Prostate cancer is a leading cause of global cancer-related death but attempts to improve diagnoses and develop novel therapies have been confounded by significant patient heterogeneity. In recent years, the applicati...Prostate cancer is a leading cause of global cancer-related death but attempts to improve diagnoses and develop novel therapies have been confounded by significant patient heterogeneity. In recent years, the application of next-generation sequencing to hundreds of prostate tumours has defined novel molecular subtypes and characterized extensive genomic aberration underlying disease initiation and progression. It is now clear that the heterogeneity observed in the clinic is underpinned by a molecular landscape rife with complexity, where genomic rearrangements and rare mutations combine to amplify transcriptomic diversity. This review dissects our current understanding of prostate cancer ＇omics＇, including the sentinel role of copy number variation, the growing spectrum of oncogenic fusion genes, the potential influence of chromothripsis, and breakthroughs in defining mutation-associated subtypes. Increasing evidence suggests that genomic lesions frequently converge on specific cellular functions and signalling pathways, yet recurrent gene aberration appears rare. Therefore, it is critical that we continue to define individual tumour genomes, especially in the context of their expressed transcriptome. Only through improved characterisation of tumour to tumour variability can we advance to an age of precision therapy and personalized oncology.展开更多
Alternative splicing （AS） is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence impli...Alternative splicing （AS） is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence implicates splice isoforms in most if not all hallmarks of cancer, including growth, apoptosis, invasion and metastasis, angiogenesis, and metabolism. AS has important clinical implications since it can be manipulated therapeutically to treat cancer and represents a mechanism of resistance to therapy. In prostate cancer （PCa） AS also plays a prominent role and this review will summarize the current knowledge of alternatively spliced genes with important functional consequences. We will highlight accumulating evidence on AS of the components of the two critical pathways in PCa： androgen receptor （AR） and phosphoinositide 3-kinase （PI3K）. These observations together with data on dysregulation of splice factors in PCa suggest that AR and PI3K pathways may be interconnected with previously unappreciated splicing regulatory networks. In addition, we will discuss several lines of evidence implicating splicing regulation in the development of the castration resistance.展开更多
Prostate cancers(PCa)have been reported to actively suppress antitumor immune responses by creating an immune-suppressive microenvironment.There is mounting evidence that PCas may undergo an‘‘Epithelial Immune Cell-...Prostate cancers(PCa)have been reported to actively suppress antitumor immune responses by creating an immune-suppressive microenvironment.There is mounting evidence that PCas may undergo an‘‘Epithelial Immune Cell-like Transition’’(EIT)by expressing molecules conventionally associated with immune cells(e.g.,a variety of cytokines/receptors,immune transcription factors,Ig motifs,and immune checkpoint molecules),which subsequently results in the suppression of anti-cancer immune activity within the tumor microenvironment.Recent progress within the field of immune therapy has underscored the importance of immune checkpoint molecules in cancer development,thus leading to the development of novel immunotherapeutic approaches.Here,we review the expression of select immune checkpoint molecules in PCa epithelial and associated immune cells,with particular emphasis on clinical data supporting the concept of an EIT-mediated phenotype in PCa.Furthermore,we summarize current advances in anti-immune checkpoint therapies,and provide perspectives on their potential applicability.展开更多
Significant advances in breast cancer treatment have been made where it is now possible to treat localized disease to a curable state. However, for approximately 30% of women with primary disease, metastatic breast ca...Significant advances in breast cancer treatment have been made where it is now possible to treat localized disease to a curable state. However, for approximately 30% of women with primary disease, metastatic breast cancer (MBC) or recurrent disease, treatment has remained challenging. Major obstacles in the effective treatment of breast cancer in these populations include: 1) the molecular heterogeneity of the disease;2) treatment of MBC and more specifically brain metastasis;and 3) defining combination therapies that address the evolution of resistance with disease relapse. The acknowledgement of these difficulties has led to an effort to further understand the roadblocks to therapy with the anticipation that more appropriate treatments will result. Here we describe the current state of breast cancer treatment, and the potential for improved therapy.展开更多
Ethnicity might be associated with treatment outcomes in advanced prostate cancer.This study aimed to evaluate the efficacy and safety of androgen deprivation therapy(ADT)combined with apalutamide in East Asians with ...Ethnicity might be associated with treatment outcomes in advanced prostate cancer.This study aimed to evaluate the efficacy and safety of androgen deprivation therapy(ADT)combined with apalutamide in East Asians with metastatic castration-sensitive prostate cancer(mCSPC).The original phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen(TITAN)trial was conducted at 260 sites in 23 countries.This subgroup analysis included patients enrolled in 62 participating centers in China,Japan,and Korea.Radiographic progression-free survival(PFS),time to prostate-specific antigen(PSA)progression,and PSA changes from baseline were compared between groups in the East Asian population.The intent-to-treat East Asian population included 111 and 110 participants in the apalutamide and placebo groups,respectively.The 24-month radiographic PFS rates were 76.1%and 52.3%in the apalutamide and placebo groups,respectively(apalutamide vs placebo:hazard ratio[HR]=0.506;95%confidence interval[CI],0.302–0.849;P=0.009).Median time to PSA progression was more favorable with apalutamide than placebo(HR=0.210;95%CI,0.124–0.357;P<0.001).Median maximum percentages of PSA decline from baseline were 99.0%and 73.9%in the apalutamide and placebo groups,respectively.The most common adverse event(AE)was rash in the apalutamide group,with a higher rate than that in the placebo group(37.3%vs 9.1%).The most common grade 3 or 4 AEs were rash(12[10.9%])and hypertension(12[10.9%])for apalutamide.The efficacy and safety of apalutamide in the East Asian subgroup of the TITAN trial are consistent with the global results.展开更多
