AIM to evaluate the association of body mass index(b MI) with the overall survival of pancreatic ductal adenocarcinoma(PDAC) patients.METHODS A retrospective analysis of PDAC patients diagnosed in the National Cancer ...AIM to evaluate the association of body mass index(b MI) with the overall survival of pancreatic ductal adenocarcinoma(PDAC) patients.METHODS A retrospective analysis of PDAC patients diagnosed in the National Cancer Center of China between January 1999 and December 2014 was performed. these patients were categorized into four b MI groups(< 18.5, 18.5-22.9, 23-27.4 and ≥ 27.5 kg/m2). χ2 tests for comparison of the proportions of categorical variables, and Student's t-test or Mann-Whitney test for continuous variables were employed. Survival analysis was performed with the Kaplan-Meyer method. their HRs of mortality and 95%CIs were estimated using the Cox proportional hazards model.RESULTS With a median age of 59.6 years(range: 22.5-84.6 years), in total 1783 PDAC patients were enrolled in this study. their mean usual b MI was 24.19 ± 3.53 for the whole cohort. More than half of the patients(59.3%) experienced weight loss during the disease onset and progression. Compared with healthy-weight individuals, newly diagnosed patients who were overweight or obese had more severe weight loss during their disease onset and progression(P < 0.001). Individuals who were overweight or obese were associated with positive smoking history(P < 0.001). A significant difference in comorbidity of diabetes(P = 0.044) and coronary artery disease(P < 0.001) was identified between high b MI and normal-weight patients. After a median follow-up of 8 mo, the survival analysis showed no association between b MI and the overall survival(P = 0.90, n = 1783). When we stratified the whole cohort by pancreatic cancer stage, no statistically significant association between b MI and overall survival was found for resectable(P = 0.99, n = 217), unresectable locally advanced(P = 0.90, n = 316) and metastatic patients(P = 0.88, n = 1250), respectively. the results did not change when we used the b MI at diagnosis.CONCLUSION Our results showed no significance of b MI for the overall survival of PDAC patients.展开更多
This perspective article highlights the leukocyte-cancer cell hybrid theory as a mechanism for cancer metastasis. Beginning from the first proposal of the theory more than a century ago and continuing today with the f...This perspective article highlights the leukocyte-cancer cell hybrid theory as a mechanism for cancer metastasis. Beginning from the first proposal of the theory more than a century ago and continuing today with the first proof for this theory in a human cancer, the hybrid theory offers a unifying explanation for metastasis. In this scenario, leukocyte fusion with a cancer cell is a secondary disease superimposed upon the early tumor, giving birth to a new, malignant cell with a leukocyte-cancer cell hybrid epigenome.展开更多
We report a case of pseudocirrhosis arising in the setting of regression of liver metastases from pancreatic cancer. A 55-year-old asymptomatic woman presented to our clinic with newly diagnosed metastatic pancreatic ...We report a case of pseudocirrhosis arising in the setting of regression of liver metastases from pancreatic cancer. A 55-year-old asymptomatic woman presented to our clinic with newly diagnosed metastatic pancreatic cancer with extensive liver metastases. She underwent systemic chemotherapy with gemcitabine and oxaliplatin (GEMOX). After 8 cycles of therapy, she had a remarkable response to the therapy evidenced by decline of carcinoembryonic antigen (CEA) and CA19 by > 50% and nearly complete resolution of hepatic metastases in computed tomography (CT) scan. Shortly after, she developed increasing bilateral ankle edema and ascites, associated with dyspnea, progressive weight gain, and declining performance status. Gemcitabine and oxaliplatin were discontinued as other causes of her symptoms such as congestive heart disease or venous thrombosis were ruled out. CT scan 6 mo after the initiation of GEMOX revealed worsening ascites with a stable pancreatic mass. However, it also revealed a lobular hepatic contour, segmental atrophy, and capsular retraction mimicking the appearance of cirrhosis. She was managed with aggressive diuresis and albumin infusions which eventually resulted in a resolution of the above- mentioned symptoms as well as complete resolution of pseudocirrhotic appearance of the liver and ascites in CT scan. This case demonstrates that pancreatic cancer patients can develop pseudocirrhosis. Clinicians and radiologist should be well aware of this entity asearly recognition and management can lead to a near complete recovery of liver function and much improved quality of life as illustrated in this case.展开更多
There are differences between African-American and white patients with colorectal cancer, concerning their characteristics before and after diagnosis. Whites are more likely to adhere to screening guidelines. This is ...There are differences between African-American and white patients with colorectal cancer, concerning their characteristics before and after diagnosis. Whites are more likely to adhere to screening guidelines. This is also the case among people with positive family history. Colorectal cancer is more frequent in Blacks. Studies have shown that that since 1985, colon cancer rates have dipped 20% to 25% for Whites, while rates have gone up for African-American men and stayed the same for African-American women. Overall, African-Americans are 38% to 43% more likely to die from colon cancer than are Whites. Furthermore, it seems that there is an African-American predominance in right-sited tumors. African Americans tend to be diagnosed at a later stage, to suffer from better differentiated tumors, and to have worse prognosis when compared with Whites. Moreover, less black patients receive adjuvant chemotherapy for resectable colorectal cancer or radiation therapy for rectal cancer. Caucasians seem to respond better to standard chemotherapy regimens than AfricanAmericans. Concerning toxicity, it appears that patients of African-American descent are more likely to develop 5-FU toxicity than Whites, possibly because of their different dihydropyridine dehydrogenase status. Last but not least, screening surveillance seems to be higher among white than among black long-term colorectal cancer survivors. Socioeconomic and educational status account for most of these differences whereas little evidence exists for a genetic contribution in racial disparity. Understanding the nature of racial differences in colorectal cancer allows tailoring of screening and treatment interventions.展开更多
