Specificity protein(Sp)transcription factors(TFs)Sp1,Sp3 and Sp4,and the orphan nuclear receptor 4A1(NR4A1)are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patien...Specificity protein(Sp)transcription factors(TFs)Sp1,Sp3 and Sp4,and the orphan nuclear receptor 4A1(NR4A1)are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patient survival.Results of knockdown and overexpression of Sp1,Sp3 and Sp4 in pancreatic and other cancer lines show that these TFs are individually pro-oncogenic factors and loss of one Sp TF is not compensated by other members.NR4A1 is also a prooncogenic factor and both NR4A1 and Sp TFs exhibit similar functions in pancreatic cancer cells and regulate cell growth,survival,migration and invasion.There is also evidence that Sp TFs and NR4A1 regulate some of the same genes including survivin,epidermal growth factor receptor,PAX3-FOXO1,α5-andα6-integrins,β1-,β3-andβ4-integrins;this is due to NR4A1 acting as a cofactor and mediating NR4A1/Sp1/4-regulated gene expression through GC-rich gene promoter sites.Several studies show that drugs targeting Sp downregulation or NR4A1 antagonists are highly effective inhibitors of Sp/NR4A1-regulated pathways and genes in pancreatic and other cancer cells,and the triterpenoid celastrol is a novel dual-acting agent that targets both Sp TFs and NR4A1.展开更多
BACKGROUND Colorectal cancer(CRC)is the third leading cause of cancer-related death in males and females in the United States.Approximately,20%-22%of patients have metastatic disease at the time of presentation,and 50...BACKGROUND Colorectal cancer(CRC)is the third leading cause of cancer-related death in males and females in the United States.Approximately,20%-22%of patients have metastatic disease at the time of presentation,and 50%-60%will develop metastasis over the course of their disease.Despite advances in systemic therapies,there remains a paucity of effective third-and later-line therapies for patients with ongoing disease progression.However,rechallenging chemoresistant CRC tumors with previously administered therapies is an emerging concept that may be a life-prolonging option for heavily treated metastatic colorectal cancer(mCRC).CASE SUMMARY A 41-year-old man with no previous medical history initially presented with worsening diffuse abdominal tenderness.Computed tomography was significant for a splenic flexure mass and hepatic lesions concerning for metastatic disease.He underwent a colectomy with anastomosis.Postoperative pathology was diagnostic for moderately to well-differentiated adenocarcinoma(T4bN1bM1a).He received adjuvant 5-fluorouracil,leucovorin,and oxaliplatin(FOLFOX),but therapy was discontinued due to the development of atrial fibrillation.Additional workup indicated a carcinoembryonic antigen level of 508.2 ng/mL,and mutational analysis found that the tumor was microsatellite instability-high and KRAS/BRAF wild-type.He was started on irinotecan with oxaliplatin(IROX),and bevacizumab(14 cycles),developed disease progression,was transitioned to FOLFOX and cetuximab,and then eventually three cycles of pembrolizumab.Following disease progression,he was rechallenged with IROX therapy,as he previously responded well to oxaliplatin-based therapy.The IROX rechallenge provided this patient with a ten-month survival benefit,decreased metastatic burden,and marked improvement in his clinical condition.CONCLUSION Rechallenge of previous lines of well-tolerated systemic chemotherapy regimens may be a valuable therapeutic strategy in patients with heavily-treated mCRC.展开更多
BACKGROUND The impact of pancreatic tumor location on patient survival has been studied in large national data-based analyses which yielded controversial results.AIM To explore if pancreatic head cancer(PHC)and pancre...BACKGROUND The impact of pancreatic tumor location on patient survival has been studied in large national data-based analyses which yielded controversial results.AIM To explore if pancreatic head cancer(PHC)and pancreatic body/tail cancer(PBTC)have different overall survival(OS),molecular signature and response to chemotherapy.METHODS We retrospectively queried patient records from July 2016 to June 2020 in our institution.Patient demographics,cancer stage on