Recently, a novel comprehensive treatment consisting of cytoreductive surgery(CRS) and perioperative chemotherapy(POC) was developed for the treatment of peritoneal metastasis(PM) with a curative intent. In the treatm...Recently, a novel comprehensive treatment consisting of cytoreductive surgery(CRS) and perioperative chemotherapy(POC) was developed for the treatment of peritoneal metastasis(PM) with a curative intent. In the treatment, the macroscopic disease is completely removed by the peritonectomy techniques in combination with POC. This article reviews the results of the comprehensive treatment for PM from gastric cancer, and verifies the effects of CRS and POC, including neoadjuvant chemotherapy(NAC) and hyperthermic intraoperative intraperitoneal chemotherapy(HIPEC). Completeness of cytoreduction, peritoneal carcinomatosis index(PCI) less than the threshold levels after NAC,absence of ascites, cytologic status, pathologic response after NAC are the independent prognostic factors. Among these prognostic factors, PCI threshold level is the most valuable independent prognostic factor. After staging laparoscopy, patients with PM from gastric cancer are recommended to treat with NAC before CRS. After NAC, indication for CRS is determined by laparoscopy. The indications of the comprehensive treatment are patients with PCI less than the threshold levels, negative cytology, and responders after NAC. Patients satisfy these factors are the candidates for the CRS and HIPEC.展开更多
Rarely,scientific developments centered around the patient as a whole arepublished.Our multidisciplinary group,headed by gastrointestinal surgeons,applied this research philosophy considering the most important aspect...Rarely,scientific developments centered around the patient as a whole arepublished.Our multidisciplinary group,headed by gastrointestinal surgeons,applied this research philosophy considering the most important aspects of thediseases“colon-and rectal cancer”in the long-term developments.Good expertcooperation/knowledge at the Comprehensive Cancer Center Ulm(CCCU)wereapplied in several phase III trials for multimodal treatments of primary tumors(MMT)and metastatic diseases(involving nearly 2000 patients and 64 centers),fortreatment individualization of MMT and of metastatic disease,for psychooncology/quality of life involving the patients’wishes,and for disease prevention.Most of the targets initially were heavily rejected/discussed in thescientific communities,but now have become standards in treatments andnational guidelines or are topics in modern translational research protocolsinvolving molecular biology for e.g.,“patient centered individualized treatment”.In this context we also describe the paths we had to tread in order to realize ournew goals,which at the end were highly beneficial for the patients from manypoints of view.This description is also important for students and youngresearchers who,with an actual view on our recent developments,might want toknow how medical progress was achieved.展开更多
Immune checkpoint inhibitors(ICIs)and cellular immunotherapy have revolutionized cancer treatment.Although these therapies have significantly improved cancer patients’survival,they are associated with a range of immu...Immune checkpoint inhibitors(ICIs)and cellular immunotherapy have revolutionized cancer treatment.Although these therapies have significantly improved cancer patients’survival,they are associated with a range of immunerelated adverse events(irAEs)that can affect patients’quality of life.Neuromuscular complications related to cancer immunotherapy are rare(<5%with monotherapy and up to 14%with combination therapy),but they can be fatal if not addressed promptly.Early diagnosis and intervention are crucial to improving the quality of life and survival of cancer patients affected by neuromuscular complications associated with immunotherapy.However,symptoms can be diverse and nonspecific,including weakness,numbness,imbalance,dysarthria,dysphagia,and even difficulty in breathing,which presents significant challenges for diagnosis and management.This review summarizes the current understanding of the mechanisms,clinical features,diagnostic challenges,and management strategies for neuromuscular complications related to cancer immunotherapy.Understanding the complex interplay between T cells,B cells,and cytokines in the pathogenesis of neuromuscular irAEs is essential for guiding their management.It is important for healthcare providers,including oncologists,neurologists,primary care physicians,and other practitioners,to be familiar with the multidisciplinary clinical management of neuromuscular irAEs.This knowledge will help reduce the mortality and morbidity associated with these complications.展开更多
