There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades.While immunothe...There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades.While immunotherapy with checkpoint inhibitors has revolutionized the treatment of urothelial carcinoma,unfortunately,only a minority of patients respond to immunotherapy.Treatment options for patients who do not respond and/or progress on immunotherapy are very limited and overall prognosis remains dismal in metastatic urothelial carcinoma.The first targeted therapy targeting the fibroblast growth factor receptor(FGFR)was recently approved for bladder cancer,but it is effective only in select patients harboring the FGFR2 and FGFR 3 mutations.Antibody drug conjugates like enfortumab vedotin have shown promising activity in clinical trials.Development of novel targeted therapies remains an area of investigation and an unmet need in bladder cancer.Exploitation of androgen receptor(AR)is a potential strategy for targeted drug development in bladder cancer.A significant proportion of urothelial carcinoma patients express AR irrespective of gender.AR signaling in urothelial carcinoma has been linked to progression through multiple mechanisms,including activation of human epidermal growth factor receptor-2(EGFR or HER-2)signaling and epithelial to mesenchymal transition(EMT).Furthermore,AR is enriched in the luminal papillary mRNA subtype of urothelial carcinoma and also mediates resistance to cisplatin-based chemotherapy.Preclinical evidence suggests that AR inhibition can successfully inhibit urothelial carcinoma growth as monotherapy and is synergistic with cisplatin-based chemotherapy.We review the preclinical and clinical evidence supporting the putative role of AR signaling in urothelial carcinoma pathogenesis,progression and its role as a novel therapeutic target and future directions.展开更多
Acute myeloid leukemia(AML) is a clonal disorder characterized by the accumulation of complex genomic alterations that define the disease pathophysiology and overall outcome. Recent advances in sequencing technologies...Acute myeloid leukemia(AML) is a clonal disorder characterized by the accumulation of complex genomic alterations that define the disease pathophysiology and overall outcome. Recent advances in sequencing technologies have described the molecular landscape of AML and identified several somatic alterations that impact overall survival. Despite all these advancement, several challenges remain in translating this information into effective therapy. Herein we will review the molecular landscape of AML and discuss the impact of the most common somatic mutations on disease biology and outcome.展开更多
BACKGROUND Epstein-Barr virus associated smooth muscle tumor(EBV-SMT)is a rare oncological entity.However,there is an increasing incidence of EBV-SMTs,as the frequency of organ transplantation and immunosuppression gr...BACKGROUND Epstein-Barr virus associated smooth muscle tumor(EBV-SMT)is a rare oncological entity.However,there is an increasing incidence of EBV-SMTs,as the frequency of organ transplantation and immunosuppression grows.EBV-SMT diagnosis relies on histopathology and immunochemical staining to distinguish it from post-transplant lymphoproliferative disorder(PTLD).There is no clear consensus on the treatment of EBV-SMTs.However,surgical resection,chemotherapy,radiation therapy,and immunosuppression reduction have been explored with varying degrees of success.CASE SUMMARY Our case series includes six cases of EBV-SMTs across different age groups,with different treatment modalities,adding to the limited existing literature on this rare tumor.The median latency time between immunosuppression and disease diagnosis is four years.EBV-SMTs present with variable degrees of aggressiveness and seem to have worse clinical outcomes in patients with tumor multiplicity and worse immunocompetency.CONCLUSION It is imperative to continue building on this knowledge and keeping EBV-SMTs on the differential in immunocompromised individuals.展开更多
BACKGROUND In patients undergoing peritoneal dialysis(PD),catheter dysfunction is a common complication.A misplaced catheter is one of the reasons contributing to its dysfunction.The present study aimed to describe a ...BACKGROUND In patients undergoing peritoneal dialysis(PD),catheter dysfunction is a common complication.A misplaced catheter is one of the reasons contributing to its dysfunction.The present study aimed to describe a case of misplaced PD catheter with an unusual location of the catheter tip.CASE SUMMARY A 61-year-old man undergoing PD for 4 years was investigated for progressive nausea and fatigue of 3 mo.Dialysis adequacy studies indicated inefficient dialysis.Imaging discovered that the PD catheter tip was mispositioned in the pelvic cavity with its tip outside the peritoneal cavity.Despite the dialysate accumulating outside the peritoneal cavity,the patient had not developed perineal or scrotal edema.The patient had experienced a sustainable prolonged dialysis efficacy in this case until the renal function deteriorated further in view of the poor dialysis outcome and worsening health condition.The patient was subsequently transitioned to hemodialysis.CONCLUSION Proper placement of the catheter in the peritoneal cavity should always be confirmed and rechecked when necessary in patients undergoing PD to ensure dialytic adequacy.展开更多
