The efficacy and side effects of rigosertib combined with chemotherapy in KRAS mutant colorectal cancer mice / 中华肿瘤杂志

Objective: To investigate the effect of rigosertib (RGS) combined with classic chemotherapy drugs including 5-fluorouracil, oxaliplatin, and irinotecan in colorectal cancer. Methods: Explore the synergy effects of RGS and 5-fluorouracil (5-FU), oxaliplatin (OXA), and irinotecan (IRI) on colorectal cancer by subcutaneously transplanted tumor models of mice. The mice were randomly divided into control group, RGS group, 5-FU group, OXA group, IRI group, 5-FU+ RGS group, OXA+ RGS group and IRI+ RGS group. The synergy effects of RGS and OXA on KRAS mutant colorectal cancer cell lines in vitro was detected by CCK-8. Ki-67 immunohistochemistry and TdT-mediated dUTP nick-end labeling (TUNEL) staining were performed on the mouse tumor tissue sections, and the extracted tumor tissue was analyzed by western blot. The blood samples of mice after chemotherapy and RGS treatment were collected, blood routine and liver and kidney function analysis were conducted, and H&E staining on liver sections was performed to observe the side effects of chemotherapy and RGS. Results: The subcutaneously transplanted tumor models were established successfully in all groups. 55 days after administration, the fold change of tumor size of OXA+ RGS group was 37.019±8.634, which is significantly smaller than 77.571±15.387 of RGS group (P=0.029) and 92.500±13.279 of OXA group (P=0.008). Immunohistochemical staining showed that the Ki-67 index of tumor tissue in control group, OXA group, RGS group and OXA+ RGS group were (100.0±16.8)%, (35.6±11.3)%, (54.5±18.1)% and (15.4±3.9)%, respectively. The Ki-67 index of OXA+ RGS group was significantly lower than that in control group (P=0.014), but there was no significant difference compared to OXA group and RGS group (OXA: P=0.549; RGS: P=0.218). TUNEL fluorescence staining showed that the apoptotic level of OXA+ RGS group was 3.878±0.547, which was significantly higher than 1.515±0.442 of OXA group (P=0.005) and 1.966±0.261 of RGS group (P=0.008). Western blot showed that the expressions of apoptosis related proteins such as cleaved-PARP, cleaved-caspase 3 and cleaved-caspase 8 in the tumor tissues of mice in the OXA+ RGS group were higher than those in control group, OXA group and RGS group. After the mice received RGS combined with chemotherapy drugs, there was no significant effect on liver and kidney function indexes, but the combined use of oxaliplatin and RGS significantly reduced the white blood cells [(0.385±0.215)×10(9)/L vs (5.598±0.605)×10(9)/L, P<0.001] and hemoglobin[(56.000±24.000)g/L vs (153.333±2.231)g/L, P=0.001] of the mice. RGS, chemotherapy combined with RGS and chemotherapy alone did not significantly increase the damage to liver cells. Conclusions: The combination of RGS and oxaliplatin has a stronger anti-tumor effect on KRAS mutant colorectal cancer. RGS single agent will not cause significant bone marrow suppression and hepatorenal injury in mice, but its side effects may increase correspondingly after combined with chemotherapy.

Combination of anlotinib and irinotecan in the second-line treatment of metastatic colorectal cancer: a multicenter phase 1/2 trial / 中华肿瘤杂志

Objective: To evaluate the safety and efficacy of anlotinib plus irinotecan in the second-line treatment of patients with metastatic colorectal cancer (mCRC). Methods: This prospective phase 1/2 study was conducted in 2 centers in China (Cancer Hospital of Chinese Academy of Medical Sciences and Jiangsu Province Hospital). We enrolled patients with mCRC whose disease had progressed after first-line systemic therapy and had not previously treated with irinotecan to receive anlotinib plus irinotecan. In the phase 1 of the trial, patients received anlotinib (8 mg, 10 mg or 12 mg, po, 2 weeks on/1 week off) in combination with fixed-dose irinotecan (180 mg/m(2), iv, q2w) to define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). In the phase 2, patients were treated with the RP2D of anlotinib and irinotecan. The primary endpoints were MTD and objective response rate (ORR). Results: From May 2018 to January 2020, a total of 31 patients with mCRC were enrolled. Anlotinib was well tolerated in combination with irinotecan with no MTD identified in the phase 1, and the RP2D was 12 mg. Thirty patients were evaluable for efficacy analysis. Eight patients achieved partial response, and 21 had stable disease, 1 had progressive disease. The ORR was 25.8% and the disease control rate was 93.5%. With a median follow-up duration of 29.5 months, the median progression-free survival and overall survival were 6.9 months (95% CI: 3.7, 9.3) and 17.6 months (95% CI: 12.4, not evaluated), respectively. The most common grade 3 treatment-related adverse events (≥10%) were neutropenia (25.8%) and diarrhea (16.1%). There was no treatment-related death. Conclusion: The combination of anlotinib and irinotecan has promising anti-tumor activity in the second-line treatment of mCRC with a manageable safety profile.

