Preclinical evaluation of cyclophosphamide and fludarabine combined with CD19 CAR-T in the treatment of B-cell hematologic malignancies in vivo

Background:Chimeric antigen receptor T(CAR-T)cell therapy has achieved marked therapeutic success in ameliorating hematological malignancies.However,there is an extant void in the clinical guidelines concerning the most effective chemotherapy regimen prior to chimeric antigen receptor T(CAR-T)cell therapy,as well as the optimal timing for CAR-T cell infusion post-chemotherapy.Materials and Methods:We employed cell-derived tumor xenograft(CDX)murine models to delineate the optimal pre-conditioning chemotherapy regimen and timing for CAR-T cell treatment.Furthermore,transcriptome sequencing was implemented to identify the therapeutic targets and elucidate the underlying mechanisms governing the treatment regimen.Results:Our preclinical in vivo evaluation determined that a combination of cyclophosphamide and fludarabine,followed by the infusion of CD19 CAR-T cells five days subsequent to the chemotherapy,exerts the most efficacious therapeutic effect in B-cell hematological malignancies.Concurrently,RNA-seq data indicated that the therapeutic efficacy predominantly perturbs tumor cell metabolism,primarily through the inhibition of key mitochondrial targets,such as C-Jun Kinase enzyme(C-JUN).Conclusion:In summary,the present study offers critical clinical guidance and serves as an authoritative reference for the deployment of CD19 CAR-T cell therapy in the treatment of B-cell hematological malignancies.

The roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies

Prior research establishing that bone interacts in coordination with the bone marrow microenvironment(BMME)to regulate hematopoietic homeostasis was largely based on analyses of individual bone-associated cell populations.Recent advances in intravital imaging has suggested that the expansion of hematopoietic stem cells(HSCs)and acute myeloid leukemia cells is restricted to bone marrow microdomains during a distinct stage of bone remodeling.These findings indicate that dynamic bone remodeling likely imposes additional heterogeneity within the BMME to yield differential clonal responses.A holistic understanding of the role of bone remodeling in regulating the stem cell niche and how these interactions are altered in age-related hematological malignancies will be critical to the development of novel interventions.To advance this understanding,herein,we provide a synopsis of the cellular and molecular constituents that participate in bone turnover and their known connections to the hematopoietic compartment.Specifically,we elaborate on the coupling between bone remodeling and the BMME in homeostasis and age-related hematological malignancies and after treatment with bone-targeting approaches.We then discuss unresolved questions and ambiguities that remain in the field.

Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer:Unravelling challenges and future directions

Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

Optimization of colorectal cancer screening strategies: New insights

In this editorial,we discuss the article by Agatsuma et al.We concentrate specifically on the current routinely used screening tests recommended by society guidelines and delve into the significance of early diagnosis of colorectal cancer(CRC)and its substantial impact on both incidence and mortality rates.Screening is highly recommended,and an early diagnosis stands out as the most crucial predictor of survival for CRC patients.Therefore,it is essential to identify and address the barriers hindering adherence to screening measures,as these barriers can vary among different populations.Furthermore,we focus on screening strategy optimization by selecting high-risk groups.Patients with comorbidities who regularly visit hospitals have been diagnosed at an early stage,showing no significant difference compared to patients undergoing regular screening.This finding highlights the importance of extending screening measures to include patients with comorbidities who do not routinely visit the hospital.

Navigating the complex terrain of hepatitis B virus reactivation in the era of Bruton tyrosine kinase inhibitors

In this editorial,we offer a summary of the risk associated with hepatitis B reactivation(HBVr)in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase(BTK)inhibitors,with insights derived from current studies.Furthermore,we emphasize the critical need for a framework regarding robust risk evaluation in patients undergoing such treatments.This framework is essential for identifying those at increased risk of HBVr,enabling healthcare providers to implement proactive measures to prevent reactivation and ensure the safe administration of BTK inhibitor therapy.

