Treatment Of Colorectal Carcinoma Research Articles

Introducing a time out consultation with the general practitioner between diagnosis and start of colorectal cancer treatment: Patient-reported outcomes.

ObjectiveTo evaluate the introduction of a “time out consultation” with the general practitioner (GP) recommended to patients following the diagnosis of colorectal carcinoma (CRC) before start of treatment.MethodsA prospective study using questionnaires to compare the number of GP consultations, with their content and outcomes before and after the introduction of an additional consultation with the GP to improve decision‐making and adequate support.Results72 patients before and 98 patients after the introduction of the “time out consultation” participated. Introduction of the consultation increased the number of patients to contact their GP from 67% to 80%, but did not change kind or content of the consultations. Patients felt the consultation was comforting and were more satisfied with the GP after the introduction. There was no difference in outcomes measured by the questionnaires in all patients combined, but men, older patients and patients with palliative treatment options only did improve on specific outcomes after the introduction.ConclusionThe introduction of the “time out consultation” did not change the kind or content of GP consultations before start of CRC treatment, but patients did feel more comforted and satisfied. Subgroups of patients benefited on specific outcomes.

MiR-9-5p suppresses cell metastasis and epithelial-mesenchymal transition through targeting FOXP2 and predicts prognosis of colorectal carcinoma.

Colorectal carcinoma (CRC) is a common malignant tumor of the digestive tract that occurs in the colon, and the incidence is the third in the gastrointestinal tumor. Recently, the dysregulated expression of microRNA-9 (miR-9) has been identified in many human cancers. However, the special function of miR-9 in the progression of colorectal carcinoma (CRC) remains unknown. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to detect the expression of miR-9-5p in 72 pairs of CRC tissues and cell lines. The correlation between miR-9-5p expression and clinical features or prognosis of CRC patients was analyzed. In addition, we examined the mRNA and protein expression levels of forkhead box P2 (FOXP2) using Western blot analysis and qRT-PCR. The functions of miR-9-5p and FOXP2 were investigated using transwell assay and epithelial-mesenchymal transition (EMT). The relation between miR-9-5p and FOXP2 was confirmed by the dual-luciferase assay. In this study, down-regulation of miR-9-5p and up-regulation of the forkhead box P2 (FOXP2) were detected in CRC tissues and cell lines. Moreover, miR-9-5p was found to inhibit cell metastasis and EMT in CRC. In addition, it was confirmed that miR-9-5p directly targeted FOXP2 in CRC. Furthermore, FOXP2 had a carcinogenic effect on CRC. And the overexpression of FOXP2 weakened the suppressive effect of miR-9-5p in CRC. Of note, we observed found that the low expression of miR-9-5p and the high expression of FOXP2 were correlated with poor prognosis of CRC patients. MiR-9-5p suppressed cell metastasis and EMT through targeting FOXP2. Furthermore, dysregulation of miR-9-5p predicted the prognosis of CRC patients. Therefore, miR-9-5p may be a biomarker for cell metastasis and a prognostic factor for CRC patients. MiR-9-5p/FOXP2 axis will provide a new breakthrough in the diagnosis and treatment of CRC.

Polymer-based nanoparticles for chemo/gene-therapy: Evaluation its therapeutic efficacy and toxicity against colorectal carcinoma

Combination treatment through simultaneous delivery of anticancer drugs and gene with nano-formulation has been demonstrated to be an elegant and efficient approach for colorectal cancer therapy. Recently, sorafenib being studied in combination therapy in colorectal cancer (CRC) attracted attention of researchers. On the basis of our previous study, pigment epithelium-derived factor (PEDF) loaded nanoparticles showed good effect on CRC in vitro and in vivo. Herein, we designed a combination therapy for sorafenib (Sora), a multi-kinase inhibitor and PEDF, a powerful antiangiogenic gene, in a nano-formulation aimed to increase anti-tumor effect on CRC for the first time. Sora and PEDF were simultaneously encapsulated in PEG-PLGA based nanoparticles by a modified double-emulsion solvent evaporation method. The obtained co-encapsulated nanoparticles (Sora@PEDF-NPs) showed high entrapment efficiency of both Sora and PEDF — and exhibited a uniform spherical morphology. The release profiles of Sora and PEDF were in a sustained manner. The most effective tumor growth inhibition in the C26 cells and C26-bearing mice was observed in the Sora@PEDF-NPs in comparison with none-drug nanoparticles, free Sora, mono-drug nanoparticles (Sora-NPs and PEDF-NPs) and the mixture of Sora-NPs and equivalent PEDF-NPs (Mix-NPs). More importantly, Sora@PEDF-NPs showed lower toxicity than free Sora in mice according to the acute toxicity test. The serologic biochemical analysis and mice body weight during therapeutic period revealed that Sora@PEDF-NPs had no obvious toxicity. All the data demonstrated that the simultaneously loaded nanoparticles with multi-kinase inhibitor and anti-angiogenic gene might be one of the most potential formulations in the treatment of colorectal carcinoma in clinic and worthy of further investigation.