Rational design of multifunctional nanoplatforms capable of combining therapeutic effects with real-time monitoring of drug distribution and tumor status is emerging as a promising approach in cancer nanomedicine.Here...Rational design of multifunctional nanoplatforms capable of combining therapeutic effects with real-time monitoring of drug distribution and tumor status is emerging as a promising approach in cancer nanomedicine.Here,we introduce pyropheophorbide a-bisaminoquinoline conjugate lipid nanoparticles(PPBC LNPs)as a bimodal system for image-guided phototherapy in bladder cancer treatment.PPBC LNPs not only demonstrate both powerful photodynamic and photothermal effects upon light activation,but also exhibit potent autophagy blockage,effectively inducing bladder cancer cell death.Furthermore,PPBC LNPs possess remarkable photoacoustic(PA)and fluorescence(FL)imaging capabilities,enabling imaging with high-resolution,deep tissue penetration and high sensitivity for tracking drug biodistribution and phototherapy efficacy.Specifically,PA imaging confirms the efficient accumulation of PPBC LNPs within tumor and predicts therapeutic outcomes of photodynamic therapy,while FL imaging confirms their prolonged retention at the tumor site for up to 6 days.PPBC LNPs significantly suppress bladder tumor growth,with several tumors completely ablated following just two doses of the nanoparticles and laser treatment.Additionally,PPBC LNPs were formulated with lipid-based excipients and assembled using microfluidic technology to enhance biocompatibility,stability,and scalability,showing potential for clinical translation.This versatile nanoparticle represents a promising candidate for further development in bladder cancer therapy.展开更多
Esophageal cancer(EC),a common malignant tumor of the digestive tract,requires early diagnosis and timely treatment to improve patient prognosis.Automated detection of EC using medical imaging has the potential to inc...Esophageal cancer(EC),a common malignant tumor of the digestive tract,requires early diagnosis and timely treatment to improve patient prognosis.Automated detection of EC using medical imaging has the potential to increase screening efficiency and diagnostic accuracy,thereby significantly improving long-term survival rates and the quality of life of patients.Recent advances in deep learning(DL),particularly convolutional neural networks,have demons-trated remarkable performance in medical imaging analysis.These techniques have shown significant progress in the automated identification of malignant tumors,quantitative analysis of lesions,and improvement in diagnostic accuracy and efficiency.This article comprehensively examines the research progress of DL in medical imaging for EC,covering various imaging modalities such as digital pathology,endoscopy,computed tomography,etc.It explores the clinical value and application prospects of DL in EC screening and diagnosis.Additionally,the article addresses several critical challenges that must be overcome for the clinical translation of DL techniques,including constructing high-quality datasets,promoting multimodal feature fusion,and optimizing artificial intelligence-clinical workflow integration.By providing a detailed overview of the current state of DL in EC imaging and highlighting the key challenges and future directions,this article aims to guide future research and facilitate the clinical implementation of DL technologies in EC management,ultimately contributing to better patient outcomes.展开更多
Objective:To determine the safety and the role of modulating cytokines and proteases in the immune response to intravesical Bacillus Calmette-Guérin(BCG)when primed with systemic intradermal BCG.Methods:Phase 1 a...Objective:To determine the safety and the role of modulating cytokines and proteases in the immune response to intravesical Bacillus Calmette-Guérin(BCG)when primed with systemic intradermal BCG.Methods:Phase 1 and mechanistic longitudinal,prospective,single-blind randomized study(NCT04806178).Twenty-one non-muscle invasive urothelial bladder cancer patients undergoing intravesical adjuvant BCG after transurethral resection of bladder tumor(TURBT)in a teaching hospital between September 2021 and April 2023 were randomized to 0.1 mL of intradermal BCG vaccine or placebo(0.9%saline)administered 15 days before the start of intravesical BCG therapy.Blood samples were evaluated mechanistically regarding eight cytokines serum levels interferon-induced transmembrane protein 3 Gene(IFITM3),Interleukin 