Germline pathogenic variants among high hereditary risk patients with breast and ovarian cancer and unaffected subjects in Lebanese Arab women

BACKGROUND The prevalence of germline pathogenic variants in high hereditary risk breast and/or ovarian cancer patients and unaffected subjects referred for testing is an unmet need in low and middle-income countries.AIM To determine the prevalence of germline pathogenic variants in high hereditary risk patients with breast and/or ovarian cancer and unaffected individuals.METHODS We retrospectively reviewed records of patients and unaffected subjects referred for germline pathogenic variant testing due to high hereditary risk between 2010-2020.Data was collected and analyzed on Excel sheet.RESULTS In total,358 individuals were included,including 257 patients and 101 unaffected individuals with relatives with breast or ovarian cancer.The prevalence of breast cancer susceptibility gene(BRCA)1/2 pathogenic variants was 8.63%(19/220)in patients with breast cancer,and 15.1%(5/33)in those with ovarian cancer.Among the 25 of 220 patients with breast cancer tested by next-generation sequencing,3 patients had pathogenic variants other than BRCA1/2.The highest risk was observed in those aged 40 years with breast cancer and a positive family history,where the BRCA1/2 prevalence was 20.1%(9/43).Among the unaffected subjects,31.1%(14/45)had the same BRCA1/2 pathogenic variants in their corresponding relatives.Among the subjects referred because of a positive family history of cancer without known hereditary factors,5.35%(3/56)had pathogenic variants of BRCA1 and BRCA2.The c.131G>T nucleotide change was noted in one patient and two unrelated unaffected subjects with a BRCA1 pathogenic variant.CONCLUSION This study showed a 8.63%prevalence of pathogenic variants in patients with breast cancer and a 15.1%prevalence in patients with ovarian cancer.Among the relatives of patients with BRCA1/2 pathogenic variants,31%tested positive for the same variant,while 5.3%of subjects who tested positive due to a family history of breast cancer had a BRCA pathogenic variant.

^(18)F-FDG PET显像对不同亚型淋巴瘤的诊断价值

目的 探讨1 8F 脱氧葡萄糖 (FDG)PET显像对霍奇金淋巴瘤 (HL)和以世界卫生组织(WHO)分类标准分类的不同亚型非霍奇金淋巴瘤 (NHL)的诊断价值。方法 对 2 36例淋巴瘤 (6 2例HL和 174例NHL)患者的FDGPET全身显像结果进行回顾性分析 ,并与WHO病理分型的结果比较。结果 PET显像对淋巴瘤的检出阳性率为 94 % (2 2 1 2 36例 ) ,对HL和NHL的阳性率分别为 97% (6 0 6 2例 )和 93% (16 1 174例 )。在不同NHL亚型中 ,8例套细胞淋巴瘤 ,99% (76 77例 )的弥漫性大B细胞淋巴瘤 (DLBCL) ,95 % (5 5 5 8例 )的滤泡性淋巴瘤 (FL) ,73% (8 11例 )的淋巴结边缘区淋巴瘤(MZL) ,2 3例黏膜相关性 (MALL型 )结外边缘区B细胞淋巴瘤 (MALT MZL) ,5 8例的无其他特征外周T细胞淋巴瘤 (PTCL) ,2 3例的伯基特淋巴瘤 (BL) ,2例间变性大细胞性淋巴瘤和覃样肉芽肿、小淋巴细胞性淋巴瘤和NK T细胞型淋巴瘤各 1例FDG摄取异常 ,而 13例 (3例MZL ,3例PTCL ,3例FL ,MALT MZL、DLBCL、BL和前体T淋巴母细胞淋巴瘤各 1例 )未见异常FDG分布。结论 1 8F FDGPET显像对常见的NHL亚型检出阳性率较高 ,对相对少见的NHL亚型检出阳性率较低。

As_2O_3通过下调AnnexinⅡ抑制NB4细胞侵袭能力的研究

目的:旨在探讨三氧化二砷(arsenic trioxide,As2O3)通过下调钙依赖性磷脂结合蛋白AnnexinⅡ(AnxA2)抑制人急性早幼粒白血病(acute promyelocytic leukemia,APL)细胞NB4侵袭力的作用。方法:体外培养NB4细胞,FCM检测不同浓度As2O3对NB4细胞膜表面AnxA2蛋白表达的影响;Transwell法检测As2O3和AnxA2抗体对NB4细胞侵袭力的影响。结果:As2O3在0.31、0.63和1.25μg/mL质量浓度条件下均能诱导NB4细胞膜表面AnxA2蛋白水平表达下降(P<0.05),呈剂量依赖性;AnxA2抗体质量浓度为0.01、0.02和0.04μg/mL以及AS2O3质量浓度为0.31、0.63和1.25μg/mL条件下均能使NB4细胞的侵袭力下降(P<0.05),并呈剂量依赖关系。结论:AnxA2抗体可抑制NB4细胞的侵袭力,As2O3可通过下调AnxA2蛋白在细胞膜表面的表达,从而抑制NB4细胞的侵袭能力。