Abstract 3599: BAY 2402234: Preclinical evaluation of a novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of colorectal carcinomas

Abstract Colorectal carcinoma (CRC) is the third most common malignancy in the US, being responsible for approximately 50,000 deaths per year. The overall 5-year survival rates are high for localized disease (~90%), but low for metastatic disease (~14%), thereby underlining the high unmet medical need for novel therapeutics for CRC patients. DHODH is a key enzyme in the de novo pyrimidine synthesis, converting dihydroorotate to orotate. We recently discovered its role in AML differentiation (Sykes et al 2016, Cell) and we are investigating BAY 2402234 in an ongoing phase I study in myeloid malignancies (NCT03404726). Since then, several publications have also described a role of DHODH in solid tumor indications. Herein we disclose the functional preclinical characterization of the novel DHODH inhibitor BAY 2402234 in CRC. BAY 2402234 is a selective low-nanomolar inhibitor of human DHODH enzymatic activity. In vitro it potently inhibits proliferation of CRC cell lines in the sub-nanomolar to low-nanomolar range. The anti-proliferative effects can be rescued by uridine supplementation which is known to bypass DHODH via the salvage pathway and demonstrates the on-target specificity of the inhibitor. Interestingly, not all CRC cell lines are sensitive to the inhibitor. Similar to the in vitro observations, BAY 2402234 exhibits strong in vivo anti-tumor efficacy in monotherapy in some, but not all, subcutaneous CRC xenograft models. A large CRC PDX in vivo screen revealed tumor growth inhibition in over 60% of the models in response to BAY 2402234 treatment. To elucidate the mode of action of BAY 2402234 in CRC we analyzed transcriptomic changes in CRC PDX models in vivo after single treatment with BAY 2402234, and identified several hundred differentially regulated genes at early time points. These in vivo PDX models were also used to explore potential effects of BAY 2402234 treatment on a large panel of metabolites. These preclinical results support the clinical evaluation of BAY 2402234 in patients with CRC, and such a clinical study is planned for early in 2019. Citation Format: Claudia Merz, Sven Christian, Ashley Eheim, Henrik Seidel, Ralf Lesche, Merlin Luetke- Eversloh, Hanna Meyer, Steven Ferrara, Marcus Bauser, Andrea Haegebarth, Stefan Gradl, Andreas Janzer. BAY 2402234: Preclinical evaluation of a novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of colorectal carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3599.

Abstract 3958: FAK inhibition reduces tumor infiltration of Tregs via restricting CCL5 release and boosts the present therapeutic regimen for BRAFV600E-mutated colorectal carcinoma