Molecular mechanism of resveratrol combined with irinotecan in treatment of colorectal cancer / 中国中药杂志

This study aimed to investigate the mechanism of resveratrol(RES) combined with irinotecan(IRI) in the treatment of colorectal cancer(CRC). The targets of RES, IRI, and CRC were obtained from databases, and the targets of RES combined with IRI in the treatment of CRC were acquired by Venn diagram. The protein functional cluster analysis, GO and KEGG enrichment analyses were performed. In addition, the protein-protein interaction(PPI) network was constructed. The core target genes were screened out and the target-signaling pathway network was set up. IGEMDOCK was used to dock the core target gene molecules. Besides, the relationship between the expression level of key target genes and the prognosis and immune infiltration of CRC was analyzed. Based on the in vitro cell experiment, the molecular mechanism of RES combined with IRI in the treatment of CRC was explored and analyzed. According to the results, 63 potential targets of RES combined with IRI were obtained for CRC treatment. Furthermore, cluster analysis revealed that protein functions included 23% transmembrane signal receptors, 22% protein modifying enzymes, and 14% metabolite converting enzymes. GO analysis indicated that BPs were mainly concentrated in protein autophosphorylation, CCs in receptor complex and plasma membrane, and MFs in transmembrane receptor protein tyrosine kinase activity. Moreover, KEGG signaling pathways were mainly enriched in central carbon metabolism in cancer. The key targets of RES combined with IRI in the treatment of CRC were PIK3CA, EGFR, and IGF1R, all of which were significantly positively correlated with the immune infiltration of CRC. As shown by the molecular docking results, PIK3CA had the most stable binding with RES and IRI. Compared with the results in the control group, the proliferation ability and EGFR protein expression of CRC cells in the RES-treated group, the IRI-treated group, and the RES+IRI treated group significantly decreased. Moreover, the cell proliferation ability and EGFR protein expression level of CRC cells in the RES+IRI treated group were remarkably lower than those in the IRI-treated group. In conclusion, PIK3CA, EGFR, and IGF1R are the key targets of RES combined with IRI in CRC treatment. In addition, RES can inhibit the proliferation of CRC cells and improve IRI chemoresistance by downregulating the EGFR signaling pathway.

Efecto de la dieta CAF sobre la capacidad de EX4 de modular la expresión de marcadores proteicos de oxidación de ácidos grasos y termogénesis en músculo de ratones / Effect of the CAF diet on the ability of EX4 to modulate the expression of protein markers of fatty acid oxidation and thermogenesis in mouse muscle

El ambiente obesogénico promueve la obesidad al facilitar el acceso y consumo de una amplia variedad de alimentos palatables altos en calorías. La activación del receptor de GLP1 (GLP1R) reduce la ingesta de alimentos, enlentece el vaciamiento gástrico y promueve un balance energético negativo a través de su acción en distintos órganos como el músculo esquelético, disminuyendo así el peso corporal. La obesidad inducida por dieta alta en grasa disminuye el efecto anorexigénico de la administración sistémica vía intra-peritoneal de EX4 (agonista de GLP1R). Sin embargo, se desconoce si la exposición a un ambiente obesogénico previo a la manifestación de obesidad disminuye los efectos anorexigénicos de EX4 o un posible efecto de EX4 sobre marcadores de oxidación de ácidos grasos y termogénesis en músculo esquelético. El objetivo de esta investigación fue determinar el efecto a corto plazo de la dieta CAF, un modelo del ambiente obesogénico humano, sobre la capacidad de EX4 de reducir la ingesta y modular la expresión de marcadores proteicos de oxidación de ácidos grasos y termogénesis (CPT1 y UCP2) en músculo de ratones. Nuestros datos muestran que una inyección intraperitoneal de EX4 a ratones C57BL/6J alimentados con dieta CAF o dieta control durante 10 días no altera la ingesta calórica total, peso corporal, o la expresión de proteínas marcadoras de los procesos de beta-oxidación y de termogénesis (CPT1 y UCP2). Estos datos sugieren que protocolos alternativos de administración de EX4 son necesarios para observar los efectos fisiológicos de la activación de GLP1R.

