Clinical efficacy and pharmacoeconomic evaluation of bevacizumab or cetuximab combined with chemotherapy in the treatment of advanced colorectal cancer / 中国医师进修杂志

Objective:To compare the clinical efficacy and pharmacoeconomic evaluation of bevacizumab or cetuximab combined with chemotherapy in the treatment of advanced colorectal cancer.Methods:The clinical data of 68 patients with advanced colorectal cancer from January 2018 to December 2020 in Baotou Tumor Hospital were retrospectively analyzed. Among them, 40 patients with treated with bevacizumab combined with chemotherapy (bevacizumab group), 28 patients were treated with cetuximab combined with chemotherapy (cetuximab group), and the chemotherapy of two group was FOLFOX/FOLFIRI program. The short-term clinical efficacy, adverse reactions and pharmacoeconomic evaluation result were compared between two groups.Results:There were no statistical differences in effective rate and disease control rate between bevacizumab group and cetuximab group: 30.00% (12/40) vs. 28.57% (8/28) and 67.5% (27/40) vs. 60.71% (17/28), P>0.05. The incidence of Ⅲ to Ⅳ grade erythra in bevacizumab group was significantly lower than that in cetuximab group: 2.50% (1/40) vs. 71.43% (20/28), and there was statistical difference ( P<0.01); there were no statistical differences in the incidences of Ⅲ to Ⅳ grade bone marrow suppression, nausea vomiting, hepatic functional lesion and diarrhea between two groups ( P>0.05). The pharmacoeconomic evaluation result showed that the cost of monoclonal antibody and total cost in bevacizumab group were significantly lower than those in cetuximab group: (9 009 ± 1 500) yuan vs. (27 840 ± 2 202) yuan and (11 242 ± 1 731) yuan vs. (29 867 ± 3 002) yuan, and there were statistical differences ( P<0.01); the cost-effectiveness ratio in bevacizumab group was 37 473.3, and it in cetuximab group was 104 430.1, the incremental cost-effectiveness ratio of two programs was 11 640.6. Conclusions:In the treatment of advanced colorectal cancer, the efficacy of bevacizumab combined with chemotherapy is similar to that of cetuximab combined with chemotherapy, but bevacizumab combined with chemotherapy has lower costs and fewer adverse reactions, so bevacizumab is more economical and applicable.

Clinical efficacy and adverse reactions of SBRT combined with mFOLFOXIRI and cetuximab in liver metastases after colorectal cancer surgery / 国际肿瘤学杂志

Objective:To investigate the efficacy of stereotactic body radiotherapy (SBRT) combined with modified FOLFOXIRI (mFOLFOXIRI, irinotecan, oxaliplatin, leucovorin and fluorouracil) and cetuximab in the treatment of postoperative liver metastases in patients with KRAS, BRAF and NRAS gene wild-type colorectal cancer, and to evaluate treatment-related adverse reactions.Methods:A total of 86 patients with postoperative liver metastases from colorectal cancer diagnosed in Shandong Daizhuang Hospital from January 2018 to January 2021 were selected, all of whom were KRAS, BRAF and NRAS gene wild-type. All patients were divided into control group and study group according to the random number table method, with 43 cases in each group. The patients in the control group were treated with mFOLFOXIRI and cetuximab, 14 days a cycle, for a total of 12 cycles. The patients in the study group were treated with SBRT for liver metastases on the basis of the control group. Two patients in the control group were withdrawn from the study due to intolerance of myelosuppression (grade 4), and patients in the study group were withdrawn from the study due to intolerance of 1 case of myelosuppression, 1 case of gastrointestinal reaction and 1 case of abnormal liver function (all grade 4). The efficacy, median progression-free survival (PFS), median overall survival (OS) and adverse reactions were compared between the two groups after treatment.Results:After 12 cycles of treatment, the objective response rate (ORR) and disease control rate (DCR) of the study group were 55.00% (22/40) and 80.00% (32/40) respectively, which were higher than 31.71% (13/41) and 58.54% (24/41) of the control group, with statistically significant differences ( χ2=4.48, P=0.034; χ2=4.37, P=0.037). After treatment, 14 patients (35.00%) in the study group were resectable, which was higher than 6 patients (14.63%) in the control group, with a statistically significant difference ( χ2=4.52, P=0.034). The median PFS and median OS of the study group were 9.2 months and 19.5 months respectively, which were longer than 6.5 months and 15.2 months of the control group, with statistically significant differences ( χ2=8.83, P=0.015; χ2=7.52, P=0.027). There were no significant differences in incidences of leukopenia [55.00% (22/40) vs. 46.34% (19/41), χ2=0.61, P=0.436], anemia [45.00% (18/40) vs. 39.02% (16/41), χ2=0.30, P=0.585], thrombocytopenia [37.50% (15/40) vs. 31.71% (13/41), χ2=0.30, P=0.584], nausea and vomiting [55.00% (22/40) vs. 48.78% (20/41), χ2=0.31, P=0.575], constipation and diarrhea [20.00% (8/40) vs. 17.07% (7/41), χ2=0.12, P=0.734], liver function damage [35.00% (14/40) vs. 29.27% (12/41), χ2=0.31, P=0.581], peripheral sensory neuropathy [30.00% (12/40) vs. 26.83% (11/41) ), χ2=0.10, P=0.752], acute cholinergic syndrome [12.50% (5/40) vs. 14.63% (6/41), χ2=0.08, P=0.779] and fatigue [52.50% (21/40) vs. 43.90% (18/41), χ2=0.60, P=0.439]. Conclusion:SBRT combined with mFOLFOXIRI and cetuximab is more effective than drug therapy alone in patients with liver metastases after colorectal cancer surgery, which can effectively prolong the survival period, and the adverse reactions are tolerable.