Ⅰ期-Ⅲ期非转移性非小细胞肺癌的系统性治疗演变

早期肺癌患者的治疗是以治愈为目标的。针对手术可切除性和可操作性的多学科讨论模式决定了最终的局部治疗方式(手术或放疗)和相关的系统性治疗方案,从而进一步提高患者治愈的可能性。研究证据支持以顺铂为基础的辅助化疗用于切除术后,或与放疗同步使用。共识指南支持以新辅助化疗代替辅助化疗,并支持对不符合顺铂治疗条件的患者采用基于卡铂的治疗方案。由于研究设计效率低下,需要长时间随访来评估生存终点以及对晚期疾病的持续关注,将新药物(现在是IV期肺癌患者的标准药物)纳入以治愈为目标的治疗范式的工作一直滞后。目前正在研究中的替代性终点(例如病理缓解)将可能缩短研究的时间。2018年,抗程序性死亡配体(programmed cell death ligand 1,PD-L1)抗体度伐利尤单抗获批用于治疗同步放、化疗后的Ⅲ期肺癌患者,自那时起,针对早期肺癌患者的靶向治疗和免疫治疗的研究迅速发展。在本篇综述中,我们介绍了对于目前早期肺癌患者治疗方案的考虑因素,探讨并展望非转移性肺癌系统性治疗的临床研究现状和未来。

老年癌症患者的免疫治疗

癌症常见于老年人。初诊为恶性肿瘤的患者的中位年龄为66岁,癌症相关死亡的中位年龄为72岁[1]。老年人是癌症患病率增长最快的人群之一[2]。免疫治疗的发展,尤其是免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的问世,彻底改变了所有年龄层包括老年人在内的肿瘤患者的常规治疗方案。细胞毒性T淋巴细胞相关抗原4、程序性死亡受体1(programmed death receptor-1,PD-1)及其配体(programmed death-ligand 1,PD-L1)的抑制剂可改善多种肿瘤患者的总生存期(overall survival,OS)[3],且部分患者可获得持续缓解[4]。

PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance

Prostate cancer （PCa） is the second most common malignancy among men in the world. Castration-resistant prostate cancer （CRPC） is the lethal form of the disease, which develops upon resistance to first line androgen deprivation therapy （ADT）. Emerging evidence demonstrates a key role for the PI3K-AKT-mTOR signaling axis in the development and maintenance of CRPC. This pathway, which is deregulated in the majority of advanced PCas, serves as a critical nexus for the integration of growth signals with downstream cellular processes such as protein synthesis, proliferation, survival, metabolism and differentiation, thus providing mechanisms for cancer cells to overcome the stress associated with androgen deprivation. Furthermore, preclinical studies have elucidated a direct connection between the PI3K-AKT-mTOR and androgen receptor （AR） signaling axes, revealing a dynamic interplay between these pathways during the development of ADT resistance. Thus, there is a clear rationale for the continued clinical development of a number of novel inhibitors of the PI3K pathway, which offer the potential of blocking CRPC growth and survival. In this review, we will explore the relevance of the PI3K-AKT-mTOR pathway in PCa progression and castration resistance in order to inform the clinical development of specific pathway inhibitors in advanced PCa. In addition, we will highlight current deficiencies in our clinical knowledge, most notably the need for biomarkers that can accurately predict for response to PI3K pathway inhibitors.