Cancer stem cells(CSC) are thought to be malignant cells that have the capacity to initiate and maintain tumor growth and survival. Studies have described CSC in various gastrointestinal neoplasms such as colon, pancr...Cancer stem cells(CSC) are thought to be malignant cells that have the capacity to initiate and maintain tumor growth and survival. Studies have described CSC in various gastrointestinal neoplasms such as colon, pancreas and liver and gastroesophageal tumors. The mechanism by which CSC develop remains unclear. Several studies have explored the role of dysregulation of the Wnt/β-catenin, transformation growth factor-beta and hedhog pathways in generation of CSC. In this review, we discuss the various molecular abnormalities that may be related to formation of CSC in gastrointestinal malignancies, strategies to identify CSC and therapeutic strategies that are based on these concepts. Identification and targeting CSC is an intriguing area and may provide a new therapeutic option for patients with cancer including gastrointestinal malignancies. Although great progress has been made, many issues need to be addressed. Precise targeting of CSC will require precise isolation and characterization of those cells. This field is also evolving but further research is needed to identify markers that are specific for CSC.Although the application of this field has not entered the clinic yet, there continues to be significant optimism about its potential utility in overcoming cancer resistance and curing patients with cancer.展开更多
Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation,repair and regeneration.Through cell fusion somatic cells undergo rapid nuclear reprogramming and e...Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation,repair and regeneration.Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations.Factors that stimulate cell fusion are inflammation and hypoxia.Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes,e.g.,reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition.There is now considerable in vitro,in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis.Of the many changes in cancer cells after hybridizing with leucocytes,it is notable that hybrids acquire resistance to chemo-and radiation therapy.One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization.Regardless of the mechanism of polyploid cell formation,it happens in response to genotoxic stresses and enhances a cancer cell’s ability to survive.Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis.In addition,we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors.展开更多
Surgery is the only curative option for patients with liver metastases of colorectal cancer, but few patients present with resectable hepatic lesions. Chemotherapy is increasingly used to downstage initially unresecta...Surgery is the only curative option for patients with liver metastases of colorectal cancer, but few patients present with resectable hepatic lesions. Chemotherapy is increasingly used to downstage initially unresectable disease and allow for potentially curative surgery. Standard chemotherapy regimens convert 10%-20% of cases to resectable disease in unselected populations and 30%-40% of those with disease confined to the liver. One strategy to further increase the number of candidates eligible for surgery is the addition of active targeted agents such as cetuximab and bevacizumab to standard chemotherapy. Data from a phase Ⅲ trial indicate that cetuximab increases the number of patients eligible for secondary hepatic resection, as well as the rate of complete resection when combined with first-line treatment with the FOLFIRI regimen. The safety profiles of preoperative cetuximab or bevacizumab have not been thoroughly assessed, but preliminary evidence indicates that these agents do not increase surgical mortality or exacerbate chemotherapyrelated hepatotoxicity, such as steatosis （5-fluorouracil）, steatohepatitis （irinotecan）, and sinusoidal obstruction （oxaliplatin）. Secondary resection is a valid treatment goal for certain patients with initially unresectable liver metastases and an important end point for future clinical trials.展开更多
In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer （CRPC） have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for t...In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer （CRPC） have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for the development of new drugs to target prostate cancer, and our understanding of genetic mutations may give us new tools with which to more accurately diagnose and be able to predict the course of this heterogeneous disease. This article summarizes the recent advances in the understanding of the development of CRPC, as well as the new drugs and targets, which have evolved from this basic research.展开更多
