The molecular basis for enhanced chemosensitivity of testicular germ cell tumors （GCT） has been an area of great interest, as it could potentially give us therapeutic leads in other resistant malignancies. Thus far,...The molecular basis for enhanced chemosensitivity of testicular germ cell tumors （GCT） has been an area of great interest, as it could potentially give us therapeutic leads in other resistant malignancies. Thus far, however, the increased sensitivity of C＆T has been variously attributed to multiple factors -- an inability to detoxify cisplatin, a lack of export pumps, an inability to repair the DNA damage, an intact apoptotic cascade and lack of p53 mutation; but a unifying underlying etiology leading to the aforementioned processes and having a translational implication has so far been elusive. Herein, we offer evidence to support a potential significant role for the previously demonstrated low hypoxia inducible factor-la （HIF-la） expression in mediating the general exquisite chemosensitivity of testicular GCT, through the aforementioned processes. This molecular mechanism based hypothesis could have a significant translational implication in platinum refractory GCT as well as other platinum resistant malignancies.展开更多
This study analyzed RNA expression of genes for three serum tumor markers,alpha fetoprotein(AFP),human chorionic gonadotropin(hCG),and lactate dehydrogenase(LDH),in patients with testicular germ cell tumors(TGCT)type ...This study analyzed RNA expression of genes for three serum tumor markers,alpha fetoprotein(AFP),human chorionic gonadotropin(hCG),and lactate dehydrogenase(LDH),in patients with testicular germ cell tumors(TGCT)type 2.The gene AFP encodes AFP,the gene for chorionic gonadotropin beta polypeptide 5(CGB5)encodes a major part of the specific beta subunit of hCG,and the genes for LDH subunit A(LDHA),LDH subunit B(LDHB),and LDH subunit C(LDHC)encode three different subunits of LDH.LDHB encodes the LDHB subunit present as a tetramer in LDH isoenzyme 1(LDH-1).We examined three datasets with 203 samples of normal testis tissue(NT)and TGCT type 2.Yolk sac tumor(YST)expressed RNA of AFP fourteen thousand times higher than seminoma(SE),embryonal carcinoma(EC),and teratoma(TER)combined(P=0.00015).In the second microarray,choriocarcinoma(CC)expressed RNA of CGB5 ten times higher than other histologic types of TGCT combined.EC expressed RNA of LDHB twice higher than SE,YST and TER combined(P=0.000041).EC expressed RNA of LDHB higher than that YST expressed RNA of AFP and that CC expressed RNA of CGB5.In conclusion,TGCT type 2 expressed RNA of LDHB markedly higher than the RNA of 23 other candidate genes for TGCT type 2.展开更多
Accumulating evidence supports the significance of aberrant alternative splicing(AS)events in cancer;however,genome-wide profiling of progression-free survival(PFS)-related AS events in testicular germ cell tumors(TGC...Accumulating evidence supports the significance of aberrant alternative splicing(AS)events in cancer;however,genome-wide profiling of progression-free survival(PFS)-related AS events in testicular germ cell tumors(TGCT)has not been reported.Here,we analyzed high-throughput RNA-sequencing data and percent-spliced-in values for 150 patients with TGCT.Using univariate and multivariate Cox regression analysis and a least absolute shrinkage and selection operator method,we identified the top 15 AS events most closely associated with disease progression.A risk-associated AS score(ASS)for the 15 AS events was calculated for each patient.ASS,pathological stage,and T stage were significantly associated with disease progression by univariate analysis,but only ASS and pathological stage remained significant by multivariate analysis.The ability of these variables to predict 5-year progression was assessed using receiver operating characteristic curve analysis.ASS had stronger predictive value than a combination of age,pathological stage,and T stage(area under the curve=0.899 and 0.715,respectively).Furthermore,Kaplan—Meier analysis of patients with low and high ASS demonstrated that high ASS was associated with significantly worse PFS than low ASS(P=1.46 × 10^(-7)).We also analyzed the biological functions of the PFS-related AS-related genes and found enrichment in pathways associated with DNA repair and modification.Finally,we identified a regulatory network of splicing factors with expression levels that correlated significantly with AS events in TGCT.Collectively,this study identifies a novel method for risk stratification of patients and provides insight into the molecular events underlying TGCT.展开更多
