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 gas...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.展开更多
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...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.展开更多
AIM:To investigate the clinicopathologic features of patients with extra-gastrointestinal stromal tumors(EGISTs)in South Korea.METHODS:A total of 51 patients with an EGIST were identified.The clinicopathologic feature...AIM:To investigate the clinicopathologic features of patients with extra-gastrointestinal stromal tumors(EGISTs)in South Korea.METHODS:A total of 51 patients with an EGIST were identified.The clinicopathologic features,including sex,age,location,tumor size,histology,mitotic rate,immunohistochemical features,genetic status and survival data,were analyzed.RESULTS:The median age was 55 years(range:29-80years),and male:female ratio was 1:1.04.The most common site was in the mesentery(n=15)followed by the retroperitoneum(n=13)and omentum(n=8).The median tumor size was 9.0 cm(range:2.6-30.0cm)and the median mitotic rate was 5.0/50HPF.(1/50-185/50).KIT was analyzed in 16,which revealed 10cases with wild-type KIT and 6 cases with an exon 11mutation.Among 51 patients,31 patients had undergone surgery,and 10 had unresectable disease and had taken palliative imatinib,which resulted in 22.7 mo of progression-free survival.Of the patients who had undergone surgery,18 did not take adjuvant imatinib,and 8 of these were categorized as"high risk"according to the risk criteria.However,the relapse-free survival was not different(P=0.157)between two groups.CONCLUSION:Because the biologic behaviors of GISTs differ according to the location of the tumor,a more stratified strategy is required for managing EGISTs including incorporation of molecular features.展开更多
Background and Objective: The outcome of locally advanced and metastatic urothelial carcinoma LA/mUC has improved over the past years with a plethora of new treatments and the approval of immune checkpoint inhibitors ...Background and Objective: The outcome of locally advanced and metastatic urothelial carcinoma LA/mUC has improved over the past years with a plethora of new treatments and the approval of immune checkpoint inhibitors (ICIs), antibody-drug conjugates, and targeted agents, to identify locally advanced metastatic urothelial carcinoma’s current management practices in Lebanon and the implication of the ongoing economic crisis on the medical practice. Methods: An online questionnaire was used to survey ten Lebanese oncologists from six different hospitals, between July 5 and July 11, 2022, requesting information pertaining to their current clinical practice in the pharmacological treatment of locally advanced metastatic urothelial carcinoma. Key Findings: Cisplatin-based chemotherapy was the most frequently reported initial treatment of locally advanced metastatic urothelial carcinoma. Participants reported using immune checkpoint inhibitors in platinum-ineligible patients and those with PDL1 positive tumors. Also, they would not consider the concomitant use of immunotherapy and chemotherapy in the first-line setting. Participants believed that avelumab maintenance is effective in the absence of progression after first-line platinum-based chemotherapy;they would consider initiating it 2 - 10 weeks after completion of chemotherapy. Conclusions and Clinical Implications: After comparing with current international guidelines, this study shows that Lebanese oncologists follow international guidelines and have deep knowledge of recent clinical trials for the management of locally advanced metastatic urothelial carcinoma, regardless of economic crisis challenges.展开更多
AIM： To study the factors that may affect survival of cholangiocarcinoma in Lebanon. METHODS： A retrospective review of the medical records of 55 patients diagnosed with cholangio- carcinoma at the American Universi...AIM： To study the factors that may affect survival of cholangiocarcinoma in Lebanon. METHODS： A retrospective review of the medical records of 55 patients diagnosed with cholangio- carcinoma at the American University of Beirut between 1990 and 2005 was conducted. Univariate and multivariate analyses were performed to determine the impact of surgery, chemotherapy, body mass index, bilirubin level and other factors on survival. RJ^SULTS： The median survival of all patients was 8.57 mo （0.03-105.2）. Univariate analysis showed that low bilirubin level （〈 10 mg/dL）, radical surgery and chemotherapy administration were significantly associated with better survival （P = 0.012, 0.038 and 0.038, respectively）, in subgroup analysis on patients who had no surgery, chemotherapy administration prolonged median survival significantly （17.0 mo vs 3.5 mo, P = 0.001）. Multivariate analysis identified only low bilirubin level 〈 10 mg/dL and chemotherapy administration as independent predictors associated with better survival （P 〈 0.05）. CONCLUSION： Our data show that palliative and postoperative chemotherapy as well as a bilirubin level 〈 10 mg/dL are independent predictors of a significant increase in survival in patients with cholangiocarcinoma.展开更多
Integrins are cell adhesion molecules that are composed of an alpha(a)subunit and a beta(b)subunit with affinity for different extracellular membrane components.The integrin family includes 24 known members that activ...Integrins are cell adhesion molecules that are composed of an alpha(a)subunit and a beta(b)subunit with affinity for different extracellular membrane components.The integrin family includes 24 known members that actively regulate cellular growth,differentiation,and apoptosis.Each integrin heterodimer has a particular function in defined contexts as well as some partially overlapping features with other members in the family.As many reviews have covered the general integrin family in molecular and cellular studies in life science,this review will focus on the specific regulation,function,and signaling of integrin a2 subunit(CD49b,VLA-2;encoded by the gene ITGA2)in partnership with b1(CD29)subunit in normal and cancer cells.Its roles in cell adhesion,cell motility,angiogenesis,stemness,and immune/blood cell regulations are discussed.The pivotal role of integrin a2 in many diseases such as cancer suggests its potential to be used as a novel therapeutic target.展开更多