Analysis of the correlation between circular RNA circ_0008274 and cetuximab resistance in colorectal cancer cells / 中华消化杂志

Objective:To analyze the expression of circular RNA circ_0008274 in cetuximab-resistant colorectal cancer cells using bioinformatics technology and to explore its involvement in the development of cetuximab resistance.Methods:Five concentrations of cetuximab (10, 50, 100, 150, 200 nmol/L) were set. Cetuximab-resistant cells DiFi-R and Caco-2-R were screened out and established by concentration increasing method using colorectal cancer cells DiFi and Caco-2. The expression of circ_0008274 in DiFi-R and Caco-2-R cells was detected by reverse transcription-polymerase chain reaction(RT-PCR). The interaction and regulation between circ_0008274 and microRNA(miR)-140-3p were analyzed by double-luciferase reporter assay. The highly expressed gene SMARCC1 related to cetuximab resistance was determined by Western blotting. Circ_0008274 in DiFi-R and Caco-2-R cells were knocked out with small interfering RNA si-circ_0008274 transfection. After knock out, the differences in the colony formation and cell proliferation in DiFi-R and Caco-2-R cells were compared. MiR-140-3p mimic and blank control miR were transfected into DiFi-R and Caco-2-R cells. After transfection the difference in cell proliferation between transfected with miR-140-3p mimic and blank control miR in DiFi-R and Caco-2-R cells were analyzed. After Caco-2-R cell was knocked out with si-circ_0008274, the changes of SMARCC1 protein expression rescued by pcDNA3.1 SMARCC1 and cell viability were analyzed. The tumor specimens of 15 colorectal cancer patients hospitalized in Renmin Hospital of Wuhan University from March 2019 to August 2020 were included. According to the treatment effect, the patients were divided into sensitive group (11 cases) and drug-resistant group (4 cases). The relative expression levels of circ_0008274, downstream SMARCC1and miR-140-3p in colorectal cancer tissues in the two groups were detected by RT-PCR. Independent sample t test was used for statistical analysis. Results:The level of circ_0008274 in DiFi-R cells was 2.33±0.12 times of that of DiFi cells, while the level in Caco-2-R was (2.92±0.42) times of that of Caco-2 cells, and the differences were statistically significant ( t=19.97 and 7.80, both P<0.05). The results of double-luciferase reporter showed that after miR-140-3p mimic combined with wild-type circ_0008274, the relative fluorescence intensity was lower than before (0.28±0.04 vs. 1.00±0.00), and the difference was statistically significant ( t=-30.71, P=0.001). The expression of SMARCC1 protein in DiFi-R and Caco-2-R cells was significantly increased, the expression at protein level was higher than that of DiFi and Caco-2 cells (2.22±0.36 vs. 0.61±0.17, 0.85±0.11 vs. 0.35±0.08), and the differences were statistically significant ( t=6.23 and 6.32, both P<0.01). After circ_0008274 was knocked out, the numbers of colony formation of DiFi-R and Caco-2-R cells were both lower than those of before knockout (36.67±4.04 vs. 66.00±9.54, 17.35±4.04 vs. 52.33±8.02), the relative active cell ratios after interventing by 10, 50, 100, 150 and 200 nmol/L cetuximab were also lower than those of before knockout (DiFi-R cells: (73.75±2.75)% vs. (88.10±2.48)%, (56.50±6.66)% vs. (75.15±6.03)%, (35.75±5.32)% vs. (59.63±6.67)%, (24.25±3.30)% vs. (52.40±6.71)%, (6.25±2.75)% vs. (48.60±5.38)%; Caco-2-R cells: (63.74±5.25)% vs. (85.76±4.79)%, (56.50±4.20)% vs.(83.50±3.90)%, (46.00±2.94)% vs. (80.00±6.05)%, (35.30±5.56)% vs. (68.30±4.57)%, (12.25±7.37)% vs. (62.40±7.51)%), and the differences were statistically significant ( t=4.90, 6.71, -7.75, -4.16, -5.60, -7.53, -14.02, -6.19, -8.33, -10.10, -9.17 and -9.56, all P<0.01). After transfecting with miR-140-3p mimic, the relative active cell ratios of DiFi-R and Caco-2-R cells interventing by 10, 50, 100, 150 and 200 nmol/L cetuximab were both lower than those transfected with blank control miR (DiFi-R cells: (71.55±4.97)% vs. (85.90±2.66)%, (51.58±3.91)% vs. (74.95±6.35)%, (41.23±8.84)% vs. (58.43±7.05)%, (28.60±5.26)% vs. (53.75±5.65)%, (18.90±5.13)% vs. (51.30±3.30)%; Caco-2-R cells: (61.75±2.22)% vs. (90.10±1.41)%, (53.25±4.17)% vs. (86.18±2.69)%, (46.38±4.55)% vs. (77.75±6.70)%, (36.10±8.76)% vs. (70.15±4.18)%, (24.25±2.63)% vs. (65.10±7.62)%), and the differences were statistically significant ( t=-5.09, -6.47, -3.05, -6.28, -10.30, -21.48, -12.83, -8.01, -6.79 and -10.12, all P<0.01). After circ_0008274 was knocked out, the SMARCC1 protein level of Caco-2-R cells rescued by pcDNA3.1 SMARCC1 was higher than that of before rescue (0.63±0.19 vs. 0.09±0.03), and the relative active cell ratios after interventing by 10, 50, 100, 150 and 200 nmol/L cetuximab were also higher than that of before rescue ((93.10±3.56)% vs. (83.83±3.97)%, (83.28±4.26)% vs. (60.90±7.02)%, (61.83±2.12)% vs. (50.10±5.59)%, (53.20±3.74)% vs. (40.50±3.42)%, (46.20±4.08)% vs. (30.80±4.82)%), and the differences were statistically significant( t=3.55, 3.52, 5.44, 3.87, 4.64 and 4.88, all P<0.01). The relative expression levels of circ_0008274 and downstream SMARCC1 of colon cancer tissues in the drug-resistant group were higher than those in the sensitive group (6.45±1.32 vs. 2.26±1.39, 12.53±1.60 vs. 3.82±1.56), and the relative expression level of miR-140-3p was lower than that in the sensitive group (3.91±1.25 vs. 7.43±2.23), and the differences were statistically significant ( t=5.22, 9.51, -2.93, all P<0.01). Conclusions:Circular RNA circ_0008274 is highly expressed in colorectal cancer tissues and cetuximab resistant cells, interacts and inhibits miR-140-3p expression, up-regulates SMARCC1, and participates in the occurrence of cetuximab resistance. PcDNA3.1 SMARCC1 rescue can block the sensitization effect of si-circ_0008274 on cetuximab, and can significantly increase cetuximab resistance of colorectal cancer cells.