Testicular germ cell tumors(TGCTs)are a cancer pharmacology success story with a majority of patients cured even in the highly advanced and metastatic setting.Successful treatment of TGCTs is primarily due to the exqu...Testicular germ cell tumors(TGCTs)are a cancer pharmacology success story with a majority of patients cured even in the highly advanced and metastatic setting.Successful treatment of TGCTs is primarily due to the exquisite responsiveness of this solid tumor to cisplatin-based therapy.However,a significant percentage of patients are,or become,refractory to cisplatin and die from progressive disease.Mechanisms for both clinical hypersensitivity and resistance have largely remained a mystery despite the promise of applying lessons to the majority of solid tumors that are not curable in the metastatic setting.Recently,this promise has been heightened by the realization that distinct(and perhaps pharmacologically replicable)epigenetic states,rather than fixed genetic alterations,may play dominant roles in not only TGCT etiology and progression but also their curability with conventional chemotherapies.In this review,it discusses potential mechanisms of TGCT cisplatin sensitivity and resistance to conventional chemotherapeutics.展开更多
Testicular cancer is rare. The authors report the case of a young Senegalese 21, who has consulted for an occlusive syndrome evolving for 48 hours that prompted his hospitalization. Note that the patient has consulted...Testicular cancer is rare. The authors report the case of a young Senegalese 21, who has consulted for an occlusive syndrome evolving for 48 hours that prompted his hospitalization. Note that the patient has consulted several times to persistent inguinal scrotal pain, a big right purse with chronic analgesic requirements and anti-inflammatory. Occlusive before this table, abdominal pelvic CT was performed and highlighted the presence of lung metastases, a large pelvic lymph node casting bridging the inter vesico-rectal space and responsible for extrinsic compression of the small intestine, lymph node inter casting aorto-cellar and latero aortic liver and multiple secondary locations. Faced with this bundle of arguments, clinical and laboratory, metastatic testicular tumor was raised and measured tumor markers. A right orchiectomy by inguinal was made with histology: A non-seminomatous germ cell tumor stage III. After orchiectomy germinal markers were still high and there was the problem of persistent occlusive syndrome despite resuscitation. A chemotherapy regimen was initiated with 4 cycles of chemotherapy according to the protocol BEP (bleomycin, etoposide, cisplatin). A significant regression of occlusive syndrome with a decline in clinical symptoms was noted. The revaluation at 3 months, 6 months and 1 year were highlighted: A normal clinical examination associated with a persistent correction rate of germline markers and lack of active lesion at thoraco-abdominopelvic CT.展开更多
Introduction: Testicular cancer accounts for 5% of urological tumors, predominantly affecting young men. The aim of our study was to report the diagnostic and evolutionary aspects of testicular cancer cases treated in...Introduction: Testicular cancer accounts for 5% of urological tumors, predominantly affecting young men. The aim of our study was to report the diagnostic and evolutionary aspects of testicular cancer cases treated in our center. Patients and Methods: A retrospective study conducted over a 15-year period involving 12 patients treated for testicular cancer at the University Hospital of Brazzaville. Results: The median age was 31 years (range 11 to 49 years), with a median consultation delay of 10.6 months (range 3 to 27 months). Scrotal mass was the most common reason for consultation. Cancer was bilateral in two patients. Two patients were admitted with metastatic disease. Histopathological examination favored germ cell tumors in 7 cases, two cases of non-Hodgkin’s malignant lymphoma, and one case of epididymo-testicular adenocarcinoma. Adjuvant chemotherapy resulted in complete remission in patients with germ cell tumors. However, neoadjuvant chemotherapy was not effective in patients admitted with advanced-stage disease. Conclusion: Testicular cancer is a rare condition that is curable in the majority of cases, but its management is often complicated in our setting due to delayed diagnosis caused by taboos surrounding genital organ pathologies.展开更多