Venous thromboembolism(VTE)is a complication in children with acute lymphoblastic leukemia(ALL).The Chinese Children’s Cancer Group-ALL-2015 protocol was carried out in China,and epidemiology,clinical characteristics...Venous thromboembolism(VTE)is a complication in children with acute lymphoblastic leukemia(ALL).The Chinese Children’s Cancer Group-ALL-2015 protocol was carried out in China,and epidemiology,clinical characteristics,and risk factors associated with VTE were analyzed.We collected data on VTE in a multiinstitutional clinical study of 7640 patients with ALL diagnosed in 20 hospitals from January 2015 to December 2019.First,VTE occurred in 159(2.08%)patients,including 90(56.6%)during induction therapy and 108(67.92%)in the upper extremities.T-ALL had a 1.74-fold increased risk of VTE(95%CI 1.08–2.8,P=0.022).Septicemia,as an adverse event of ALL treatment,can significantly promote the occurrence of VTE(P<0.001).Catheter-related thrombosis(CRT)accounted for 75.47%(n=120);and,symptomatic VTE,58.49%(n=93),which was more common in patients aged 12–18 years(P=0.023),non-CRT patients(P<0.001),or patients with cerebral thrombosis(P<0.001).Of the patients with VTE treated with anticoagulation therapy(n=147),4.08%(n=6)had bleeding.The VTE recurrence rate was 5.03%(n=8).Patients with VTE treated by non-ultrasoundguided venous cannulation(P=0.02),with residual thrombus(P=0.006),or with short anticoagulation period(P=0.026)had high recurrence rates.Thus,preventing repeated venous puncture and appropriately prolonged anticoagulation time can reduce the risk of VTE recurrence.展开更多
Background: Controlled-release oxycodone/naloxone(OXN-CR) maintains the effect of opioid-induced analgesia through oxycodone while reducing the occurrence rate of opioid-induced constipation through naloxone. The pres...Background: Controlled-release oxycodone/naloxone(OXN-CR) maintains the effect of opioid-induced analgesia through oxycodone while reducing the occurrence rate of opioid-induced constipation through naloxone. The present study was designed to assess the non-inferiority of OXN-CR to controlled-release oxycodone(OX-CR) for the control of cancer-related pain in Korean patients.Methods: In this randomized, open-labeled, parallel-group, phase IV study, we enrolled patients aged 20 years or older with moderate to severe cancer-related pain [numeric rating scale(NRS) pain score ≥4] from seven Korean oncology/hematology centers. Patients in the intention-to-treat(ITT) population were randomized(1:1) to OXNCR or OX-CR groups. OXN-CR was administered starting at 20 mg/10 mg per day and up-titrated to a maximum of80 mg/40 mg per day for 4 weeks, and OX-CR was administered starting at 20 mg/day and up-titrated to a maximum of 80 mg/day for 4 weeks.The primary efficacy endpoint was the change in NRS pain score from baseline to week4, with non-inferiority margin of-1.5. Secondary endpoints included analgesic rescue medication intake, patientreported change in bowel habits, laxative intake, quality of life(QoL), and safety assessments.Results: Of the ITT population comprising 128 patients, 7 with missing primary efficacy data and 4 who violated the eligibility criteria were excluded from the efficacy analysis. At week 4, the mean change in NRS pain scores was not significantly different between the OXN-CR group(n = 58) and the OX-CR group(n = 59)(-1.586 vs.-1.559,P = 0.948). The lower limit of the one-sided 95% confidence interval(-0.776 to 0.830) for the difference exceeded the non-inferiority margin(P < 0.001). The OXN-CR and OX-CR groups did not differ significantly in terms of analgesic rescue medication intake, change in bowel habits, laxative intake, QoL, and safety assessments.Conclusions: OXN-CR was non-inferior to OX-CR in terms of pain reduction after 4 weeks of treatment and had a similar safety profile. Studies in展开更多
Background:The response rate and survival improvement for rituximab,a CD20-targeting monoclonal antibody,have been demonstrated in marginal zone lymphoma(MZL)as monotherapy and in combination with chemotherapeutic reg...Background:The response rate and survival improvement for rituximab,a CD20-targeting monoclonal antibody,have been demonstrated in marginal zone lymphoma(MZL)as monotherapy and in combination with chemotherapeutic regimens,yet relapses still occur despite treatment completion.Thus,extending the period of remission in MZL patients remains an essential goal.This multicenter,single-arm,open-label phase II study evaluated the survival efficacy of 2 years of rituximab-maintenance therapy in patients with stage III-IV CD20-positive MZL who had responded to first-line R-CVP(rituximab,cyclophosphamide,vincristine,and prednisolone).The objective of this study was to determine whether rituximab maintenance following R-CVP warrants further investigation.Methods:Prior to rituximab-maintenance therapy,patients received 6-8 cycles of first-line R-CVP therapy for stage III-IV MZL.Rituximab(375 mg/m^(2)),cyclophosphamide(750 mg/m^(2)),and vincristine(1.4 mg/m^(2);maximum 2 mg)were administered via an intravenous infusion on day 1 of each 3-week cycle,while oral prednisolone(100 mg)was given on days 1-5 of each 3-week cycle.The patients who achieved complete response(CR),partial response(PR),or stable disease(SD)to R-CVP treatment,were prescribed rituximab-maintenance therapy which was administered intravenously at a dose of 375 mg/m^(2) every 8 weeks for up to 12 cycles.The primary endpoint was progression-free survival(PFS).Secondary endpoints were overall survival(OS)and treatment safety.Results:47 patients were enrolled,of whom,45(96%)received rituximab-maintenance treatment.Fifteen(33%)patients had nodal MZL.Following R-CVP first-line therapy,20(44%),22(49%),and 3(7%)patients achieved CR,PR,and SD,respectively.After a median follow-up of 38.2 months,their observed 3-year PFS rate was 81%.During the rituximab-maintenance,6 PR and 1 SD patients achieved CR following the administration of R-CVP.Elevated LDH and the presence of B symptoms were found to be significant prognostic factors for PFS(P=0.003)and demonstrated a 3-year O展开更多