Retroperitoneal fibrosis secondary to malignant disease is a rare condition associated with a dismal prognosis. We herein present the first ever reported case of ret-roperitoneal fibrosis related to esophageal adenoca...Retroperitoneal fibrosis secondary to malignant disease is a rare condition associated with a dismal prognosis. We herein present the first ever reported case of ret-roperitoneal fibrosis related to esophageal adenocarcinoma in a 63-year-old patient who developed bilateral ureteral obstruction due to extensive retroperitoneal fibrosis 18 mo after having completed neoadjuvant chemoradation followed by surgery for a pT3N0 ad-enocarcinoma of the distal esophagus. We also report the case of a previously healthy woman who presented with bilateral ureteral obstruction and diffuse narrowing of the common biliary duct and was found to have extensive retroperitoneal fibrosis as a consequence of metastatic gastric adenocarcinoma. Both patients had poor performance status and were unsuitable for pallia-tive chemotherapy. This paper shows that urinary and biliary obstructive symptoms might represent retroperi-toneal fibrosis as a consequence of gastroesophageal malignancy.展开更多
BACKGROUND Over the last decade,multiple agents have demonstrated efficacy for advanced esophagogastric cancer(EGC).Despite the availability of later lines of therapy,there remains limited real-world data about the tr...BACKGROUND Over the last decade,multiple agents have demonstrated efficacy for advanced esophagogastric cancer(EGC).Despite the availability of later lines of therapy,there remains limited real-world data about the treatment attrition rates between lines of therapy.AIM To characterize the use and attrition rates between lines of therapy for patients with advanced EGC.METHODS We identified patients who received at least one cycle of chemotherapy for advanced EGC between July 1,2017 and July 31,2018 across six regional centers in British Columbia(BC),Canada.Clinicopathologic,treatment,and outcomes data were extracted.RESULTS Of 245 patients who received at least one line of therapy,median age was 66 years(IQR 58.2-72.3)and 186(76%)were male,Eastern Cooperative Oncology Group(ECOG)performance status 0/1(80%),gastric vs GEJ(36%vs 64%).Histologies included adenocarcinoma(78%),squamous cell carcinoma(8%),and signet ring(14%),with 31%HER2 positive.72%presented with de novo disease,and 25%had received previous chemoradiation.There was a high level of treatment attrition,with patients receiving only one line of therapy n=122,50%),two lines n=83,34%),three lines n=34,14%),and four lines n=6,2%).Kaplan-Meier analysis demonstrated improved survival with increasing lines of therapy(median overall survival 7.7 vs 16.6 vs 22.8 vs 40.4 mo,P<0.05).On multivariable Cox regression,improved survival was associated with better baseline ECOG and increased lines of therapy(P<0.05).CONCLUSION The steep attrition rates between therapies highlight the unmet need for more efficacious early-line treatment options for patients with advanced EGC.展开更多
AIM: To show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death. METHODS: MA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years ...AIM: To show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death. METHODS: MA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years of octreotide 90 mg, given by depot intramuscular injections monthly. Event-free survival was the primary endpoint of MA.14; at median 7.9 years, the tamoxifen+octreotide and tamoxifen arms had similar event-free survival(P = 0.62). Overall survival was a secondary endpoint, and the two trial arms also had similar overall survival(P = 0.86). We used the median 9.8 years follow-up to examine by intention-to-treat, the multivariate time-to-breast cancer-specific(Br Ca) and other cause(OC) mortality with log-normal survival analysis adjusted by treatment and stratification factors. We tested whether baseline factors including Insulin-like growth factor 1(IGF1), IGF binding protein-3, C-peptide, body mass index, and 25-OH vitamin D were associated with(1) all cause mortality, and if so; and(2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models.RESULTS: The analyses were performed on 329 patients allocated tamoxifen and 329 allocated tamoxifen+octreotide. The median age of MA.14 patients was 60.1 years: 447(82%) < 70 years and 120(18%) ≥ 70 years. There were 170 deaths: 106(62.3%) BrC a; 55(32.4%) OC, of which 24 were other malignancies, 31 other causes of death; 9(5.3%) patients with unknown cause of death were excluded from competing risk assessments. BrC a and OC deaths were not significantly different by treatment arm(P = 0.40): tamoxifen patients experienced 50 BrC a and 32 OC deaths, while tamoxifen + octreotide patients experienced 56 Br Ca and 23 OC deaths. Proportionately more deaths(P = 0.004) were from BrC a for patients< 70 years, where 70% of deaths were due to Br Ca, compared to 54% for those ≥ 70 years of age. The proportion of deaths from OC increased with increasing body mass index(BMI)(P = 0.02). Higher pathologic T and N were associated with more BrC a deaths(P < 0.0001 and 0.002, respectively). The cumulative hazard plot for Br Ca and OC mortality indicated the concurrent accrual of both types of death throughout followup, that is the existence of competing risks of mortality. MA.14 therapy did not impact mortality(P = 0.77). Three baseline patient and tumor characteristics were differentially associated with cause of death: older patients experienced more OC(P = 0.01) mortality; patients with T1 tumors and hormone receptor positive tumors had less BrC a mortality(respectively, P = 0.01, P = 0.06). Additionally, step-wise cause-specific models indicated that patients with node negative disease experienced less BrC a mortality(P = 0.002); there was weak evidence that, lower C-peptide(P = 0.08) was associated with less BrC a mortality, while higher BMI(P = 0.01) was associated with worse OC mortality.CONCLUSION: We demonstrate here a new paradigm of simultaneous testing of therapeutics directed at multiple diseases for which postmenopausal women are concurrently at risk. Octreotide LAR did not significantly impact breast cancer or other cause mortality, although different baseline factors influenced type of death.展开更多