Changes of circulating tumor DNA, circulating B cell-specific Moloney leukemia virus insertion site 1 mRNA and microRNA-21 levels before and after cetuximab treatment in advanced colorectal cancer / 中国医师进修杂志

Objective:To investigate the changes of circulating tumor DNA (ctDNA), circulating B cell-specific Moloney leukemia virus insertion site 1 mRNA (Bmi-1 mRNA) and microRNA-21 (miR-21) before and after treatment with epidermal growth factor receptor (EGFR) monoclonal antibody in advanced colorectal cancer, and analyze their association with treatment response.Methods:The clinical data of 98 patients with advanced colorectal cancer from March 2019 to March 2021 in Yantai Yuhuangding Hospital were retrospectively analyzed. After treatment with cetuximab, complete remission was in 4 cases, partial remission in 26 cases, stable disease in 39 cases, and progressive disease in 29 cases. The patients with complete remission and partial remission were classified as remission group (30 cases), the stable disease and progressive disease were classified as non-remission group (68 cases). Before treatment and after 2 cycles of treatment, the plasma level of ctDNA was detected by high-throughput sequencing; the levels of Bmi-1mRNA and miR-21 were detected by real-time fluorescence quantitative polymerase chain reaction. Spearman correlation was used to analyze the relationship between ctDNA, Bmi-1mRNA, miR-21 and treatment responsiveness after 2 cycles of treatment; multivariate Logistic regression was used to analyze the independent risk factors affecting treatment responsiveness; receiver operating characteristic (ROC) curve was drawn to evaluate the value of ctDNA, Bmi-1mRNA and miR-21 in predicting remission after 2 cycles of treatment.Results:There were no significant differences in ctDNA, Bmi-1mRNA and miR-21 before treatment between 2 groups ( P>0.05); the ctDNA, Bmi-1mRNA and miR-21 after 2 cycles of treatment in remission group were significantly lower than those in non-remission group: (10.03 ± 3.32) μg/L vs. (15.33 ± 5.14) μg/L, 0.13 ± 0.04 vs. 0.19 ± 0.05 and 0.81 ± 0.26 vs. 1.08 ± 0.24, and there were statistical differences ( P<0.01). Spearman correlation analysis result showed that ctDNA, Bmi-1mRNA and miR-21 were negatively correlated with treatment response ( r = -0.500, -0.506 and -0.531; P<0.01). Multivariate Logistic regression analysis result showed that, after controlling for the number of distant metastatic organs and clinical stage, ctDNA, Bmi-1mRNA and miR-21 were still independent risk factors for treatment response in patients with advanced colorectal cancer ( OR = 3.342, 2.725 and 1.838; 95% CI 3.116 to 3.584, 2.647 to 2.805 and 1.768 to 1.911; P<0.01). ROC curve analysis result showed that the area under the curve (AUC) of ctDNA, Bmi-1mRNA combined with miR-21 after 2 cycles of treatment to predict the treatment response was the largest with 0.922. Conclusions:The changes of ctDNA, Bmi-1mRNA and miR-21 in patients with advanced colorectal cancer before and after treatment with EGFR monoclonal antibody are related to the treatment response. Combined detection is helpful for screening patients sensitive to EGFR-targeted therapy, and can provide reference for new targets of molecular intervention.

