Objective: Patients with BRAF-mutant colorectal cancer(CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs tha...Objective: Patients with BRAF-mutant colorectal cancer(CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs that radiosensitise CRC cells with known BRAF status.Methods: We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for BRAF. Hits from rank product analysis were validated in a 16-cell line panel of human CRC cell lines, using clonogenic survival assays and xenograft models in vivo.Results: Most consistently identified hits were drugs targeting cell growth/proliferation or DNA damage repair. The most effective class of drugs that radiosensitised wild-type and mutant cell lines was PARP inhibitors. In clonogenic survival assays, talazoparib produced a radiation enhancement ratio of 1.9 in DLD1(BRAF-wildtype) cells and 1.8 in RKO(BRAF V600 E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth(P ≤ 0.01).Conclusions: Our method for screening large drug libraries for radiosensitisation has identified PARP inhibitors as promising radiosensitisers of colorectal cancer cells with wild-type and mutant BRAF backgrounds.展开更多
The therapeutic landscape of metastatic colorectal cancer(mCRC)has changed substantially with the emergence of new molecularly targeted agents(MTA)usedas single agents or alongside standard chemotherapy.The use of the...The therapeutic landscape of metastatic colorectal cancer(mCRC)has changed substantially with the emergence of new molecularly targeted agents(MTA)usedas single agents or alongside standard chemotherapy.The use of these MTAs extended the overall survival ofpatients with mCRC to a level that current chemotherapeutics alone could not achieve.In addition,improvement in surgical techniques and ablation modalities offer cure to a limited subset of patients with mCRC andMTAs have been found to have a significant role heretoo,as they aid resectability.However,for the majority of patients,mCRC remains an invariably incurabledisease necessitating continued courses of combinedtreatment modalities.During the course of these treatments,either cytotoxic or biological,cancer cells maintain their ability to acquire mitogenic mutations whichrender them resistant to treatment.Key challengesremain to identify appropriate subsets of patients whowill most likely benefit from these new MTAs and effectively select these based on validated biomarkers.Moreover,better knowledge of the biology of colorectal cancer and the mechanisms via which it bypasses blockade of known signalling pathways will help us design better and more rational sequencing of these treatments,so that we can maximise the survivorship of mCRC patients.This review outlines treatment strategies for known molecular alterations with new MTAs and highlights some promising strategies.展开更多
A spate of high-powered genome-wide association studies （GWAS） have recently identified numerous single-nucleotide polymorphisms （SNPs） robustly linked with complex disease. Despite interrogating the majority of c...A spate of high-powered genome-wide association studies （GWAS） have recently identified numerous single-nucleotide polymorphisms （SNPs） robustly linked with complex disease. Despite interrogating the majority of common human variation, these SNPs only account for a small proportion of the phenotypic variance, which suggests genetic factors are acting in concert with non-genetic factors. Although environmental measures are logical covariants for genotype-phenotype investigations, another non-genetic intermediary exists： epigenetics. Epigenetics is the analysis of somatically-acquired and, in some cases, transgenerationally inherited epigenetic modifications that regulate gene expression, and offers to bridge the gap between genetics and environment to understand phenotype. The most widely studied epigenetic mark is DNA methylation. Aberrant methylation at gene promoters is strongly implicated in disease etiology, most notably cancer. This review will highlight the importance of DNA methylation as an epigenetic regulator, outline techniques to characterize the DNA methylome and present the idea of reverse phenotyping, where multiple layers of analysis are integrated at the individual level to create personalized digital phenotypes and, at a phenotype level, to identify novel molecular signatures of disease.展开更多
