Objective： To investigate fotemustine plus dacarbazine （DTIC） with dendritic cell （DC） vaccines on patients with advanced acral lentiginous melanoma （ALM）. Fotemustine is a cytotoxic alkylating agent with a rem...Objective： To investigate fotemustine plus dacarbazine （DTIC） with dendritic cell （DC） vaccines on patients with advanced acral lentiginous melanoma （ALM）. Fotemustine is a cytotoxic alkylating agent with a remarkable antitumor activity as single agent but also in association with （DTIC）. DC is the strongest antigen presenting cell which could induce durable clinical responses. Methods： This was a single-center study. Between July 2003 and June 2006, twenty-eight chemotherapy-naive patients of advanced ALM received fotemustine 100 mg/m^2, dr, 12, DTIC 400 mg/d d2-6, DC vaccines subcutaneously dT, 9, 13 repeated every 28 days. Ten HLA-A02＋24＋ patients received vaccines pulsed with melanoma antigen derived peptides, melanoma antigen recognized by T-cells 1 （Mart-i） and S-100. Eighteen patients received DC loaded with allogeneic melanoma lysate. The primary end-point was progression free survival （PFS）. Secondary end-points were overall survival （OS）, overall response rate （ORR） and toxicity. Tumor assessment was performed every 8 weeks and evaluated according to response evaluation criteria in solid tumors （RECIST）. Results： The 15 men and 13 women had a median age of 51 years. 16 patients had stage Mlc disease and 11/16 had liver metastasis. Patients received an average of 3.82±1.25 cycles. Follow-up for the 18 surviving patients ranged from 7-41 months with a median of 12 months. Median PFS was 8.5 months （95% CI： 7.86-15.21） with 12 patients remaining progression free. Only 10 patients died. Median OS was 12 months （95% CI： 10.33-18.24）. ORR （CR＋PR） was 35.7% including 3 complete response （CR） and 7 partial response （PR）. Six patients had disease stable. A total of 19 Grade Ⅲ/Ⅳ toxicities were observed including thrombocytopenia （n=8）, neutropenia （n=5）, fatigue （n=6） and hypersensitivity reaction （n=1）. One patient died of Grade IV thrombocytopenia. Conclusion： Fotemustine and dacarbazine plus DC vaccines are safe and tolerable to Chinese ALM patients. The regimen brings clinical benefit with a higher ORR and may provide a survival advantage. Updated survival data will be presented.展开更多
O6-methylguanine DNA methyltransferase(MGMT) gene promoter methylation plays an important role in colorectal carcinogenesis, occurring in about 30%-40% of metastatic colorectal cancer. Its prognostic role has not been...O6-methylguanine DNA methyltransferase(MGMT) gene promoter methylation plays an important role in colorectal carcinogenesis, occurring in about 30%-40% of metastatic colorectal cancer. Its prognostic role has not been defined yet, but loss of expression of MGMT, which is secondary to gene promoter methylation, results in an interesting high response to alkylating agents such as dacarbazine and temozolomide. In a phase 2 study on heavily pre-treated patients with MGMT methylated metastatic colorectal cancer, temozolomide achieved about 30% of disease control rate. Activating mutations of RAS or BRAF genes as well as mismatch repair deficiency may represent mechanisms of resistance to alkylating agents, but a dose-dense schedule of temozolomide may potentially restore sensitivity in RAS-mutant patients. Further development of temozolomide in MGMT methylated colorectal cancer includes investigation of synergic combinations with other agents such as fluoropyrimidines and research for additional biomarkers, in order to better define the role of temozolomide in the treatment of individual patients.展开更多
Colorectal cancer(CRC)poses a severe global health challenge with high incidence and mortality rates.USP37 has been identified as the bona fide deubiquitinase of SND1,playing a critical role in stabilizing SND1,thereb...Colorectal cancer(CRC)poses a severe global health challenge with high incidence and mortality rates.USP37 has been identified as the bona fide deubiquitinase of SND1,playing a critical role in stabilizing SND1,thereby augmenting its oncogenic potential.The interaction between USP37 and SND1 was confirmed through extensive proteomics,ubiquitinomics,and interactomics,underscoring their synergistic effects on CRC proliferation and metastasis.Additionally,CDK1 has emerged as a pivotal regulator of USP37,phosphorylating it at threonine 631 rather than serine 628,enhancing its deubiquitinase activity,and consequently stabilizing SND1 to drive CRC malignancy further.Histological analyses of human CRC samples linked the upregulation of CDK1 and USP37 with increased SND1 levels and poor patient prognosis.High-throughput virtual screening and subsequent experimental validation identified Dacarbazine as a pharmacological inhibitor of USP37,and its inhibition disrupted SND1 stability,hindering CRC cell proliferation and metastasis.This study reveals a novel and promising molecular mechanism driving CRC progression through the CDK1-SP37-ND1 axis,highlighting the clinical importance of targeting this pathway to improve patient outcomes.展开更多
Hodgkin’s lymphoma is a highly treatable malignancy. It has high cure rates yet there are many patients who relapse or are refractory to treatment. Traditionally, treatment has been with conventional chemotherapy;how...Hodgkin’s lymphoma is a highly treatable malignancy. It has high cure rates yet there are many patients who relapse or are refractory to treatment. Traditionally, treatment has been with conventional chemotherapy;however, the development of brentuximab vedotin and immune checkpoint inhibitors has revolutionized the care of Hodgkin’s lymphoma. This is a review of the current advances in the management of Hodgkin’s lymphoma and a review of ongoing clinical trials in the field.展开更多