Background and Aim:Inflammatory bowel disease(IBD)is associated with an increased risk of colorectal cancer(CRC).Studies have shown tumorigenetic and histomorphological differences between IBD-associated CRC and non-I...Background and Aim:Inflammatory bowel disease(IBD)is associated with an increased risk of colorectal cancer(CRC).Studies have shown tumorigenetic and histomorphological differences between IBD-associated CRC and non-IBD CRC,suggesting differences in tumor behavior and response to treatment.We aimed to compare tumor recurrence and survival rates following postoperative chemotherapy in CRC patients with and without IBD.Methods:Search of the Cleveland Clinic’s CRC database revealed 65 patients who had IBD-associated CRC and received postoperative adjuvant chemotherapy between 1994 and 2010.Twenty-one patients were excluded due to incomplete clinical data.Propensity score-matching based on age,surgery intent,CRC site,tumor grade,American Joint Committee on Cancer(AJCC)stage and T stage was used to match IBD and non-IBD patients(1:4).Competing risk and Cox regression models were used to analyze differences in disease-free survival and overall survival,respectively.Results:Forty-four patients with IBD-associated CRC were matched to 176 patients with non-IBD CRC.Among IBD patients,29(66%)had ulcerative colitis,14(32%)had Crohn’s disease,and one(2%)had indeterminate colitis.Mean IBD diagnosis age was 28.1±14.5 years,and mean IBD duration at time of CRC treatment was 21.5±12.6 years.Ten(23%)IBD patients had tumor recurrence compared with 34(19%)non-IBD patients(P=.074).There was no significant difference in disease-free survival(hazard ratio[HR]=0.60;95%CI:0.35–1.05;P=0.074)or overall survival(HR=0.87;95%CI:0.54–1.4;P=0.58)between IBD and non-IBD patients.Conclusion:Patients with IBD-associated CRC have comparable rates of tumor recurrence and survival following postoperative chemotherapy as CRC patients without IBD.Prospective studies are needed to confirm these findings and guide therapeutic decisions.展开更多
As a dioxygenase. Ten-Eleven Translocation 2 （TET2） catalyzes subsequent steps of 5-methylcytosine （5mC） oxidation. TET2 plays a critical role in the self-renewal, proliferation, and differentiation of hei-natopoi...As a dioxygenase. Ten-Eleven Translocation 2 （TET2） catalyzes subsequent steps of 5-methylcytosine （5mC） oxidation. TET2 plays a critical role in the self-renewal, proliferation, and differentiation of hei-natopoietic stem cells, but its impact on mature hematopoietic cells is not well-characterized. Here we show that Tet2 plays an essential role in osteoclastogenesis. Dele- tion of Tet2 impairs the differentiation of osteoclast precursor cells （macrophages） and their matu- ration into bone-resorbing osteoclasts in vitro. Furthermore, Tet2 / mice exhibit mild osteopetrosis, accompanied by decreased number of osteoclasts in vivo. Tet2 loss in macrophages results in the altered expression of a set of genes implicated in osteoclast differentiation, such as Cehpa, Mafb, and Nfkbiz. Tet2 deletion also leads to a genome-wide alteration in the level of 5-hydroxymethylcytosine （ShmC） and altered expression of a specific subset of macrophage genes associated with osteoclast differentiation. Furthermore, Tet2 interacts with Runxl and negatively modulates its transcriptional activity. Our studies demonstrate a novel molecular mechanism controlling osteoclast differentiation and function by Tet2, that is, through interactions with Runxl and the maintenance of genomie 5hmC. Targeting Tet2 and its pathway could be a potential therapeutic strategy for the prevention and t,＇eatment of abnormal bone mass caused by the deregulation of osteoclast activities.展开更多