Abstract Background: BRAFV600E-mutated colorectal carcinoma (CRC) is a refractory disease with poor prognosis and limited therapeutic approaches. Recently, researches have indicated that the recruitment of Tregs in tumor tissue promoted by BRAFV600E is responsible for the weakened antitumor immunity. Whereas, as the main targeting therapy for this intractable carcinoma, BRAFV600E inhibitor has little response. In addition, FAK, being the novel therapeutic target in CRC, is considered to have an impact on the release of chemokines. In this study, we sought to explore the capacity of FAK inhibitor restricting Treg infiltration in tumor and its mechanism, as well as the synergistic antitumor effect with the present therapeutic strategy for BRAFV600E-mutated CRC. Methods: Cell proliferation was determined by CCK-8 assay and colony formation assay. Migration ability was detected by transwell assay. Cell cycle and cell group analysis were assessed by flow cytometry. Western blot, Elisa and RT-qPCR analysis were conducted for mechanism exploration. Immunohistochemistry and immunofluorescence analysis were performed to confirm the link between BRAFV600E, FAK and Tregs. CRC xenograft models were established to detect the Treg recruitment and evaluate the synergistic antitumor effect in vivo. Results: BRAFV600E-mutated CRC was of higher expression of FAK, and hence more sensitive to FAK inhibitor APG-2449. Besides, BRAFV600E-mutated in CRC was linked with more Treg infiltration in tumor site, therefore contributed to the attenuated antitumor immunity. What’s more, despite directly inhibiting tumor proliferation and migration, one of the important mechanisms of FAK blockade restricting the growth of BRAFV600E-mutated CRC, was by downregulating the release of Treg chemokine CCL5 from tumor cells through FAK-IL33 axis. With the recruitment of Tregs decreasing induced by FAK inhibitor APG-2449, the number of CD8+T cells relatively elevated in tumor tissue. In BRAFV600E-mutated CRC xenotransplantation models, we revealed that the combination of FAK inhibitor APG-2449 and Vemurafenib was of no significant difference with the combination of Vemurafenib and cetuximab. While adding APG-2449 to the current combination strategy achieved greater tumor suppressing effect than not adding. Conclusions: BRAFV600E-mutated CRC is associated with a higher expression level of FAK, as well as the tumor infiltration of Tregs. FAK inhibitor APG-2449 can promote antitumor immunity by restricting Treg number in tumor tissue, and shows a synergistic effect with the present therapeutic strategy for BRAFV600E-mutated CRC treatment. Citation Format: Luping Yuan, Wentao Pan, Suna Zhou, Qiuyun Luo, Xianglei Yan, Yuxin Zhang, Mengxian Pan, Lin Zhang, Miaozhen Qiu, Dajun Yang. FAK inhibition reduces tumor infiltration of Tregs via restricting CCL5 release and boosts the present therapeutic regimen for BRAFV600E-mutated colorectal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3958.

MicroRNA-760 inhibits the biological progression of colorectal carcinoma by directly targeting FOXA1 and regulating epithelial-to-mesenchymal transition and PI3K/AKT signaling pathway.

Colorectal carcinoma (CRC) is one of the most common factors for tumor-associated mortalities globally. In recent years, microRNAs (miRNAs) have been identified as novel therapeutic biomarkers for cancer treatment. The purpose of the current study was to unravel the clinical significance and underlying molecular mechanisms of miR-760 in CRC progression. Fifty-four pairs of CRC tissue samples and adjacent para-carcinoma tissue samples were collected from CRC patients who underwent surgical resection. We measured miR-760 expressions in CRC using quantitative Real-time polymerase chain reaction (qRT-PCR) analysis. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assays and transwell assays were performed to determine the functions of miR-760 in CRC cell proliferation, invasion and migration. Dual-luciferase reporter assays and Western blots were used to investigate the underlying molecular mechanisms. Moreover, the association between miR-760 expressions and clinicopathological features was analyzed. In this study, the results showed that the down-regulated miR-760 expressions were related to the poor prognosis and malignant clinicopathologic features of CRC patients. Furthermore, functional assays revealed that miR-760 restoration obviously suppressed CRC cell proliferation, migration and invasion through modulating phosphatidylinositol 3-kinase/ protein kinase B (PI3K/AKT) pathway and epithelial-mesenchymal transition (EMT). FOXA1 was also considered as a functional target of miR-760 in CRC cells. Furthermore, miR-760 up-regulation also significantly repressed tumorigenesis in vivo. These results suggested that miR-760 exerted cancer-suppressive functions in CRC, providing a therapeutic strategy for CRC treatment.

RKI-1447 suppresses colorectal carcinoma cell growth via disrupting cellular bioenergetics and mitochondrial dynamics.