Acute myeloid leukemia(AML)represents a heterogeneous group of high-grade myeloid neoplasms of the elderly with variable outcomes.Though remissioninduction is an important first step in the management of AML,additiona...Acute myeloid leukemia(AML)represents a heterogeneous group of high-grade myeloid neoplasms of the elderly with variable outcomes.Though remissioninduction is an important first step in the management of AML,additional treatment strategies are essential to ensure long-term disease-free survival.Recent pivotal advances in understanding the genetics and molecular biology of AML have allowed for a risk-adapted approach in its management based on relapse-risk.Allogeneic hematopoietic cell transplantation(allo-HCT)represents an effective therapeutic strategy in AML providing the possibility of cure with potent graft-versus-leukemia reactions,with a demonstrable survival advantage in younger patients with intermediate-or poor-risk cytogenetics.Herein we review the published data regarding the role of allo-HCT in adults with AML.We searched MEDLINE/PubMed and EMBASE/Ovid.In addition,we searched reference lists of relevant articles,conference proceedings and ongoing trial databases.We discuss the role of allo-HCT in AML patients stratified by cytogenetic-and molecular-risk in first complete remission,as well as allo-HCT as an option in relapsed/refractory AML.Besides the conventional sibling and unrelated donor allografts,we review the available data and recent advances for alternative donor sources such as haploidentical grafts and umbilical cord blood.We also discuss conditioning regimens,including reduced intensity conditioning which has broadened the applicability of allo-HCT.Finally we explore recent advances and future possibilities and directions of allo-HCT in AML.Practical therapeutic recommendations have been made where possible based on available data and expert opinion.展开更多
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 c...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.展开更多
Pancreatic cancer(PC)remains one of the most challenging diseases,with a very poor 5-year overall survival of around 11.5%.Kirsten rat sarcoma virus(KRAS)mutation is seen in 90%-95%of PC patients and plays an importan...Pancreatic cancer(PC)remains one of the most challenging diseases,with a very poor 5-year overall survival of around 11.5%.Kirsten rat sarcoma virus(KRAS)mutation is seen in 90%-95%of PC patients and plays an important role in cancer cell proliferation,differentiation,metabolism,and survival,making it an essential mutation for targeted therapy.Despite extensive efforts in studying this oncogene,there has been little success in finding a drug to target this pathway,labelling it for decades as“undruggable”.In this article we summarize some of the efforts made to target the KRAS pathway in PC,discuss the challenges,and shed light on promising clinical trials.展开更多
AIM： TO investigate the impact of mucin production on prognosis in colorectal cancer, in terms of overall survival （OS） and time to disease progression （TTP） in patients with mucinous compared to those with nonmu...AIM： TO investigate the impact of mucin production on prognosis in colorectal cancer, in terms of overall survival （OS） and time to disease progression （TTP） in patients with mucinous compared to those with nonmucinous colorectal cancer （NMCRC）, matched for age, gender, and tumor stage. METHODS： Thirty five patients with mucinous colorectal cancer （MCRC） were matched for age, gender, and tumor stage with 35 controls having NMCRC. OS and TTP were compared among 4 groups divided according to mucin content： group A （50%-75% mucin）, group B （75%-100% mucin）, group C or controls （〈 50% mucin）. Group D consisted of all patients with tumors having 〈 75% mucin （controls and groups A together）. RESULTS： Median survival in MCRC and NMCRC groups was 46.2 and 112.9 mo, respectively （P = 0.26）. OS in groups A and B was 70.1 and 32.8 mo （P = 0.46）, and in groups B and D was 32.8 and 70.1 mo, respectively （P = 0.143）. TTP in MCRC and NMCRC was 50.17 and 44.77 too, respectively （P = 0.795）. TTP in groups A, B, and D was 70.1, 24.8, and 65.5 too, respectively. Twenty-eight percent of patients with MCRC had poorly differentiated adenocarcinoma versus 8.6% in NMCRC patients （P = 0.028）. CONCLUSION： MCRC is associated with a non-significant decrease in median survival and TTP, particularly when mucin content is 〉 75% of tumor volume. However, it tends to be more poorly differentiated. A larger study matching for stage and grade is needed.展开更多