The obesogenic environment promotes obesity by facilitating access to and consumption of a wide variety of palatable, high-calorie foods. Activation of the GLP1 receptor (GLP1R) reduces food intake, slows gastric emptying, and promotes a negative energy balance by acting on organs such as skeletal muscle, thus decreasing body weight. Obesity induced by a high-fat diet decreased the anorexigenic effect of intraperitoneal systemic administration of EX4 (GLP1R agonist). However, it is unknown whether exposure to an obesogenic environment before the manifestation of obesity diminishes the anorexigenic effects of EX4 or a possible effect of EX4 on markers of fatty acid oxidation and thermogenesis in skeletal muscle. This investigation aimed to determine the short-term effect of the CAF diet, a model of the human obesogenic environment, on the ability of EX4 to reduce intake and modulate the expression of protein markers of fatty acid oxidation and thermogenesis (CPT1 and UCP2) in mouse muscle. Our data show that intraperitoneal injection of EX4 to C57BL/6J mice fed CAF diet or control diet for ten days does not alter total caloric intake, body weight, or expression of proteins markers of beta-oxidation and thermogenesis processes (CPT1 and UCP2). These data suggest that alternative EX4 administration protocols are necessary to observe the physiological effects of GLP1R activation.

Oxaliplatin versus Irinotecan no câncer colorretal avançado / Oxaliplatin versus Irinotecan in advanced colorectal cancer

O câncer colorretal é uma neoplasia com alta prevalência e letalidade. A razão desse elevado número de mortes é a detecção da doença em estágios metastáticos, de difícil cura e que necessitam de terapia quimioterápica adjuvante ou paliativa. Na atualidade, o principal tratamento quimioterápico dessa neoplasia tem como base as drogas Oxaliplatina ou Irinotecano, isolados ou combinados com outros medicamentos. O objetivo desta revisão sistemática é avaliar se há superioridade do esquema quimioterápico com Irinotecano sobre o regime com Oxaliplatina. Foi realizada a análise de ensaios clínicos randomizados, fase II ou III, nas bases de dados eletrônicas Central e PubMed. Critérios de inclusão: ensaios clínicos randomizados comparando regimes à base de irinotecano ou oxaliplatina como tratamentos de primeira linha para câncer colorretal metastático. O desfecho primário analisado foi a superioridade entre os quimioterápicos sobre a sobrevida global. Os desfechos secundários incluíram sobrevida livre de progressão, taxa de resposta e efeitos colaterais. Registro na PROSPERO: CRD42019130339. Não houve diferença significativa nos 13 estudos sobre a sobrevida dos pacientes. Sobre os efeitos colaterais dos medicamentos, os regimes baseados em irinotecano foram associados a uma alta incidência de neutropenia e diarreia grave. Já os associados com oxaliplatin cursaram com alta incidência de neuropatia sensitiva. Não houve diferença estatisticamente significativa sobre a sobrevida global, sobrevivência livre de progressão e na taxa de resposta quando comparamos os pacientes que receberam oxaliplatina e irinotecano (AU)

