BACKGROUND BRIP1 is a helicase that partners with BRCA1 in the homologous recombination(HR) step in the repair of DNA inter-strand cross-link lesions. It is a rare cause of hereditary ovarian cancer in patients with n...BACKGROUND BRIP1 is a helicase that partners with BRCA1 in the homologous recombination(HR) step in the repair of DNA inter-strand cross-link lesions. It is a rare cause of hereditary ovarian cancer in patients with no mutations of BRCA1 or BRCA2. The role of the protein in other cancers such as gastrointestinal(GI) carcinomas is less well characterized but given its role in DNA repair it could be a candidate tumor suppressor similarly to the two BRCA proteins.AIM To analyze the role of helicase BRIP1(FANCJ) in GI cancers pathogenesis.METHODS Publicly available data from genomic studies of esophageal, gastric, pancreatic,cholangiocarcinomas and colorectal cancers were interrogated to unveil the role of BRIP1 in these carcinomas and to discover associations of lesions in BRIP1 with other more common molecular defects in these cancers.RESULTS Molecular lesions in BRIP1 were rare(3.6% of all samples) in GI cancers and consisted almost exclusively of mutations and amplifications. Among mutations,40% were possibly pathogenic according to the Onco KB database. A majority of BRIP1 mutated GI cancers were hyper-mutated due to concomitant mutations in mismatch repair or polymerase ε and δ1 genes. No associations were discovered between amplifications of BRIP1 and any mutated genes. In gastroesophageal cancers BRIP1 amplification commonly co-occurs with ERBB2 amplification.CONCLUSION Overall BRIP1 molecular defects do not seem to play a major role in GI cancers whereas mutations frequently occur in hypermutated carcinomas and co-occur with other HR genes mutations. Despite their rarity, BRIP1 defects may present an opportunity for therapeutic interventions similar to other HR defects.展开更多
Tumor budding, defined as a small number of cancer cells observed in pathology sections detached from the main tumor mass, is a common phenomenon in cancer. It issuggested that cells in buds are in the process of acti...Tumor budding, defined as a small number of cancer cells observed in pathology sections detached from the main tumor mass, is a common phenomenon in cancer. It issuggested that cells in buds are in the process of actively moving away from the primary tumor in the first step of metastasis. Tumor budding has been observed in a variety of carcinomas and is best studied in colorectal cancers where it portends poor prognosis. More recently, tumor budding was found to be of prognostic significance in other cancers including breast cancer. Tumor budding in breast cancer is associated with other adverse pathologic factors, such as larger tumor size and lymphovascular invasion, but may have additional independent prognostic value. In the future, standardization of the quantification criteria for tumor budding may further aid in its adoption as a prognostic marker.展开更多
The field of tumor immunology has produced in the recent years a revolution in cancer therapeutics putting an end in the long lasting frustration of investigators in the area stemming from largely unsuccessful strides...The field of tumor immunology has produced in the recent years a revolution in cancer therapeutics putting an end in the long lasting frustration of investigators in the area stemming from largely unsuccessful strides to develop cancer vaccines. This progress has come from the introduction of immune checkpoint inhibitors, monoclonal antibodies blocking ligand/receptor pairs with inhibitory effects for immune cells. Through this blockade immune checkpoint blockers are able to ac-tivate the immune system and create an anti-tumoral effect. A significant sub-set of patients with various types of cancers such as melanoma, lung carcinomas and urothelial cancers benefit from treatment with these drugs and survivals have improved in some ca-ses. However other cancers are primarily resistant to immune blockers and secondary resistance is also the norm. Radiation therapy is often used in the palliative treatment of patients with advanced cancers and, in addition to the local effect in the irradiated field, it may in rare cases produce a systemic antitumor effect, termed "abscopal". This effect has been suggested to be produced by immune mechanisms. Thus an opportunity presents for a synergistic effect of immune stimulation between radiation and immune blockade inhibitors. The therapeutic opportunities presented with the combination of radiation and these drugs for gastrointestinal cancers will be discussed in this editorial overview.展开更多
Background:Immunity plays a major role in carcinogenesis and this is the case also for hepatocellular carcinomas(HCC).Checkpoint inhibitors,novel drugs that enhance the immune system’s ability to attack cancers,have ...Background:Immunity plays a major role in carcinogenesis and this is the case also for hepatocellular carcinomas(HCC).Checkpoint inhibitors,novel drugs that enhance the immune system’s ability to attack cancers,have been successfully introduced for the therapy of various malignancies including HCC.An important target of these drugs is the PD-L1/PD-1 ligand/receptor pair and several clinically available inhibitors of this pair exist.Data sources:A search of the literature until April 20,2019 was performed in the MEDLINE/PubMed database,the Embase database and the Cochrane Central Register of Controlled Trials.The clinical studies describing treatment with PD-L1/PD-1 inhibitors as monotherapy in HCC patients were retrieved.Patient characteristics with relevance for treatment efficacy,such as liver function,disease extend and previous treatment,were extracted from identified articles.Response and survival outcomes were the primary focus of the meta-analysis.Summary estimates of response rates and survival were calculated using a random or fixed effect model,depending on heterogeneity.Most common adverse effects were also recorded and summarized.Results:Three studies(two on nivolumab and one on pembrolizumab)with a total of 400 patients were included in the analysis.The summary response rate(RR)was 17.3%[95%confidence interval(CI):13.2%–21.4%].The summary disease control rate(DCR)was 56.6%(95%CI:44.7%–68.5%).Summary progression free survival(PFS)was 3.5 months(95%CI:2.8–4.2 months).Summary overall survival(OS)was 10.4 months(95%CI:3.5–17.2 months).Adverse effect rate was low and also consistent with the adverse effect profile of PD-L1/PD-1 inhibitors in other disease locations.Conclusions:Pembrolizumab and nivolumab are the only checkpoint inhibitors with data in HCC.Metaanalysis of their effectiveness discloses rates not dissimilar to other systemic therapies available for this disease.Of interest also are the observed long responses in a sub-set of responders.Further development is clearly warranted.展开更多