AIM: To assess the efficacy and safety of weekly docetaxel plus a fixed-dose rate(FDR) of gemcitabine in metastatic esophageal squamous cell carcinoma(SCC).METHODS: A multi-center, open-label, prospective phase Ⅱ stu...AIM: To assess the efficacy and safety of weekly docetaxel plus a fixed-dose rate(FDR) of gemcitabine in metastatic esophageal squamous cell carcinoma(SCC).METHODS: A multi-center, open-label, prospective phase Ⅱ study was designed.Thirty-three esophageal SCC patients with documented progression after fluoropyrimidine/platinum-based first-line chemotherapy were enrolled and treated with docetaxel 35 mg/m2 and gemcitabine 1000 mg/m2 iv at a FDR(10 mg/m2 per minute) on days 1 and 8.Treatment was repeatedevery twenty-one days until disease progression, unacceptable toxicity, or consent withdrawal.The primary endpoint was response rate(RR), and secondary endpoints were safety, progression-free survival(PFS) and overall survival(OS).RESULTS: Combination of weekly docetaxel and FDR gemcitabine was well tolerated: the most common treatment-related adverse events were anemia(97%), fatigue(64%) and neutropenia(55%).One patient with multiple lung and lymph node metastases died of respiratory failure after receiving four cycles of chemotherapy, and the possibility of drug-induced pneumonitis could not be completely excluded.Disease control(objective response plus stable disease) in the ITT population was achieved in 88% of patients, and the overall RR was 30%(95%CI: 15%-46%).The median PFS and OS were 4.0(95%CI: 3.4-4.6) and 8.8 mo(95%CI: 7.8-9.8 mo), respectively.CONCLUSION: A combination of weekly docetaxel and FDR gemcitabine showed promising antitumor activity and tolerability in previously treated, metastatic esophageal SCC.展开更多
The first cell fate choice in the mammalian embryo, the segregation of the inner cell mass （ICM） and trophectoderm （TE）, is regulated by the mutually antagonistic effects of the transcription factors, Oct4 and Cdx...The first cell fate choice in the mammalian embryo, the segregation of the inner cell mass （ICM） and trophectoderm （TE）, is regulated by the mutually antagonistic effects of the transcription factors, Oct4 and Cdx2, while the pluripotency factor, Nanog, is essential to specify the epiblast. We have analyzed the promoters of Nanog and Cdx2, and have found that these two transcription factors are likewise regulated reciprocally. Using an embryonic stem cell line with conditional TE differentiation, we show that Nanog overexpression suppresses the upregulation of TE markers, while Nanog knockdown upregulates the expression of TE markers. We further show that Nanog and Cdx2 bind to and repress each other＇s promoters. However, whereas Nanog knockout results in detectable Cdx2 expression in the ICM, we observe no overt disruption of blastocyst development, indicating that Nanog plays a subservient role to Oct4 in segregation of the ICM and TE.展开更多
AIM:To identify blood donors with occult hepatitis B virus(HBV) infection(OBI) to promote safe blood donation.METHODS:Descriptive cross sectional study was conducted on 3167 blood donors negative for hepatitis B surfa...AIM:To identify blood donors with occult hepatitis B virus(HBV) infection(OBI) to promote safe blood donation.METHODS:Descriptive cross sectional study was conducted on 3167 blood donors negative for hepatitis B surface antigen(HBsAg),hepatitis C antibody(HCV Ab) and human immunodeficiency virus Ab.They were subjected to the detection of alanine aminotransferase(ALT) and aspartate transaminase(AST) and screening for anti-HBV core antibodies(total) by two different techniques;[Monoliza antibodies to hepatitis B core(Anti-HBc) Plus-Bio-Rad] and(ARC-HBc total-ABBOT).Positive samples were subjected to quantitative detection of antibodies to hepatitis B surface(anti-HBs)(ETI-AB-AUK-3,Dia Sorin-Italy).Serum anti-HBs titers > 10 IU/L was considered positive.Quantitative HBV DNA by real time polymerase chain reaction(PCR)(QIAGEN-Germany) with 3.8 IU/mL detection limit was estimated for blood units with negative serum anti-HBs and also for 32 whose anti-HBs serum titers were > 1000 IU/L.Also,265 recipients were included,34 of whom were followed up for 3-6 mo.Recipients were investigated for ALT and AST,HBV serological markers:HBsAg(ETI-MAK-4,Dia Sorin-Italy),anti-HBc,quantitative detection of anti-HBs and HBV-DNA.RESULTS:525/3167(16.6%) of blood units were positive for total anti-HBc,64% of those were antiHBs positive.Confirmation by ARCHITECT anti-HBc assay were carried out for 498/525 anti-HBc positive samples,where 451(90.6%) confirmed positive.Reactivity for anti-HBc was considered confirmed only if two positive results were obtained for each sample,giving an overall prevalence of 451/3167(14.2%) for total anti-HBc.HBV DNA was quantified by real time PCR in 52/303(17.2%) of anti-HBc positive blood donors(viral load range:5 to 3.5 x 105 IU/mL) with a median of 200 IU/mL(mean:1.8 x 104 ± 5.1 x 104 IU/mL).AntiHBc was the only marker in 68.6% of donors.Univariate and multivariate logistic analysis for identifying risk factors associated with anti-HBc and HBV-DNA positivity among blood donors showed that age above thirty 展开更多
Epithelial ovarian cancer(EOC)is treated in the first-line setting with combined platinum and taxane chemotherapy,often followed by a maintenance poly(ADP-ribose)polymerase inhibitor(PARPi).Responses to first-line tre...Epithelial ovarian cancer(EOC)is treated in the first-line setting with combined platinum and taxane chemotherapy,often followed by a maintenance poly(ADP-ribose)polymerase inhibitor(PARPi).Responses to first-line treatment are frequent.For many patients,however,responses are suboptimal or short-lived.Over the last several years,multiple new classes of agents targeting DNA damage response(DDR)mechanisms have advanced through clinical development.In this review,we explore the preclinical rationale for the use of ATR inhibitors,CHK1 inhibitors,and WEE1 inhibitors,emphasizing their application to chemotherapy-resistant and PARPi-resistant ovarian cancer.We also present an overview of the clinical development of the leading drugs in each of these classes,emphasizing the rationale for monotherapy and combination therapy approaches.展开更多
基金Supported by Basic Science Research Program through the National Research of Korea(NRF)funded by the Ministry of Education,Science and Technology,NRF-2009-0076540,NRF-2009-0067256
文摘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.