BACKGROUND Mixed neuroendocrine non-neuroendocrine neoplasm(MiNEN)is a rare diagnosis,mainly encountered in the gastro-entero-pancreatic tract.There is limited knowledge of its epidemiology,prognosis and biology,and t...BACKGROUND Mixed neuroendocrine non-neuroendocrine neoplasm(MiNEN)is a rare diagnosis,mainly encountered in the gastro-entero-pancreatic tract.There is limited knowledge of its epidemiology,prognosis and biology,and the best management for affected patients is still to be defined.AIM To investigate clinical-pathological characteristics,treatment modalities and survival outcomes of a retrospective cohort of patients with a diagnosis of MiNEN.METHODS Consecutive patients with a histologically proven diagnosis of MiNEN were identified at 5 European centres.Patient data were retrospectively collected from medical records.Pathological samples were reviewed to ascertain compliance with the 2017 World Health Organisation definition of MiNEN.Tumour responses to systemic treatment were assessed according to the Response Evaluation Criteria in Solid Tumours 1.1.Kaplan-Meier analysis was applied to estimate survival outcomes.Associations between clinical-pathological characteristics and survival outcomes were explored using Log-rank test for equality of survivors functions(univariate)and Cox-regression analysis(multivariable).RESULTS Sixty-nine consecutive patients identified;Median age at diagnosis:64 years.Males:63.8%.Localised disease(curable):53.6%.Commonest sites of origin:colon-rectum(43.5%)and oesophagus/oesophagogastric junction(15.9%).The neuroendocrine component was;predominant in 58.6%,poorly differentiated in 86.3%,and large cell in 81.25%,of cases analysed.Most distant metastases analysed(73.4%)were occupied only by a poorly differentiated neuroendocrine component.Ninety-four percent of patients with localised disease underwent curative surgery;53%also received perioperative treatment,most often in line with protocols for adenocarcinomas from the same sites of origin.Chemotherapy was offered to most patients(68.1%)with advanced disease,and followed protocols for pure neuroendocrine carcinomas or adenocarcinomas in equal proportion.In localised cases,median recurrence free survival(RFS);14.0 months(95%CI:9.2-24.4),and median overall survival(OS):28.6 months(95%CI:18.3-41.1).On univariate analysis,receipt of perioperative treatment(vs surgery alone)did not improve RFS(P=0.375),or OS(P=0.240).In advanced cases,median progression free survival(PFS);5.6 months(95%CI:4.4-7.4),and median OS;9.0 months(95%CI:5.2-13.4).On univariate analysis,receipt of palliative active treatment(vs best supportive care)prolonged PFS and OS(both,P<0.001).CONCLUSION MiNEN is most commonly driven by a poorly differentiated neuroendocrine component,and has poor prognosis.Advances in its biological understanding are needed to identify effective treatments and improve patient outcomes.展开更多
Augustus Volney Wal ler was a renowned British neurophysiologist who birthed the axon degeneration field in 1850 by describing curdling and fragmentation of the glossopharyngeal and hypoglossal cranial nerves of a fro...Augustus Volney Wal ler was a renowned British neurophysiologist who birthed the axon degeneration field in 1850 by describing curdling and fragmentation of the glossopharyngeal and hypoglossal cranial nerves of a frog following a transection injury.The degeneration of axons after a transection injury is now known as Wallerian degeneration(WD).Waller’s work was expanded by Santiago Ramón y Cajal who described in detail the morphological stages of WD from monitory fragmentation of the axon and the granular disintegration of the neurofibrils to the final resorption of the axon.展开更多
BACKGROUND The coronavirus disease 2019(COVID-19)pandemic has resulted in seismic changes in healthcare delivery.As a result of this,hospital footfall required to be reduced due to increased risk of transmission of in...BACKGROUND The coronavirus disease 2019(COVID-19)pandemic has resulted in seismic changes in healthcare delivery.As a result of this,hospital footfall required to be reduced due to increased risk of transmission of infection.To ensure patients can safely access healthcare,we introduced orthopaedic clinic telephone consultations in our busy district general hospital.AIM To investigate patients’and clinicians’perspective of telephone consultations during COVID-19,and whether this method of consultation could be a viable option in the post-pandemic future.METHODS This is a single centre,prospective study conducted in a busy National Health Service district general hospital.In May 2020,100 non-consecutive adult patients were contacted by independent investigators within 48 h of their orthopaedic clinic telephone consultation to complete a telephone satisfaction questionnaire.The questions assessed satisfaction regarding various aspects of the consultation including overall satisfaction and willingness to use this approach long term.Satisfaction and perspective of 25 clinicians conducting these telephone consultations was also assessed via an online survey tool.RESULTS 93%of patients were overall satisfied with telephone consultations and 79%were willing to continue this method of consultation post-pandemic.Patients found telephone consultations to reduce personal cost and inconvenience