Accumulated evidence suggested the importance of the Rho/Rho-kinase (ROCK) signaling pathway in cancer proliferation and invasion. However, its role in colorectal carcinoma (CRC) is not well understood. This study evaluated the effect of ROCK signaling pathway on CRC behavior on the basis of a novel Rho/ROCK inhibitor RKI-1447. Here, we found RKI-1447 could drastically suppress HCT-8 and HCT-116 cell growth and promoted apoptosis. Our in vitro data indicated suppressed cytoskeletal dynamics induced by RKI-1447 inhibition on mitochondrial respiration, which was evidenced by basal and maximal respiration rates, and ATP production. Simultaneously, cellular basal and maximal glycolytic rates, and glycolytic capacity were also reduced in response to RKI-1447. Moreover, RKI-1447 caused excessive reactive oxygen species generation and membrane depolarization as well as activated ER-stress. We also demonstrated CHOP is essential for RKI-1447 induced cell apoptosis. Finally, we proved inhibition of ROCK by RKI-1447 could effectively inhibit CRC growth in vivo. Taken together, this study demonstrated that inhibition of ROCK signaling pathway by RKI-1447 could suppress CRC via cytoskeleton associated mitochondrial dysfunction and cellular bioenergetics disruption. Our data suggest RKI-1447 may be an attractive antitumor drug candidate for the treatment of CRC.

MicroRNA‑214 suppresses the viability, migration and invasion of human colorectal carcinoma cells via targeting transglutaminase 2.

Colorectal carcinoma (CRC) is a common malignancy of the digestive tract. MicroRNA (miR)-214 is considered a key hub that controls tumor networks; therefore, the effects of miR-214 on CRC were examined and its target gene was investigated in this study. The expression levels of transglutaminase 2 (TGM2) and miR-214 were detected in CRC and adjacent normal tissues by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting, and luciferase activity was analyzed by dual luciferase reporter analysis. In addition, cell viability, invasion and migration were measured by Cell Counting kit-8 and Transwell assays, respectively. The expression levels of epithelial-mesenchymal transition-related proteins, and phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt) signaling-associated factors were detected using RT-qPCR and western blotting. The results demonstrated that miR-214 expression was downregulated in CRC tissue, whereas TGM2 expression was upregulated. According to TargetScan prediction, miR-214 possesses a binding site to TGM2. In addition, transfection with miR-214 mimics markedly suppressed the viability of LoVo cells. miR-214 overexpression also inhibited cell invasion and migration by increasing E-cadherin and tissue inhibitor of metalloproteinases-2 expression, and decreasing matrix metalloproteinase (MMP)-2 and MMP-9 expression. Furthermore, miR-214 downregulated phosphorylation of PI3K and Akt; however, the expression levels of total PI3K and Akt were not affected by miR-214. In conclusion, this study indicated that TGM2 was a target gene of miR-214, and a negative correlation between miR-214 and TGM2 expression was determined in CRC. Notably, miR-214 markedly suppressed the viability, invasion and migration of CRC cells, which may be associated with a downregulation in PI3K/Akt signaling. These findings suggested that miR-214 may be considered a novel target for the treatment of CRC.

Preceding endoscopic submucosal dissection for T1 colorectal carcinoma does not affect the prognosis of patients who underwent additional surgery: a large multicenter propensity score-matched analysis.

We analyzed the influence of preceding endoscopic submucosal dissection (ESD) on the prognosis of patients with T1 colorectal carcinoma (CRC) after additional surgery using propensity-score matching. 1638 consecutive patients with T1 CRC were retrospectively identified between January 1998 and December 2016 at the Hiroshima GI Endoscopy Research Group. We assessed 602 patients with 602 T1 CRC who underwent additional surgery after ESD (n = 216) or surgery alone (n = 386). The enrolled patients were treated according to the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016, and were defined as non-endoscopically curable (non-e-curable) when they did not satisfy its curative criteria. We analyzed the pathological characteristics and the prognosis of non-e-curable patients using propensity-score matching between the additional surgery after ESD and surgery alone groups. There were no cases of recurrence and lymph node metastasis among the e-curable patients. The rate of lymph node metastasis and recurrences in the non-e-curable patients were 10.8% and 2.6%, respectively. After propensity-score matching, there were no significant differences in the 5-year overall survival rates (96.9% vs. 92.0%), 5-year disease-free survival rates (96.7% vs. 96.7%) and 5-year disease-specific survival rates (100% vs. 98.6%) after treatment of T1 CRCs between the 2 groups in non-e-curable patients. Preceding ESD with histological en bloc resection for patients with T1 CRC did not affect their oncologic behavior adversely after additional surgery.

