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.

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.

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.

Long-term outcome of pancreatic function following oncological surgery in children:Institutional experience and review of the literature

BACKGROUND Pancreatic neoplasms are uncommon in children and in most cases they are benign or have low malignant potential.Pancreatoblastoma and solid pseudopapillary tumor are the most frequent types in early and late childhood,respectively.Complete resection,although burdened by severe complications,is the only curative treatment for these diseases.Pancreatic surgery may result in impaired exocrine and endocrine pancreatic function.However,limited data are available on the long-term pediatric pancreatic function following surgical resection.AIM To investigate endocrine and exocrine pancreatic function and growth after oncological pancreatic surgery in a pediatric series.METHODS A retrospective analysis of all pediatric patients who underwent surgery for pancreatic neoplasm in our Institution from January 31,2002 to the present was performed.Endocrine and exocrine insufficiency,auxological and fat-soluble vitamin status(A,D,E and clotting tests)were assessed at diagnosis and at every follow-up visit.Exocrine insufficiency was defined as steatorrhea with fecal elastase-1<200μg/g stool,while endocrine insufficiency was identified as onset of Diabetes or Impaired Glucose Tolerance.Growth was evaluated based on body mass index(BMI)z-score trend.RESULTS Sixteen patients(12 girls and 4 boys,mean age 10.7±5.3 years),were included.Nine patients(56%)had a neoplasm in the pancreatic head,4 in the body/tail,2 in the tail and 1 in the body.Histological findings were as follows:Solid pseudopapillary tumor in 10 patients(62.5%),insulinoma in 2 patients,neuroendocrine tumor in 2 patients and acinar cell carcinoma in 2 patients.The most frequent surgery was pancreaticoduodenectomy(50%).Exocrine failure occurred in 4 patients(25%)and endocrine failure in 2 patients(12.5%).Exocrine insufficiency occurred early(within 6 mo after surgery)and endocrine insufficiency later(8 and 10 years after surgery).Mean BMI z-score was 0.36±1.1 at diagnosis and 0.27±0.95 at the last assessment.Vitamin D was insufficient(<30 ng/mL)in 8 of the 16 patients during the follow-up period.Vitamins A,E and clotting test were into the normal ranges in all patients.CONCLUSION Careful and long-term monitoring should follow any pancreatic surgery,to recognize and promptly treat exocrine and endocrine pancreatic insufficiency,which can occur after surgery.

Local recurrence after successful endoscopic submucosal dissection for rectal mucinous mucosal adenocarcinoma:A case report

BACKGROUND Mucinous adenocarcinoma of the colorectum is a rare histological subtype characterized by an abundant mucinous component.Mucinous tumors are frequently diagnosed at an advanced stage,which indicates an aggressive subtype.However,few case reports have been published,and little information is available concerning genetic alterations in mucinous adenocarcinoma.CASE SUMMARY A 76-year-old man underwent en bloc endoscopic submucosal dissection(ESD)for the management of a type 0-Is+IIa lesion.Histological examination revealed an intramucosal mucinous adenocarcinoma with signet-ring cell carcinoma and well-to-moderately differentiated tubular adenocarcinoma.Three years after the ESD,local recurrence was detected by an endoscopic examination,revealing a new 0-Is+IIa lesion with a phenotype similar to the previously resected lesion.Re-ESD was chosen for the management of the recurrent tumor,and the histological examination showed positive tumor infiltration at the vertical margin.Additional surgical resection was performed for the curative treatment.Genetic analysis showed pathogenic alterations in RNF43 and TP53 in the adenoma and an additional SMAD4 alteration in the carcinoma.CONCLUSION This mucinous mucosal adenocarcinoma case was suggested to have an aggressive phenotype and a careful and close follow-up are required.

Cholecystoenteric fistula in a patient with advanced gallbladder cancer: A case report and review of literature