CXC chemokines and chemokine receptors in gastric cancer: From basic findings towards therapeutic targeting

Gastric cancer is the fourth most common cancer,and the second-highest cause of cancer-related deaths worldwide.Despite extensive research to identify novel diagnostic and therapeutic agents,patients with advanced gastric cancer suffer from a poor quality of life and poor prognosis,and treatment is dependent mainly on conventional cytotoxic chemotherapy.To improve the quality of life and survival of gastric cancer patients,a better understanding of the underlying molecular pathologies,and their application towards the development of novel targeted therapies,is urgently needed.Chemokines are a group of small proteins associated with cytoskeletal rearrangements,the directional migration of several cell types during development and physiology,and the host immune response via interactions with G-protein coupled receptors.There is also growing evidence to suggest that chemokines not only play a role in the immune system,but are also involved in the development and progression of tumors.In gastric cancer,CXC chemokines and chemokine receptors regulate the trafficking of cells in and out of the tumor microenvironment.CXC chemokines and their receptors can also directly influence tumorigenesis by modulating tumor transformation,survival,growth,invasion and metastasis,as well as indirectly by regulating angiogenesis,and tumor-leukocyte interactions.In this review,we will focus on the roles of CXC chemokines and their receptors in the development,progression,and metastasis of gastric tumors,and discuss their therapeutic potential for gastric cancer.

Recent developments in palliative chemotherapy for locally advanced and metastatic pancreas cancer

In spite of advances made in the management of the other more common cancers of the gastrointestinal tract,significant progress in the treatment of pancreatic cancer remains elusive.Nearly as many deaths occur from pancreatic cancer as are diagnosed each year reflecting the poor prognosis typically associated with this disease.Until recently,the only treatment with an impact on survival was surgery.In the palliative setting,gemcitabine(Gem) has been a standard treatment for advanced pancreatic cancer since it was shown a decade ago to result in a superior clinical benefit response and survival compared with bolus 5-fluorouracil.Since then,clinical trials have explored the pharmacokinetic modulation of Gem by fixed dose administration and the combination of Gem with other cytotoxic or the biologically"targeted"agents.However,promising trial results in small phaseⅡtrials have not translated into survival improvements in larger phaseⅢrandomized trials in the advanced disease setting.Two trials have recently reported modest survival improvements with the use of combination treatment with Gem and capecitabine(United Kingdom National Cancer Research GEMCAP trial) or erlotinib(National Cancer Institute of CanadaClinical Trials Group PA.3 trial) .This review will focus on the use of systemic therapy for advanced and metastatic pancreatic cancer,summarizing the results of several recent clinical trials and discuss their implications for clinical practice.We will also discuss briefly the second-line chemotherapy options for advanced pancreatic cancer.

Near-infrared fluorescence sentinel lymph node detection in gastric cancer: A pilot study

AIM: To investigate feasibility and accuracy of near-infrared fluorescence imaging using indocyanine green: nanocolloid for sentinel lymph node (SLN) detection in gastric cancer.METHODS: A prospective, single-institution, phase I feasibility trial was conducted. Patients suffering from gastric cancer and planned for gastrectomy were included. During surgery, a subserosal injection of 1.6 mL ICG:Nanocoll was administered around the tumor. NIR fluorescence imaging of the abdominal cavity was performed using the Mini-FLARE&#x02122; NIR fluorescence imaging system. Lymphatic pathways and SLNs were visualized. Of every detected SLN, the corresponding lymph node station, signal-to-background ratio and histopathological diagnosis was determined. Patients underwent standard-of-care gastrectomy. Detected SLNs outside the standard dissection planes were also resected and evaluated.RESULTS: Twenty-six patients were enrolled. Four patients were excluded because distant metastases were found during surgery or due to technical failure of the injection. In 21 of the remaining 22 patients, at least 1 SLN was detected by NIR Fluorescence imaging (mean 3.1 SLNs; range 1-6). In 8 of the 21 patients, tumor-positive LNs were found. Overall accuracy of the technique was 90% (70%-99%; 95%CI), which decreased by higher pT-stage (100%, 100%, 100%, 90%, 0% for respectively Tx, T1, T2, T3, T4 tumors). All NIR-negative SLNs were completely effaced by tumor. Mean fluorescence signal-to-background ratio of SLNs was 4.4 (range 1.4-19.8). In 8 of the 21 patients, SLNs outside the standard resection plane were identified, that contained malignant cells in 2 patients.CONCLUSION: This study shows successful use of ICG:Nanocoll as lymphatic tracer for SLN detection in gastric cancer. Moreover, tumor-containing LNs outside the standard dissection planes were identified.