1 beta(IL1-BETA),interleukin-2 receptor alpha chain(IL2 RA),Interleukin 6(IL 6),Interleukin 10(IL 10),Tumor necrosis factor alpha(TNF-α),Interferon-β,AXL,and one protease CASPASE 8.Results:After 1 exclusion,twenty patients were randomized to intradermal BCG(n=11)and intradermal placebo(n=9).There was no difference in adverse effects emerging from the intravesical Onco-BCG therapy,and no difference in the expression of the cytokines and proteases analyzed between control and intervention,and over time.Conclusions:Intradermal BCG administration before intravesical application was safe,with no increase in adverse effects.It also does not seem to change the analyzed targets during the intravesical induction-phase BCG.Other immune targets should be explored in the future.The Brazilian tuberculosis-endemic status,where BCG vaccination is mandatory,might have affected the results.展开更多
In spite of advances made in the management of the other more common cancers of the gastrointestinal tract,significant progress in the treatment of pancreatic cancer remains elusive.Nearly as many deaths occur from pa...In spite of advances made in the management of the other more common cancers of the gastrointestinal tract,significant progress in the treatment of pancreatic cancer remains elusive.Nearly as many deaths occur from pancreatic cancer as are diagnosed each year reflecting the poor prognosis typically associated with this disease.Until recently,the only treatment with an impact on survival was surgery.In the palliative setting,gemcitabine(Gem) has been a standard treatment for advanced pancreatic cancer since it was shown a decade ago to result in a superior clinical benefit response and survival compared with bolus 5-fluorouracil.Since then,clinical trials have explored the pharmacokinetic modulation of Gem by fixed dose administration and the combination of Gem with other cytotoxic or the biologically"targeted"agents.However,promising trial results in small phaseⅡtrials have not translated into survival improvements in larger phaseⅢrandomized trials in the advanced disease setting.Two trials have recently reported modest survival improvements with the use of combination treatment with Gem and capecitabine(United Kingdom National Cancer Research GEMCAP trial) or erlotinib(National Cancer Institute of CanadaClinical Trials Group PA.3 trial) .This review will focus on the use of systemic therapy for advanced and metastatic pancreatic cancer,summarizing the results of several recent clinical trials and discuss their implications for clinical practice.We will also discuss briefly the second-line chemotherapy options for advanced pancreatic cancer.展开更多
The incidence and mortality of gastric cancer have fallen dramatically in US and elsewhere over the past several decades. Nonetheless, gastric cancer remains a major public health issue as the fourth most common cance...The incidence and mortality of gastric cancer have fallen dramatically in US and elsewhere over the past several decades. Nonetheless, gastric cancer remains a major public health issue as the fourth most common cancer and the second leading cause of cancer death worldwide. Demographic trends differ by tumor location and histology. While there has been a marked decline in distal, intestinal type gastric cancers, the incidence of proximal, diffuse type adenocarcinomas of the gastric cardia has been increasing, particularly in the Western countries. Incidence by tumor sub-site also varies widely based on geographic location, race, and socioeconomic status. Distal gastric cancer predominates in developing countries, among blacks, and in lower socioeconomic groups, whereas proximal tumors are more common in developed countries, among whites, and in higher socio-economic classes. Diverging trends in the incidence of gastric cancer by tumor location suggest that they may represent two diseases with different etiologies. The main risk factors for distal gastric cancer include Helicobacter pylori （H pylori） infection and dietary factors, whereas gastroesophageal reflux disease and obesity play important roles in the development of proximal stomach cancer. The purpose of this review is to examine the epidemiology and risk factors of gastric cancer, and to discuss strategies for primary prevention.展开更多