Background:The stage at diagnosis is a major factor in making treatment strategies and cancer control policies.However,the stage distribution for liver cancer in China was not well studied.In this multi-center hospita...Background:The stage at diagnosis is a major factor in making treatment strategies and cancer control policies.However,the stage distribution for liver cancer in China was not well studied.In this multi-center hospital-based study,we aimed to identify the distribution and factors associated with stage at diagnosis for liver cancer in China.Methods:We included patients diagnosed with primary liver cancer in 13 hospitals of 10 provinces covering various geographic and socioeconomic populations during 2016-2017 in China.The stage distribution overall,and by sex and age at diagnosis were analyzed.We used logistic regression to identify the factors associated with stage Ⅲ-Ⅳ disease.We further compared these estimates with data from the USA.Results:We included 2,991 patients with known stage at diagnosis in China.The proportion of patients diagnosed with stageⅠ,Ⅱ,Ⅲ,and Ⅳ was 17.5%,25.6%,29.3%,and 27.6%,respectively.The proportion of stage Ⅲ-Ⅳ cases was higher in women[65.1%vs 54.9%,adjusted odds ratio(OR)=1.5,95%CI:1.2,1.8]and those≥60 years(61.6%vs 52.8%,OR=1.4,95%CI:1.2,1.6).We found an increased risk of stage Ⅲ-Ⅳ among drinkers and those without a family history of cancer.Compared to the USA,our study population had a substantially higher proportion of stage Ⅲ-Ⅳ cases(56.9%vs 45.6%).Conclusion:The disparities in liver cancer stage at diagnosis among different populations within China,and between China and the USA,imply the necessity for improving cancer awareness and early detection for liver cancer in China.展开更多
Dear Editor,Prostate cancer is the second most common cancer among men worldwide and leading cancer in incidence among men in the United States(US).In 2018,the US had over 190,000 new prostate cancer cases,accounting ...Dear Editor,Prostate cancer is the second most common cancer among men worldwide and leading cancer in incidence among men in the United States(US).In 2018,the US had over 190,000 new prostate cancer cases,accounting for almost 1 in 5 new male cancer diagnoses[1].A recent review of dietary factors in relation to prostate cancer risk did not find evidence regarding nut consumption as neither a risk nor protective factor,though it has been hypothesized to be associated with a decreased cancer risk through multi-ple mechanisms[2].展开更多
Pancreatic cancer is a fatal malignancy with an increasing incidence in Shanghai, China. A genomewide association study(GWAS) and other work have shown that ABO alleles are associated with pancreatic cancer risk. We c...Pancreatic cancer is a fatal malignancy with an increasing incidence in Shanghai, China. A genomewide association study(GWAS) and other work have shown that ABO alleles are associated with pancreatic cancer risk. We conducted a population-based case-control study involving 256 patients with pathologically confirmed pancreatic ductal adenocarcinoma(PDAC) and 548 healthy controls in Shanghai, China, to assess the relationships between GWAS-identified ABO alleles and risk of PDAC. Carriers of the C allele of rs505922 had an increased cancer risk [adjusted odds ratio(OR) = 1.42, 95% confidence interval(CI): 1.02-1.98] compared to TT carriers. The T alleles of rs495828 and rs657152 were also significantly associated with an elevated cancer risk(adjusted OR = 1.58, 95% CI: 1.17-2.14; adjusted OR = 1.51, 95% CI: 1.09-2.10). The rs630014 variant was not associated with risk. We did not find any significant gene-environment interaction with cancer risk using a multifactor dimensionality reduction(MDR) method. Haplotype analysis also showed that the haplotype CTTC was associated with an increased risk of PDAC(adjusted OR = 1.46, 95% CI: 1.12-1.91) compared with haplotype TGGT. GWAS-identified ABO variants are thus also associated with risk of PDAC in the Chinese population.展开更多
Objective Most acute promyelocytic leukemia cases are characterized by the PML-RARa fusion oncogene and low white cell counts in peripheral blood.Methods Based on the frequent overexpression of miR-125-family miRNAs i...Objective Most acute promyelocytic leukemia cases are characterized by the PML-RARa fusion oncogene and low white cell counts in peripheral blood.Methods Based on the frequent overexpression of miR-125-family miRNAs in acute promyelocytic leukemia,we examined the consequence of this phenomenon by using an inducible mouse model overexpressing human miR-125b.Results MiR-125b expression significantly accelerates PML-RARa-induced leukemogenesis,with the resultant induced leukemia being partially dependent on continued miR-125b overexpression.Interestingly,miR-125b expression led to low peripheral white cell counts to bone marrow blast percentage ratio,confirming the clinical observation in acute promyelocytic leukemia patients.Conclusion This study suggests that dysregulated miR-125b expression is actively involved in disease progression and pathophysiology of acute promyelocytic leukemia,indicating that targeting miR-125b may represent a new therapeutic option for acute promyelocytic leukemia.展开更多
The brain tumor perivascular niche(PVN),the region in the vicinity of microvessels is a prime location for brain tumor stem-like cells(BTSCs)[1].Tumor microvasculature creates a complex microenvironment consisting of ...The brain tumor perivascular niche(PVN),the region in the vicinity of microvessels is a prime location for brain tumor stem-like cells(BTSCs)[1].Tumor microvasculature creates a complex microenvironment consisting of various cell types,the extracellular matrix,and soluble factors that mediate cell-cell interaction.The brain tumor PVN controls maintenance,expansion,and differentiation of BTSCs via direct cell contact or paracrine signaling cues.BTSCs often receive bidirectional crosstalk from endothelial cells and other cell types in the niche[2].In addition,the perivascular zone may serve as a path for tumor cells to migrate over long distances(3,4)Unlike other solid tumors,glioblastoma multiforme(GBM)cells rarely metastasize to other organs,but they can invade the entire brain by migrating along specific brain tissue structures,such as blood vessels or white matter tracts,leading to high rates of relapse.Despite the success in modeling diffuse brain tumors in both