BACKGROUND Barrett esophagus(BE),a metaplastic adaptive process to gastrointestinal reflux,is associated with a higher risk of developing esophageal adenocarcinoma.However,the factors and mechanism that drive the mali...BACKGROUND Barrett esophagus(BE),a metaplastic adaptive process to gastrointestinal reflux,is associated with a higher risk of developing esophageal adenocarcinoma.However,the factors and mechanism that drive the malignant progression of BE is not well understood.AIM To investigate the role of bile acids,a component of the reflux fluid,in the malignant progression of BE.METHODS Using engineered green fluorescent protein-labeled adult tissue-resident stem cells isolated from BE clinical biopsies(BE-ASCs)as the target,we studied the effect of hydrophobic deoxycholic acid(DCA)and hydrophilic tetrahydroxylated bile acids(THBA)on cell viability by fluorescence intensity analysis,mucin production by dark density measurement,tissue structure by pathology analysis,expression of different pro-inflammatory factors gene by quantitative polymerase chain reaction and proteins by Western blot.RESULTS We found that hydrophobic DCA has cytotoxic and proinflammatory effects through activation of interleukin-1β(IL-1β)-nuclear factor kappa-B(NF-κB)inflammatory pathway on BE-ASCs.This action results in impaired cell viability,tissue intactness,reduced mucin production,and increased transition to disorganized atypical cells without intestinal features.In contrast,co-culture with hydrophilic THBA inhibited the IL-1β-NF-κB inflammatory pathway with maintenance of mature intestinal type cellular and histomorphology.CONCLUSION Our data indicates that the hydrophilic bile acid THBA can counteract the cytotoxic and proinflammatory effect of hydrophobic DCA and prevent the malignant progression of BE by inhibiting the IL-1β-NF-κB pathway.展开更多
Mixed neuroendocrine-non-neuroendocrine neoplasms(MiNENs)are rare mixed tumors containing both neuroendocrine(NE)and non-NE components.Each component must occupy at least 30%of the tumor volume by definition.Recent mo...Mixed neuroendocrine-non-neuroendocrine neoplasms(MiNENs)are rare mixed tumors containing both neuroendocrine(NE)and non-NE components.Each component must occupy at least 30%of the tumor volume by definition.Recent molecular evidence suggests MiNENs are clonal neoplasms and potentially harbor targetable mutations similar to conventional carcinomas.There have been multiple changes in the nomenclature and classification of MiNENs which has created some confusion among pathologists on how to integrate the contributions of each component in a MiNEN,an issue which in turn has resulted in confusion in communication with front-line treating oncologists.This mini review summarizes our current understanding of MiNENs and outline diagnosis,prognosis,and management of these neoplasms.The authors emphasize the importance of treating the most aggressive component of the tumor regardless of its percentage volume.展开更多
Neuroendocrine tumors are rare neoplasms that infrequently metastasize to the orbit.Given that patients with these tumors may have prolonged survival despite dissemination,maintaining quality of life by providing earl...Neuroendocrine tumors are rare neoplasms that infrequently metastasize to the orbit.Given that patients with these tumors may have prolonged survival despite dissemination,maintaining quality of life by providing early diagnosis and effective treatment to preserve vision and comfort is a fundamental issue.We report the case of a79-year old woman who presented with well-differentiated metastatic neuroendocrine tumor to the liver with no carcinoid syndrome and was started on intramuscular long-acting octreotide with disease stabilization.Two years later she developed right-sided diplopia associated with mild eye discomfort,proptosis and reddening.An magnetic resonance imaging showed a 2.1 cm mass in the right orbit and further biopsy confirmed a neuroendocrine tumor metastasis.The patient was treated with a four-week course of stereotactic radiotherapy to the right orbital metastasis(4000 cGy in 20 fractions)with minor conjunctivitis as the only side effect.Eighteen months later,she remains well with no visual loss.展开更多
Multi-photon microscopy(MPM)and coherent anti-Stokes Raman scattering(CARS)are two advanced nonlinear optical imaging techniques,which provide complementary information and have great potential in combination for noni...Multi-photon microscopy(MPM)and coherent anti-Stokes Raman scattering(CARS)are two advanced nonlinear optical imaging techniques,which provide complementary information and have great potential in combination for noninvasive in vrito biomedical applications.This paper provides a detailed discussion of the basics,development and applications of these technologies for in vrivo skin research,covering the following topics:The principle and advantage of MPM and CARS,instrumentation development for in vino applications,MPM and CARS of normal skin,application of MPM and CARS in skin cancer and disease diagnosis;application of MPM in skin disease intervention,ie.,imaging guided two-photon photothermolysis.展开更多
Purpose: This study provides a simple protocol for validation of the gamma passing rates and to identify the optimum values of % dose and mm criteria for dose distributions measured with a detector array. Methods: We ...Purpose: This study provides a simple protocol for validation of the gamma passing rates and to identify the optimum values of % dose and mm criteria for dose distributions measured with a detector array. Methods: We chose ArcCHECK detector array to illustrate the concepts. We used plans with uniform or quasi-uniform dose distributions along the detector array for testing in the presence of dose errors. For testing sensitivity to spatial shift we employed a plan with approximately constant dose gradient along the axis of the instrument. Results: We identified a representative set of parameters which describe performance of a detector array. We determined the minimum gamma-index acceptance criteria allowing the passing rates to reach 100% in the absence of errors, and identified the minimum fully detectable errors for such criteria. For our baseline plans delivered to ArcCHECK, 100% passing rates were obtained for 1.5% dose criterion together with ±3% minimum error detectable at 100% rate, and for 1.5 mm criterion together with the minimum fully detectable error of ±3 mm. We inspected the impact of selected program options on the passing rates. Conclusions: The protocol we developed provides a simple method of commissioning-style analysis of a detector array without a need for analysis of a large number of clinical plans.展开更多
Early massively-parallel sequencing stu-dies have revealed the mutational land-scape of protein-coding genes in prostate cancer. However, most of these studies have not explored the extensive influence of geno- mic re...Early massively-parallel sequencing stu-dies have revealed the mutational land-scape of protein-coding genes in prostate cancer. However, most of these studies have not explored the extensive influence of geno- mic rearrangement in prostate cancer. In a recent Cell article, Baca and colleagues used whole-genome sequencing to tackle this issue, comprehensively surveying the abun-dance of genomic rearrangements present in a large cohort of 57 prostate cancers. They characterized a wide-spread phenomenon termed ＇chromoplexy＇, which may drive can-cer evolution through the phenomena of punctuated equilibrium by concurrently dys-regulating numerous cancer genes across multiple chromosomes. While the causes of this event still require elucidation, this defin-ing discovery undoubtedly offers an impor- tant glimpse into the evolutionary process of prostate cancer.展开更多