Colorectal cancer is a highly prevalent and lethal neoplasm. The reason for this high number of deaths is the detection of the disease in metastatic stages, which are difficult to cure and require adjuvant or palliative chemotherapy therapy. Currently, the main chemotherapeutic treatment of this neoplasm is based on the drugs Oxaliplatin or Irinotecan, alone or combined with other drugs. The objective of this systematic review is to evaluate whether there is superiority of the chemotherapy regimen with Irinotecan over that with Oxaliplatin. Analysis of randomized clinical trials, phase II or III, was performed in the electronic databases Central and PubMed. Inclusion criteria: randomized clinical trials comparing irinotecan- or oxaliplatin-based regimens as first-line treatments for metastatic colorectal cancer. The primary endpoint analyzed was the superiority between chemotherapies on overall survival. Secondary endpoints included progression-free survival, response rate, and side effects. PROSPERO registration: CRD42019130339. There was no significant difference in the 13 studies on patient survival. On drug side effects, irinotecan-based regimens were associated with a high incidence of neutropenia and severe diarrhea. Those associated with oxaliplatin were associated with a high incidence of sensory neuropathy. There was no statistically significant difference in overall survival, progression-free survival, and response rate when comparing patients receiving oxaliplatin and irinotecan (AU)

Association between UGT1A1*28 gene polymorphism and severe neutropenia due to colorectal cancer treatment with irinotecan: evidence based on meta-analysis / Associação entre o polimorfismo do gene UGT1A1*28 e a neutropenia severa decorrente do tratamento do câncer colorretal com irinotecano: evidências baseadas em meta-análise

Abstract Objective The present study aimed to evaluate the relationship between UGT1A1*28 gene polymorphism and the prevalence of neutropenia in patients with colorectal cancer treated with irinotecan. Method Thirteen studies were included. These papers were selected from the Virtual Health Library, Scientific Electronic Library Online, International Health Sciences Literature and PubMed, and their data were collected and evaluated using the BioEstat 5.3 software (BioEstat, Belém, PA, Brazil). Results Three genotypes were analyzed, namely 6/6 (wild type), 6/7, and 7/7. In total, 2,146 patients were included in the present study; of these, 55.6% (n=1,193) had 6/6 genotype, 37.3% (n=801) were heterozygous (6/7), and 7.1% (n=152) had the 7/7 genotype. A total of 1,672 (77.9%) patients displayed mild neutropenia, whereas 474 (22.1%) had severe neutropenia. When contrasting the 6/7 and 7/7 genotypes with the 6/6 genotype using statistical tests for meta-analysis, patients with the 7 allele, either Conclusion The analysis of the UGT1A1*28 gene polymorphism can aid the choice of treatment for patients with colorectal cancer in personalized medicine, increasing the chances of therapeutic success.

Resumo Objetivo Avaliar a relação do polimorfismo do gene UGT1A1*28 com a prevalência de neutropenia em pacientes com câncer colorretal submetidos a tratamento com o irinotecano. Método Foram incluídos 13 estudos sobre o tema proposto, selecionados nas bases de dados da Biblioteca Virtual de Saúde, Scientific Electronic Library Online, International Health Sciences Literature e PubMed.Os dados foramcoletados dos artigos científicos selecionados e avaliados com o auxílio do software BioEstat 5.3 (BioEstat, Belém, PA, Brasil). Resultados Osgenótipos analisados foram6/6 (tipo selvagem), 6/7 e 7/7. Foramincluídos 2.146 pacientes. Destes, 55,6% (n=1.193) apresentaram genótipo 6/6, 37,3% (n=801) eramheterozigotos (6/7) e 7,1%(n=152) tinhamo genótipo 7/7.Umtotal de 1.672 (77,9%) pacientes apresentou neutropenia leve e 474 (22,1%) neutropenia severa. Ao contrastar os genótipos 6/7 e 7/7 como 6/6, percebeu-se, coma execução dos testes estatísticos demetaanálise, que os pacientes como alelo 7, emhomozigose ou heterozigose, tinhammaior risco de desenvolver neutropenia severa que pacientes com o genótipo 6/6 (razão de chances =1,559; intervalo de confiança de 95%=1,163-2,090; p=0,003). Conclusão A análise do polimorfismo do gene UGT1A1*28 pode auxiliar na escolha do tratamento do paciente comcâncer colorretal, no contexto da medicina personalizada, ampliando, assim, as chances de sucesso terapêutico.