associated with attending a hospital appointment.72%of clinicians reported overall satisfaction with this service and 80%agreed that telephone consultations should be used in the future.The majority found it less laborious in time and administration in comparison to face to face consultations.Patients and clinicians expressed their desire for video consultations as a method of further improving their experience with remote consultations.CONCLUSION Our study has shown that telephone consultations are a safe and rapid method of adaptation to the COVID-19 pandemic,achieving the aim of reducing hospital footfall.This method of consultation has resulted in immense clinician and patient satisfaction.Our findings suggest that this tool has benefits in post pandemic healthcare delivery.It has also highlighted that telephone consultations can act as a steppingstone to the introduction of the more complex platform of video consulting.展开更多
Borderline ovarian tumors （BOTs） represent approxi-mately 10% of ovarian neoplasms and are a heteroge-neous group of tumors with variable biological behav-iour. The majority present with disease confned to the ovary...Borderline ovarian tumors （BOTs） represent approxi-mately 10% of ovarian neoplasms and are a heteroge-neous group of tumors with variable biological behav-iour. The majority present with disease confned to the ovary and have an excellent prognosis after surgical removal. A small proportion subsequently has recur-rent disease or progression to invasive cancer. Tumor recurrence can occur up to 20 years after surgical resection. There are no robust clinical, histological or molecular markers that distinguish high risk cases and no satisfactory treatment for patients with progressive disease. This results in great variability in management in different centres. We conducted a national survey on the management of borderline ovarian tumors in cancer centres representing different regions in the United Kingdom. In this article we review the literature for the current concepts in diagnosis, treatment and follow up of BOTs and we report the results of the survey of current practice in the United Kingdom. On that basis we provide recommendations for the management of patients with BOTs.展开更多
Definitions of platinum resistance have been questioned and changed over the last five years,even though no predictive biomarker of resistance exists.These have sculpted how we approach platinum retreatment and,conseq...Definitions of platinum resistance have been questioned and changed over the last five years,even though no predictive biomarker of resistance exists.These have sculpted how we approach platinum retreatment and,consequently,how we devise new treatment strategies for those patients with tumour progression on platinum therapy.Platinum-non-eligible ovarian cancer is treated with single-agent non-platinum drugs.When bevacizumab can be added to chemotherapy,progression-free survival improves significantly.For patients with a BRCA mutation,PARP inhibitor monotherapy is an option compared to chemotherapy.There is currently no clearly identified role for immune-checkpoint inhibition in this patient population.This review describes some of the challenges in treating patients with platinum resistance and suggests refinements in the selection of patients most likely to benefit from targeting a DNA damage response,angiogenesis or immune modulation.It also describes novel agents of interest and possible mechanisms of the synergy of therapeutic combinations.展开更多
Dear Editor, According to the cancer stem cell （CSC） hypothesis, cancer ceils are organized in a hierarchical manner （Reya et al, 2001）. Indeed, the differentiation state of cancer cells has been linked to their ...Dear Editor, According to the cancer stem cell （CSC） hypothesis, cancer ceils are organized in a hierarchical manner （Reya et al, 2001）. Indeed, the differentiation state of cancer cells has been linked to their proliferative potential, drug response, and ability to metastasize （Clevers, 2011）. Targeting self- renewing, undifferentiated cancer ceils could therefore be of importance for the success of cancer therapies. A classical case of a tumor composed of undifferenti- ated and differentiated cells is the tumor induced by pluripotent stem cells （PSCs） （Ben-David and Benvenisty, 2011）. We have recently identified several small mole- cules termed pluripotent-specific inhibitors （PluriSIns） that selectively target undif- ferentiated tumorigenic PSCs （Ben-David et aL, 2013）. Several of these compounds, including PluriSIn#1, inhibit the activity of stearoyl-coA desaturase （SCD1） （Ben- David et al, 2013）. SCD1 is an endoplasmic reticulum （ER）-membrane protein that plays a key role in the biosynthesis of the mono-unsaturated fatty acid oleate. This novel metabolic vulnerability is in line with the unique metabolome described in PSCs （Panopoulos et al, 2012）.展开更多