文摘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.
文摘AIM:To investigate the clinicopathologic features of patients with extra-gastrointestinal stromal tumors(EGISTs)in South Korea.METHODS:A total of 51 patients with an EGIST were identified.The clinicopathologic features,including sex,age,location,tumor size,histology,mitotic rate,immunohistochemical features,genetic status and survival data,were analyzed.RESULTS:The median age was 55 years(range:29-80years),and male:female ratio was 1:1.04.The most common site was in the mesentery(n=15)followed by the retroperitoneum(n=13)and omentum(n=8).The median tumor size was 9.0 cm(range:2.6-30.0cm)and the median mitotic rate was 5.0/50HPF.(1/50-185/50).KIT was analyzed in 16,which revealed 10cases with wild-type KIT and 6 cases with an exon 11mutation.Among 51 patients,31 patients had undergone surgery,and 10 had unresectable disease and had taken palliative imatinib,which resulted in 22.7 mo of progression-free survival.Of the patients who had undergone surgery,18 did not take adjuvant imatinib,and 8 of these were categorized as"high risk"according to the risk criteria.However,the relapse-free survival was not different(P=0.157)between two groups.CONCLUSION:Because the biologic behaviors of GISTs differ according to the location of the tumor,a more stratified strategy is required for managing EGISTs including incorporation of molecular features.
文摘Background and Objective: The outcome of locally advanced and metastatic urothelial carcinoma LA/mUC has improved over the past years with a plethora of new treatments and the approval of immune checkpoint inhibitors (ICIs), antibody-drug conjugates, and targeted agents, to identify locally advanced metastatic urothelial carcinoma’s current management practices in Lebanon and the implication of the ongoing economic crisis on the medical practice. Methods: An online questionnaire was used to survey ten Lebanese oncologists from six different hospitals, between July 5 and July 11, 2022, requesting information pertaining to their current clinical practice in the pharmacological treatment of locally advanced metastatic urothelial carcinoma. Key Findings: Cisplatin-based chemotherapy was the most frequently reported initial treatment of locally advanced metastatic urothelial carcinoma. Participants reported using immune checkpoint inhibitors in platinum-ineligible patients and those with PDL1 positive tumors. Also, they would not consider the concomitant use of immunotherapy and chemotherapy in the first-line setting. Participants believed that avelumab maintenance is effective in the absence of progression after first-line platinum-based chemotherapy;they would consider initiating it 2 - 10 weeks after completion of chemotherapy. Conclusions and Clinical Implications: After comparing with current international guidelines, this study shows that Lebanese oncologists follow international guidelines and have deep knowledge of recent clinical trials for the management of locally advanced metastatic urothelial carcinoma, regardless of economic crisis challenges.
文摘AIM： To study the factors that may affect survival of cholangiocarcinoma in Lebanon. METHODS： A retrospective review of the medical records of 55 patients diagnosed with cholangio- carcinoma at the American University of Beirut between 1990 and 2005 was conducted. Univariate and multivariate analyses were performed to determine the impact of surgery, chemotherapy, body mass index, bilirubin level and other factors on survival. RJ^SULTS： The median survival of all patients was 8.57 mo （0.03-105.2）. Univariate analysis showed that low bilirubin level （〈 10 mg/dL）, radical surgery and chemotherapy administration were significantly associated with better survival （P = 0.012, 0.038 and 0.038, respectively）, in subgroup analysis on patients who had no surgery, chemotherapy administration prolonged median survival significantly （17.0 mo vs 3.5 mo, P = 0.001）. Multivariate analysis identified only low bilirubin level 〈 10 mg/dL and chemotherapy administration as independent predictors associated with better survival （P 〈 0.05）. CONCLUSION： Our data show that palliative and postoperative chemotherapy as well as a bilirubin level 〈 10 mg/dL are independent predictors of a significant increase in survival in patients with cholangiocarcinoma.
基金This manuscript is partially supported by the funds from the National Institutes of Health/National Cancer Institute(NIH/NCI)R00CA160638(H.L.)its Supplement for Diversity(V.A.),American Cancer Society 127951-RSG-15-025-01-CSM(H.L.)+1 种基金Susan G.Komen Foundation CCR15332826(H.L.)Department of Defense W81XWH-16-1-0021(H.L.).