Long-term prognosis after treatment for T1 carcinoma of laterally spreading tumors: a multicenter retrospective study.

Long-term prognosis of T1 laterally spreading tumors (LSTs) after treatment have not been clarified. This study compared clinicopathological characteristics and long-term prognosis of T1 LSTs. We retrospectively assessed 169 patients with 169 T1 LSTs between January 1992 and December 2008 by ten hospitals. Patients who did not meet the Japanese Society for Cancer of the Colon and Rectum (JSCCR) 2016 guidelines for the treatment of colorectal carcinoma (CRC) criteria were defined as non-endoscopically curable. The number of non-endoscopically curable patients with LST-granular/nodular mixed (LST-G-M) was 61, that with LST-non-granular/ flat elevated (LST-NG-FE) was 23, and that with LST-non-granular/ pseudo depressed (LST-NG-PD) was 23. Clinicopathological variables and long-term prognosis were analyzed. For overall patients, tumor size, number of non-endoscopically curable cases, and rate of submucosal invasion depth ≥ 1000μm for the LST-G-M group were significantly higher than those in the other groups. For non-endoscopically curable patients, the tumor size for those with LST-G-M was significantly larger than those in the other groups. The rate of submucosal invasion width ≥ 4000μm and type B/C muscularis mucosae with LST-G-M was higher than that with LST-NG-FE. All recurrences occurred in non-endoscopically curable patients with LST-G-M. Five-year overall and disease-free survivals for non-endoscopically curable patients with LST-G-M were significantly shorter than those for patients with non-endoscopically curable LST-NG-FE and PD. Our data supported adequacy of the JSCCR guidelines for the treatment of CRC criteria for endoscopically curable patients after T1 LSTs treatment. Patients with T1 LST-G-M should be followed up more carefully.

Cellular localization of PD-L1 expression in mismatch-repair-deficient and proficient colorectal carcinomas

Blockade of the interaction between PD-1 and its ligands PD-L1 has shown clinical efficacy across several tumor types, especially in mismatch-repair-deficient colorectal carcinoma. The aim of this study was to examine the pattern and cellular localization of PD-L1 expression in the different molecular subtypes of mismatch-repair-deficient colorectal cancers vs. their mismatch-repair-proficient counterparts. PD-L1/SATB2 double-antibody-immunohistochemistry was utilized to distinguish tumor cell from immune cell staining. We observed in our series of 129 colorectal adenocarcinomas that PD-L1 expression occurred primarily in tumor-associated-immune cells and most prominently at the tumor-stroma-interface of the invasive front. The level of invasive front immune cell staining was significantly higher in mismatch-repair-deficient tumors compared to mismatch-repair-proficient tumors (p < 0.001), but no difference was observed among the different subtypes of mismatch-repair-deficient tumors: Lynch syndrome-associated vs. MLH1-methylated vs. unexplained. While selected mismatch-repair-proficient tumors exhibited unusually high tumor-infiltrating-lymphocytes and had high level immune cell PD-L1 expression, a positive correlation between PD-L1 expression and high lymphocyte count was detected only in mismatch-repair-deficient tumors (r = 0.39, p < 0.001) and not in mismatch-repair-proficient tumors. Notably, true tumor cell PD-L1 expression in colorectal carcinoma was rare, present in only 3 of 129 tumors (2.3%): 2 MLH1-methylated and 1 mismatch-repair-proficient with high tumor-infiltrating-lymphocytes; and the staining in the tumor cells in all 3 was diffuse (>=50% of the tumor). These findings may serve to inform further efforts aiming to evaluate PD-L1 immunohistochemistry vis-à-vis molecular sub-classification as predictive biomarkers in the treatment of colorectal carcinoma.

The effect of routine lymphadenectomy of the hepatic basin on the duration of the liver resection due to colorectal carcinoma metastases

Background/Aim. Today, lymphatic metastases are only a relative contraindication for the surgical treatment of colorectal carcinoma (CRC). The aim of this study was to evaluate the effect of routine lymphadenectomy of the hepatic basin on the duration of the liver resection for CRC metachronous liver metastases. Methods. A total of 50 patients with CRC metachronous liver metastases underwent the liver resection with routine hepatic basin lymphadenectomy. Results. Larger volume of metastases (in mL), the number of affected segments, and the number of metastases as well the diameter of the largest lesion (in mm), determine the duration of the liver resection itself and the surgical procedure overall. The duration of lymphadenectomy was 25?55 min (32.2 min on average). Conclusion. Routine lymphadenectomy of the hepatic basin following the liver resection for CRC metachronous liver metastases, minimally prolongs the duration of the operation.