BACKGROUND Cholecystoenteric fistula(CEF)involves the formation of a spontaneous ano-malous tract between the gallbladder and the adjacent gastrointestinal tract.Chronic gallbladder inflammation can lead to tissue necrosis,perforation,and fistulogenesis.The most prevalent cause of CEF is chronic cholelithiasis,which rarely results from malignancy.Because the symptoms and laboratory findings associated with CEF are nonspecific,the condition is often misdiagnosed,pre-senting a challenge to the surgeon when detected intraoperatively.Therefore,a preoperative diagnosis of CEF is crucial.We present the case of a 57-year-old male with advanced gallbladder cancer(GBC)who arrived at the emergency room with persistent vomiting,abdominal pain,and diarrhea.An abdominopelvic computed tomography scan revealed a contracted gallbladder with bubbles in the fundus connected to the second por-tion of the duodenum and transverse colon.We suspected that GBC had invaded the adjacent gastrointestinal tract through a cholecystoduodenal fistula(CDF)or a cholecystocolonic fistula(CCF).He underwent multiple examinations,including esophagogastroduodenoscopy,an upper gastrointestinal series,colo-noscopy,and magnetic resonance cholangiopancreatography;the results of these tests con-firmed a diagnosis of synchronous CDF and CCF.The patient underwent a Roux-en-Y gastrojejunostomy and loop ileostomy to address the severe adhesions that were previously observed to cover the second portion of the duodenum and hepatic flexure of the colon.His symptoms improved with supportive treatment while hospitalized.He initiated oral targeted therapy with lenvatinib for further anticancer treatment.CONCLUSION The combination of imaging and surgery can enhance preoperative diagnosis and alleviate symptoms in patients with GBC complicated by CEF.

Comprehensive molecular analysis to predict the efficacy ofchemotherapy containing bevacizumab in patients with metastaticcolorectal cancer

Background:Although bevacizumab is an important treatment for metastatic colorectal cancer(CRC),not allpatients with CRC benefit from it;in unselected patient populations,only modest survival benefits have been reported.Methods:We evaluated clinical outcomes in 110 patients using comprehensive molecular characterization to identifybiomarkers for a response to bevacizumab-containing treatment.The molecular analysis comprised whole-exomesequencing,ribonucleic acid sequencing,and a methylation array on patient tissues.Results:Genomic and molecularcharacterization was successfully conducted in 103 patients.Six of 103 CRC samples were hypermutated,and none ofthe non-hypermutant tumors were microsatellite unstable.Among those 103 patients,89 had adenocarcinoma(ADC),15 were diagnosed with mucinous ADC,and six had signet-ring cell carcinoma(SRCC).Consensus molecular subtype(CMS)2 was unique to ADC.Of the four SRCCs,two were CMS1,one was CMS4,and the other was CMS3.APCmutation status was a significantly enriched factor in responders to bevacizumab treatment.Fibroblast growth factorreceptor(FGFR)1/2 signaling was upregulated in non-responders,whereas cell cycle,transfer ribonucleic acidprocessing,nucleotide excision repair,and oxidative phosphorylation pathways were enriched in responders.Inaddition,IGF1 was differentially expressed in non-responders(log2 fold change=−1.43,p=4.11×10^(−5),falsediscovery rate=0.098),and FLT1 was highly methylated in non-responders(p=7.55×10^(−3)).When the molecularpathways were reanalyzed separately according to the backbone chemotherapy(FOLFOX vs.FOLFIRI),thesignificance of the molecular pathways varied according to the backbone chemotherapy.Conclusions:This studysought a subset of CRC patients with a distinct clinical response to chemotherapy containing bevacizumab.Ourresults need to be validated in a large group of homogenous patient cohort and examined according to the differentchemotherapy backbones to create personalized therapeutic opportunities in CRC.

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。

Neoadjuvant treatment of esophageal cancer

The management of esophageal cancer has been evolving over the past 30 years. In the United States, multimodality treatment combining chemotherapy and radiotherapy (RT) prior to surgical resection has come to be accepted by many as the standard of care, although debate about its overall effect on survival still exists, and rightfully so. Despite recent improvements in detection and treatment, the overall survival of patients with esophageal cancer remains lower than most solid tumors, which highlights why further advances are so desperately needed. The aim of this article is to provide a complete review of the history of esophageal cancer treatment with the addition of chemotherapy, RT, and more recently, targeted agents to the surgical management of resectable disease.

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.

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

AIM: To investigate feasibility and accuracy of nearinfrared fluorescence imaging using indocyanine green: nanocolloid for sentinel lymph node(SLN) detection in gastric cancer.METHODS: A prospective, single-institution, phaseI feasibility trial was conducted. Patients suffering from gastric cancer and planned for gastrectomy were included. During surgery, a subserosal injection of 1.6 m L ICG:Nanocoll was administered around the tumor. NIR fluorescence imaging of the abdominal cavity was performed using the Mini-FLARE? 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 p T-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 = 0.030, 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.