genetically-modified and patient-derived xenograft(PDX)animals,there is an unmet need for an in vitro system that can bridge conventional cell culture and animal models by mimicking not only the anatomy but also the function of the PVN to study the dynamics of BTSCs.In this presentation,I will describe the use of a microvasculature-on-a-chip system as a PVN model to evaluate the dynamics of BTSCs ex vivo from 10 glioblastoma patients [5].We observed that BTSCs preferentially localize in the perivascular zone.Live cell tracking showed that the cells residing in the vicinity of microvessels had the lowest motility,while a fraction of cells on the microvessels unexpectedly possessed the highest motility and migrated over the longest distance.These results indicate that the perivascular zone is a niche for BTSCs,while the microvascular tracks are also a path for long-distance tumor cell migration and invasion.Additionally,the degree of co-localization between tumor cells and microvessels varied significantly across patients.To validate the results from our microvasculature-on-a-chip system,we used single-cell transcriptome sequencing(10 patients and 21,750 single cells in total)to identify the subtype of each tumor cell.The co-localization coefficient was found to correlate positively with proneural(stem-like)or mesenchymal(invasive)but not classical(proliferative)tumor cells.Furthermore,we found that a gene signature profile including PDGFRA correlated strongly with the'homing'of brain tumor cells to the PVN.Our findings demonstrated that ex vivo dynamics of human brain tumor cells in a microvasculature-on-a-chip model can recapitulate in vivo tumor cell dynamics,heterogeneity,and subtypes,representing a new route to the study of human tumor cell biology and uncover patient-specific tumor cell functions.Acknowledgments:We thank Drs.Laura Niklason,Eric Holland,Franziska Michor,and Frank Szulzewsky for scientific discussion.We thank Misha Guy,Vladimir Polejaev,Zhenting Jiang,and Alice Yun for suggestions and help on the simulation computing and SEM/confocal imaging process.This research was supported by the Packard Fellowship for Science and Engineering(R.F.),National Science Foundation CAREER Award CBET-1351443(R.F.),U54 CA193461(R.F.),U54CA209992(Sub-Project ID:7297 to R.F.),R01 NS095817(J.Z.),Yale Cancer Center Co-Pilot Grant(to R.F.).The molds for microfluidic devices were fabricated in the Yale School of Engineering and Applied Science cleanroom.Sequencing was performed at the Yale Center for Genome Analysis(YCGA)facility.Data was analyzed at Yale High Performance Computing(HPC)center.Super resolution confocal imaging was performed at Yale Center for Cellular and Molecular Imaging(CCMI).展开更多
Rapid growth in biomedical research coupled with dramatic advancement in biotechnology has signi fi cantly improved our understanding of the molecular basis involving cancer development and progression. This improveme...Rapid growth in biomedical research coupled with dramatic advancement in biotechnology has signi fi cantly improved our understanding of the molecular basis involving cancer development and progression. This improvement has led to the discovery of new molecular markers for cancer diagnosis and prognosis as well as new molecular targets for cancer treatment and intervention. Continuous emergence of some new developing area in molecular profi ling, new therapeutic agents, tissue microenvironment and systems biology have made signifi cant progress in clinical oncology. Clinical research and investi-gation that focus on these new developments have begun to show exciting results that indicate future promises in improving patient management and survival.展开更多
Background:Hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(ICC)are the most common subtypes of primary liver cancer,but nationwide incidence of both liver cancer subtypes have never been reported in C...Background:Hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(ICC)are the most common subtypes of primary liver cancer,but nationwide incidence of both liver cancer subtypes have never been reported in China.We aimed to estimate the most recent incidence of HCC and ICC and temporal trends in China based on the most updated data from high qualified population-based cancer registries(covering 13.1%of the national population),in comparison to those in the United States at the same period.Methods:We used data from 188 Chinese population-based cancer registries covering 180.6 million population of China to estimate the nationwide incidence of HCC and ICC in 2015.And 22 population-based cancer registries’data were used to estimate the trends of HCC and ICC incidence from 2006 to 2015.Multiple imputation by chained equations method was used to impute liver cancer cases with unknown subtype(50.8%).We used data from 18 population-based registries from the Surveillance,Epidemiology,and End Results program to analyze incidence of HCC and ICC in the United States.Results:In China,an estimated 301,500 and 61,900 newly diagnosed HCC and ICC occurred in 2015.The overall age-standardized rates(ASRs)of HCC incidence decreased by 3.9%per year.For ICC incidence,the overall ASR was relatively stable,but increased in the population of over 65 years old.Subgroup analysis by age showed that the ASR of HCC incidence had the sharpest decline in population who were less than 14 years old and received neonatally hepatitis B virus(HBV)vaccination.In the United States,though the incidence of HCC and ICC were lower than those in China,the overall HCC and ICC incidence increased by 3.3%and 9.2%per year.Conclusions:China still faces with a heavy burden of liver cancer incidence.Our results may further support the beneficial effect of Hepatitis B vaccination on reduction of HCC incidence.Both healthy lifestyle promotion and infection control are needed for future liver cancer control and prevention for China and the United States.展开更多