Background and aims The intrahepatic processes associated with chronic hepatitis B(CHB),especially in the context of hepatitis delta virus(HDV)and HIV co-infection,require a better understanding.Spatial transcriptomic...Background and aims The intrahepatic processes associated with chronic hepatitis B(CHB),especially in the context of hepatitis delta virus(HDV)and HIV co-infection,require a better understanding.Spatial transcriptomics can provide new insights into the complex intrahepatic biological processes,guiding new personalised treatments.Our aim is to evaluate this method characterising the intrahepatic transcriptional landscape,cellular composition and biological pathways in liver biopsy samples from patients with hepatitis B virus(HBV)and HDV or HIV co-infection.Method The NanoString GeoMx digital spatial profiling platform was employed to assess expression of HBV surface antigen and CD45 in formalin-fixed paraffin-embedded(FFPE)biopsies from three treatment-naive patients with chronic HBV and HDV or HIV co-infection.The GeoMx Human Whole Transcriptome Atlas assay quantified the expression of genes enriched in specific regions of interest(ROIs).Cell type proportions within ROIs were deconvoluted using a training matrix from the human liver cell atlas.A weighted gene correlation network analysis evaluated transcriptomic signatures across sampled regions.Results Spatially discrete transcriptomic signatures and distinct biological pathways were associated with HBV infection/disease status and immune responses.Shared features including‘cytotoxicity’and‘B cell receptor signalling’were consistent across patients,suggesting common elements alongside individual traits.HDV/HBV co-infection exhibited upregulated genes linked to apoptosis and immune cell recruitment,whereas HIV/HBV co-infection featured genes related to interferon response regulation.Varied cellular characteristics and immune cell populations,with an abundance ofγδT cells in the HDV/HBV sample,were observed within analysed regions.Transcriptional differences in hepatocyte function suggest disrupted metabolic processes in HDV/HBV co-infection potentially impacting disease progression.Conclusion This proof-of-principle study shows the value of this platform in investigating the complex immune landscape,highlighting relevant host pathways to disease pathogenesis.展开更多
Approximately 25%of individuals with colorectal cancer(CRC)present with metastatic disease,and it is estimated that throughout the course of the disease,up to 50%of individuals may develop liver metastases,the majorit...Approximately 25%of individuals with colorectal cancer(CRC)present with metastatic disease,and it is estimated that throughout the course of the disease,up to 50%of individuals may develop liver metastases,the majority of which are unresectable(1).However,thermal ablation is a treatment modality increasingly used to manage individuals with liver metastases.Recently Takahashi et al.published a comprehensive review of the various approaches to thermal ablation and summarised the recent evidence demonstrating an associated survival benefit supporting its use in the management of metastatic CRC(mCRC)(2).It is however critical to analyse the studies evaluated to ensure the strength of the evidence presented.展开更多
基金supported by Bowel Disease Research FoundationOxford Cancer Research Centre+4 种基金the National Institute for Health Research University College London Hospitals Biomedical Research Centrethe Cancer Research UK University College London Experimental Cancer Medicine CentreCRUK-UCL Centre Award (Grant No. C416/ A25145)the Cancer Research UK Centers Network Accelerator Award Grant (Grant No.A21993) to the ART-NET Consortiumthe NIHR Oxford Biomedical Research Centre
文摘Objective: Patients with BRAF-mutant colorectal cancer(CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs that radiosensitise CRC cells with known BRAF status.Methods: We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for BRAF. Hits from rank product analysis were validated in a 16-cell line panel of human CRC cell lines, using clonogenic survival assays and xenograft models in vivo.Results: Most consistently identified hits were drugs targeting cell growth/proliferation or DNA damage repair. The most effective class of drugs that radiosensitised wild-type and mutant cell lines was PARP inhibitors. In clonogenic survival assays, talazoparib produced a radiation enhancement ratio of 1.9 in DLD1(BRAF-wildtype) cells and 1.8 in RKO(BRAF V600 E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth(P ≤ 0.01).Conclusions: Our method for screening large drug libraries for radiosensitisation has identified PARP inhibitors as promising radiosensitisers of colorectal cancer cells with wild-type and mutant BRAF backgrounds.