文摘BACKGROUND BRIP1 is a helicase that partners with BRCA1 in the homologous recombination(HR) step in the repair of DNA inter-strand cross-link lesions. It is a rare cause of hereditary ovarian cancer in patients with no mutations of BRCA1 or BRCA2. The role of the protein in other cancers such as gastrointestinal(GI) carcinomas is less well characterized but given its role in DNA repair it could be a candidate tumor suppressor similarly to the two BRCA proteins.AIM To analyze the role of helicase BRIP1(FANCJ) in GI cancers pathogenesis.METHODS Publicly available data from genomic studies of esophageal, gastric, pancreatic,cholangiocarcinomas and colorectal cancers were interrogated to unveil the role of BRIP1 in these carcinomas and to discover associations of lesions in BRIP1 with other more common molecular defects in these cancers.RESULTS Molecular lesions in BRIP1 were rare(3.6% of all samples) in GI cancers and consisted almost exclusively of mutations and amplifications. Among mutations,40% were possibly pathogenic according to the Onco KB database. A majority of BRIP1 mutated GI cancers were hyper-mutated due to concomitant mutations in mismatch repair or polymerase ε and δ1 genes. No associations were discovered between amplifications of BRIP1 and any mutated genes. In gastroesophageal cancers BRIP1 amplification commonly co-occurs with ERBB2 amplification.CONCLUSION Overall BRIP1 molecular defects do not seem to play a major role in GI cancers whereas mutations frequently occur in hypermutated carcinomas and co-occur with other HR genes mutations. Despite their rarity, BRIP1 defects may present an opportunity for therapeutic interventions similar to other HR defects.
文摘Tumor budding, defined as a small number of cancer cells observed in pathology sections detached from the main tumor mass, is a common phenomenon in cancer. It issuggested that cells in buds are in the process of actively moving away from the primary tumor in the first step of metastasis. Tumor budding has been observed in a variety of carcinomas and is best studied in colorectal cancers where it portends poor prognosis. More recently, tumor budding was found to be of prognostic significance in other cancers including breast cancer. Tumor budding in breast cancer is associated with other adverse pathologic factors, such as larger tumor size and lymphovascular invasion, but may have additional independent prognostic value. In the future, standardization of the quantification criteria for tumor budding may further aid in its adoption as a prognostic marker.
文摘The field of tumor immunology has produced in the recent years a revolution in cancer therapeutics putting an end in the long lasting frustration of investigators in the area stemming from largely unsuccessful strides to develop cancer vaccines. This progress has come from the introduction of immune checkpoint inhibitors, monoclonal antibodies blocking ligand/receptor pairs with inhibitory effects for immune cells. Through this blockade immune checkpoint blockers are able to ac-tivate the immune system and create an anti-tumoral effect. A significant sub-set of patients with various types of cancers such as melanoma, lung carcinomas and urothelial cancers benefit from treatment with these drugs and survivals have improved in some ca-ses. However other cancers are primarily resistant to immune blockers and secondary resistance is also the norm. Radiation therapy is often used in the palliative treatment of patients with advanced cancers and, in addition to the local effect in the irradiated field, it may in rare cases produce a systemic antitumor effect, termed "abscopal". This effect has been suggested to be produced by immune mechanisms. Thus an opportunity presents for a synergistic effect of immune stimulation between radiation and immune blockade inhibitors. The therapeutic opportunities presented with the combination of radiation and these drugs for gastrointestinal cancers will be discussed in this editorial overview.
文摘Background:Immunity plays a major role in carcinogenesis and this is the case also for hepatocellular carcinomas(HCC).Checkpoint inhibitors,novel drugs that enhance the immune system’s ability to attack cancers,have been successfully introduced for the therapy of various malignancies including HCC.An important target of these drugs is the PD-L1/PD-1 ligand/receptor pair and several clinically available inhibitors of this pair exist.Data sources:A search of the literature until April 20,2019 was performed in the MEDLINE/PubMed database,the Embase database and the Cochrane Central Register of Controlled Trials.The clinical studies describing treatment with PD-L1/PD-1 inhibitors as monotherapy in HCC patients were retrieved.Patient characteristics with relevance for treatment efficacy,such as liver function,disease extend and previous treatment,were extracted from identified articles.Response and survival outcomes were the primary focus of the meta-analysis.Summary estimates of response rates and survival were calculated using a random or fixed effect model,depending on heterogeneity.Most common adverse effects were also recorded and summarized.Results:Three studies(two on nivolumab and one on pembrolizumab)with a total of 400 patients were included in the analysis.The summary response rate(RR)was 17.3%[95%confidence interval(CI):13.2%–21.4%].The summary disease control rate(DCR)was 56.6%(95%CI:44.7%–68.5%).Summary progression free survival(PFS)was 3.5 months(95%CI:2.8–4.2 months).Summary overall survival(OS)was 10.4 months(95%CI:3.5–17.2 months).Adverse effect rate was low and also consistent with the adverse effect profile of PD-L1/PD-1 inhibitors in other disease locations.Conclusions:Pembrolizumab and nivolumab are the only checkpoint inhibitors with data in HCC.Metaanalysis of their effectiveness discloses rates not dissimilar to other systemic therapies available for this disease.Of interest also are the observed long responses in a sub-set of responders.Further development is clearly warranted.