Menetrier's disease. A diagnostic and therapeutic challenge / Enfermedad de Menetrier. Un desafío diagnóstico y terapéutico

Abstract We present a rare case of hypertrophic gastropathy associated with protein loss. A 35-year-old man was hospitalized for bowel habit changes, abdominal pain, generalized edema and symptomatic anemia. Pertinent laboratory findings included iron deficiency anemia (Hb 6.7g/dl, ferritin 5 ng/ml) and marked hypoalbuminemia (albumin 2.5 g/dl). Endoscopic biopsy samples of giant gastric folds observed along the greater gastric curvature revealed foveolar hyperplasia and significant parietal cell loss. Endoscopic ultrasonography showed gastric parietal thickening with preserved architecture and normal gastric wall layers. Menetrier disease was diagnosed and the patient treated with cetuximab, a monoclonal antibody that inhibits ligand binding of trans forming growth factor alpha (TGFa), preventing gastric mucosa cell proliferation. After twelve months of treatment, the patient referred symptoms improvement, and gastric biopsy levels of the proliferation marker protein Ki-67 had decreased.

Resumen Presentamos un caso infrecuente de gastropatía hipertrófica asociada a pérdida de proteínas. Un hombre de 35 años fue hos pitalizado por cambios en los hábitos intestinales, dolor abdominal, edema generalizado y anemia sintomática. Los hallazgos de laboratorio pertinentes incluyeron anemia ferropénica (Hb 6.7 g/dl, ferritina 5 ng/ml) e hipoal buminemia marcada (albúmina 2.5 g/dl). Las muestras de biopsia endoscópica de pliegues gástricos gigantes observados a lo largo de la curvatura mayor gástrica revelaron hiperplasia foveolar y pérdida significativa de células parietales. La ecografía endoscópica mostró engrosamiento parietal gástrico con arquitectura conservada y capas de pared gástrica normales. Se diagnosticó enfermedad de Menetrier y se trató al paciente con cetuximab, un anticuerpo monoclonal que inhibe la unión del ligando del factor de crecimiento transformante alfa (TGFa), evitando la proliferación de células de la mucosa gástrica. Después de doce meses de tratamiento, el paciente refirió mejoría de los síntomas y los niveles de la proteína marcadora de proliferación Ki-67 en biopsia gástrica habían disminuido.

Construction and in vitro evaluation of targeted cisplatin-loaded nanoparticles for chemo-photothermal cancer therapy / 中国药科大学学报

@#To improve the therapeutic effect of cisplatin and reduce its side effects, a multifunctional drug delivery system with targeted and chemo-photothermal effect was constructed.Using polyethylene glycol polylactic acid block copolymer as a carrier, nanoparticles loaded with antitumor drug cisplatin and photosensitizer indocyanine green were prepared by ultrasonic emulsification, and the surface was then modified by cetuximab to prepare cetuximab-decorated and near-infrared (NIR)-activated nanoparticles (CPINPs).The physicochemical properties were characterized by mean particle size, Zeta potential, mAb conjugating rate and photothermal effect; the in vitro cell uptake was measured by laser confocal microscopy; and the in vitro antitumor activity was evaluated by CCK8 assay.The results indicated that CPINPs had mean particle diameter of (263.9 ± 3.73) nm, polydispersity index of 0.18 ± 0.03, Zeta potential of -(23.43 ± 0.42) mV, and cetuximab conjugating rate of (44.0 ± 1.72)%.The in vitro photothermal experiments showed that CPINPs upon NIR irradiation induced a photothermal effect, thus destroying the tumor cells. The in vitro cell uptake experiments demonstrated that NIR irradiation could promote cell uptake, and that more CPINPs were effectively internalized into A549 cells. The in vitro cytotoxicity test indicated that CPINPs treated with NIR irradiation had the effect of combined chemo-photothermal therapy, leading to higher cytotoxicity than that of free cisplatin or treatment without NIR, with IC50 values being (8.67 ± 0.04) μmol/L for 24 h incubation.To sumup the multifunctional drug delivery system constructed in the current work expected to be a more efficient targeted therapy strategy for lung cancer.

