fraction 1.8Gy) concomitant to Dx 15mg/m2 on days 1, 8, 15, 22 and 5-FU 300mg/m2 CI on the days of RT followed by resection or definitive RT up to 59.6 Gy in case of inoperability. Results: See table . Grade 3/4 toxicity (n/%): neutropenia 10/43%, diarrhea 4/18%, alopecia 2/9%; deep vein thrombosis 1/5%, blurred vision 1/5%, fever 1/5%, pulmonary embolus 1/5%, arterial hypertension 1/5%. 1 pt died 39 days post resection due to fatal anastomical bleeding. 6/16 operated pts (37%) showed morbidity (anastomical stenosis/insufficiency, fistula, nervus recurrens palsy). 4/22 pts (18%) died 7- 25 months after therapy due to metastatic disease. At a median follow-up of 12 months 18 pts (82%) are alive, median survival has not been reached yet. Conclusions: Triple induction CT and CRT with Dx, Cis, and 5-FU is safe, feasible, and effective with CPR in 31%, downstaging in 81% and R0-resection in 100% of pts. Main toxicities are neutropenia (43%) and postoperative morbidity (37%). A follow-up phase II trial of triple induction therapy in combination with an EGFR-directed antibody is planned. [Table: see text] No significant financial relationships to disclose.

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