Although the natural history of recurrence/progression in patients with intraductal papillary mucinous neoplasms (IPMN) of the pancreas has not been studied thoroughly, the three principal mechanisms have been identif...Although the natural history of recurrence/progression in patients with intraductal papillary mucinous neoplasms (IPMN) of the pancreas has not been studied thoroughly, the three principal mechanisms have been identified: (a) presence of residual disease at the transection margin, (b) presence of intraductal/intraparenchymal metastases and (c) development of new primary lesions. Mechanisms (a) and (b) result in metastatic lesions that are genetically related to the primary, while new primary lesions (mechanism c) are genetically distinct. Interestingly, recurrence/progression in IPMN displays conceptual parallels with the well-established paradigm of disease recurrence in patients with hepatocellular carcinoma (HCC). Specifically, patients with HCC may also develop recurrent tumors due to microscopic residual disease/intrahepatic metastasis which are genetically similar to the primary while the development of genetically unrelated, de novo HCC after curative-intent resection is also common. The latter has been attributed to the presence of a widespread genetic abnormality ( "field defect" ) in the liver (ie, cirrhosis). Given the conceptual similarities between IPMN and HCC, a pancreatic "field defect" may also be hypothesized to exist. This review does not suggest that HCC and IPMN have identical pathogeneses, but rather that they have conceptual similarities in tumor recurrence/progression;thus, lessons learned from HCC could be applied to IPMN research and subsequent management. Conceptual similarities in tumor progression and recurrence may also be observed between IPMN and other malignancies. However, HCC was selected because it is well studied and can serve as a paradigm.展开更多
Hepatocellular carcinoma(HCC)represents a leading cause of cancer-related mortality globally.Due to frequently complex disease presentation and comorbid underlying cirrhosis,many patients are not ideal candidates for ...Hepatocellular carcinoma(HCC)represents a leading cause of cancer-related mortality globally.Due to frequently complex disease presentation and comorbid underlying cirrhosis,many patients are not ideal candidates for surgical resection,transplantation,or other local ablative treatments.External beam radiation therapy(EBRT)has emerged as a promising alternative.EBRT has gained prominence due to advancements in targeting and treatment delivery technology.Advanced modalities such as intensity-modulated radiotherapy(IMRT),image-guided radiotherapy(IGRT),stereotactic body radiation therapy(SBRT),and proton beam therapy(PBT)have dramatically improved the precision of radiation delivery,resulting in a far more favorable therapeutic ratio.Here we cover the evolution of current practice and future prospects of EBRT in treating HCC,emphasizing the enhanced efficacy and reduced toxicity provided by these advanced technologies,and improved integration with other loco-regional and systemic therapies in reviewing the current indications for treatment.展开更多
文摘There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades.While immunotherapy with checkpoint inhibitors has revolutionized the treatment of urothelial carcinoma,unfortunately,only a minority of patients respond to immunotherapy.Treatment options for patients who do not respond and/or progress on immunotherapy are very limited and overall prognosis remains dismal in metastatic urothelial carcinoma.The first targeted therapy targeting the fibroblast growth factor receptor(FGFR)was recently approved for bladder cancer,but it is effective only in select patients harboring the FGFR2 and FGFR 3 mutations.Antibody drug conjugates like enfortumab vedotin have shown promising activity in clinical trials.Development of novel targeted therapies remains an area of investigation and an unmet need in bladder cancer.Exploitation of androgen receptor(AR)is a potential strategy for targeted drug development in bladder cancer.A significant proportion of urothelial carcinoma patients express AR irrespective of gender.AR signaling in urothelial carcinoma has been linked to progression through multiple mechanisms,including activation of human epidermal growth factor receptor-2(EGFR or HER-2)signaling and epithelial to mesenchymal transition(EMT).Furthermore,AR is enriched in the luminal papillary mRNA subtype of urothelial carcinoma and also mediates resistance to cisplatin-based chemotherapy.Preclinical evidence suggests that AR inhibition can successfully inhibit urothelial carcinoma growth as monotherapy and is synergistic with cisplatin-based chemotherapy.We review the preclinical and clinical evidence supporting the putative role of AR signaling in urothelial carcinoma pathogenesis,progression and its role as a novel therapeutic target and future directions.
文摘Acute myeloid leukemia(AML) is a clonal disorder characterized by the accumulation of complex genomic alterations that define the disease pathophysiology and overall outcome. Recent advances in sequencing technologies have described the molecular landscape of AML and identified several somatic alterations that impact overall survival. Despite all these advancement, several challenges remain in translating this information into effective therapy. Herein we will review the molecular landscape of AML and discuss the impact of the most common somatic mutations on disease biology and outcome.