Anti-ENO1 antibody combined with metformin reverses the resistance of human non-small cell lung cancer A549 cells to cetuximab by targeting cancer stem cells / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To explore the effect of anti-ENO1 (enolase 1) antibody and metformin (MET) treatment on the proliferation, migration, invasion and stemness of cetuximab (CTX) -resistant non-small cell lung cancer (NSCLC) cells through targeting cancer stem cells and the possible mechanism. Methods: 10 mmol/L MET combined with 40 μg/ml anti-ENO1 antibody was used to treat CTX(35 µg/ml)-resistant NSCLC A549 cells for 4 d, and the effects of combined treatment on A549 cells were detected with proliferation experiment, colony formation assay, migration and invasion experiments and methylcellulose ball formation experiment. In the meanwhile, FCM was used to detect the effects of CTX, MET and anti-ENO1 antibody single-drug treatment as well as the three-drug combination treatment on ALDH+ and CD44+ lung cancer stem cell subsets. Results: CTX combined with MET and anti-ENO1 antibody treatment significantly inhibited the proliferation, migration, invasion and self-renewal capacity of A549 cells. FCM analysis found that MET could significantly inhibit ALDH+ stem cell subpopulations, while anti-ENO1 antibody could significantly inhibit CD44+ stem cell subpopulations, and the three-drug combination treatment could simultaneously suppress ALDH+ and CD44+ stem cell subpopulations. Conclusion: MET and anti-ENO1 antibody respectively target ALDH+ and CD44+ cancer stem cell subsets, and the combined treatment of MET and anti-ENO1 antibody can effectively reverse the resistance of A549 cells to CTX, and thereby more effectively inhibiting stemness, proliferation, metastasis of A549 cells and tumor recurrence.

Hypertrichosis, trichomegaly, and androgenic alopecia related to cetuximab treatment

Anti-epidermal growth factor receptor (EGFR) antibodies are mainly used in the treatment of advanced stages of solid tumors as a targeted therapy to inhibit tumor proliferation. They cause many dermatological adverse reactions through inhibition of EGFR pathway in the skin. A 39-year-old female patient diagnosed with metastatic colon adenocarcinoma received oxaliplatin, fluorouracil, and folinic acid regimen with cetuximab. The patient noticed increase in fairy hair especially at facial area as well as in the whole body beginning after the first few cycles of treatment, after 3 months. Obvious hypertrichosis, androgenic alopecia, and trichomegaly were observed. Blood tests for androgenetic alopecia and hirsutism were studied. Hormonal levels were in normal range. Upper abdominal imaging to rule out any adrenal lesion was also normal. Previous studies reported found that cetuximab may cause alopecia, hypertrichosis on face and body, and trichomegaly. We have not encountered a combination of hypertrichosis, androgenic type alopecia, and trichomegaly in the literature

Autophagy induced synergistic inhibitory effect of cetuximab in combination with triptolide on proliferation and metastasis of colorectal SW480 cells / 中国药理学通报

Aim: To investigate the effect of triptolide combined with epidermal growth factor receptor monoclonal antibody cetuximab on the biological behavior of human colorectal cancer cell line SW480. Methods: MTT assay was used for estimating the survival rates of SW480 cells exposed to different concentrations and different durations of triptolid and cetuximab. Colony formation assay was used for showing the proliferation and wound healing assay was performed to assess the effects of drugs on cell migration, Western blot was used for testing the expression of LC3-II, p62, E-cadherin, Vimentin, mTOR, Snail, and Twist. Results: The SW480 growth of cells was inhibited by triptolide in a dose- and time-dependent manner and cetuximab was only in a dose-dependent manner. The combination regimen of cetuximab and triptolide exerted a synergistic effect. Triptolide could decrease expression of p62 increase expression of LC3-II and induce autophagic apoptosis. Triptolide monotherapy group and combination group could significantly inhibit EMT in SW480 cells, and the E-cadherin protein was up-regulated, Vimentin protein was down-regulated, and key molecules Snail and Twist were down-regulated. Conclusion: Triptolide combined with cetuximab has a synergistic effect on the inhibition of proliferation and metastasis of SW480 cells. Triptolide induces autophagic apoptosis by inhibiting the mTOR pathway. Autophagy mediated by triptolide can inhibit EMT of SW480 cells and may be a mechanism to reverse the resistance of cetuximab.

Short-term efficacy of combination of 125I seed brachytherapy and cetuximab in postoperation recurrent rectum cancer / 中华消化杂志

Objective To evaluate the short-term efficacy of combination of 125 I seed brachytherapy and cetuximab in postoperation recurrent rectum cancer.Methods From July 2014 to June 2018,at Affiliated Hospital of Shandong Academy of Medical Sciences,57 patients with postoperation recurrent rectal cancer were recruited.According to therapy the patients were divided into two groups:the radiotherapy group (30 cases) treated with radioactive 125I seeds alone and the combination treatment group (27 cases) treated with combination of radioactive 125I seeds and cetuximab.The tumor size,pain relief and adverse reactions were observed in both groups.Chi-square test were performed for statistical analysis.Results After treatment for six months,the total efficacy rate and local control rate of combination treatment group were 54.2％ (13/24) and 87.5％ (21/24),respectively;and which were higher than those of radiotherapy group (17.9％,5/28 and 39.3％,11/28),and the differences were statistically significant (x2 =15.01 and 2.55,both P ＜ 0.05).At one month after treatment,the pain relief rate of radiotherapy group and combination treatment group was 70.0％ (21/30) and 85.2％ (23/27),respectively,and there was no statistically significant difference between the two groups (P ＞ 0.05).After treatment for six months,the rates of adverse reactions of radiotherapy group and combination treatment group were 46.7 ％ (14/30) and 63.0％ (17/27),respectively,there was no statistically significant difference between the two groups (P ＞ 0.05).The symptoms of patients with radiation injury significantly improved after symptomatic treatment.Conclusion The short-term efficacy of combination of 125 I seed brachytherapy and cetuximab is better than that of 125 I seed brachytherapy alone in patients with postoperation recurrent rectum cancer.