The estrogen receptor(ER) pathway plays a critical role in breast cancer development and progression. Endocrine therapy targeting estrogen action is the most important systemic therapy for ER positive breast cancer. H...The estrogen receptor(ER) pathway plays a critical role in breast cancer development and progression. Endocrine therapy targeting estrogen action is the most important systemic therapy for ER positive breast cancer. However its efficacy is limited by intrinsic and acquired resistance. Mechanisms responsible for endocrine resistance include deregulation of the ER pathway itself, including loss of ER expression, posttranslational modification of ER, deregulation of ER coactivators; increased receptor tyrosine kinase signaling leading to activation of various intracellular pathways involved in signal transduction, proliferation and cell survival, including growth factor receptor tyrosine kinases human epidermal growth factor receptor-2, epidermal growth factor receptor, PI3K/AKT/mammalian target of rapamycin(m TOR), Mitogen activated kinase(MAPK)/ERK, fibroblast growth factor receptor, insulin-like growth factor-1 receptor; alterations in cell cycle and apoptotic machinery; Epigenetic modificationincluding dysregulation of DNA methylation, histone modification, and nucleosome remodeling; and altered expression of specific micro RNAs. Functional genomics has helped us identify a catalog of genetic and epigenetic alterations that may be exploited as potential therapeutic targets and biomarkers of response. New treatment combinations targeting ER and such oncogenic signaling pathways which block the crosstalk between these pathways have been proven effective in preclinical models. Results of recent clinical studies suggest that subsets of patients benefit from the combination of inhibitor targeting certain oncogenic signaling pathway with endocrine therapy. Especially, inhibition of the m TOR signaling pathway, a key component implicated in mediating multiple signaling cascades, offers a promising approach to restore sensitivity to endocrine therapy in breast cancer. We systematically reviewed important publications cited in Pub Med, recent abstracts from ASCO annual meetings and San Antonio Breast Cancer Symposium, and relevant trials registered at Clinical Trials.gov. We present the molecular mechanisms contributing to endocrine resistance, in particular focusing on the biological rationale for the clinical development of novel targeted agents in endocrine resistant breast cancer. We summarize clinical trials utilizing novel strategies to overcome therapeutic resistance, highlighting the need to better identify the appropriate patients whose diseases are most likely to benefit from these specific strategies.展开更多
The interplay between inflammation and cancer progression is a growing area of research. A combination of clinical, epidemiological, and basic science investigations indicate that there is a relationship between infla...The interplay between inflammation and cancer progression is a growing area of research. A combination of clinical, epidemiological, and basic science investigations indicate that there is a relationship between inflammatory changes in the pancreas and neoplastic progression. Diets high in ω-6 polyunsaturated fatty acids provide increased substrate for arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) to form eicosanoids. These eicosanoids directly contribute to pancreatic cancer cell proliferation. Both COX-2 and 5-LOX are upregulated in multiple cancer types, including pancreatic cancer. In vitro studies using pancreatic cancer cell lines have demonstrated upregulation of COX-2 and 5-LOX at both the mRNA and protein levels. When COX-2 and 5-LOX are blocked via a variety of mechanisms, cancer cell proliferation is abrogated both in vitro and in vivo. The mechanism of COX-2 has been shown to include effects on apoptosis as well as angiogenesis. 5-LOX has been implicated in apoptosis. The use of COX-2 and 5-LOX inhibitors in clinical studies in patients with pancreatic cancer has been limited. Patient enrollment has been restricted to those with advanced disease which makes evaluation of these drugs as chemopreventive agents difficult. COX-2 and 5-LOX expression have been shown to be present during the early neoplastic changes of pancreatic cancer, well before progression to invasive disease. This indicates that the ideal role for these interventions is early in the disease process as preventive agents, perhaps in patients with chronic pancreatitis or hereditary pancreatitis.展开更多