文摘Integrins are cell adhesion molecules that are composed of an alpha(a)subunit and a beta(b)subunit with affinity for different extracellular membrane components.The integrin family includes 24 known members that actively regulate cellular growth,differentiation,and apoptosis.Each integrin heterodimer has a particular function in defined contexts as well as some partially overlapping features with other members in the family.As many reviews have covered the general integrin family in molecular and cellular studies in life science,this review will focus on the specific regulation,function,and signaling of integrin a2 subunit(CD49b,VLA-2;encoded by the gene ITGA2)in partnership with b1(CD29)subunit in normal and cancer cells.Its roles in cell adhesion,cell motility,angiogenesis,stemness,and immune/blood cell regulations are discussed.The pivotal role of integrin a2 in many diseases such as cancer suggests its potential to be used as a novel therapeutic target.
基金VIVA-China Children's Cancer Foundation and Prof.Pui team.
文摘Venous thromboembolism(VTE)is a complication in children with acute lymphoblastic leukemia(ALL).The Chinese Children’s Cancer Group-ALL-2015 protocol was carried out in China,and epidemiology,clinical characteristics,and risk factors associated with VTE were analyzed.We collected data on VTE in a multiinstitutional clinical study of 7640 patients with ALL diagnosed in 20 hospitals from January 2015 to December 2019.First,VTE occurred in 159(2.08%)patients,including 90(56.6%)during induction therapy and 108(67.92%)in the upper extremities.T-ALL had a 1.74-fold increased risk of VTE(95%CI 1.08–2.8,P=0.022).Septicemia,as an adverse event of ALL treatment,can significantly promote the occurrence of VTE(P<0.001).Catheter-related thrombosis(CRT)accounted for 75.47%(n=120);and,symptomatic VTE,58.49%(n=93),which was more common in patients aged 12–18 years(P=0.023),non-CRT patients(P<0.001),or patients with cerebral thrombosis(P<0.001).Of the patients with VTE treated with anticoagulation therapy(n=147),4.08%(n=6)had bleeding.The VTE recurrence rate was 5.03%(n=8).Patients with VTE treated by non-ultrasoundguided venous cannulation(P=0.02),with residual thrombus(P=0.006),or with short anticoagulation period(P=0.026)had high recurrence rates.Thus,preventing repeated venous puncture and appropriately prolonged anticoagulation time can reduce the risk of VTE recurrence.
文摘Background: Controlled-release oxycodone/naloxone(OXN-CR) maintains the effect of opioid-induced analgesia through oxycodone while reducing the occurrence rate of opioid-induced constipation through naloxone. The present study was designed to assess the non-inferiority of OXN-CR to controlled-release oxycodone(OX-CR) for the control of cancer-related pain in Korean patients.Methods: In this randomized, open-labeled, parallel-group, phase IV study, we enrolled patients aged 20 years or older with moderate to severe cancer-related pain [numeric rating scale(NRS) pain score ≥4] from seven Korean oncology/hematology centers. Patients in the intention-to-treat(ITT) population were randomized(1:1) to OXNCR or OX-CR groups. OXN-CR was administered starting at 20 mg/10 mg per day and up-titrated to a maximum of80 mg/40 mg per day for 4 weeks, and OX-CR was administered starting at 20 mg/day and up-titrated to a maximum of 80 mg/day for 4 weeks.The primary efficacy endpoint was the change in NRS pain score from baseline to week4, with non-inferiority margin of-1.5. Secondary endpoints included analgesic rescue medication intake, patientreported change in bowel habits, laxative intake, quality of life(QoL), and safety assessments.Results: Of the ITT population comprising 128 patients, 7 with missing primary efficacy data and 4 who violated the eligibility criteria were excluded from the efficacy analysis. At week 4, the mean change in NRS pain scores was not significantly different between the OXN-CR group(n = 58) and the OX-CR group(n = 59)(-1.586 vs.-1.559,P = 0.948). The lower limit of the one-sided 95% confidence interval(-0.776 to 0.830) for the difference exceeded the non-inferiority margin(P < 0.001). The OXN-CR and OX-CR groups did not differ significantly in terms of analgesic rescue medication intake, change in bowel habits, laxative intake, QoL, and safety assessments.Conclusions: OXN-CR was non-inferior to OX-CR in terms of pain reduction after 4 weeks of treatment and had a similar safety profile. Studies in
基金This study was supported by the Dong-A University Research FundThe study and manuscript were funded by the authors through the Dong-A University Research Fund.Rituximab was donated by Roche KoreaRituximab was kindly provided by Roche,Korea.