文摘BACKGROUND Epstein-Barr virus associated smooth muscle tumor(EBV-SMT)is a rare oncological entity.However,there is an increasing incidence of EBV-SMTs,as the frequency of organ transplantation and immunosuppression grows.EBV-SMT diagnosis relies on histopathology and immunochemical staining to distinguish it from post-transplant lymphoproliferative disorder(PTLD).There is no clear consensus on the treatment of EBV-SMTs.However,surgical resection,chemotherapy,radiation therapy,and immunosuppression reduction have been explored with varying degrees of success.CASE SUMMARY Our case series includes six cases of EBV-SMTs across different age groups,with different treatment modalities,adding to the limited existing literature on this rare tumor.The median latency time between immunosuppression and disease diagnosis is four years.EBV-SMTs present with variable degrees of aggressiveness and seem to have worse clinical outcomes in patients with tumor multiplicity and worse immunocompetency.CONCLUSION It is imperative to continue building on this knowledge and keeping EBV-SMTs on the differential in immunocompromised individuals.
基金National Natural Science Foundation of China,No.81900692.
文摘BACKGROUND In patients undergoing peritoneal dialysis(PD),catheter dysfunction is a common complication.A misplaced catheter is one of the reasons contributing to its dysfunction.The present study aimed to describe a case of misplaced PD catheter with an unusual location of the catheter tip.CASE SUMMARY A 61-year-old man undergoing PD for 4 years was investigated for progressive nausea and fatigue of 3 mo.Dialysis adequacy studies indicated inefficient dialysis.Imaging discovered that the PD catheter tip was mispositioned in the pelvic cavity with its tip outside the peritoneal cavity.Despite the dialysate accumulating outside the peritoneal cavity,the patient had not developed perineal or scrotal edema.The patient had experienced a sustainable prolonged dialysis efficacy in this case until the renal function deteriorated further in view of the poor dialysis outcome and worsening health condition.The patient was subsequently transitioned to hemodialysis.CONCLUSION Proper placement of the catheter in the peritoneal cavity should always be confirmed and rechecked when necessary in patients undergoing PD to ensure dialytic adequacy.
文摘Background and Aim:Inflammatory bowel disease(IBD)is associated with an increased risk of colorectal cancer(CRC).Studies have shown tumorigenetic and histomorphological differences between IBD-associated CRC and non-IBD CRC,suggesting differences in tumor behavior and response to treatment.We aimed to compare tumor recurrence and survival rates following postoperative chemotherapy in CRC patients with and without IBD.Methods:Search of the Cleveland Clinic’s CRC database revealed 65 patients who had IBD-associated CRC and received postoperative adjuvant chemotherapy between 1994 and 2010.Twenty-one patients were excluded due to incomplete clinical data.Propensity score-matching based on age,surgery intent,CRC site,tumor grade,American Joint Committee on Cancer(AJCC)stage and T stage was used to match IBD and non-IBD patients(1:4).Competing risk and Cox regression models were used to analyze differences in disease-free survival and overall survival,respectively.Results:Forty-four patients with IBD-associated CRC were matched to 176 patients with non-IBD CRC.Among IBD patients,29(66%)had ulcerative colitis,14(32%)had Crohn’s disease,and one(2%)had indeterminate colitis.Mean IBD diagnosis age was 28.1±14.5 years,and mean IBD duration at time of CRC treatment was 21.5±12.6 years.Ten(23%)IBD patients had tumor recurrence compared with 34(19%)non-IBD patients(P=.074).There was no significant difference in disease-free survival(hazard ratio[HR]=0.60;95%CI:0.35–1.05;P=0.074)or overall survival(HR=0.87;95%CI:0.54–1.4;P=0.58)between IBD and non-IBD patients.Conclusion:Patients with IBD-associated CRC have comparable rates of tumor recurrence and survival following postoperative chemotherapy as CRC patients without IBD.Prospective studies are needed to confirm these findings and guide therapeutic decisions.