Streaking artifacts on computed tomography (CT) images are caused by high density materials such as hip prosthesis, surgical clips and dental fillings. The artifacts can lead to compromised clinical outcome due to the...Streaking artifacts on computed tomography (CT) images are caused by high density materials such as hip prosthesis, surgical clips and dental fillings. The artifacts can lead to compromised clinical outcome due to the inability to differentiate tumor volume and the uncertainties in dose calculation. The goals of our study are to evaluate how GE’s smart metal artifact reduction (MAR) algorithm impacts image quality on phantoms and dosimetry on head and neck patients with dental fillings and pelvic patients with hip prosthesis. Treatment plans calculated on the MAR and non-MAR datasets with the same beam arrangements and fluence are compared. Dose differences between the MAR and non-MAR datasets are not significant. However, substantial reductions of metal artifacts are observed when MAR algorithm is applied. Planning on the MAR dataset is recommended since it improves image quality and CT number accuracy. It also negates the need to contour the artifacts and override the density which can be time consuming.展开更多
This first issue of the World Journal of Hematology(WJH) marks the birth of a new member of the World Series Journal family and comes at one of the most exciting times in stem cell biology and translational medicine. ...This first issue of the World Journal of Hematology(WJH) marks the birth of a new member of the World Series Journal family and comes at one of the most exciting times in stem cell biology and translational medicine. The pace of discovery in the field of hematology has accelerated signeificantly in recent years, due to important scientific discoveries and new technologies for purification of hematopoietic stem cells and identification of specific stem cell biomarkers; whole genome sequencing using next-generation sequencing technology; and development of molecularly-targeted therapies, leading to the translation of highly promising science into advanced diagnosis and proven targeted therapies for hematopoietic disorders. The WJH is an open-access, peer-reviewed journal, which is officially published on June 6, 2012. The WJH Editorial Board consists of 102 experts in hematology from 26 countries. There is clearly a niche for this new journal, which provides access to all articles without boundaries to all internet users throughout the world. The WJH aims to provide rapid access to high impact publications in fundamental and clinical hematology, with multidisciplinary coverage, through an established system that is targeted at dissemination to the scientific community via online openaccess.展开更多
Treatment-induced neuroendocrine prostate cancer(NEPC)represents a lethal evolution of prostate adenocarcinoma under androgen receptor pathway inhibition,posing a significant clinical challenge.In a recent landmark st...Treatment-induced neuroendocrine prostate cancer(NEPC)represents a lethal evolution of prostate adenocarcinoma under androgen receptor pathway inhibition,posing a significant clinical challenge.In a recent landmark study,Wang et al.introduced an innovative internal Z-score based approach to comprehensively characterize the transcription factor(TF)landscape in prostate cancer progression,uncovering distinct TF profiles associated with adenocarcinoma and NEPC lineages.Notably,the study proposes a three-phase model of NEPC transdifferentiation-comprising de-differentiation,dormancy,and re-differentiation-revealing dynamic shifts in TF expression that underpin lineage plasticity and therapeutic resistance.This commentary critically evaluates the methodological advancements,the functional significance of the identified TF signatures,and the broader implications of these findings for developing novel therapeutic strategies.By delineating the molecular events driving the transition from androgen receptor(AR)-dependent adenocarcinoma to treatment-resistant NEPC,this work underscores the potential of targeting early and dormant phases of transdifferentiation to improve patient outcomes.展开更多
Aim:Lung cancer remains a major global health challenge,and this study presents a censor-aware semi-supervised learning framework(SSL)that integrates clinical and imaging data to improve prognostic modeling and addres...Aim:Lung cancer remains a major global health challenge,and this study presents a censor-aware semi-supervised learning framework(SSL)that integrates clinical and imaging data to improve prognostic modeling and address biases in handling censored data.Methods:We analyzed clinical,positron emission tomography(PET),and computed tomography(CT)data from 199 lung cancer patients from public and local databases,focusing on overall survival time as the primary outcome.Handcrafted(HRF)and Deep Radiomics features were extracted after preprocessing using Visualized&Standardized Environment for Radiomics Analysis(ViSERA)software and were combined with clinical features.Features were reduced using Pearson’s correlation coefficient regression(RR)and the F-test for regression(FR),followed by supervised learning(SL)and SSL.In SSL,censored data were pseudo-labeled using the Weibull accelerated failure time(AFT)model to enrich the training data.Seven regressors and three hazard ratio survival analyses(HRSAs)were optimized using five-fold cross-validation,grid search,and holdout test bootstrapping.Results:For PET-HRFs,the SSL approach reduced the mean absolute error by 14.81%,achieving 1.04 years with FR+AdaBoost Regression(ABR)compared to 1.20 years with SL.For clinical features,SSL with RR+ABR reached a mean absolute error of 1.04 years,outperforming SL(1.09 years)with a 4.9%improvement.In HRSA,CT_HRF combined with principal component analysis(PCA)+Component-Wise Gradient Boosting Survival Analysis yielded an external C-index of 0.65±0.02,effectively distinguishing high-and low-risk groups.Conclusions:The SSL strategy applied to HRFs from PET imaging significantly enhanced survival prediction compared to SL and uncovered complementary biological information that may remain hidden when only limited labeled data are used.展开更多