Interdisciplinary treatment of oncological patients in certified colorectal cancer centers - networks for patients

Interdisciplinary treatment of oncological patients in certified colorectal cancer centers - networks for patients Abstract. The modern, guideline-oriented treatment of colorectal carcinoma requires interdisciplinary and interprofessional cooperation of various disciplines. The certification system of the German Cancer Society is based on a three-stage model, consisting of organ cancer centers, oncological centers and oncological centers of excellence. The result is a network built for the patient, which covers all phases of treatment and care. The certification of an oncology care network documents the treatment quality of all partners involved with the help of key figures and quality indicators. It is audited annually by independent experts as part of an audit. The results contribute to the internal improvement of quality and structure of the center, which makes it possible to benchmark and compare to other certified centers. This article is intended to provide an overview of the historical development and concept of certification as a quality tool and to outline the process and possible benefits.

Bone Marrow T Cell Changes By Multiplex IHC after Treatment with Flotetuzumab, a CD123 x CD3 Bispecific Dart® Protein, in a Primary Refractory t-AML Patient

Therapy-related acute myelogenous leukemia (t-AML) is associated with adverse genetic lesions, complex karyotype, and TP53 mutation; it is challenging to treat and confers a poor prognosis. We describe a 74-year-old female patient with AML that developed 9 years after receiving 6 cycles of cytotoxic (FOLFOX) chemotherapy as adjuvant treatment of colorectal carcinoma. At diagnosis, the bone marrow (BM) biopsy revealed blast count of 35%, with normal karyotype, 5q loss and AML1 (RUNX1) locus (21q22) amplification by fluorescence in situ hybridization (FISH). Initial treatment with 5 cycles of azacitidine (AZA) failed to induce a response. The patient was subsequently treated on a Phase 1 trial of flotetuzumab (MGD006/S80880) (FLZ), a novel T-cell redirecting (CD123 x CD3) DART protein [NCT02152956]. Prior to FLZ, BM blasts demonstrated clonal evolution with a complex karyotype (92,XXXX, t(14;21)(q22;q22)) and new IDH1, and TET2 mutations.Patient received a total of 3 cycles (28 days/cycle) of FLZ. After one FLZ cycle, the patient achieved a (complete response) CR, with normal cytogenetics, and residual IDH1 and TET2 mutations. After 2 additional cycles of FLZ consolidation, the CR was maintained, with loss of the IDH1 mutation, but persistence of the TET2 mutation. CR was maintained with no additional therapy for approximately 7 months. Serial BM samples were evaluated for T cells (CD3, CD4, CD8, FOXP3 and PD-L1) using multiplex IHC (Fig 1). BM T cells were unchanged during AZA treatment. At the initial bone marrow on FLZ (CR), significant increases in CD3+, CD3+CD8-, CD3+ CD8+, and FOXP3-positive T cells and PD-L1 expression compared to baseline were noted. CD3+CD8+ T cells persisted in the BM 1 month beyond completion of the additional 2 cycles of consolidation with FLZ, while other T cells subsets and PD-L1 expression returned to baseline (Fig. 1) Three months after the last FLZ treatment, all T cell subsets had returned to baseline, with an early increase in leukemic blasts (8%), but normal cytogenetics. Five months after FLZ treatment blasts were unchanged, but a new abnormal cytogenetic clone, with additional mutations, accompanied by a rise in PD-L1 expression cells was observed. Seven months after FLZ treatment, frank leukemia with 50% blasts developed, and all T cell subsets and PD-L1 expression had returned to pre-treatment levels.Consistent with its proposed mechanism of action, these data highlight for the first time the induction of an increase in T-cell infiltration, which persist beyond FLZ, in the bone marrow microenvironment of an AML patient that also achieved a complete and durable anti-leukemic response after treatment with FLZ. [Display omitted] DisclosuresLelièvre:Servier: Employment. Wigginton:MacroGenics: Employment. Davidson-Moncada:MacroGenics: Employment. Fox:MacroGenics: Research Funding.