Primary germ cell tumors of lung are extremely rare. The prognosis is usually poor, with various symptoms seriously affecting quality of life. In this paper we describe the unique case of a patient affected by an embr...Primary germ cell tumors of lung are extremely rare. The prognosis is usually poor, with various symptoms seriously affecting quality of life. In this paper we describe the unique case of a patient affected by an embryonal carcinoma of lung and a testicular seminoma after ten years. We also report literature about pulmonary extragonadal germ cell tumors.展开更多
文摘The molecular basis for enhanced chemosensitivity of testicular germ cell tumors （GCT） has been an area of great interest, as it could potentially give us therapeutic leads in other resistant malignancies. Thus far, however, the increased sensitivity of C＆T has been variously attributed to multiple factors -- an inability to detoxify cisplatin, a lack of export pumps, an inability to repair the DNA damage, an intact apoptotic cascade and lack of p53 mutation; but a unifying underlying etiology leading to the aforementioned processes and having a translational implication has so far been elusive. Herein, we offer evidence to support a potential significant role for the previously demonstrated low hypoxia inducible factor-la （HIF-la） expression in mediating the general exquisite chemosensitivity of testicular GCT, through the aforementioned processes. This molecular mechanism based hypothesis could have a significant translational implication in platinum refractory GCT as well as other platinum resistant malignancies.
文摘This study analyzed RNA expression of genes for three serum tumor markers,alpha fetoprotein(AFP),human chorionic gonadotropin(hCG),and lactate dehydrogenase(LDH),in patients with testicular germ cell tumors(TGCT)type 2.The gene AFP encodes AFP,the gene for chorionic gonadotropin beta polypeptide 5(CGB5)encodes a major part of the specific beta subunit of hCG,and the genes for LDH subunit A(LDHA),LDH subunit B(LDHB),and LDH subunit C(LDHC)encode three different subunits of LDH.LDHB encodes the LDHB subunit present as a tetramer in LDH isoenzyme 1(LDH-1).We examined three datasets with 203 samples of normal testis tissue(NT)and TGCT type 2.Yolk sac tumor(YST)expressed RNA of AFP fourteen thousand times higher than seminoma(SE),embryonal carcinoma(EC),and teratoma(TER)combined(P=0.00015).In the second microarray,choriocarcinoma(CC)expressed RNA of CGB5 ten times higher than other histologic types of TGCT combined.EC expressed RNA of LDHB twice higher than SE,YST and TER combined(P=0.000041).EC expressed RNA of LDHB higher than that YST expressed RNA of AFP and that CC expressed RNA of CGB5.In conclusion,TGCT type 2 expressed RNA of LDHB markedly higher than the RNA of 23 other candidate genes for TGCT type 2.
文摘Accumulating evidence supports the significance of aberrant alternative splicing(AS)events in cancer;however,genome-wide profiling of progression-free survival(PFS)-related AS events in testicular germ cell tumors(TGCT)has not been reported.Here,we analyzed high-throughput RNA-sequencing data and percent-spliced-in values for 150 patients with TGCT.Using univariate and multivariate Cox regression analysis and a least absolute shrinkage and selection operator method,we identified the top 15 AS events most closely associated with disease progression.A risk-associated AS score(ASS)for the 15 AS events was calculated for each patient.ASS,pathological stage,and T stage were significantly associated with disease progression by univariate analysis,but only ASS and pathological stage remained significant by multivariate analysis.The ability of these variables to predict 5-year progression was assessed using receiver operating characteristic curve analysis.ASS had stronger predictive value than a combination of age,pathological stage,and T stage(area under the curve=0.899 and 0.715,respectively).Furthermore,Kaplan—Meier analysis of patients with low and high ASS demonstrated that high ASS was associated with significantly worse PFS than low ASS(P=1.46 × 10^(-7)).We also analyzed the biological functions of the PFS-related AS-related genes and found enrichment in pathways associated with DNA repair and modification.Finally,we identified a regulatory network of splicing factors with expression levels that correlated significantly with AS events in TGCT.Collectively,this study identifies a novel method for risk stratification of patients and provides insight into the molecular events underlying TGCT.