This commentary discusses a ground-breaking study on the use of personalized mRNA cancer vaccines for treating pancreatic ductal adenocarcinoma(PDAC),a highly malignant form of cancer.The study,which capitalizes on li...This commentary discusses a ground-breaking study on the use of personalized mRNA cancer vaccines for treating pancreatic ductal adenocarcinoma(PDAC),a highly malignant form of cancer.The study,which capitalizes on lipid nanoparticles for mRNA vaccine delivery,aims to induce an immune response against patient-specific neoantigens and offers a potential ray of hope for improving patient prognosis.Initial results from a Phase 1 clinical trial indicated a significant T cell response in half of the subjects,opening new avenues for PDAC treatment.However,despite the promising nature of these findings,the commentary emphasizes the challenges that remain.These include the complexity of identifying suitable antigens,the possibility of tumor immune escape,and the requirement for extensive large-scale trials to confirm long-term safety and efficacy.This commentary underscores the transformative potential of mRNA technology in oncology while highlighting the hurdles that need to be overcome for its widespread adoption.展开更多
文摘Prostate cancer is a leading cause of global cancer-related death but attempts to improve diagnoses and develop novel therapies have been confounded by significant patient heterogeneity. In recent years, the application of next-generation sequencing to hundreds of prostate tumours has defined novel molecular subtypes and characterized extensive genomic aberration underlying disease initiation and progression. It is now clear that the heterogeneity observed in the clinic is underpinned by a molecular landscape rife with complexity, where genomic rearrangements and rare mutations combine to amplify transcriptomic diversity. This review dissects our current understanding of prostate cancer ＇omics＇, including the sentinel role of copy number variation, the growing spectrum of oncogenic fusion genes, the potential influence of chromothripsis, and breakthroughs in defining mutation-associated subtypes. Increasing evidence suggests that genomic lesions frequently converge on specific cellular functions and signalling pathways, yet recurrent gene aberration appears rare. Therefore, it is critical that we continue to define individual tumour genomes, especially in the context of their expressed transcriptome. Only through improved characterisation of tumour to tumour variability can we advance to an age of precision therapy and personalized oncology.
文摘Alternative splicing （AS） is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence implicates splice isoforms in most if not all hallmarks of cancer, including growth, apoptosis, invasion and metastasis, angiogenesis, and metabolism. AS has important clinical implications since it can be manipulated therapeutically to treat cancer and represents a mechanism of resistance to therapy. In prostate cancer （PCa） AS also plays a prominent role and this review will summarize the current knowledge of alternatively spliced genes with important functional consequences. We will highlight accumulating evidence on AS of the components of the two critical pathways in PCa： androgen receptor （AR） and phosphoinositide 3-kinase （PI3K）. These observations together with data on dysregulation of splice factors in PCa suggest that AR and PI3K pathways may be interconnected with previously unappreciated splicing regulatory networks. In addition, we will discuss several lines of evidence implicating splicing regulation in the development of the castration resistance.
文摘Prostate cancers(PCa)have been reported to actively suppress antitumor immune responses by creating an immune-suppressive microenvironment.There is mounting evidence that PCas may undergo an‘‘Epithelial Immune Cell-like Transition’’(EIT)by expressing molecules conventionally associated with immune cells(e.g.,a variety of cytokines/receptors,immune transcription factors,Ig motifs,and immune checkpoint molecules),which subsequently results in the suppression of anti-cancer immune activity within the tumor microenvironment.Recent progress within the field of immune therapy has underscored the importance of immune checkpoint molecules in cancer development,thus leading to the development of novel immunotherapeutic approaches.Here,we review the expression of select immune checkpoint molecules in PCa epithelial and associated immune cells,with particular emphasis on clinical data supporting the concept of an EIT-mediated phenotype in PCa.Furthermore,we summarize current advances in anti-immune checkpoint therapies,and provide perspectives on their potential applicability.
文摘Significant advances in breast cancer treatment have been made where it is now possible to treat localized disease to a curable state. However, for approximately 30% of women with primary disease, metastatic breast cancer (MBC) or recurrent disease, treatment has remained challenging. Major obstacles in the effective treatment of breast cancer in these populations include: 1) the molecular heterogeneity of the disease;2) treatment of MBC and more specifically brain metastasis;and 3) defining combination therapies that address the evolution of resistance with disease relapse. The acknowledgement of these difficulties has led to an effort to further understand the roadblocks to therapy with the anticipation that more appropriate treatments will result. Here we describe the current state of breast cancer treatment, and the potential for improved therapy.
基金This study was funded by Janssen Pharmaceutical Ltd.,which designed the study.
文摘Ethnicity might be associated with treatment outcomes in advanced prostate cancer.This study aimed to evaluate the efficacy and safety of androgen deprivation therapy(ADT)combined with apalutamide in East Asians with metastatic castration-sensitive prostate cancer(mCSPC).The original phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen(TITAN)trial was conducted at 260 sites in 23 countries.This subgroup analysis included patients enrolled in 62 participating centers in China,Japan,and Korea.Radiographic progression-free survival(PFS),time to prostate-specific antigen(PSA)progression,and PSA changes from baseline were compared between groups in the East Asian population.The intent-to-treat East Asian population included 111 and 110 participants in the apalutamide and placebo groups,respectively.The 24-month radiographic PFS rates were 76.1%and 52.3%in the apalutamide and placebo groups,respectively(apalutamide vs placebo:hazard ratio[HR]=0.506;95%confidence interval[CI],0.302–0.849;P=0.009).Median time to PSA progression was more favorable with apalutamide than placebo(HR=0.210;95%CI,0.124–0.357;P<0.001).Median maximum percentages of PSA decline from baseline were 99.0%and 73.9%in the apalutamide and placebo groups,respectively.The most common adverse event(AE)was rash in the apalutamide group,with a higher rate than that in the placebo group(37.3%vs 9.1%).The most common grade 3 or 4 AEs were rash(12[10.9%])and hypertension(12[10.9%])for apalutamide.The efficacy and safety of apalutamide in the East Asian subgroup of the TITAN trial are consistent with the global results.