Comparative safety assessments of the biosimilar APZ001 and Erbitux in pre-clinical animal models

Abstract Purpose: To evaluate the toxicity of Erbitux as well as its biosimilar APZ001 antibody (APZ001) in pre-clinical animal models including mice, rabbits and cynomolgus monkeys. Methods: We performed analysis of normal behavior activity, autonomic and non-autonomic nervous functions, nervous-muscle functions, nervous excitability and sensorimotor functions on CD-1 mice. Subsequently, we studied that effects of APZ001 and Erbitux on respiratory system, cardiovascular system and kidney in Cynomolgus monkey models and performed local tolerance experiments on New Zealand rabbits. Results: The comparisons between APZ001 and Erbitux showed no significant differences in mice autonomic nervous system, nervous muscle functions, non-autonomic nervous functions, nervous excitability and sensorimotor functions between treated and untreated group (p>0.05). APZ001 and Erbitux showed negative effect on CD-1 mice in the present of pentobarbital sodium anesthesia (p>0.05). Single administrations of high, medium or low doses of APZ001 did not lead to monkey urine volume alterations (p>0.05). In human tissues, APZ001 and Erbitux showed positive signals in endocardium, lung type II alveolar epithelial cell and surrounding vessels, but showed negative results in kidney and liver tissues. No hemolysis phenomenon and serious side-effects in vessels and muscles were observed in rabbits when administrated with APZ001 and Erbitux respectively. Conclusion: The safety comparisons between APZ001 antibody and Erbitux showed that these two antibodies showed highly similarities in mice, rabbits and cynomolgus monkey animal models in consideration of pharmaceutical effects, indicating APZ001 might be a suitable substitute for Erbitux.

Exosomes promote cetuximab resistance via the PTEN/Akt pathway in colon cancer cells

Cetuximab is widely used in patients with metastatic colon cancer expressing wildtype KRAS. However, acquired drug resistance limits its clinical efficacy. Exosomes are nanosized vesicles secreted by various cell types. Tumor cell-derived exosomes participate in many biological processes, including tumor invasion, metastasis, and drug resistance. In this study, exosomes derived from cetuximab-resistant RKO colon cancer cells induced cetuximab resistance in cetuximab-sensitive Caco-2 cells. Meanwhile, exosomes from RKO and Caco-2 cells showed different levels of phosphatase and tensin homolog (PTEN) and phosphor-Akt. Furthermore, reduced PTEN and increased phosphorylated Akt levels were found in Caco-2 cells after exposure to RKO cell-derived exosomes. Moreover, an Akt inhibitor prevented RKO cell-derived exosome-induced drug resistance in Caco-2 cells. These findings provide novel evidence that exosomes derived from cetuximab-resistant cells could induce cetuximab resistance in cetuximab-sensitive cells, by downregulating PTEN and increasing phosphorylated Akt levels.

Evidence-based treatment for a patient with advanced rectal cancer with BRAF V600E mutation / 肿瘤

Objective: Based on evidence-based clinical evidence, an appropriate individualized treatment strategy was established for one patient with V-raf murine sarcomarosoncovirus oncogene homologous B (BRAF) V600E-mutant recurrent metastatic rectal cancer after chemotherapy. Methods: After evaluating the case data completely, the treatmentrelated clinical problems were put forward. Cochrance Library, PubMed, CBM (SinoMed), Embase, Chinese Journal Full-Text Database and Wanfang database were retrieved by computer to find the randomized controlled trial, systematic review and Meta-analysis about metastatic rectal cancer with BRAF V600E mutation. The 2001 Oxford Centre for Evidence-based Medicine Levels of Evidence was used to grade the literatures. Results: A total of 14 relevant studies were retrieved, most of which were grade A evidence, with high evidence intensity and reliable conclusion. Based on evidence-based clinical evidence, a suitable individualized treatment strategy was established for this patient, which was antiepidermal growth factor receptor (EGFR) antibody combined with BRAF inhibitor treatment. The short-term incidence rate of adverse reactions was low, the clinical symptoms were well controlled, and the result of response evaluation was partial response. Conclusion: Based on evidence-based clinical evidence, a reasonable treatment plan for patients with BRAF V600E-mutant metastatic colorectal cancer can effectively improve the therapeutic effect and prognosis.