基金This work was supported by NIHNational Cancer Institute grant(R01CA211875),(R03CA223709)a Reach Grant from the Alex’s Lemonade Stand Foundation(MJS).
文摘Testicular germ cell tumors(TGCTs)are a cancer pharmacology success story with a majority of patients cured even in the highly advanced and metastatic setting.Successful treatment of TGCTs is primarily due to the exquisite responsiveness of this solid tumor to cisplatin-based therapy.However,a significant percentage of patients are,or become,refractory to cisplatin and die from progressive disease.Mechanisms for both clinical hypersensitivity and resistance have largely remained a mystery despite the promise of applying lessons to the majority of solid tumors that are not curable in the metastatic setting.Recently,this promise has been heightened by the realization that distinct(and perhaps pharmacologically replicable)epigenetic states,rather than fixed genetic alterations,may play dominant roles in not only TGCT etiology and progression but also their curability with conventional chemotherapies.In this review,it discusses potential mechanisms of TGCT cisplatin sensitivity and resistance to conventional chemotherapeutics.
文摘Testicular cancer is rare. The authors report the case of a young Senegalese 21, who has consulted for an occlusive syndrome evolving for 48 hours that prompted his hospitalization. Note that the patient has consulted several times to persistent inguinal scrotal pain, a big right purse with chronic analgesic requirements and anti-inflammatory. Occlusive before this table, abdominal pelvic CT was performed and highlighted the presence of lung metastases, a large pelvic lymph node casting bridging the inter vesico-rectal space and responsible for extrinsic compression of the small intestine, lymph node inter casting aorto-cellar and latero aortic liver and multiple secondary locations. Faced with this bundle of arguments, clinical and laboratory, metastatic testicular tumor was raised and measured tumor markers. A right orchiectomy by inguinal was made with histology: A non-seminomatous germ cell tumor stage III. After orchiectomy germinal markers were still high and there was the problem of persistent occlusive syndrome despite resuscitation. A chemotherapy regimen was initiated with 4 cycles of chemotherapy according to the protocol BEP (bleomycin, etoposide, cisplatin). A significant regression of occlusive syndrome with a decline in clinical symptoms was noted. The revaluation at 3 months, 6 months and 1 year were highlighted: A normal clinical examination associated with a persistent correction rate of germline markers and lack of active lesion at thoraco-abdominopelvic CT.
文摘Introduction: Testicular cancer accounts for 5% of urological tumors, predominantly affecting young men. The aim of our study was to report the diagnostic and evolutionary aspects of testicular cancer cases treated in our center. Patients and Methods: A retrospective study conducted over a 15-year period involving 12 patients treated for testicular cancer at the University Hospital of Brazzaville. Results: The median age was 31 years (range 11 to 49 years), with a median consultation delay of 10.6 months (range 3 to 27 months). Scrotal mass was the most common reason for consultation. Cancer was bilateral in two patients. Two patients were admitted with metastatic disease. Histopathological examination favored germ cell tumors in 7 cases, two cases of non-Hodgkin’s malignant lymphoma, and one case of epididymo-testicular adenocarcinoma. Adjuvant chemotherapy resulted in complete remission in patients with germ cell tumors. However, neoadjuvant chemotherapy was not effective in patients admitted with advanced-stage disease. Conclusion: Testicular cancer is a rare condition that is curable in the majority of cases, but its management is often complicated in our setting due to delayed diagnosis caused by taboos surrounding genital organ pathologies.
文摘Primary germ cell tumors of lung are extremely rare. The prognosis is usually poor, with various symptoms seriously affecting quality of life. In this paper we describe the unique case of a patient affected by an embryonal carcinoma of lung and a testicular seminoma after ten years. We also report literature about pulmonary extragonadal germ cell tumors.