In the past decade,chimeric antigen receptor(CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers,demonstrating remarkable efficacy in relapsed/refractory hematological malig...In the past decade,chimeric antigen receptor(CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers,demonstrating remarkable efficacy in relapsed/refractory hematological malignancies in both pediatric and adult patients.CAR-natural killer(CAR-NK)cell complements CAR-T cell therapy by offering several distinct advantages.CAR-NK cells do not require HLA compatibility and exhibit low safety concerns.Moreover,CAR-NK cells are conducive to“off-the-shelf”therapeutics,providing significant logistic advantages over CAR-T cells.Both CAR-T and CAR-NK cells have shown consistent and promising results in hematological malignancies.However,their efficacy against solid tumors remains limited due to various obstacles including limited tumor trafficking and infiltration,as well as an immuno-suppressive tumor microenvironment.In this review,we discuss the recent advances and current challenges of CAR-T and CAR-NK cell immunotherapies,with a specific focus on the obstacles to their application in solid tumors.We also analyze in depth the advantages and drawbacks of CAR-NK cells compared to CAR-T cells and highlight CAR-NK CAR optimization.Finally,we explore future perspectives of these adoptive immunotherapies,highlighting the increasing contribution of cutting-edge biotechnological tools in shaping the next generation of cellular immunotherapy.展开更多
基金Supported by National Natural Science Foundation of China,No.81401947Beijing Nova Program,No.xxjh2015A090Cancer Hospital of the Chinese Academy of Medical Sciences,No.LC2015L11
文摘AIM to evaluate the association of body mass index(b MI) with the overall survival of pancreatic ductal adenocarcinoma(PDAC) patients.METHODS A retrospective analysis of PDAC patients diagnosed in the National Cancer Center of China between January 1999 and December 2014 was performed. these patients were categorized into four b MI groups(< 18.5, 18.5-22.9, 23-27.4 and ≥ 27.5 kg/m2). χ2 tests for comparison of the proportions of categorical variables, and Student's t-test or Mann-Whitney test for continuous variables were employed. Survival analysis was performed with the Kaplan-Meyer method. their HRs of mortality and 95%CIs were estimated using the Cox proportional hazards model.RESULTS With a median age of 59.6 years(range: 22.5-84.6 years), in total 1783 PDAC patients were enrolled in this study. their mean usual b MI was 24.19 ± 3.53 for the whole cohort. More than half of the patients(59.3%) experienced weight loss during the disease onset and progression. Compared with healthy-weight individuals, newly diagnosed patients who were overweight or obese had more severe weight loss during their disease onset and progression(P < 0.001). Individuals who were overweight or obese were associated with positive smoking history(P < 0.001). A significant difference in comorbidity of diabetes(P = 0.044) and coronary artery disease(P < 0.001) was identified between high b MI and normal-weight patients. After a median follow-up of 8 mo, the survival analysis showed no association between b MI and the overall survival(P = 0.90, n = 1783). When we stratified the whole cohort by pancreatic cancer stage, no statistically significant association between b MI and overall survival was found for resectable(P = 0.99, n = 217), unresectable locally advanced(P = 0.90, n = 316) and metastatic patients(P = 0.88, n = 1250), respectively. the results did not change when we used the b MI at diagnosis.CONCLUSION Our results showed no significance of b MI for the overall survival of PDAC patients.
基金supported in part by the Amway Corporation and by institutional funds from Yale School of Medicine, the University of Colorado School of Medicine, and the Denver Police Crime Lab
文摘This perspective article highlights the leukocyte-cancer cell hybrid theory as a mechanism for cancer metastasis. Beginning from the first proposal of the theory more than a century ago and continuing today with the first proof for this theory in a human cancer, the hybrid theory offers a unifying explanation for metastasis. In this scenario, leukocyte fusion with a cancer cell is a secondary disease superimposed upon the early tumor, giving birth to a new, malignant cell with a leukocyte-cancer cell hybrid epigenome.
文摘We report a case of pseudocirrhosis arising in the setting of regression of liver metastases from pancreatic cancer. A 55-year-old asymptomatic woman presented to our clinic with newly diagnosed metastatic pancreatic cancer with extensive liver metastases. She underwent systemic chemotherapy with gemcitabine and oxaliplatin (GEMOX). After 8 cycles of therapy, she had a remarkable response to the therapy evidenced by decline of carcinoembryonic antigen (CEA) and CA19 by > 50% and nearly complete resolution of hepatic metastases in computed tomography (CT) scan. Shortly after, she developed increasing bilateral ankle edema and ascites, associated with dyspnea, progressive weight gain, and declining performance status. Gemcitabine and oxaliplatin were discontinued as other causes of her symptoms such as congestive heart disease or venous thrombosis were ruled out. CT scan 6 mo after the initiation of GEMOX revealed worsening ascites with a stable pancreatic mass. However, it also revealed a lobular hepatic contour, segmental atrophy, and capsular retraction mimicking the appearance of cirrhosis. She was managed with aggressive diuresis and albumin infusions which eventually resulted in a resolution of the above- mentioned symptoms as well as complete resolution of pseudocirrhotic appearance of the liver and ascites in CT scan. This case demonstrates that pancreatic cancer patients can develop pseudocirrhosis. Clinicians and radiologist should be well aware of this entity asearly recognition and management can lead to a near complete recovery of liver function and much improved quality of life as illustrated in this case.