diagnosis,tumor location,somatic mutations,treatment,and survival are recorded and analyzed.A test is considered statistically significant if the P value was<0.05.RESULTS We reviewed 101 patients with complete records,among which 67(66.34%)were PHC and 34(33.66%)were PBTC.More PHC were diagnosed at younger age[61.49 vs 68.97,P=0.010],earlier stages(P=0.006)and underwent surgical resection(P=0.025).There were no significant differences among all mutations and pathways studied except for TP53 mutations(37.0%in PHC vs 70.0%in PBTC,P=0.03).OS was not statistically different between PHC and PBTC(P=0.636)in the overall population and in subgroups according to surgical resection status or stages.In terms of response to chemotherapy,chemotherapy regimens(FOLFIRINOX-based vs gemcitabine-based)didn’t impact disease free interval in those who had surgical resection in either PHC(P=0.546)or PBTC(P=0.654),or the duration of response to first line palliative treatment in those with advanced disease in PHC(P=0.915)or PBTC(P=0.524).CONCLUSION Even though PHC and PBTC have similar poor OS and response to chemotherapy,the different presentations and molecular profiles indicate they are different diseases.Utilization of molecular profiling to develop targeted therapy for individualization of treatment is needed.展开更多
BACKGROUND Pancreatic adenocarcinoma is an aggressive malignancy with a high propensity to metastasize.Esophageal metastasis manifesting as dysphagia is rarely reported in the literature and has not to our knowledge b...BACKGROUND Pancreatic adenocarcinoma is an aggressive malignancy with a high propensity to metastasize.Esophageal metastasis manifesting as dysphagia is rarely reported in the literature and has not to our knowledge been reported prior to the appearance of the primary disease.CASE SUMMARY A patient presented with progressive dysphagia to solids and a persistent earache.Computed tomography of the neck and chest revealed a 3.0 cm×1.8 cm heterogeneous mass originating from the upper third of the esophagus,necrotic cervical and supraclavicular lymphadenopathy,and bilateral pulmonary nodules.She underwent a core needle biopsy of a right cervical node,which suggested a well-differentiated adenocarcinoma of unknown primary.She had an upper endoscopy with biopsy of the esophageal mass suggestive of a welldifferentiated adenocarcinoma.Positron emission tomography imaging revealed increased uptake in the esophageal mass,cervical,and mediastinal lymph nodes.She was started on folinic acid,fluorouracil,and oxaliplatin.Prior to initiation of cycle 8,the patient was found to have a pancreatic body mass that was not present on prior radiographic imaging,confirmed by endoscopic ultrasonography and biopsy to be pancreatic adenocarcinoma.CA19-9 was>10000 U/m L,suggesting a primary pancreaticobiliary origin.CONCLUSION Esophageal metastasis diagnosed before primary pancreatic adenocarcinoma is rare.This case highlights the profound metastatic potential of pancreatic adenocarcinoma.展开更多
基金Supported by Houston Methodist Cancer Center Innovation Award。
文摘Specificity protein(Sp)transcription factors(TFs)Sp1,Sp3 and Sp4,and the orphan nuclear receptor 4A1(NR4A1)are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patient survival.Results of knockdown and overexpression of Sp1,Sp3 and Sp4 in pancreatic and other cancer lines show that these TFs are individually pro-oncogenic factors and loss of one Sp TF is not compensated by other members.NR4A1 is also a prooncogenic factor and both NR4A1 and Sp TFs exhibit similar functions in pancreatic cancer cells and regulate cell growth,survival,migration and invasion.There is also evidence that Sp TFs and NR4A1 regulate some of the same genes including survivin,epidermal growth factor receptor,PAX3-FOXO1,α5-andα6-integrins,β1-,β3-andβ4-integrins;this is due to NR4A1 acting as a cofactor and mediating NR4A1/Sp1/4-regulated gene expression through GC-rich gene promoter sites.Several studies show that drugs targeting Sp downregulation or NR4A1 antagonists are highly effective inhibitors of Sp/NR4A1-regulated pathways and genes in pancreatic and other cancer cells,and the triterpenoid celastrol is a novel dual-acting agent that targets both Sp TFs and NR4A1.