文摘The therapeutic landscape of metastatic colorectal cancer(mCRC)has changed substantially with the emergence of new molecularly targeted agents(MTA)usedas single agents or alongside standard chemotherapy.The use of these MTAs extended the overall survival ofpatients with mCRC to a level that current chemotherapeutics alone could not achieve.In addition,improvement in surgical techniques and ablation modalities offer cure to a limited subset of patients with mCRC andMTAs have been found to have a significant role heretoo,as they aid resectability.However,for the majority of patients,mCRC remains an invariably incurabledisease necessitating continued courses of combinedtreatment modalities.During the course of these treatments,either cytotoxic or biological,cancer cells maintain their ability to acquire mitogenic mutations whichrender them resistant to treatment.Key challengesremain to identify appropriate subsets of patients whowill most likely benefit from these new MTAs and effectively select these based on validated biomarkers.Moreover,better knowledge of the biology of colorectal cancer and the mechanisms via which it bypasses blockade of known signalling pathways will help us design better and more rational sequencing of these treatments,so that we can maximise the survivorship of mCRC patients.This review outlines treatment strategies for known molecular alterations with new MTAs and highlights some promising strategies.
文摘A spate of high-powered genome-wide association studies （GWAS） have recently identified numerous single-nucleotide polymorphisms （SNPs） robustly linked with complex disease. Despite interrogating the majority of common human variation, these SNPs only account for a small proportion of the phenotypic variance, which suggests genetic factors are acting in concert with non-genetic factors. Although environmental measures are logical covariants for genotype-phenotype investigations, another non-genetic intermediary exists： epigenetics. Epigenetics is the analysis of somatically-acquired and, in some cases, transgenerationally inherited epigenetic modifications that regulate gene expression, and offers to bridge the gap between genetics and environment to understand phenotype. The most widely studied epigenetic mark is DNA methylation. Aberrant methylation at gene promoters is strongly implicated in disease etiology, most notably cancer. This review will highlight the importance of DNA methylation as an epigenetic regulator, outline techniques to characterize the DNA methylome and present the idea of reverse phenotyping, where multiple layers of analysis are integrated at the individual level to create personalized digital phenotypes and, at a phenotype level, to identify novel molecular signatures of disease.
文摘BACKGROUND Mixed neuroendocrine non-neuroendocrine neoplasm(MiNEN)is a rare diagnosis,mainly encountered in the gastro-entero-pancreatic tract.There is limited knowledge of its epidemiology,prognosis and biology,and the best management for affected patients is still to be defined.AIM To investigate clinical-pathological characteristics,treatment modalities and survival outcomes of a retrospective cohort of patients with a diagnosis of MiNEN.METHODS Consecutive patients with a histologically proven diagnosis of MiNEN were identified at 5 European centres.Patient data were retrospectively collected from medical records.Pathological samples were reviewed to ascertain compliance with the 2017 World Health Organisation definition of MiNEN.Tumour responses to systemic treatment were assessed according to the Response Evaluation Criteria in Solid Tumours 1.1.Kaplan-Meier analysis was applied to estimate survival outcomes.Associations between clinical-pathological characteristics and survival outcomes were explored using Log-rank test for equality of survivors functions(univariate)and Cox-regression analysis(multivariable).RESULTS Sixty-nine consecutive patients identified;Median age at diagnosis:64 years.Males:63.8%.Localised disease(curable):53.6%.Commonest sites of origin:colon-rectum(43.5%)and oesophagus/oesophagogastric junction(15.9%).The neuroendocrine component was;predominant in 58.6%,poorly differentiated in 86.3%,and large cell in 81.25%,of cases analysed.Most distant metastases analysed(73.4%)were occupied only by a poorly differentiated neuroendocrine component.Ninety-four percent of patients with localised disease underwent curative surgery;53%also received perioperative treatment,most often in line with protocols for adenocarcinomas from the same sites of origin.Chemotherapy was offered to most patients(68.1%)with advanced disease,and followed protocols for pure neuroendocrine carcinomas or adenocarcinomas in equal proportion.In localised cases,median recurrence free survival(RFS);14.0 months(95%CI:9.2-24.4),and median overall survival(OS):28.6 months(95%CI:18.3-41.1).On univariate analysis,receipt of perioperative treatment(vs surgery alone)did not improve RFS(P=0.375),or OS(P=0.240).In advanced cases,median progression free survival(PFS);5.6 months(95%CI:4.4-7.4),and median OS;9.0 months(95%CI:5.2-13.4).On univariate analysis,receipt of palliative active treatment(vs best supportive care)prolonged PFS and OS(both,P<0.001).CONCLUSION MiNEN is most commonly driven by a poorly differentiated neuroendocrine component,and has poor prognosis.Advances in its biological understanding are needed to identify effective treatments and improve patient outcomes.