文摘There are differences between African-American and white patients with colorectal cancer, concerning their characteristics before and after diagnosis. Whites are more likely to adhere to screening guidelines. This is also the case among people with positive family history. Colorectal cancer is more frequent in Blacks. Studies have shown that that since 1985, colon cancer rates have dipped 20% to 25% for Whites, while rates have gone up for African-American men and stayed the same for African-American women. Overall, African-Americans are 38% to 43% more likely to die from colon cancer than are Whites. Furthermore, it seems that there is an African-American predominance in right-sited tumors. African Americans tend to be diagnosed at a later stage, to suffer from better differentiated tumors, and to have worse prognosis when compared with Whites. Moreover, less black patients receive adjuvant chemotherapy for resectable colorectal cancer or radiation therapy for rectal cancer. Caucasians seem to respond better to standard chemotherapy regimens than AfricanAmericans. Concerning toxicity, it appears that patients of African-American descent are more likely to develop 5-FU toxicity than Whites, possibly because of their different dihydropyridine dehydrogenase status. Last but not least, screening surveillance seems to be higher among white than among black long-term colorectal cancer survivors. Socioeconomic and educational status account for most of these differences whereas little evidence exists for a genetic contribution in racial disparity. Understanding the nature of racial differences in colorectal cancer allows tailoring of screening and treatment interventions.
文摘Cancer stem cells(CSC) are thought to be malignant cells that have the capacity to initiate and maintain tumor growth and survival. Studies have described CSC in various gastrointestinal neoplasms such as colon, pancreas and liver and gastroesophageal tumors. The mechanism by which CSC develop remains unclear. Several studies have explored the role of dysregulation of the Wnt/β-catenin, transformation growth factor-beta and hedhog pathways in generation of CSC. In this review, we discuss the various molecular abnormalities that may be related to formation of CSC in gastrointestinal malignancies, strategies to identify CSC and therapeutic strategies that are based on these concepts. Identification and targeting CSC is an intriguing area and may provide a new therapeutic option for patients with cancer including gastrointestinal malignancies. Although great progress has been made, many issues need to be addressed. Precise targeting of CSC will require precise isolation and characterization of those cells. This field is also evolving but further research is needed to identify markers that are specific for CSC.Although the application of this field has not entered the clinic yet, there continues to be significant optimism about its potential utility in overcoming cancer resistance and curing patients with cancer.
文摘Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation,repair and regeneration.Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations.Factors that stimulate cell fusion are inflammation and hypoxia.Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes,e.g.,reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition.There is now considerable in vitro,in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis.Of the many changes in cancer cells after hybridizing with leucocytes,it is notable that hybrids acquire resistance to chemo-and radiation therapy.One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization.Regardless of the mechanism of polyploid cell formation,it happens in response to genotoxic stresses and enhances a cancer cell’s ability to survive.Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis.In addition,we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors.
文摘Surgery is the only curative option for patients with liver metastases of colorectal cancer, but few patients present with resectable hepatic lesions. Chemotherapy is increasingly used to downstage initially unresectable disease and allow for potentially curative surgery. Standard chemotherapy regimens convert 10%-20% of cases to resectable disease in unselected populations and 30%-40% of those with disease confined to the liver. One strategy to further increase the number of candidates eligible for surgery is the addition of active targeted agents such as cetuximab and bevacizumab to standard chemotherapy. Data from a phase Ⅲ trial indicate that cetuximab increases the number of patients eligible for secondary hepatic resection, as well as the rate of complete resection when combined with first-line treatment with the FOLFIRI regimen. The safety profiles of preoperative cetuximab or bevacizumab have not been thoroughly assessed, but preliminary evidence indicates that these agents do not increase surgical mortality or exacerbate chemotherapyrelated hepatotoxicity, such as steatosis （5-fluorouracil）, steatohepatitis （irinotecan）, and sinusoidal obstruction （oxaliplatin）. Secondary resection is a valid treatment goal for certain patients with initially unresectable liver metastases and an important end point for future clinical trials.
文摘In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer （CRPC） have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for the development of new drugs to target prostate cancer, and our understanding of genetic mutations may give us new tools with which to more accurately diagnose and be able to predict the course of this heterogeneous disease. This article summarizes the recent advances in the understanding of the development of CRPC, as well as the new drugs and targets, which have evolved from this basic research.
基金supported by the National Key R&D Program of China(grant numbers:2022YFC3600805,2016YFC1302502).
文摘Background:The stage at diagnosis is a major factor in making treatment strategies and cancer control policies.However,the stage distribution for liver cancer in China was not well studied.In this multi-center hospital-based study,we aimed to identify the distribution and factors associated with stage at diagnosis for liver cancer in China.Methods:We included patients diagnosed with primary liver cancer in 13 hospitals of 10 provinces covering various geographic and socioeconomic populations during 2016-2017 in China.The stage distribution overall,and by sex and age at diagnosis were analyzed.We used logistic regression to identify the factors associated with stage Ⅲ-Ⅳ disease.We further compared these estimates with data from the USA.Results:We included 2,991 patients with known stage at diagnosis in China.The proportion of patients diagnosed with stageⅠ,Ⅱ,Ⅲ,and Ⅳ was 17.5%,25.6%,29.3%,and 27.6%,respectively.The proportion of stage Ⅲ-Ⅳ cases was higher in women[65.1%vs 54.9%,adjusted odds ratio(OR)=1.5,95%CI:1.2,1.8]and those≥60 years(61.6%vs 52.8%,OR=1.4,95%CI:1.2,1.6).We found an increased risk of stage Ⅲ-Ⅳ among drinkers and those without a family history of cancer.Compared to the USA,our study population had a substantially higher proportion of stage Ⅲ-Ⅳ cases(56.9%vs 45.6%).Conclusion:The disparities in liver cancer stage at diagnosis among different populations within China,and between China and the USA,imply the necessity for improving cancer awareness and early detection for liver cancer in China.