FOLFOX/XELOX plus cetuximab administered weekly versus biweekly as a first-line treatment for patients with KRAS/RAS wild-type metastatic colorectal cancer: a retro-spective study / 中国肿瘤临床

To compare the efficacy and safety of cetuximab biweekly regimen with those of standard weekly regimen as a first-line therapy of KRAS/RAS wild-type metastatic colorectal cancer. Methods: Patients who received weekly or biweekly administra-tion of cetuximab plus FOLFOX/XELOX as a first-line therapy from July 2010 to December 2017 in Cancer Hospital, Chinese Academy of Medical Sciences were retrospectively screened for eligibility. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and frequencies of adverse events (AEs) between the two groups were compared. Results: Of 152 eligible patients, 55 were in the biweekly group and 43 were in the weekly group. The biweekly group had significantly higher ORR than the weekly group (76.3% vs. 54.8%, P=0.025). Median PFS in the biweekly and weekly groups were 10.3 and 8.8 months, respectively (P=0.288), and the median OS were 33.5 and 27.4 months, respectively (P=0.563). The two groups showed no significant difference in PFS and OS. For overall AEs, the biweekly group presented significantly more stomatitis (32.7% vs. 14.0% , P=0.032) and tended to show substantially more acne-like rash (80.0% vs. 62.8%, P=0.058) and leukopenia and/or neutropenia (72.7% vs. 55.8%, P=0.081). The frequency of 3/4 grade acne-like rash in the biweekly and weekly groups were 18.2% and 7.0%, respectively (P=0.105). The frequency of all grade 3/4 AEs between the two groups showed no significant difference (P>0.05). Conclusions: Biweekly regimen of cetuximab plus FOLFOX/XE-LOX had similar efficacy and higher ORR compared with those of standard weekly regimen. Cetuximab administered biweekly may be an optional choice in clinical practice, with close attention paid to increased frequency of certain AEs.

The effect of near-infrared fluorescence conjugation on the anti-cancer potential of cetuximab / 한국실험동물학회지

This study investigated the anti-cancer potential of a near-infrared fluorescence (NIRF) molecule conjugated with Cetuximab (Cetuximab-NIRF) in six-week-old female BALB/c athymic (nu+/nu+) nude mice. A431 cells were cultured and injected into the animals to induce solid tumors. Paclitaxel (30 mg/kg body weight (BW)), Cetuximab (1 mg/kg BW), and Cetuximab-NIRF (0.25, 0.5 and 1.0 mg/kg BW) were intraperitoneally injected twice a week into the A431 cell xenografts of the nude mice. Changes in BW, tumor volume and weight, fat and lean mass, and diameter of the peri-tumoral blood vessel were determined after two weeks. Tumor volumes and weights were significantly decreased in the Cetuximab-NIRF (1 mg/kg BW) group compared with the control group (P < 0.001). Lean mass and total body water content were also conspicuously reduced in the Cetuximab-NIRF (1 mg/kg BW) group compared with the vehicle control group. Peri-tumoral blood vessel diameters were very thin in the Cetuximab-NIRF groups compared with those of the paclitaxel group. These results indicate that the conjugation of Cetuximab with NIRF does not affect the anti-cancer potential of Cetuximab and NIRF can be used for molecular imaging in cancer treatments.

Development of radioimmunoconjugate for diagnosis and management of head-and-neck subclinical cancer and colorectal carcinoma

ABSTRACT Scientific innovations in diagnostic methods are important drivers of cancer control and prevention. Noninvasive imaging of the epidermal growth factor receptor (EGFR) in head-and-neck squamous, cell carcinoma and colorectal cancer could be valuable to select patients for EGFR-targeted therapy, as well as to monitor the efficacy and occurrence of resistance to immunotherapy. In order to develop the first Brazilian radioimmunoconjugate for diagnosis, Cetuximab has been conjugated to p-SCN-Bn-DTPA chelator and radiolabeled with Indium-111. The conjugation methodology was optimized using different mAb:DTPA molar ratios, time was then reduced for immunoconjugate preparation, besides the protein recovery' percentage increased after purification (m = 83.8 ± 0.91 %). The stability of Cetuximab-DTPA at - 20 oC was evaluated for six months, and its integrity was greater than 90% (m =93.9 ± 1.5%, N = 24). The radioimmunoconjugate with specific activity of 185 MBq/mg showed radiochemical purity above 95% (m=96.8 ± 1.31 %, N = 15). We conclude that the radioimmunoconjugate 111In-DTPA-cetuximab is stable and may be applied to the diagnosis of EGFR-positive tumors.