Gastric leptomeningeal carcinomatosis: Multi-center retrospective analysis of 54 cases

AIM： To identify the clinical features and outcomes of infrequently reported leptomeningeal carcinomatosis （LMC） of gastric cancer.METHODS： We analyzed 54 cases of cytologically confirmed gastric LMC at four institutions from 1994 to 2007.RESULTS： The male-to-female ratio was 32：22, and the patients ranged in age from 28 to 78 years （median,48.5 years）. The majority of patients had advanced disease at initial diagnosis of gastric cancer. The clini-cal or pathologic tumor, node and metastasis stage ofthe primary gastric cancer wasin 38 patients （70%）.The median interval from diagnosis of the primarymalignancy to the diagnosis of LMC was 6.3 mo, rang-ing between 0 and 73.1 mo. Of the initial endoscopic f indings for the 45 available patients, 23 （51%） of the patients were Bormann typeand 15 （33%） patientswere Bormann type. Pathologically, 94% of cases proved to be poorly differentiated adenocarcinomas. Signet ring cell component was also observed in 40% of patients. Headache （85%） and nausea/vomiting （58%） were the most common presenting symptoms of LMC. A gadolinium-enhanced magnetic resonance imaging was conducted in 51 patients. Leptomeningeal enhancement was noted in 45 cases （82%）. Intrathecal （IT） chemotherapy was administered to 36 patients-primarily methotrexate alone （61%）, but also in combi-nation with hydrocortisone/± Ara-C （39%）. The median number of IT treatments was 7 （range, 1-18）. Concomitant radiotherapy was administered to 18 patients, and concomitant chemotherapy to seven patients. Sev-enteen patients （46%） achieved cytological negative conversion. Median overall survival duration from the diagnosis of LMC was 6.7 wk （95% CI： 4.3-9.1 wk）. In the univariate analysis of survival duration, hemoglobin, IT chemotherapy, and cytological negative conversion showed superior survival duration （P = 0.038, P = 0.010, and P = 0.002, respectively）. However, in our multivariate analysis, only cytological negative conversion was predictive of relatively longer survival duration （3.6, 6.7 and 14.6 wk, P = 0.03, RR： 0.415, 95% CI：0.188-0.918）.CONCLUSION： Although these patients had a fatal clinical course, cytologic negative conversion by IT chemotherapy may improve survival.

Pancreatic acinar cell carcinoma: A review on molecular profiling of patient tumors

Pancreatic carcinomas with acinar differentiation are rare,accounting for 1%-2% of adult pancreatic tumors; they include pancreatic acinar cell carcinoma(PACC),pancreatoblastoma,and carcinomas of mixed differentiation. Patients with PACC have a prognosis better than pancreatic ductal adenocarcinomas but worse than pancreatic neuroendocrine tumors. Reports of overall survival range from 18 to 47 mo. A literature review on PACCs included comprehensive genomic profiling and whole exome sequencing on a series of more than 70 patients as well as other diagnostic studies including immunohistochemistry. Surgical resection of PACC is the preferred treatment for localized and resectable tumors. The efficacy of adjuvant treatment is unclear. Metastatic PACCs are generally not curable and treated with systemic chemotherapy. They are moderately responsive to chemotherapy with different regimens showing various degrees of response in case reports/series. Most of these regimens were developed to treat patients with pancreatic ductal adenocarcinomas or colorectal adenocarcinomas. Review of PACC's molecular profiling showed a number of gene alterations such as: SMAD4,BRAF,BRCA2,TP53,RB1,MEN1,JAK-1,BRCA-1,BRCA-2,and DNA mismatch repair abnormalities. PACCs had multiple somatic mutations with some targetable with available drugs. Therefore,molecular profiling of PACC should be an option for patients with refractory PACC.