基金supported in part by the Intramural Research Program of the US National Institutes of Health,National Cancer Institute.
文摘Dear Editor,Prostate cancer is the second most common cancer among men worldwide and leading cancer in incidence among men in the United States(US).In 2018,the US had over 190,000 new prostate cancer cases,accounting for almost 1 in 5 new male cancer diagnoses[1].A recent review of dietary factors in relation to prostate cancer risk did not find evidence regarding nut consumption as neither a risk nor protective factor,though it has been hypothesized to be associated with a decreased cancer risk through multi-ple mechanisms[2].
基金supported by the U.S.National Cancer Institute(5R01CA114421)the Science and Technology Commission of the Shanghai Municipality(08411954100)
文摘Pancreatic cancer is a fatal malignancy with an increasing incidence in Shanghai, China. A genomewide association study(GWAS) and other work have shown that ABO alleles are associated with pancreatic cancer risk. We conducted a population-based case-control study involving 256 patients with pathologically confirmed pancreatic ductal adenocarcinoma(PDAC) and 548 healthy controls in Shanghai, China, to assess the relationships between GWAS-identified ABO alleles and risk of PDAC. Carriers of the C allele of rs505922 had an increased cancer risk [adjusted odds ratio(OR) = 1.42, 95% confidence interval(CI): 1.02-1.98] compared to TT carriers. The T alleles of rs495828 and rs657152 were also significantly associated with an elevated cancer risk(adjusted OR = 1.58, 95% CI: 1.17-2.14; adjusted OR = 1.51, 95% CI: 1.09-2.10). The rs630014 variant was not associated with risk. We did not find any significant gene-environment interaction with cancer risk using a multifactor dimensionality reduction(MDR) method. Haplotype analysis also showed that the haplotype CTTC was associated with an increased risk of PDAC(adjusted OR = 1.46, 95% CI: 1.12-1.91) compared with haplotype TGGT. GWAS-identified ABO variants are thus also associated with risk of PDAC in the Chinese population.
基金supported in part by NIH grants[R01CA149109,R01GM099811]Connecticut Regenerative Medicine Fund grant[15-RMB-YALE-06]National Clinical Research Center for Geriatric Diseases&Chinese PLA General Hospital grant[NCRCG-PLAGH-2022011]
文摘Objective Most acute promyelocytic leukemia cases are characterized by the PML-RARa fusion oncogene and low white cell counts in peripheral blood.Methods Based on the frequent overexpression of miR-125-family miRNAs in acute promyelocytic leukemia,we examined the consequence of this phenomenon by using an inducible mouse model overexpressing human miR-125b.Results MiR-125b expression significantly accelerates PML-RARa-induced leukemogenesis,with the resultant induced leukemia being partially dependent on continued miR-125b overexpression.Interestingly,miR-125b expression led to low peripheral white cell counts to bone marrow blast percentage ratio,confirming the clinical observation in acute promyelocytic leukemia patients.Conclusion This study suggests that dysregulated miR-125b expression is actively involved in disease progression and pathophysiology of acute promyelocytic leukemia,indicating that targeting miR-125b may represent a new therapeutic option for acute promyelocytic leukemia.
文摘The brain tumor perivascular niche(PVN),the region in the vicinity of microvessels is a prime location for brain tumor stem-like cells(BTSCs)[1].Tumor microvasculature creates a complex microenvironment consisting of various cell types,the extracellular matrix,and soluble factors that mediate cell-cell interaction.The brain tumor PVN controls maintenance,expansion,and differentiation of BTSCs via direct cell contact or paracrine signaling cues.BTSCs often receive bidirectional crosstalk from endothelial cells and other cell types in the niche[2].In addition,the perivascular zone may serve as a path for tumor cells to migrate over long distances(3,4)Unlike other solid tumors,glioblastoma multiforme(GBM)cells rarely metastasize to other organs,but they can invade the entire brain by migrating along specific brain tissue structures,such as blood vessels or white matter tracts,leading to high rates of relapse.Despite the success in modeling diffuse brain tumors in both genetically-modified and patient-derived xenograft(PDX)animals,there is an unmet need for an in vitro system that can bridge conventional cell culture and animal models by mimicking not only the anatomy but also the function of the PVN to study the dynamics of BTSCs.In this presentation,I will describe the use of a microvasculature-on-a-chip system as a PVN model to evaluate the dynamics of BTSCs ex vivo from 10 glioblastoma patients [5].We observed that BTSCs preferentially localize in the perivascular zone.Live cell tracking showed that the cells residing in the vicinity of microvessels had the lowest motility,while a fraction of cells on the microvessels unexpectedly possessed the highest motility and migrated over the longest distance.These results indicate that the perivascular zone is a niche for BTSCs,while the microvascular tracks are also a path for long-distance tumor cell migration and invasion.Additionally,the degree of co-localization between tumor cells and microvessels varied significantly across patients.To validate the results from our microvasculature-on-a-chip system,we used single-cell transcriptome sequencing(10 patients and 21,750 single cells in total)to identify the subtype of each tumor cell.The co-localization coefficient was found to correlate positively with proneural(stem-like)or mesenchymal(invasive)but not classical(proliferative)tumor cells.Furthermore,we found that a gene signature profile including PDGFRA correlated strongly with the'homing'of brain tumor cells to the PVN.Our findings demonstrated that ex vivo dynamics of human brain tumor cells in a microvasculature-on-a-chip model can recapitulate in vivo tumor cell dynamics,heterogeneity,and subtypes,representing a new route to the study of human tumor cell biology and uncover patient-specific tumor cell functions.Acknowledgments:We thank Drs.Laura Niklason,Eric Holland,Franziska Michor,and Frank Szulzewsky for scientific discussion.We thank Misha Guy,Vladimir Polejaev,Zhenting Jiang,and Alice Yun for suggestions and help on the simulation computing and SEM/confocal imaging process.This research was supported by the Packard Fellowship for Science and Engineering(R.F.),National Science Foundation CAREER Award CBET-1351443(R.F.),U54 CA193461(R.F.),U54CA209992(Sub-Project ID:7297 to R.F.),R01 NS095817(J.Z.),Yale Cancer Center Co-Pilot Grant(to R.F.).The molds for microfluidic devices were fabricated in the Yale School of Engineering and Applied Science cleanroom.Sequencing was performed at the Yale Center for Genome Analysis(YCGA)facility.Data was analyzed at Yale High Performance Computing(HPC)center.Super resolution confocal imaging was performed at Yale Center for Cellular and Molecular Imaging(CCMI).