Chinese expert consensus on the clinical application of the Chinese modified triplet combination with irinotecan, oxaliplatin and continuous infusional 5-fluorouracil/leucovorin for colorectal cancer / 中华胃肠外科杂志

Colorectal cancer is the second most common malignant tumor in China. The FOLFOXIRI regimen, which combines 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan, is a high-intensity and highly effective chemotherapy regimen. However, the original regimen is poorly tolerated in Chinese patients. In order to promote the standardized and rational application of FOLFOXIRI regimen by clinicians in China, "

FOLFIRI as second-line treatment of metastatic biliary tract cancer patients

The combination of cisplatin and gemcitabine is the standard first-line treatment of metastatic biliary tract cancer (BTC) patients. The benefit of second-line chemotherapy in these patients is controversial. This study aims to evaluate the activity of FOLFIRI (fluorouracil and irinotecan) after failure to the first-line platinum and gemcitabine-based chemotherapy in metastatic BTC patients. We present a single-institution, retrospective cohort study. Patients with locally advanced or metastatic BTC who progressed after at least one line of chemotherapy, consecutively treated at our Institution between 2007 and 2017 were included. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), clinical benefit rate (CBR) and safety profile of FOLFIRI. Twelve patients were included in the analysis, with a median follow up of 5 months (95% CI 2.77-7.20). The median number of cycles received was 3 (range 1 to 9). Four grade 3 toxicities were recorded; no grade 4 toxicities and no treatment-related deaths occurred. The median PFS was 1.7 months (95% CI; 0.66-2.67), and median OS was 5 months (95% CI; 2.77-7.20). Two patients presented stable disease, providing a CBR of 17%. We concluded that FOLFIRI presented a favorable toxicity profile and a modest activity in metastatic BTC patients who had progressed to platinum and gemcitabine and may be considered in patients who are able to tolerate additional lines of chemotherapy. Immunotherapy and targeted therapies selected according to the tumoral genomic profile are promising alternatives to improve the outcomes of second-line treatment in BTC.

Terapia de conversión en cáncer gástrico estadio IV: a propósito de un caso / Case Report of Conversion Therapy in Stage IV Gastric Cancer

Resumen Se reporta el caso de una paciente de 47 años, con diagnóstico inicial de un tumor de Krukenberg por una lesión anexial de 10 cm de diámetro y una lesión corporal gástrica de 3 cm. La biopsia mostró un adenocarcinoma pobremente diferenciado con células en anillo de sello. Una laparoscopia inicial mostró un índice de carcinomatosis peritoneal (ICP) de 24, por lo cual se le indica a la paciente quimioterapia con intención paliativa (cisplatino y capecitabina). Con mejoría clínica importante, respuesta adecuada y favorable a la quimioterapia, la paciente se remitió a una salpingo-ooforectomía bilateral. Continúa con quimioterapia evidenciándose mejoría de las imágenes tomográficas y una excelente respuesta clínica. Por este motivo, se decide en conjunto con la familia llevarla a cirugía. Se le practica una gastrectomía total con linfadenectomía D2 con intención curativa. La paciente recibe quimioterapia con capecitabina y cisplatino por 3 meses más, hasta cuando se evidencia compromiso ganglionar paraaórtico, por lo que es necesario reiniciar la quimioterapia con un nuevo esquema, entonces se le formula irinotecán. La paciente completa 22 meses desde el diagnóstico inicial, la condición clínica es muy buena y está asintomática.

Abstract We report the case of a 47-year-old patient initially diagnosed with a Krukenberg tumor, an adnexal lesion 10 cm in diameter and a 3 cm lesion in the gastric corpus. A biopsy showed a poorly differentiated adenocarcinoma with signet ring cells. Initial laparoscopy showed an index of peritoneal carcinomatosis of 24 which indicated chemotherapy with palliative intent (cisplatin and capecitabine). The patient improved significantly and underwent a total hysterectomy with salpingo-oophorectomy. Chemotherapy continued with excellent clinical response as evidenced in CT scans. Together with the patient's family, it was decided that she should undergo surgery. A total gastrectomy with D2 lymphadenectomy with curative intent was performed. The patient continued to receive capecitabine and cisplatin for three more months until para-aortic lymph node involvement was demonstrated and it became necessary to restart chemotherapy with a new scheme using iriniotecan. The patient has completed 22 months after the initial diagnosis in very good and clinical condition without symptoms.