文摘Objective： To investigate fotemustine plus dacarbazine （DTIC） with dendritic cell （DC） vaccines on patients with advanced acral lentiginous melanoma （ALM）. Fotemustine is a cytotoxic alkylating agent with a remarkable antitumor activity as single agent but also in association with （DTIC）. DC is the strongest antigen presenting cell which could induce durable clinical responses. Methods： This was a single-center study. Between July 2003 and June 2006, twenty-eight chemotherapy-naive patients of advanced ALM received fotemustine 100 mg/m^2, dr, 12, DTIC 400 mg/d d2-6, DC vaccines subcutaneously dT, 9, 13 repeated every 28 days. Ten HLA-A02＋24＋ patients received vaccines pulsed with melanoma antigen derived peptides, melanoma antigen recognized by T-cells 1 （Mart-i） and S-100. Eighteen patients received DC loaded with allogeneic melanoma lysate. The primary end-point was progression free survival （PFS）. Secondary end-points were overall survival （OS）, overall response rate （ORR） and toxicity. Tumor assessment was performed every 8 weeks and evaluated according to response evaluation criteria in solid tumors （RECIST）. Results： The 15 men and 13 women had a median age of 51 years. 16 patients had stage Mlc disease and 11/16 had liver metastasis. Patients received an average of 3.82±1.25 cycles. Follow-up for the 18 surviving patients ranged from 7-41 months with a median of 12 months. Median PFS was 8.5 months （95% CI： 7.86-15.21） with 12 patients remaining progression free. Only 10 patients died. Median OS was 12 months （95% CI： 10.33-18.24）. ORR （CR＋PR） was 35.7% including 3 complete response （CR） and 7 partial response （PR）. Six patients had disease stable. A total of 19 Grade Ⅲ/Ⅳ toxicities were observed including thrombocytopenia （n=8）, neutropenia （n=5）, fatigue （n=6） and hypersensitivity reaction （n=1）. One patient died of Grade IV thrombocytopenia. Conclusion： Fotemustine and dacarbazine plus DC vaccines are safe and tolerable to Chinese ALM patients. The regimen brings clinical benefit with a higher ORR and may provide a survival advantage. Updated survival data will be presented.
文摘O6-methylguanine DNA methyltransferase(MGMT) gene promoter methylation plays an important role in colorectal carcinogenesis, occurring in about 30%-40% of metastatic colorectal cancer. Its prognostic role has not been defined yet, but loss of expression of MGMT, which is secondary to gene promoter methylation, results in an interesting high response to alkylating agents such as dacarbazine and temozolomide. In a phase 2 study on heavily pre-treated patients with MGMT methylated metastatic colorectal cancer, temozolomide achieved about 30% of disease control rate. Activating mutations of RAS or BRAF genes as well as mismatch repair deficiency may represent mechanisms of resistance to alkylating agents, but a dose-dense schedule of temozolomide may potentially restore sensitivity in RAS-mutant patients. Further development of temozolomide in MGMT methylated colorectal cancer includes investigation of synergic combinations with other agents such as fluoropyrimidines and research for additional biomarkers, in order to better define the role of temozolomide in the treatment of individual patients.
基金supported by the National Natural Science Foundation of China(Nos.82103543,82303235,U19A2008 and 82373232)Fundamental Research Funds for the Central Universities(No.WK9110000159,China)+1 种基金the Natural Science Foundation of Anhui Province(No.2108085QH340,China)the China Postdoctoral Science Foundation(No.2021M693082).
文摘Colorectal cancer(CRC)poses a severe global health challenge with high incidence and mortality rates.USP37 has been identified as the bona fide deubiquitinase of SND1,playing a critical role in stabilizing SND1,thereby augmenting its oncogenic potential.The interaction between USP37 and SND1 was confirmed through extensive proteomics,ubiquitinomics,and interactomics,underscoring their synergistic effects on CRC proliferation and metastasis.Additionally,CDK1 has emerged as a pivotal regulator of USP37,phosphorylating it at threonine 631 rather than serine 628,enhancing its deubiquitinase activity,and consequently stabilizing SND1 to drive CRC malignancy further.Histological analyses of human CRC samples linked the upregulation of CDK1 and USP37 with increased SND1 levels and poor patient prognosis.High-throughput virtual screening and subsequent experimental validation identified Dacarbazine as a pharmacological inhibitor of USP37,and its inhibition disrupted SND1 stability,hindering CRC cell proliferation and metastasis.This study reveals a novel and promising molecular mechanism driving CRC progression through the CDK1-SP37-ND1 axis,highlighting the clinical importance of targeting this pathway to improve patient outcomes.
文摘Hodgkin’s lymphoma is a highly treatable malignancy. It has high cure rates yet there are many patients who relapse or are refractory to treatment. Traditionally, treatment has been with conventional chemotherapy;however, the development of brentuximab vedotin and immune checkpoint inhibitors has revolutionized the care of Hodgkin’s lymphoma. This is a review of the current advances in the management of Hodgkin’s lymphoma and a review of ongoing clinical trials in the field.