Lewis blood genotypes of peptic ulcer and gastric cancer patients in Taiwan

AIM: The Lewis b (Leb) antigen has been implicated as a possible binding site for attachment of Helicobacter pylori (H pylori)to gastric mucosa. However, studies both supporting and denying this association have been reported in the literature. Differences in secretor (Se)genotype have been suggested as a possible reason for previous discrepancies. Therefore, we investigated the relationship between Le and Se genotypes and H pylori infection rates in people with peptic ulcer or gastric cancer.METHODS: Peripheral blood samples were obtained from 347 patients with endoscopic evidence of peptic ulcer disease (235 cases of duodenal ulcer, 62 of gastric ulcer,and 50 of combined duodenal ulcer/gastric ulcer) and 51patients with gastric cancer on endoscopy. Peripheral blood specimens from 101 unrelated normal volunteers were used as controls. Lewis phenotype was determined using an antibody method, whereas Le and Se genotypes were determined by DNA amplification and restriction enzyme analysis. Gastric or duodenal biopsies taken from patients with endoscopic evidence of peptic ulcer or gastric cancer were cultured for H pylori. Isolates were identified as H pylori by morphology and production of urease and catalase. The H pylori infection status was also evaluated by rapid urease test (CLO test), and urea breath test (13C-UBT). Results of studies were analyzed by chi-square test (taken as significant).RESULTS: H pyloriwas isolated from 83.7% (303/347)of patients with peptic ulcer disease. Statistical analysis did not show any significant difference in Lewis phenotype or genotype between patients with and without H pylori infection. No significant association was found between Lewis genotype and peptic ulcer or gastric cancer.CONCLUSION: Lewis blood genotype or phenotype may not play a role in the pathogenesis of H pyloriinfection.However, bacterial strain differences and the presence of more than one attachment mechanism may limit the value of epidemiological studies in elucidating this matter.

Iron overload and cofactors with special reference to alcohol,hepatitis C virus infection and steatosis/insulin resistance

有几个余因子，影响身体铁新陈代谢并且加速铁超载。酒精和肝的病毒的感染是为在铁超载澄清余因子的角色的最典型的例子。处于这些条件，铁在房间和通过 Fenton 反应生产的反应的氧种类(ROS ) 有的 hepatocytes 和 Kupffer 被扔便于 transferrin 固定的铁的细胞的举起的关键角色。而且， hepcidin，主要在肝生产的抗菌剂肽为肠的铁吸收和网状内皮组织的铁版本也负责。在有血浆铜蓝蛋白缺乏的病人，在肝和 neurodegeneration 的贫血症和第二等的铁超载被报导。而且，正在积累没有酒精和肥胖的脂肪酸累积自己修改铁超载状态的证据。无效红血球生成也是一个重要因素加速铁超载，它与象地中海贫血和 myelodysplastic 症候群那样的疾病被联系。当这个条件坚持时，饮食的铁吸收由于骨髓红血球生成的增长被增加，织物铁超载愿望此后发生。在迟发性皮肤卟啉症，铁是在肝积累的在第二。

Acute myelogenous leukemia and acute leukemic appendicitis:A case report

Acute myelogenous leukemia(AML)can involve the gastrointestinal tract but rarely involves the appendix. We report a male patient who had 1 year partial remission from AML and who presented with apparent acute appendicitis as the initial manifestation of leu-kemia relapse.Pathological findings of the appendix revealed transmural infiltrates of myeloblasts,which indicated a diagnosis of leukemia.Unfortunately,the patient died from progression of the disease on the 19th d after admission.Although leukemic cell infiltration of the appendix is uncommon,patients with leu-kemia relapse can present with symptoms mimicking acute appendicitis.

Gastric submucosa-invasive carcinoma associated with EpsteinBarr virus and endoscopic submucosal dissection: A case report

BACKGROUND Epstein-Barr virus(EBV)-associated carcinoma is a gastric cancer subtype with a morphology characterized by gastric carcinoma with lymphoid stroma(GCLS).Clinicopathological studies have indicated a better prognosis for GCLS than for common gastric carcinomas.Some previous cases of early gastric cancer associated with EBV had been diagnosed by endoscopic resection.CASE SUMMARY We present two GCLS cases subjected to endoscopic submucosal dissection(ESD)for a definitive diagnosis.A protruded gastric lesion was identified by routine endoscopic examination,but forceps biopsy showed no atypical cells before ESD.The resected specimen showed a poorly differentiated adenocarcinoma with lymphoid cells involving the mucosa and submucosa.The final diagnosis was submucosa-invasive poorly differentiated gastric adenocarcinoma.Accordingly,additional gastrectomy was recommended to obtain a complete cure.One patient underwent additional distal gastrectomy with lymph node dissection,but the other was refused because of cardiovascular complications.Both patients remained in remission for more than half a year.EBV positivity was determined by EBV-encoded RNA in situ hybridization.We also conducted a literature review of cases of early gastric cancer associated with EBV that had been diagnosed by ESD.CONCLUSION Submucosa-invasive GCLS could be dissected using ESD,and EBV positivity should be subsequently assessed to determine whether or not any additional curative surgery is required.Further prospective investigations on the prevalence of lymph node metastasis in EBV-associated carcinoma should be performed to expand the indications for endoscopic resection.