文摘BACKGROUND Colorectal cancer(CRC)is the third leading cause of cancer-related death in males and females in the United States.Approximately,20%-22%of patients have metastatic disease at the time of presentation,and 50%-60%will develop metastasis over the course of their disease.Despite advances in systemic therapies,there remains a paucity of effective third-and later-line therapies for patients with ongoing disease progression.However,rechallenging chemoresistant CRC tumors with previously administered therapies is an emerging concept that may be a life-prolonging option for heavily treated metastatic colorectal cancer(mCRC).CASE SUMMARY A 41-year-old man with no previous medical history initially presented with worsening diffuse abdominal tenderness.Computed tomography was significant for a splenic flexure mass and hepatic lesions concerning for metastatic disease.He underwent a colectomy with anastomosis.Postoperative pathology was diagnostic for moderately to well-differentiated adenocarcinoma(T4bN1bM1a).He received adjuvant 5-fluorouracil,leucovorin,and oxaliplatin(FOLFOX),but therapy was discontinued due to the development of atrial fibrillation.Additional workup indicated a carcinoembryonic antigen level of 508.2 ng/mL,and mutational analysis found that the tumor was microsatellite instability-high and KRAS/BRAF wild-type.He was started on irinotecan with oxaliplatin(IROX),and bevacizumab(14 cycles),developed disease progression,was transitioned to FOLFOX and cetuximab,and then eventually three cycles of pembrolizumab.Following disease progression,he was rechallenged with IROX therapy,as he previously responded well to oxaliplatin-based therapy.The IROX rechallenge provided this patient with a ten-month survival benefit,decreased metastatic burden,and marked improvement in his clinical condition.CONCLUSION Rechallenge of previous lines of well-tolerated systemic chemotherapy regimens may be a valuable therapeutic strategy in patients with heavily-treated mCRC.
文摘BACKGROUND The impact of pancreatic tumor location on patient survival has been studied in large national data-based analyses which yielded controversial results.AIM To explore if pancreatic head cancer(PHC)and pancreatic body/tail cancer(PBTC)have different overall survival(OS),molecular signature and response to chemotherapy.METHODS We retrospectively queried patient records from July 2016 to June 2020 in our institution.Patient demographics,cancer stage on diagnosis,tumor location,somatic mutations,treatment,and survival are recorded and analyzed.A test is considered statistically significant if the P value was<0.05.RESULTS We reviewed 101 patients with complete records,among which 67(66.34%)were PHC and 34(33.66%)were PBTC.More PHC were diagnosed at younger age[61.49 vs 68.97,P=0.010],earlier stages(P=0.006)and underwent surgical resection(P=0.025).There were no significant differences among all mutations and pathways studied except for TP53 mutations(37.0%in PHC vs 70.0%in PBTC,P=0.03).OS was not statistically different between PHC and PBTC(P=0.636)in the overall population and in subgroups according to surgical resection status or stages.In terms of response to chemotherapy,chemotherapy regimens(FOLFIRINOX-based vs gemcitabine-based)didn’t impact disease free interval in those who had surgical resection in either PHC(P=0.546)or PBTC(P=0.654),or the duration of response to first line palliative treatment in those with advanced disease in PHC(P=0.915)or PBTC(P=0.524).CONCLUSION Even though PHC and PBTC have similar poor OS and response to chemotherapy,the different presentations and molecular profiles indicate they are different diseases.Utilization of molecular profiling to develop targeted therapy for individualization of treatment is needed.
文摘BACKGROUND Pancreatic adenocarcinoma is an aggressive malignancy with a high propensity to metastasize.Esophageal metastasis manifesting as dysphagia is rarely reported in the literature and has not to our knowledge been reported prior to the appearance of the primary disease.CASE SUMMARY A patient presented with progressive dysphagia to solids and a persistent earache.Computed tomography of the neck and chest revealed a 3.0 cm×1.8 cm heterogeneous mass originating from the upper third of the esophagus,necrotic cervical and supraclavicular lymphadenopathy,and bilateral pulmonary nodules.She underwent a core needle biopsy of a right cervical node,which suggested a well-differentiated adenocarcinoma of unknown primary.She had an upper endoscopy with biopsy of the esophageal mass suggestive of a welldifferentiated adenocarcinoma.Positron emission tomography imaging revealed increased uptake in the esophageal mass,cervical,and mediastinal lymph nodes.She was started on folinic acid,fluorouracil,and oxaliplatin.Prior to initiation of cycle 8,the patient was found to have a pancreatic body mass that was not present on prior radiographic imaging,confirmed by endoscopic ultrasonography and biopsy to be pancreatic adenocarcinoma.CA19-9 was>10000 U/m L,suggesting a primary pancreaticobiliary origin.CONCLUSION Esophageal metastasis diagnosed before primary pancreatic adenocarcinoma is rare.This case highlights the profound metastatic potential of pancreatic adenocarcinoma.