基金CSH was supported by a National Institute for Health Research(NIHR)Academic Clinical Lectureship。
文摘Augustus Volney Wal ler was a renowned British neurophysiologist who birthed the axon degeneration field in 1850 by describing curdling and fragmentation of the glossopharyngeal and hypoglossal cranial nerves of a frog following a transection injury.The degeneration of axons after a transection injury is now known as Wallerian degeneration(WD).Waller’s work was expanded by Santiago Ramón y Cajal who described in detail the morphological stages of WD from monitory fragmentation of the axon and the granular disintegration of the neurofibrils to the final resorption of the axon.
文摘BACKGROUND The coronavirus disease 2019(COVID-19)pandemic has resulted in seismic changes in healthcare delivery.As a result of this,hospital footfall required to be reduced due to increased risk of transmission of infection.To ensure patients can safely access healthcare,we introduced orthopaedic clinic telephone consultations in our busy district general hospital.AIM To investigate patients’and clinicians’perspective of telephone consultations during COVID-19,and whether this method of consultation could be a viable option in the post-pandemic future.METHODS This is a single centre,prospective study conducted in a busy National Health Service district general hospital.In May 2020,100 non-consecutive adult patients were contacted by independent investigators within 48 h of their orthopaedic clinic telephone consultation to complete a telephone satisfaction questionnaire.The questions assessed satisfaction regarding various aspects of the consultation including overall satisfaction and willingness to use this approach long term.Satisfaction and perspective of 25 clinicians conducting these telephone consultations was also assessed via an online survey tool.RESULTS 93%of patients were overall satisfied with telephone consultations and 79%were willing to continue this method of consultation post-pandemic.Patients found telephone consultations to reduce personal cost and inconvenience associated with attending a hospital appointment.72%of clinicians reported overall satisfaction with this service and 80%agreed that telephone consultations should be used in the future.The majority found it less laborious in time and administration in comparison to face to face consultations.Patients and clinicians expressed their desire for video consultations as a method of further improving their experience with remote consultations.CONCLUSION Our study has shown that telephone consultations are a safe and rapid method of adaptation to the COVID-19 pandemic,achieving the aim of reducing hospital footfall.This method of consultation has resulted in immense clinician and patient satisfaction.Our findings suggest that this tool has benefits in post pandemic healthcare delivery.It has also highlighted that telephone consultations can act as a steppingstone to the introduction of the more complex platform of video consulting.
基金Supported by The NIHR Biomedical Research Centre
文摘Borderline ovarian tumors （BOTs） represent approxi-mately 10% of ovarian neoplasms and are a heteroge-neous group of tumors with variable biological behav-iour. The majority present with disease confned to the ovary and have an excellent prognosis after surgical removal. A small proportion subsequently has recur-rent disease or progression to invasive cancer. Tumor recurrence can occur up to 20 years after surgical resection. There are no robust clinical, histological or molecular markers that distinguish high risk cases and no satisfactory treatment for patients with progressive disease. This results in great variability in management in different centres. We conducted a national survey on the management of borderline ovarian tumors in cancer centres representing different regions in the United Kingdom. In this article we review the literature for the current concepts in diagnosis, treatment and follow up of BOTs and we report the results of the survey of current practice in the United Kingdom. On that basis we provide recommendations for the management of patients with BOTs.
文摘Definitions of platinum resistance have been questioned and changed over the last five years,even though no predictive biomarker of resistance exists.These have sculpted how we approach platinum retreatment and,consequently,how we devise new treatment strategies for those patients with tumour progression on platinum therapy.Platinum-non-eligible ovarian cancer is treated with single-agent non-platinum drugs.When bevacizumab can be added to chemotherapy,progression-free survival improves significantly.For patients with a BRCA mutation,PARP inhibitor monotherapy is an option compared to chemotherapy.There is currently no clearly identified role for immune-checkpoint inhibition in this patient population.This review describes some of the challenges in treating patients with platinum resistance and suggests refinements in the selection of patients most likely to benefit from targeting a DNA damage response,angiogenesis or immune modulation.It also describes novel agents of interest and possible mechanisms of the synergy of therapeutic combinations.