基金supported by grants from the National Institutes of Health (Grant No. CA172408 to MX and FCY, Grant No. HL112294 to MX)the Leukemia & Lymphoma Society (LLS) (SCOR program to SN, FCY, and MX+7 种基金 translational grant to SN)University of Miami Sylvester Comprehensive Cancer Center (SCCC to MX and FCY), the United Statessupported by the Ministry of Science and Technology of China (Grant Nos. 2017YFA0103402to WY)National Natural Science Foundation of China (Grant Nos. 81629001 to MX, 81670102 to ZZ, 81600136 to YC, and 81421002 to WY)CAMS Innovation Fund for Medical Sciences (Grant Nos. 2017-I2M-3-015 to WY and 2016-I2M-1-017 to YC)Tianjin Application Foundation and Advanced Technology Research Program (Grant Nos. 16JCYBJC25200 to ZZ and 17JCQNJC09800 to YC)SKLEH-Pilot Research Grand (Grant No. ZK16-3 to ZZ)Peking Union Medical College Youth Fund (Grant No. 3332016092 to YC), China
文摘As a dioxygenase. Ten-Eleven Translocation 2 （TET2） catalyzes subsequent steps of 5-methylcytosine （5mC） oxidation. TET2 plays a critical role in the self-renewal, proliferation, and differentiation of hei-natopoietic stem cells, but its impact on mature hematopoietic cells is not well-characterized. Here we show that Tet2 plays an essential role in osteoclastogenesis. Dele- tion of Tet2 impairs the differentiation of osteoclast precursor cells （macrophages） and their matu- ration into bone-resorbing osteoclasts in vitro. Furthermore, Tet2 / mice exhibit mild osteopetrosis, accompanied by decreased number of osteoclasts in vivo. Tet2 loss in macrophages results in the altered expression of a set of genes implicated in osteoclast differentiation, such as Cehpa, Mafb, and Nfkbiz. Tet2 deletion also leads to a genome-wide alteration in the level of 5-hydroxymethylcytosine （ShmC） and altered expression of a specific subset of macrophage genes associated with osteoclast differentiation. Furthermore, Tet2 interacts with Runxl and negatively modulates its transcriptional activity. Our studies demonstrate a novel molecular mechanism controlling osteoclast differentiation and function by Tet2, that is, through interactions with Runxl and the maintenance of genomie 5hmC. Targeting Tet2 and its pathway could be a potential therapeutic strategy for the prevention and t,＇eatment of abnormal bone mass caused by the deregulation of osteoclast activities.
基金This work was financially supported by the NIH/NCI Cancer Center Support(No. P30 CA008748)
文摘Although the natural history of recurrence/progression in patients with intraductal papillary mucinous neoplasms (IPMN) of the pancreas has not been studied thoroughly, the three principal mechanisms have been identified: (a) presence of residual disease at the transection margin, (b) presence of intraductal/intraparenchymal metastases and (c) development of new primary lesions. Mechanisms (a) and (b) result in metastatic lesions that are genetically related to the primary, while new primary lesions (mechanism c) are genetically distinct. Interestingly, recurrence/progression in IPMN displays conceptual parallels with the well-established paradigm of disease recurrence in patients with hepatocellular carcinoma (HCC). Specifically, patients with HCC may also develop recurrent tumors due to microscopic residual disease/intrahepatic metastasis which are genetically similar to the primary while the development of genetically unrelated, de novo HCC after curative-intent resection is also common. The latter has been attributed to the presence of a widespread genetic abnormality ( "field defect" ) in the liver (ie, cirrhosis). Given the conceptual similarities between IPMN and HCC, a pancreatic "field defect" may also be hypothesized to exist. This review does not suggest that HCC and IPMN have identical pathogeneses, but rather that they have conceptual similarities in tumor recurrence/progression;thus, lessons learned from HCC could be applied to IPMN research and subsequent management. Conceptual similarities in tumor progression and recurrence may also be observed between IPMN and other malignancies. However, HCC was selected because it is well studied and can serve as a paradigm.
文摘Hepatocellular carcinoma(HCC)represents a leading cause of cancer-related mortality globally.Due to frequently complex disease presentation and comorbid underlying cirrhosis,many patients are not ideal candidates for surgical resection,transplantation,or other local ablative treatments.External beam radiation therapy(EBRT)has emerged as a promising alternative.EBRT has gained prominence due to advancements in targeting and treatment delivery technology.Advanced modalities such as intensity-modulated radiotherapy(IMRT),image-guided radiotherapy(IGRT),stereotactic body radiation therapy(SBRT),and proton beam therapy(PBT)have dramatically improved the precision of radiation delivery,resulting in a far more favorable therapeutic ratio.Here we cover the evolution of current practice and future prospects of EBRT in treating HCC,emphasizing the enhanced efficacy and reduced toxicity provided by these advanced technologies,and improved integration with other loco-regional and systemic therapies in reviewing the current indications for treatment.