文摘Retroperitoneal fibrosis secondary to malignant disease is a rare condition associated with a dismal prognosis. We herein present the first ever reported case of ret-roperitoneal fibrosis related to esophageal adenocarcinoma in a 63-year-old patient who developed bilateral ureteral obstruction due to extensive retroperitoneal fibrosis 18 mo after having completed neoadjuvant chemoradation followed by surgery for a pT3N0 ad-enocarcinoma of the distal esophagus. We also report the case of a previously healthy woman who presented with bilateral ureteral obstruction and diffuse narrowing of the common biliary duct and was found to have extensive retroperitoneal fibrosis as a consequence of metastatic gastric adenocarcinoma. Both patients had poor performance status and were unsuitable for pallia-tive chemotherapy. This paper shows that urinary and biliary obstructive symptoms might represent retroperi-toneal fibrosis as a consequence of gastroesophageal malignancy.
基金This study was reviewed and approved by Systemic Therapy-Vancouver(BC Cancer),REB number H19-01865.
文摘BACKGROUND Over the last decade,multiple agents have demonstrated efficacy for advanced esophagogastric cancer(EGC).Despite the availability of later lines of therapy,there remains limited real-world data about the treatment attrition rates between lines of therapy.AIM To characterize the use and attrition rates between lines of therapy for patients with advanced EGC.METHODS We identified patients who received at least one cycle of chemotherapy for advanced EGC between July 1,2017 and July 31,2018 across six regional centers in British Columbia(BC),Canada.Clinicopathologic,treatment,and outcomes data were extracted.RESULTS Of 245 patients who received at least one line of therapy,median age was 66 years(IQR 58.2-72.3)and 186(76%)were male,Eastern Cooperative Oncology Group(ECOG)performance status 0/1(80%),gastric vs GEJ(36%vs 64%).Histologies included adenocarcinoma(78%),squamous cell carcinoma(8%),and signet ring(14%),with 31%HER2 positive.72%presented with de novo disease,and 25%had received previous chemoradiation.There was a high level of treatment attrition,with patients receiving only one line of therapy n=122,50%),two lines n=83,34%),three lines n=34,14%),and four lines n=6,2%).Kaplan-Meier analysis demonstrated improved survival with increasing lines of therapy(median overall survival 7.7 vs 16.6 vs 22.8 vs 40.4 mo,P<0.05).On multivariable Cox regression,improved survival was associated with better baseline ECOG and increased lines of therapy(P<0.05).CONCLUSION The steep attrition rates between therapies highlight the unmet need for more efficacious early-line treatment options for patients with advanced EGC.
基金Supported by the Canadian Cancer Society through a grant to the NCIC Clinical Trials Group from the Canadian Cancer Society Research InstituteNovartis provided the NCIC CTG MA.14 drug octreotide LAR
文摘AIM: To show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death. METHODS: MA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years of octreotide 90 mg, given by depot intramuscular injections monthly. Event-free survival was the primary endpoint of MA.14; at median 7.9 years, the tamoxifen+octreotide and tamoxifen arms had similar event-free survival(P = 0.62). Overall survival was a secondary endpoint, and the two trial arms also had similar overall survival(P = 0.86). We used the median 9.8 years follow-up to examine by intention-to-treat, the multivariate time-to-breast cancer-specific(Br Ca) and other cause(OC) mortality with log-normal survival analysis adjusted by treatment and stratification factors. We tested whether baseline factors including Insulin-like growth factor 1(IGF1), IGF binding protein-3, C-peptide, body mass index, and 25-OH vitamin D were associated with(1) all cause mortality, and if so; and(2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models.RESULTS: The analyses were performed on 329 patients allocated tamoxifen and 329 allocated tamoxifen+octreotide. The median age of MA.14 patients was 60.1 years: 447(82%) < 70 years and 120(18%) ≥ 70 years. There were 170 deaths: 106(62.3%) BrC a; 55(32.4%) OC, of which 24 were other malignancies, 31 other causes of death; 9(5.3%) patients with unknown cause of death were excluded from competing risk assessments. BrC a and OC deaths were not significantly different by treatment arm(P = 0.40): tamoxifen patients experienced 50 BrC a and 32 OC deaths, while tamoxifen + octreotide patients experienced 56 Br Ca and 23 OC deaths. Proportionately more deaths(P = 0.004) were from BrC a for patients< 70 years, where 70% of deaths were due to Br Ca, compared to 54% for those ≥ 70 years of age. The proportion of deaths from OC increased with increasing body mass index(BMI)(P = 0.02). Higher pathologic T and N were associated with more BrC a deaths(P < 0.0001 and 0.002, respectively). The cumulative hazard plot for Br Ca and OC mortality indicated the concurrent accrual of both types of death throughout followup, that is the existence of competing risks of mortality. MA.14 therapy did not impact mortality(P = 0.77). Three baseline patient and tumor characteristics were differentially associated with cause of death: older patients experienced more OC(P = 0.01) mortality; patients with T1 tumors and hormone receptor positive tumors had less BrC a mortality(respectively, P = 0.01, P = 0.06). Additionally, step-wise cause-specific models indicated that patients with node negative disease experienced less BrC a mortality(P = 0.002); there was weak evidence that, lower C-peptide(P = 0.08) was associated with less BrC a mortality, while higher BMI(P = 0.01) was associated with worse OC mortality.CONCLUSION: We demonstrate here a new paradigm of simultaneous testing of therapeutics directed at multiple diseases for which postmenopausal women are concurrently at risk. Octreotide LAR did not significantly impact breast cancer or other cause mortality, although different baseline factors influenced type of death.