Chemotherapy combined with dendritic cell vaccine and cytokine-induced killer cells in the treatment of colorectal carcinoma: a meta-analysis.

AimTo investigate the efficacy and safety of dendritic cell (DC) vaccine combined with cytokine-induced killer (CIK) cell therapy in colorectal carcinoma (CRC).Patients and methodsPubMed, Embase, and Cochrane Library databases were searched systematically for clinical trials of DC vaccine and CIK cell therapy combined with chemotherapy for CRC. The primary and secondary endpoints were overall survival (OS) and disease-free survival (DFS), respectively. Pooled risk ratios were used to assess the treatment efficacy. Both random and fixed effects models were used for statistical analysis. The study population consisted of 871 CRC patients enrolled in four trials.ResultsOS and DFS were significantly improved in patients who received chemotherapy combined with DC vaccine and CIK cells, and no severe adverse events were shown.ConclusionsThe study demonstrated that the addition of DC vaccine and CIK cell therapy to chemotherapy is feasible and effective in patients with CRC.

Dendritic cell vaccine with Ag85A enhances anti-colorectal carcinoma immunity.

Dendritic cells (DCs) are able to trigger T-cell activation and thus have been considered important for vaccine production against cancers. Vaccines containing DCs have been reported to be effective for developing immunity against cancer cells. The interactions between DCs and auxiliary agents are critical in the development of second-generation vaccines. In the present study, it was evaluated whether Ag85A-mixed DCs could enhance anti-tumor immunity in laboratory mice with colorectal carcinoma. Functional and phenotypic analyses of the effects of Ag85A-mixed DCs were conducted via flow cytometry and measurement of T-cell proliferation. In addition, interferon (IFN)-γ production was assessed. The therapeutic efficacy of DC vaccination for colorectal carcinoma treatment in mice was investigated. It was identified that Ag85A-mixed DCs exhibited strong upregulation of CD80, CD86 and major histocompatibility complex class II. Cytotoxic T-lymphocytes with CT26-primed Ag85A-DCs were indicated to induce stronger responses against CT26 tumor cells and trigger IFN-γ production. Furthermore, the Ag85A-mixed DC vaccine exerted a considerable inhibitory effect on tumor progression in mice as compared with the control group. Therefore, DCs in combination with the Ag85A gene may reinforce anti-colorectal carcinoma immunity. The current study provides a novel potential strategy for cancer treatment by enhancing immunity via Ag85A-mixed DC vaccination.

Updated S3 Guidelines - Diagnosis and Treatment of Colorectal Carcinoma: Relevance for Radiological Diagnosis and Intervention.

The updated German S3 guidelines "Colorectal Carcinoma" were created as part of the oncology program of the Association of the Scientific Medical Societies (AWMF), German Cancer Society and the German Cancer Aid under the auspices of the German Society for Digestive and Metabolic Disorders (DGVS) and they replace the previous guidelines from 2013. The main changes in the updated guidelines include the latest recommendations regarding endoscopy and adjuvant/neoadjuvant therapies as well as a complete restructuring of the section regarding therapeutic approach in metastases and in the palliative situation. The present manuscript discusses the importance of the current recommendations for radiological diagnosis and treatment and is intended to enhance the quality of patient information and patient care by widespread distribution. KEY POINTS:: · Radiological recommendations for treating patients with colorectal carcinoma are presented.. · The different possibilities of radiological imaging for diagnosis are documented in detail.. · Radiologists should be acquainted with the different possibilities of oncological intervention in patients with colorectal carcinoma.. CITATION FORMAT: · Vogl TJ, Pereira PL, Schreyer AG et al. Updated S3 Guidelines - Diagnosis and Treatment of Colorectal Carcinoma: Relevance for Radiological Diagnosis and Intervention. Fortschr Röntgenstr 2019; 191: 298 - 310.