文摘Dear Editor, According to the cancer stem cell （CSC） hypothesis, cancer ceils are organized in a hierarchical manner （Reya et al, 2001）. Indeed, the differentiation state of cancer cells has been linked to their proliferative potential, drug response, and ability to metastasize （Clevers, 2011）. Targeting self- renewing, undifferentiated cancer ceils could therefore be of importance for the success of cancer therapies. A classical case of a tumor composed of undifferenti- ated and differentiated cells is the tumor induced by pluripotent stem cells （PSCs） （Ben-David and Benvenisty, 2011）. We have recently identified several small mole- cules termed pluripotent-specific inhibitors （PluriSIns） that selectively target undif- ferentiated tumorigenic PSCs （Ben-David et aL, 2013）. Several of these compounds, including PluriSIn#1, inhibit the activity of stearoyl-coA desaturase （SCD1） （Ben- David et al, 2013）. SCD1 is an endoplasmic reticulum （ER）-membrane protein that plays a key role in the biosynthesis of the mono-unsaturated fatty acid oleate. This novel metabolic vulnerability is in line with the unique metabolome described in PSCs （Panopoulos et al, 2012）.
基金supported by the US Department of Health and Human Services,National Institute of Health/National Institute of Allergy and Infectious Diseases/award(R01AI55182)to DPan Academy of Medical Sciences Starter Grant(SGL021/1030)+3 种基金Seedcorn funding Rosetrees/Stoneygate Trust(A2903)and Mid-Career Research Award from The Medical Research Foundation(MRF-044-0004-F-GILL-C0823)to USGMedical Sciences Division(0011187)Pump-Priming grant awarded to FI and JAMcKResearch in the McKeating laboratory is funded by a Wellcome Investigator Award 200838/Z/16/Z,Wellcome Discovery Award 225198/Z/22/ZChinese Academy of Medical Sciences Innovation Fund for Medical Science,China(grant number:2018-I2M-2-002).
文摘Background and aims The intrahepatic processes associated with chronic hepatitis B(CHB),especially in the context of hepatitis delta virus(HDV)and HIV co-infection,require a better understanding.Spatial transcriptomics can provide new insights into the complex intrahepatic biological processes,guiding new personalised treatments.Our aim is to evaluate this method characterising the intrahepatic transcriptional landscape,cellular composition and biological pathways in liver biopsy samples from patients with hepatitis B virus(HBV)and HDV or HIV co-infection.Method The NanoString GeoMx digital spatial profiling platform was employed to assess expression of HBV surface antigen and CD45 in formalin-fixed paraffin-embedded(FFPE)biopsies from three treatment-naive patients with chronic HBV and HDV or HIV co-infection.The GeoMx Human Whole Transcriptome Atlas assay quantified the expression of genes enriched in specific regions of interest(ROIs).Cell type proportions within ROIs were deconvoluted using a training matrix from the human liver cell atlas.A weighted gene correlation network analysis evaluated transcriptomic signatures across sampled regions.Results Spatially discrete transcriptomic signatures and distinct biological pathways were associated with HBV infection/disease status and immune responses.Shared features including‘cytotoxicity’and‘B cell receptor signalling’were consistent across patients,suggesting common elements alongside individual traits.HDV/HBV co-infection exhibited upregulated genes linked to apoptosis and immune cell recruitment,whereas HIV/HBV co-infection featured genes related to interferon response regulation.Varied cellular characteristics and immune cell populations,with an abundance ofγδT cells in the HDV/HBV sample,were observed within analysed regions.Transcriptional differences in hepatocyte function suggest disrupted metabolic processes in HDV/HBV co-infection potentially impacting disease progression.Conclusion This proof-of-principle study shows the value of this platform in investigating the complex immune landscape,highlighting relevant host pathways to disease pathogenesis.
文摘Approximately 25%of individuals with colorectal cancer(CRC)present with metastatic disease,and it is estimated that throughout the course of the disease,up to 50%of individuals may develop liver metastases,the majority of which are unresectable(1).However,thermal ablation is a treatment modality increasingly used to manage individuals with liver metastases.Recently Takahashi et al.published a comprehensive review of the various approaches to thermal ablation and summarised the recent evidence demonstrating an associated survival benefit supporting its use in the management of metastatic CRC(mCRC)(2).It is however critical to analyse the studies evaluated to ensure the strength of the evidence presented.