文摘BACKGROUND Barrett esophagus(BE),a metaplastic adaptive process to gastrointestinal reflux,is associated with a higher risk of developing esophageal adenocarcinoma.However,the factors and mechanism that drive the malignant progression of BE is not well understood.AIM To investigate the role of bile acids,a component of the reflux fluid,in the malignant progression of BE.METHODS Using engineered green fluorescent protein-labeled adult tissue-resident stem cells isolated from BE clinical biopsies(BE-ASCs)as the target,we studied the effect of hydrophobic deoxycholic acid(DCA)and hydrophilic tetrahydroxylated bile acids(THBA)on cell viability by fluorescence intensity analysis,mucin production by dark density measurement,tissue structure by pathology analysis,expression of different pro-inflammatory factors gene by quantitative polymerase chain reaction and proteins by Western blot.RESULTS We found that hydrophobic DCA has cytotoxic and proinflammatory effects through activation of interleukin-1β(IL-1β)-nuclear factor kappa-B(NF-κB)inflammatory pathway on BE-ASCs.This action results in impaired cell viability,tissue intactness,reduced mucin production,and increased transition to disorganized atypical cells without intestinal features.In contrast,co-culture with hydrophilic THBA inhibited the IL-1β-NF-κB inflammatory pathway with maintenance of mature intestinal type cellular and histomorphology.CONCLUSION Our data indicates that the hydrophilic bile acid THBA can counteract the cytotoxic and proinflammatory effect of hydrophobic DCA and prevent the malignant progression of BE by inhibiting the IL-1β-NF-κB pathway.
基金国家自然科学基金项目(60778046)福建省科技项目(2005I009)the Canadian Institutes of Health Research/National Science Foundation of China International Scientific Exchange Program(60711120031)资助
文摘Mixed neuroendocrine-non-neuroendocrine neoplasms(MiNENs)are rare mixed tumors containing both neuroendocrine(NE)and non-NE components.Each component must occupy at least 30%of the tumor volume by definition.Recent molecular evidence suggests MiNENs are clonal neoplasms and potentially harbor targetable mutations similar to conventional carcinomas.There have been multiple changes in the nomenclature and classification of MiNENs which has created some confusion among pathologists on how to integrate the contributions of each component in a MiNEN,an issue which in turn has resulted in confusion in communication with front-line treating oncologists.This mini review summarizes our current understanding of MiNENs and outline diagnosis,prognosis,and management of these neoplasms.The authors emphasize the importance of treating the most aggressive component of the tumor regardless of its percentage volume.
文摘Neuroendocrine tumors are rare neoplasms that infrequently metastasize to the orbit.Given that patients with these tumors may have prolonged survival despite dissemination,maintaining quality of life by providing early diagnosis and effective treatment to preserve vision and comfort is a fundamental issue.We report the case of a79-year old woman who presented with well-differentiated metastatic neuroendocrine tumor to the liver with no carcinoid syndrome and was started on intramuscular long-acting octreotide with disease stabilization.Two years later she developed right-sided diplopia associated with mild eye discomfort,proptosis and reddening.An magnetic resonance imaging showed a 2.1 cm mass in the right orbit and further biopsy confirmed a neuroendocrine tumor metastasis.The patient was treated with a four-week course of stereotactic radiotherapy to the right orbital metastasis(4000 cGy in 20 fractions)with minor conjunctivitis as the only side effect.Eighteen months later,she remains well with no visual loss.
文摘Multi-photon microscopy(MPM)and coherent anti-Stokes Raman scattering(CARS)are two advanced nonlinear optical imaging techniques,which provide complementary information and have great potential in combination for noninvasive in vrito biomedical applications.This paper provides a detailed discussion of the basics,development and applications of these technologies for in vrivo skin research,covering the following topics:The principle and advantage of MPM and CARS,instrumentation development for in vino applications,MPM and CARS of normal skin,application of MPM and CARS in skin cancer and disease diagnosis;application of MPM in skin disease intervention,ie.,imaging guided two-photon photothermolysis.
文摘Purpose: This study provides a simple protocol for validation of the gamma passing rates and to identify the optimum values of % dose and mm criteria for dose distributions measured with a detector array. Methods: We chose ArcCHECK detector array to illustrate the concepts. We used plans with uniform or quasi-uniform dose distributions along the detector array for testing in the presence of dose errors. For testing sensitivity to spatial shift we employed a plan with approximately constant dose gradient along the axis of the instrument. Results: We identified a representative set of parameters which describe performance of a detector array. We determined the minimum gamma-index acceptance criteria allowing the passing rates to reach 100% in the absence of errors, and identified the minimum fully detectable errors for such criteria. For our baseline plans delivered to ArcCHECK, 100% passing rates were obtained for 1.5% dose criterion together with ±3% minimum error detectable at 100% rate, and for 1.5 mm criterion together with the minimum fully detectable error of ±3 mm. We inspected the impact of selected program options on the passing rates. Conclusions: The protocol we developed provides a simple method of commissioning-style analysis of a detector array without a need for analysis of a large number of clinical plans.
文摘Early massively-parallel sequencing stu-dies have revealed the mutational land-scape of protein-coding genes in prostate cancer. However, most of these studies have not explored the extensive influence of geno- mic rearrangement in prostate cancer. In a recent Cell article, Baca and colleagues used whole-genome sequencing to tackle this issue, comprehensively surveying the abun-dance of genomic rearrangements present in a large cohort of 57 prostate cancers. They characterized a wide-spread phenomenon termed ＇chromoplexy＇, which may drive can-cer evolution through the phenomena of punctuated equilibrium by concurrently dys-regulating numerous cancer genes across multiple chromosomes. While the causes of this event still require elucidation, this defin-ing discovery undoubtedly offers an impor- tant glimpse into the evolutionary process of prostate cancer.