Antisense Oligonucleotides against miR-21 Inhibit the Growth and Metastasis of Colorectal Carcinoma via the DUSP8 Pathway

Accumulating research has documented that microRNA-21 (miR-21) plays an important role in the development of human colorectal carcinoma (CRC). Our recent work also showed that antisense oligonucleotides (ASOs) against miR-21 can impair the growth of CRC cells in vitro. However, the potential role of miR-21 in gene therapy against CRC remains to be fully elucidated. Here, we further observed the effect of ASOs against miR-21 on the growth and metastasis of CRC in vivo using a xenograft model of human CRC. We found that ASOs could effectively inhibit the growth and metastasis of CRC in vivo, accompanied by downregulated expression of miR-21 and reduced transduction of the AKT and ERK pathway. Mechanically, global gene expression analysis showed that the expression of DUSP8, a novel target of miR-21, was upregulated in tumor mass. Furthermore, overexpression of DUSP8 could remarkably suppress the proliferation and migration of CRC cells in vitro. Finally, downregulation of DUSP8 could abrogate the effects of ASOs against miR-21 on the proliferation and migration of CRC cells, as well as altered transduction of the AKT and ERK signaling pathway. Together, these data suggest that ASOs against miRNAs are an attractive and potential therapeutic for the treatment of human CRC and warrant further development.

ALDH1A3 upregulation and spontaneous metastasis formation is associated with acquired chemoresistance in colorectal cancer cells

BackgroundEfficiency of colorectal carcinoma treatment by chemotherapy is diminished as the resistance develops over time in patients. The same holds true for 5-fluorouracil, the drug used in first line chemotherapy of colorectal carcinoma.MethodsChemoresistant derivative of HT-29 cells was prepared by long-term culturing in increasing concentration of 5-fluorouracil. Cells were characterized by viability assays, flow cytometry, gene expression arrays and kinetic imaging. Immunomagnetic separation was used for isolation of subpopulations positive for cancer stem cells-related surface markers. Aldehyde dehydrogenase expression was attenuated by siRNA. In vivo studies were performed on SCID/bg mice.ResultsThe prepared chemoresistant cell line labeled as HT-29/EGFP/FUR is assigned with different morphology, decreased proliferation rate and 135-fold increased IC50 value for 5-fluorouracil in comparison to parental counterparts HT-29/EGFP. The capability of chemoresistant cells to form tumor xenografts, when injected subcutaneously into SCID/bg mice, was strongly compromised, however, they formed distant metastases in mouse lungs spontaneously. Derived cells preserved their resistance in vitro and in vivo even without the 5-fluorouracil selection pressure. More importantly, they were resistant to cisplatin, oxaliplatin and cyclophosphamide exhibiting high cross-resistance along with alterations in expression of cancer-stem cell markers such as CD133, CD166, CD24, CD26, CXCR4, CD271 and CD274. We also detected increased aldehyde dehydrogenase (ALDH) activity associated with overexpression of specific ALDH isoform 1A3. Its inhibition by siRNA approach partially sensitized cells to various agents, thus linking for the first time the ALDH1A3 and chemoresistance in colorectal cancer.ConclusionOur study demonstrated that acquired chemoresistance goes along with metastatic and migratory phenotype and can be accompanied with increased activity of aldehyde dehydrogenase. We describe here the valuable model to study molecular link between resistance to chemotherapy and metastatic dissemination.

Expression of the inhibitory B7 family molecule VISTA in human colorectal carcinoma tumors.

Colorectal carcinoma (CRC) is one of the most common malignancies in the world. PD-1/PD-L1 inhibitors have benefited cancer patients with multiple tumor types. However, their efficacy for CRC is low and this treatment in melanoma patients results in adaptive resistance through upregulation of VISTA, another checkpoint inhibitory pathway. Thus, there is an urgent need to explore additional co-inhibitory molecular pathways such as VISTA for CRC treatment. In this study, C10orf54 (encoding VISTA) expression was analyzed by RNA-seq data from 367 CRC patients in human cancer datasets. Moreover, 28 clinical CRC specimens were used to assess VISTA protein expression. Human cancer datasets showed that CRC tumors expressed higher levels of C10orf54 than CD274 (encoding PD-L1). Moreover, C10orf54 mRNA expression was significantly correlated with genes responsible for tumor immune evasion. VISTA protein expression was high in tumors compared with para-tumors and normal tissues, which is similar to PD-L1 expression. However, in contrast to PD-L1, VISTA was mainly expressed by tumor-infiltrating lymphocytes. This study is the first investigation of VISTA expression in human resected CRC tumors, and the results justify the need for future studies on the role of VISTA in anti-CRC immunity in clinical samples.