文摘Rapid growth in biomedical research coupled with dramatic advancement in biotechnology has signi fi cantly improved our understanding of the molecular basis involving cancer development and progression. This improvement has led to the discovery of new molecular markers for cancer diagnosis and prognosis as well as new molecular targets for cancer treatment and intervention. Continuous emergence of some new developing area in molecular profi ling, new therapeutic agents, tissue microenvironment and systems biology have made signifi cant progress in clinical oncology. Clinical research and investi-gation that focus on these new developments have begun to show exciting results that indicate future promises in improving patient management and survival.
基金The funding resources of this study were National Key R&D Program of China(2016YFC1302502,2017YFC0908103)Major State Basic Innovation Program of the Chinese Academy of Medical Sciences(2019-I2M-2-004).
文摘Background:Hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(ICC)are the most common subtypes of primary liver cancer,but nationwide incidence of both liver cancer subtypes have never been reported in China.We aimed to estimate the most recent incidence of HCC and ICC and temporal trends in China based on the most updated data from high qualified population-based cancer registries(covering 13.1%of the national population),in comparison to those in the United States at the same period.Methods:We used data from 188 Chinese population-based cancer registries covering 180.6 million population of China to estimate the nationwide incidence of HCC and ICC in 2015.And 22 population-based cancer registries’data were used to estimate the trends of HCC and ICC incidence from 2006 to 2015.Multiple imputation by chained equations method was used to impute liver cancer cases with unknown subtype(50.8%).We used data from 18 population-based registries from the Surveillance,Epidemiology,and End Results program to analyze incidence of HCC and ICC in the United States.Results:In China,an estimated 301,500 and 61,900 newly diagnosed HCC and ICC occurred in 2015.The overall age-standardized rates(ASRs)of HCC incidence decreased by 3.9%per year.For ICC incidence,the overall ASR was relatively stable,but increased in the population of over 65 years old.Subgroup analysis by age showed that the ASR of HCC incidence had the sharpest decline in population who were less than 14 years old and received neonatally hepatitis B virus(HBV)vaccination.In the United States,though the incidence of HCC and ICC were lower than those in China,the overall HCC and ICC incidence increased by 3.3%and 9.2%per year.Conclusions:China still faces with a heavy burden of liver cancer incidence.Our results may further support the beneficial effect of Hepatitis B vaccination on reduction of HCC incidence.Both healthy lifestyle promotion and infection control are needed for future liver cancer control and prevention for China and the United States.
基金SC is supported by the Cancer Research Institute Lloyd J.Old STAR Award(CRI4964),NIH(R33CA281702)DoD(W81XWH-21-1-0514,HT94252310472)Pershing Square Sohn Cancer Research Alliance.
文摘In the past decade,chimeric antigen receptor(CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers,demonstrating remarkable efficacy in relapsed/refractory hematological malignancies in both pediatric and adult patients.CAR-natural killer(CAR-NK)cell complements CAR-T cell therapy by offering several distinct advantages.CAR-NK cells do not require HLA compatibility and exhibit low safety concerns.Moreover,CAR-NK cells are conducive to“off-the-shelf”therapeutics,providing significant logistic advantages over CAR-T cells.Both CAR-T and CAR-NK cells have shown consistent and promising results in hematological malignancies.However,their efficacy against solid tumors remains limited due to various obstacles including limited tumor trafficking and infiltration,as well as an immuno-suppressive tumor microenvironment.In this review,we discuss the recent advances and current challenges of CAR-T and CAR-NK cell immunotherapies,with a specific focus on the obstacles to their application in solid tumors.We also analyze in depth the advantages and drawbacks of CAR-NK cells compared to CAR-T cells and highlight CAR-NK CAR optimization.Finally,we explore future perspectives of these adoptive immunotherapies,highlighting the increasing contribution of cutting-edge biotechnological tools in shaping the next generation of cellular immunotherapy.