文摘Streaking artifacts on computed tomography (CT) images are caused by high density materials such as hip prosthesis, surgical clips and dental fillings. The artifacts can lead to compromised clinical outcome due to the inability to differentiate tumor volume and the uncertainties in dose calculation. The goals of our study are to evaluate how GE’s smart metal artifact reduction (MAR) algorithm impacts image quality on phantoms and dosimetry on head and neck patients with dental fillings and pelvic patients with hip prosthesis. Treatment plans calculated on the MAR and non-MAR datasets with the same beam arrangements and fluence are compared. Dose differences between the MAR and non-MAR datasets are not significant. However, substantial reductions of metal artifacts are observed when MAR algorithm is applied. Planning on the MAR dataset is recommended since it improves image quality and CT number accuracy. It also negates the need to contour the artifacts and override the density which can be time consuming.
文摘This first issue of the World Journal of Hematology(WJH) marks the birth of a new member of the World Series Journal family and comes at one of the most exciting times in stem cell biology and translational medicine. The pace of discovery in the field of hematology has accelerated signeificantly in recent years, due to important scientific discoveries and new technologies for purification of hematopoietic stem cells and identification of specific stem cell biomarkers; whole genome sequencing using next-generation sequencing technology; and development of molecularly-targeted therapies, leading to the translation of highly promising science into advanced diagnosis and proven targeted therapies for hematopoietic disorders. The WJH is an open-access, peer-reviewed journal, which is officially published on June 6, 2012. The WJH Editorial Board consists of 102 experts in hematology from 26 countries. There is clearly a niche for this new journal, which provides access to all articles without boundaries to all internet users throughout the world. The WJH aims to provide rapid access to high impact publications in fundamental and clinical hematology, with multidisciplinary coverage, through an established system that is targeted at dissemination to the scientific community via online openaccess.
基金supported in part by the Canadian Institutes of Health Research(#173338,#180554,#186331)Terry Fox Research Institute(#1109),A PNW Prostate Cancer SPORE(P50 CA097186)pilot grant+1 种基金a Canadian Cancer Society Breakthrough Team Grant generously supported by the Lotte&John Hecht Memorial Foundation(CCS grant#707683)the BC Cancer Foundation(grant#1PRRG012).
文摘Treatment-induced neuroendocrine prostate cancer(NEPC)represents a lethal evolution of prostate adenocarcinoma under androgen receptor pathway inhibition,posing a significant clinical challenge.In a recent landmark study,Wang et al.introduced an innovative internal Z-score based approach to comprehensively characterize the transcription factor(TF)landscape in prostate cancer progression,uncovering distinct TF profiles associated with adenocarcinoma and NEPC lineages.Notably,the study proposes a three-phase model of NEPC transdifferentiation-comprising de-differentiation,dormancy,and re-differentiation-revealing dynamic shifts in TF expression that underpin lineage plasticity and therapeutic resistance.This commentary critically evaluates the methodological advancements,the functional significance of the identified TF signatures,and the broader implications of these findings for developing novel therapeutic strategies.By delineating the molecular events driving the transition from androgen receptor(AR)-dependent adenocarcinoma to treatment-resistant NEPC,this work underscores the potential of targeting early and dormant phases of transdifferentiation to improve patient outcomes.
基金supported by the UBC Department of Radiology 2023 AI Fund,and the Natural Sciences and Engineering Research Council of Canada(NSERC)Discovery Horizons Grant(DH-2025-00119).
文摘Aim:Lung cancer remains a major global health challenge,and this study presents a censor-aware semi-supervised learning framework(SSL)that integrates clinical and imaging data to improve prognostic modeling and address biases in handling censored data.Methods:We analyzed clinical,positron emission tomography(PET),and computed tomography(CT)data from 199 lung cancer patients from public and local databases,focusing on overall survival time as the primary outcome.Handcrafted(HRF)and Deep Radiomics features were extracted after preprocessing using Visualized&Standardized Environment for Radiomics Analysis(ViSERA)software and were combined with clinical features.Features were reduced using Pearson’s correlation coefficient regression(RR)and the F-test for regression(FR),followed by supervised learning(SL)and SSL.In SSL,censored data were pseudo-labeled using the Weibull accelerated failure time(AFT)model to enrich the training data.Seven regressors and three hazard ratio survival analyses(HRSAs)were optimized using five-fold cross-validation,grid search,and holdout test bootstrapping.Results:For PET-HRFs,the SSL approach reduced the mean absolute error by 14.81%,achieving 1.04 years with FR+AdaBoost Regression(ABR)compared to 1.20 years with SL.For clinical features,SSL with RR+ABR reached a mean absolute error of 1.04 years,outperforming SL(1.09 years)with a 4.9%improvement.In HRSA,CT_HRF combined with principal component analysis(PCA)+Component-Wise Gradient Boosting Survival Analysis yielded an external C-index of 0.65±0.02,effectively distinguishing high-and low-risk groups.Conclusions:The SSL strategy applied to HRFs from PET imaging significantly enhanced survival prediction compared to SL and uncovered complementary biological information that may remain hidden when only limited labeled data are used.
基金supported in part by the Canadian Institutes of Health Research(#153081,#173338,#180554,#186331)Terry Fox Research Institute(#1109)a Canadian Cancer Society Breakthrough Team Grant generously supported by the Lotte&John Hecht Memorial Foundation(CCS grant#707683)(to YW).
文摘This commentary discusses a ground-breaking study on the use of personalized mRNA cancer vaccines for treating pancreatic ductal adenocarcinoma(PDAC),a highly malignant form of cancer.The study,which capitalizes on lipid nanoparticles for mRNA vaccine delivery,aims to induce an immune response against patient-specific neoantigens and offers a potential ray of hope for improving patient prognosis.Initial results from a Phase 1 clinical trial indicated a significant T cell response in half of the subjects,opening new avenues for PDAC treatment.However,despite the promising nature of these findings,the commentary emphasizes the challenges that remain.These include the complexity of identifying suitable antigens,the possibility of tumor immune escape,and the requirement for extensive large-scale trials to confirm long-term safety and efficacy.This commentary underscores the transformative potential of mRNA technology in oncology while highlighting the hurdles that need to be overcome for its widespread adoption.