文摘Background:The response rate and survival improvement for rituximab,a CD20-targeting monoclonal antibody,have been demonstrated in marginal zone lymphoma(MZL)as monotherapy and in combination with chemotherapeutic regimens,yet relapses still occur despite treatment completion.Thus,extending the period of remission in MZL patients remains an essential goal.This multicenter,single-arm,open-label phase II study evaluated the survival efficacy of 2 years of rituximab-maintenance therapy in patients with stage III-IV CD20-positive MZL who had responded to first-line R-CVP(rituximab,cyclophosphamide,vincristine,and prednisolone).The objective of this study was to determine whether rituximab maintenance following R-CVP warrants further investigation.Methods:Prior to rituximab-maintenance therapy,patients received 6-8 cycles of first-line R-CVP therapy for stage III-IV MZL.Rituximab(375 mg/m^(2)),cyclophosphamide(750 mg/m^(2)),and vincristine(1.4 mg/m^(2);maximum 2 mg)were administered via an intravenous infusion on day 1 of each 3-week cycle,while oral prednisolone(100 mg)was given on days 1-5 of each 3-week cycle.The patients who achieved complete response(CR),partial response(PR),or stable disease(SD)to R-CVP treatment,were prescribed rituximab-maintenance therapy which was administered intravenously at a dose of 375 mg/m^(2) every 8 weeks for up to 12 cycles.The primary endpoint was progression-free survival(PFS).Secondary endpoints were overall survival(OS)and treatment safety.Results:47 patients were enrolled,of whom,45(96%)received rituximab-maintenance treatment.Fifteen(33%)patients had nodal MZL.Following R-CVP first-line therapy,20(44%),22(49%),and 3(7%)patients achieved CR,PR,and SD,respectively.After a median follow-up of 38.2 months,their observed 3-year PFS rate was 81%.During the rituximab-maintenance,6 PR and 1 SD patients achieved CR following the administration of R-CVP.Elevated LDH and the presence of B symptoms were found to be significant prognostic factors for PFS(P=0.003)and demonstrated a 3-year O
文摘Acute myeloid leukemia(AML)represents a heterogeneous group of high-grade myeloid neoplasms of the elderly with variable outcomes.Though remissioninduction is an important first step in the management of AML,additional treatment strategies are essential to ensure long-term disease-free survival.Recent pivotal advances in understanding the genetics and molecular biology of AML have allowed for a risk-adapted approach in its management based on relapse-risk.Allogeneic hematopoietic cell transplantation(allo-HCT)represents an effective therapeutic strategy in AML providing the possibility of cure with potent graft-versus-leukemia reactions,with a demonstrable survival advantage in younger patients with intermediate-or poor-risk cytogenetics.Herein we review the published data regarding the role of allo-HCT in adults with AML.We searched MEDLINE/PubMed and EMBASE/Ovid.In addition,we searched reference lists of relevant articles,conference proceedings and ongoing trial databases.We discuss the role of allo-HCT in AML patients stratified by cytogenetic-and molecular-risk in first complete remission,as well as allo-HCT as an option in relapsed/refractory AML.Besides the conventional sibling and unrelated donor allografts,we review the available data and recent advances for alternative donor sources such as haploidentical grafts and umbilical cord blood.We also discuss conditioning regimens,including reduced intensity conditioning which has broadened the applicability of allo-HCT.Finally we explore recent advances and future possibilities and directions of allo-HCT in AML.Practical therapeutic recommendations have been made where possible based on available data and expert opinion.
文摘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.
文摘Pancreatic cancer(PC)remains one of the most challenging diseases,with a very poor 5-year overall survival of around 11.5%.Kirsten rat sarcoma virus(KRAS)mutation is seen in 90%-95%of PC patients and plays an important role in cancer cell proliferation,differentiation,metabolism,and survival,making it an essential mutation for targeted therapy.Despite extensive efforts in studying this oncogene,there has been little success in finding a drug to target this pathway,labelling it for decades as“undruggable”.In this article we summarize some of the efforts made to target the KRAS pathway in PC,discuss the challenges,and shed light on promising clinical trials.
文摘AIM： TO investigate the impact of mucin production on prognosis in colorectal cancer, in terms of overall survival （OS） and time to disease progression （TTP） in patients with mucinous compared to those with nonmucinous colorectal cancer （NMCRC）, matched for age, gender, and tumor stage. METHODS： Thirty five patients with mucinous colorectal cancer （MCRC） were matched for age, gender, and tumor stage with 35 controls having NMCRC. OS and TTP were compared among 4 groups divided according to mucin content： group A （50%-75% mucin）, group B （75%-100% mucin）, group C or controls （〈 50% mucin）. Group D consisted of all patients with tumors having 〈 75% mucin （controls and groups A together）. RESULTS： Median survival in MCRC and NMCRC groups was 46.2 and 112.9 mo, respectively （P = 0.26）. OS in groups A and B was 70.1 and 32.8 mo （P = 0.46）, and in groups B and D was 32.8 and 70.1 mo, respectively （P = 0.143）. TTP in MCRC and NMCRC was 50.17 and 44.77 too, respectively （P = 0.795）. TTP in groups A, B, and D was 70.1, 24.8, and 65.5 too, respectively. Twenty-eight percent of patients with MCRC had poorly differentiated adenocarcinoma versus 8.6% in NMCRC patients （P = 0.028）. CONCLUSION： MCRC is associated with a non-significant decrease in median survival and TTP, particularly when mucin content is 〉 75% of tumor volume. However, it tends to be more poorly differentiated. A larger study matching for stage and grade is needed.
基金Supported by Dong-A ST(Seoul,Korea)for kindly provided the study drug(gemcitabine)
文摘AIM: To assess the efficacy and safety of weekly docetaxel plus a fixed-dose rate(FDR) of gemcitabine in metastatic esophageal squamous cell carcinoma(SCC).METHODS: A multi-center, open-label, prospective phase Ⅱ study was designed.Thirty-three esophageal SCC patients with documented progression after fluoropyrimidine/platinum-based first-line chemotherapy were enrolled and treated with docetaxel 35 mg/m2 and gemcitabine 1000 mg/m2 iv at a FDR(10 mg/m2 per minute) on days 1 and 8.Treatment was repeatedevery twenty-one days until disease progression, unacceptable toxicity, or consent withdrawal.The primary endpoint was response rate(RR), and secondary endpoints were safety, progression-free survival(PFS) and overall survival(OS).RESULTS: Combination of weekly docetaxel and FDR gemcitabine was well tolerated: the most common treatment-related adverse events were anemia(97%), fatigue(64%) and neutropenia(55%).One patient with multiple lung and lymph node metastases died of respiratory failure after receiving four cycles of chemotherapy, and the possibility of drug-induced pneumonitis could not be completely excluded.Disease control(objective response plus stable disease) in the ITT population was achieved in 88% of patients, and the overall RR was 30%(95%CI: 15%-46%).The median PFS and OS were 4.0(95%CI: 3.4-4.6) and 8.8 mo(95%CI: 7.8-9.8 mo), respectively.CONCLUSION: A combination of weekly docetaxel and FDR gemcitabine showed promising antitumor activity and tolerability in previously treated, metastatic esophageal SCC.