Medical oncology management of advanced hepatocellular carcinoma 2019: a reality check

In terms of global cancer-related deaths,hepatocellular carcinoma (HCC) has the fourth highest mortality rate.Up until 2017,treatment of advanced HCC was largely limited to sorafenib,an oral tyrosine kinase inhibitor,with little to no success in the development of alternative treatment options.However,in the past two years,there has been an unprecedented increase in both the number and type of treatment options available for HCC.As of 2019,the US FDA has approved four oral tyrosine kinase inhibitors,two immune checkpoint inhibitors,and one anti-angiogenesis antibody for the treatment of HCC.Even with this new variety,systemic treatment of advanced HCC remains largely unsatisfactory,and the median survival rate stands at approximately one year.The expected breakthrough of using immune checkpoint inhibitors in advanced HCC did not materialize in 2019.The use of immune checkpoint inhibitors in conjunction with oral tyrosine kinase inhibitors or antiangiogenesis medications is the current clinical research trend,the results of which are eagerly anticipated.Despite limited progress in survival,HCC research is currently experiencing a period of growth and innovation,and there is hope for significant advances in the treatment of advanced HCC as the field continues to develop.

Hepatic failure caused by plasma cell infiltration in multiple myeloma

Although plasma cell infiltration is not rare in autopsy of patients with multiple myeloma (MM), it is very rarely detected in living patients. This is because MM rarely causes significant liver dysfunction that requires further evaluation. A 49-year-old man presented with acute renal failure and was diagnosed with kappa light chain MM stage B.Thalidomide and dexamethasone were initiated.The patient developed a continuous increase in bilirubin that led to severe cholestasis.A liver biopsy revealed plasma cell infiltration.He then rapidly progressed to liver failure and died.Treatment options are limited in MM with significant liver dysfunction.espite new drug therapies in MM,those patients with rapidly progressive liver failure appear to have a dismal outcome.

uPAR expression under hypoxic conditions depends on iNOS modulated ERK phosphorylation in the MDA-MB-231 breast carcinoma cell line

尿激 plasminogen 使活跃之物受体(uPAR ) 戏在癌症侵略和转移和 uPAR 表示的一个主要角色在各种各样的癌症类型与差的预后被相关。而且， uPAR 的表示在 hypoxic 条件下面被增加。氮的氧化物(没有) 并且它可诱导的氮的氧化物 synthase (i NOS ) 生产的代谢物是 hypoxic 应力的重要产品，并且可以不激活或调制细胞外的信号调整 kinase (英皇家空军之阶级最低之兵) 。这里，我们在 MDA-MB-231 人的乳癌房间线在 hypoxic 条件，和 i NOS 并且不的调节效果下面在 A， uPAR，和激活的英皇家空军之阶级最低之兵层次上面评估了。房间在 hypoxic 或 normoxic 孵卵器被孵化并且与 PD98059 对待(一个 MEK 1/2 禁止者，它废除英皇家空军之阶级最低之兵 phosphorylation ) 并且 aminoguanidine (选择 i NOS 禁止者) 。uPAR 表示，英皇家空军之阶级最低之兵 phosphorylation，并且在 A 上面，活动被发现在 hypoxic 条件下面被增加。而且当房间在 hypoxic 条件下面与 PD98059 被对待时， uPAR 低调整，而 aminoguanidine 显著地以一种剂量依赖者方式增加了英皇家空军之阶级最低之兵 phosphorylation。而且， aminoguanidine 增加了 uPAR 表示并且由 PD98059 阻止了 uPAR 表示的抑制。这些结果证明 uPAR 被组织缺氧导致，那增加的 uPAR 表情被英皇家空军之阶级最低之兵 phosphorylation 调停，它被 iNOS/NO 接着在 MDA-MB-231 房间调制。我们结束那 iNOS/NO 在下面经由英皇家空军之阶级最低之兵小径调整在 hypoxic 条件下面调整 uPAR 的表示。