Early stage colon cancer: Current treatment standards, evolving paradigms, and future directions

Colon cancer continues to be one of the leading causes of mortality and morbidity throughout the world despite the availability of reliable screening tools and effective therapies.The majority of patients with colon cancer are diagnosed at an early stage(stages I to III),which provides an opportunity for cure.The current treatment paradigm of early stage colon cancer consists of surgery followed by adjuvant chemotherapy in a select group of patients,which is directed at the eradication of minimal residual disease to achieve a cure.Surgery alone is curative for the vast majority of colon cancer patients.Currently,surgery and adjuvant chemotherapy can achieve long term survival in about two-thirds of colon cancer patients with nodal involvement.Adjuvant chemotherapy is recommended for all patients with stage III colon cancer,while the benefit in stage II patients is not unequivocally established despite several large clinical trials.Contemporary research in early stage colon cancer is focused on minimally invasive surgical techniques,strategies to limit treatment-related toxicities,precise patient selection for adjuvant therapy,utilization of molecular and clinicopathologic information to personalize therapy and exploration of new therapies exploiting the evolving knowledge of tumor biology.In this review,we will discuss the current standard treatment,evolving treatment paradigms,and the emerging biomarkers,that will likely help improve patient selection and personalization of therapy leading to superior outcomes.

DNA damage-induced cell death： lessons from the central nervous system

DNA damage can, but does not always, induce cell death. While several pathways linking DNA damage signals to mitochondria-dependent and -independent death machineries have been elucidated, the connectivity of these pathways is subject to regulation by multiple other factors that are not well understood. We have proposed two conceptual models to explain the delayed and variable cell death response to DNA damage： integrative surveillance versus autonomous pathways. In this review, we discuss how these two models may explain the in vivo regulation of cell death induced by ionizing radiation （IR） in the developing central nervous system, where the death response is regulated by radiation dose, cell cycle status and neuronal development.

Inflammation-related gene expression profiles of salivary extracellular vesicles in patients with head trauma

At present,there is no reliable biomarker for the diagnosis of traumatic brain injury(TBI).Studies have shown that extracellular vesicles released by damaged cells into biological fluids can be used as potential biomarkers for diagnosis of TBI and evaluation of TBI severity.We hypothesize that the genetic profile of salivary extracellular vesicles in patients with head trauma differs from that in uninjured subjects.Findings from this hypothesis would help investigate the severity of TBI.This study included 19 subjects,consisting of seven healthy controls who denied history of head trauma,six patients diagnosed with concussion injury from an outpatient concussion clinic,and six patients with TBI who received treatment in the emergency department within 24 hours after injury.Real-time PCR analysis of salivary extracellular vesicles in participants was performed using TaqMan Human Inflammation array.Gene expression analysis revealed nine upregulated genes in emergency department patients(LOX5,ANXA3,CASP1,IL2RG,ITGAM,ITGB2,LTA4H,MAPK14,and TNFRSF1A)and 13 upregulated genes in concussion clinic patients compared with healthy participants(ADRB1,ADRB2,BDKRB1,HRH1,HRH2,LTB4R2,LTB4R,PTAFR,CYSLTR1,CES1,KLK1,MC2R,and PTGER3).Each patient group had a unique profile.Comparison between groups showed that 15 inflammation-related genes had significant expression change.Our results indicate that inflammation biomarkers can be used for diagnosis of TBI and evaluation of disease severity.This study was approved by the Institutional Review Board on December 18,2015(approval No.0078-12)and on June 9,2016(approval No.4093-16).

Targeted therapy in advanced metastatic colorectal cancer: Current concepts and perspectives

The introduction of new cytotoxic substances as well as agents that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling has improved clinical outcome of patients with metastatic colorectal cancer (mCRC). In this review we summarize the most relevant clinical data on VEGF and EGFR targeting regimens in mCRC. The effects of available treatment strategies for mCRC are often temporary, with resistance and disease progression developing in most patients. Thus, new treatment strategies are urgently needed. Some GI peptides including gastrin and gastrin releasing peptide, certain growth factors such as insulin-like growth factor-I&#x02005;and II and neuropeptides such as growth hormone releasing hormone (GHRH) are implicated in the growth of CRC. Experimental investigations in CRC with antagonistic analogs of bombesin/gastrin-releasing peptide, GHRH, and with cytotoxic peptides that can be targeted to peptide receptors on tumors, are summarized in the second part of the review.