文摘The first cell fate choice in the mammalian embryo, the segregation of the inner cell mass （ICM） and trophectoderm （TE）, is regulated by the mutually antagonistic effects of the transcription factors, Oct4 and Cdx2, while the pluripotency factor, Nanog, is essential to specify the epiblast. We have analyzed the promoters of Nanog and Cdx2, and have found that these two transcription factors are likewise regulated reciprocally. Using an embryonic stem cell line with conditional TE differentiation, we show that Nanog overexpression suppresses the upregulation of TE markers, while Nanog knockdown upregulates the expression of TE markers. We further show that Nanog and Cdx2 bind to and repress each other＇s promoters. However, whereas Nanog knockout results in detectable Cdx2 expression in the ICM, we observe no overt disruption of blastocyst development, indicating that Nanog plays a subservient role to Oct4 in segregation of the ICM and TE.
文摘AIM:To identify blood donors with occult hepatitis B virus(HBV) infection(OBI) to promote safe blood donation.METHODS:Descriptive cross sectional study was conducted on 3167 blood donors negative for hepatitis B surface antigen(HBsAg),hepatitis C antibody(HCV Ab) and human immunodeficiency virus Ab.They were subjected to the detection of alanine aminotransferase(ALT) and aspartate transaminase(AST) and screening for anti-HBV core antibodies(total) by two different techniques;[Monoliza antibodies to hepatitis B core(Anti-HBc) Plus-Bio-Rad] and(ARC-HBc total-ABBOT).Positive samples were subjected to quantitative detection of antibodies to hepatitis B surface(anti-HBs)(ETI-AB-AUK-3,Dia Sorin-Italy).Serum anti-HBs titers > 10 IU/L was considered positive.Quantitative HBV DNA by real time polymerase chain reaction(PCR)(QIAGEN-Germany) with 3.8 IU/mL detection limit was estimated for blood units with negative serum anti-HBs and also for 32 whose anti-HBs serum titers were > 1000 IU/L.Also,265 recipients were included,34 of whom were followed up for 3-6 mo.Recipients were investigated for ALT and AST,HBV serological markers:HBsAg(ETI-MAK-4,Dia Sorin-Italy),anti-HBc,quantitative detection of anti-HBs and HBV-DNA.RESULTS:525/3167(16.6%) of blood units were positive for total anti-HBc,64% of those were antiHBs positive.Confirmation by ARCHITECT anti-HBc assay were carried out for 498/525 anti-HBc positive samples,where 451(90.6%) confirmed positive.Reactivity for anti-HBc was considered confirmed only if two positive results were obtained for each sample,giving an overall prevalence of 451/3167(14.2%) for total anti-HBc.HBV DNA was quantified by real time PCR in 52/303(17.2%) of anti-HBc positive blood donors(viral load range:5 to 3.5 x 105 IU/mL) with a median of 200 IU/mL(mean:1.8 x 104 ± 5.1 x 104 IU/mL).AntiHBc was the only marker in 68.6% of donors.Univariate and multivariate logistic analysis for identifying risk factors associated with anti-HBc and HBV-DNA positivity among blood donors showed that age above thirty
基金Bouberhan S has accepted funds from ImmunoGen for consulting,not directly related to this review.The funders had no role in the design of this paper,the interpretation of data,or the writing of the manuscript.Bar-Peled L is a founder and consultant and holds privately held equity in Scorpion Therapeutics.Bar-Peled L was supported by grants from the NCI(CA215249)Damon Runyon Cancer Research Foundation,AACR(19-20-45-BARP)Mary Kay Ash Foundation,LUNGevity,V Foundation,Melanoma Research Foundation,American Cancer Society,and the Ludwig Cancer Center.Rueda BR is funded in part by the Nile Albright Research Foundation and the Vincent Memorial Hospital Research Foundation.
文摘Epithelial ovarian cancer(EOC)is treated in the first-line setting with combined platinum and taxane chemotherapy,often followed by a maintenance poly(ADP-ribose)polymerase inhibitor(PARPi).Responses to first-line treatment are frequent.For many patients,however,responses are suboptimal or short-lived.Over the last several years,multiple new classes of agents targeting DNA damage response(DDR)mechanisms have advanced through clinical development.In this review,we explore the preclinical rationale for the use of ATR inhibitors,CHK1 inhibitors,and WEE1 inhibitors,emphasizing their application to chemotherapy-resistant and PARPi-resistant ovarian cancer.We also present an overview of the clinical development of the leading drugs in each of these classes,emphasizing the rationale for monotherapy and combination therapy approaches.