Effect and mechanism of cetuximab on cell proliferation of SW1990 and PANC-1 cells in pancreatic carcinoma / 中国生化药物杂志

Objective To investigate the effect of cetuximab on the proliferation of pancreatic carcinoma cell lines SW1990 and PANC-1.Methods 100.0 μg/mL cetuximab added DMEM medium(cetuximab group), simple DEME medium as the control group, two groups of the pancreatic carcinoma cell lines SW1990 and PANC-1 were cultured, the SW1990 and PANC-1 were detected by MTT after cultured 12, 24, 48 h, the expression of epidermal growth factor receptor gene(EGFR-mRNA)and protein in two groups were detected by RT-PCR and Western-blot after 24 h;the cell cycle was detected by flow cytometry after 24 h, the activity of Wnt/ beta-catenin pathway was detected by double luciferase assay after 24 h.Results The OD of the cetuximab group of the SW1990 and PANC-1 cell lines proliferation were lower than the control group after 12, 24, 48 h (P<0.05);the OD of the cetuximab group of the SW1990 and PANC-1 cell lines proliferation in 24, 48 h was significantly decreased than 12 h (P<0.05);the proportion of G1 phase cells of the SW1990 and PANC-1 of the cetuximab group increased significantly than the control group (P<0.05), the proportion of S and G2 phase cells decreased significantly than the control group (P<0.05), the expression of the EGFR-mRNA and protein of the cetuximab group were lower than the control group (P<0.05),the TOP/FOP of the Wnt/beta-catenin pathways' activity of the cetuximab group was lower than that of the control group (P<0.05).Conclusion The proliferation of pancreatic carcinoma cell lines SW1990 and PANC-1 was significantly inhibited by cetuximab, which was mainly achieved by decreasing the activity of Wnt/beta-catenin pathway and the expression of EGFR-mRNA and protein.

Biosimilarity Study Regarding Product Quality of Candidate Recombinant Monoclonal Antibodies as Biosimilars / 中国药学杂志

OBJECTIVE: Nowadays, recombinant monoclonal antibodies developed as biosimilar domains in application category for Investigational New Drug in domestic. The quality similarity should be prequalified for candidate drug to be developed as biosimilar. Here, the concept of quality biosimilarity was proposed and discussed from reviewer as well as developer. METHODS: The challenge of developing and evaluating biosimilar antibodies was emphasized. Then, the domestic sponsor's common problems were sorted out and critical quality attributes of some originator antibodies were summarized. Lastly, the reasons of holding letter or case rejected were exemplified and analyzed. RESULTS: AND CONCLUSION: The sponsor are encouraged to conduct comparing exercise by state-of-art analytical technologies to conform the quality similarity between a proposed biosimilar antibody and the originator product, the reviewers should also be very cautious to assess quality differences. Joint efforts and effective communication from researcher and reviewer are critical for promoting development of domestic biosimilar and addressing the unmet medicine need.

A Case of Successful Treatment with Kampo Medicine to the Adverse Skin Reactions Induced by Cetuximab / 日本東洋医学雑誌

Molecularly-targeted agents such as cetuximab, an anti-EGFR (epidermal growth factor receptor) monoclonal antibody have been used for the treatment of head and neck cancer. However, these agents frequently induce adverse skin reactions including acne-like rash and paronychia. For these problems, minocycline oral and heparinoid or steroid ointments, are commonly used. Some patients, however, cannot be controlled just by using these drugs. This case report shows a man in his 50s, who was treated for recurrence of nasal cancer. He received a long-term cetuximab therapy for 1 year and a half, and had severe paronychia and skin rash. Medication of unseiin and shiunko ointment decreased these adverse skin reactions, especially, paronychia on his first toes didn't need to be treated by steroid ointment anymore. When the common skin therapies are not effective, these Kampo therapies are possibly one of the options for the supportive care for the patients using cetuximab.

Use of a High-Throughput Genotyping Platform (OncoMap) for RAS Mutational Analysis to Predict Cetuximab Efficacy in Patients with Metastatic Colorectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Cetuximab demonstrates improved efficacy outcomes in patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS exon 2. Resistance to cetuximab is mediated by activating less frequent mutations in the RAS genes beyond KRAS exon 2. We performed extended RAS Mutational analysis using a high-throughput genotyping platform (OncoMap) and evaluated extended RAS analysis for predicting cetuximab efficacy in patients harboring wild-type KRAS exon 2 tumors following Sanger sequencing. MATERIALS AND METHODS: Extended RAS analysis was performed on 227 wild-type KRAS exon 2 mCRC patients who received cetuximab as salvage treatment using OncoMap ver. 4.0. Targeted genes included exon 2, exon 3, and exon 4, both in KRAS and NRAS, and included BRAF exon 15. We assessed efficacy by the new RAS mutation status. RESULTS: The OncoMap detected 57 additional mutations (25.1%): 25 (11%) in KRAS exon 2 and 32 (14.1%) beyond KRAS exon 2. Survival differences were observed after dividing patients into the wild-type RAS group (n=170) and mutant RAS group (n=57) using OncoMap. Progression-free survival was 4.8 months versus 1.8 months (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.32 to 0.61), and overall survival was 11.9 months versus 8.4 months (HR, 0.65; 95% CI, 0.47 to 0.88). CONCLUSION: Sanger sequencing is not sufficient for selecting candidates for cetuximab treatment. High-throughput extended RAS genotyping is a feasible approach for this purpose and identifies patients who might benefit from cetuximab treatment.