Stereotactic body radiation therapy(SBRT) is the treatment of choice for medically inoperable patients with early stage non-small cell lung cancer(NSCLC). A literature search primarily based on PubMed electronic datab...Stereotactic body radiation therapy(SBRT) is the treatment of choice for medically inoperable patients with early stage non-small cell lung cancer(NSCLC). A literature search primarily based on PubMed electronic databases was completed in July 2018. Inclusion and exclusion criteria were determined prior to the search, and only prospective clinical trials were included. Nineteen trials from 2005 to 2018 met the inclusion criteria, reporting the outcomes of 1434 patients with central and peripheral early stage NSCLC. Patient eligibility,prescription dose and delivery, and follow up duration varied widely. Threeyears overall survival ranged from 43% to 95% with loco-regional control of up to 98% at 3 years. Up to 33% of patients failed distantly after SBRT at 3 years. SBRT was generally well tolerated with 10%-30% grade 3-4 toxicities and a few treatment-related deaths. No differences in outcomes were observed between conventionally fractionated radiation therapy and SBRT, central and peripheral lung tumors, or inoperable and operable patients. SBRT remains a reasonable treatment option for medically inoperable and select operable patients with early stage NSCLC. SBRT has shown excellent local and regional control with toxicity rates equivalent to surgery. Decreasing fractionation schedules have been consistently shown to be both safe and effective. Distant failure is common, and chemotherapy may be considered for select patients. However, the survival benefit of additional interventions, such as chemotherapy, for early stage NSCLC treated with SBRT remains unclear.展开更多
Microsatellite alterations within genomic DNA frameshift as a result of defective DNA mismatch repair(MMR). About 15% of sporadic colorectal cancers(CRCs) manifest hypermethylation of the DNA MMR gene MLH1, resulting ...Microsatellite alterations within genomic DNA frameshift as a result of defective DNA mismatch repair(MMR). About 15% of sporadic colorectal cancers(CRCs) manifest hypermethylation of the DNA MMR gene MLH1, resulting in mono-and di-nucleotide frameshifts to classify it as microsatellite instability-high(MSI-H) and hypermutated, and due to frameshifts at coding microsatellites generating neo-antigens, produce a robust protective immune response that can be enhanced with immune checkpoint blockade. More commonly, approximately 50% of sporadic nonMSI-H CRCs demonstrate frameshifts at di-and tetra-nucleotide microsatellites to classify it as MSIlow/elevated microsatellite alterations at selected tetranucleotide repeats(EMAST) as a result of functional somatic inactivation of the DNA MMR protein MSH3 via a nuclear-to-cytosolic displacement. The trigger for MSH3 displacement appears to be inflammation and/or oxidative stress, and unlike MSI-H CRC patients, patients with MSI-L/EMAST CRCs show poor prognosis. These inflammatory-associated microsatellite alterations are a consequence of the local tumor microenvironment, and in theory, if the microenvironment is manipulated to lower inflammation, the microsatellite alterations and MSH3 dysfunction should be corrected. Here we describe the mechanisms and significance of inflammatory-associated microsatellite alterations, and propose three areas to deeply explore the consequences and prevention of inflammation's effect upon the DNA MMR system.展开更多
Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androg...Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer （CRPC）. Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing ＇level-1 evidence＇ that docetaxel-based chemotherapy led to prolongation in overall survival （OS）. This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents （e.g. abiraterone and enzalutamide） have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include： how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.展开更多
Objective: Despite evidence that estrogens and insulin are involved in the development and progression of many cancers, their synergistic role in endometrial carcinoma(EC) has not been analyzed yet.Methods: Here, we i...Objective: Despite evidence that estrogens and insulin are involved in the development and progression of many cancers, their synergistic role in endometrial carcinoma(EC) has not been analyzed yet.Methods: Here, we investigated how estrogens act synergistically with insulin to promote EC progression. Cell growth in vitro and in vivo, effects of estradiol and insulin on apoptosis and cell cycle distribution, and expression and activation of estrogen receptor(ER), insulin receptor(InsR), and key proteins in the PI3K and MAPK pathways were examined after combined stimulation with estradiol and insulin.Results: Compared to EC cells treated with estradiol or insulin alone, those treated with both estradiol and insulin exhibited stronger stimulation. Estradiol significantly induced phosphorylation of InsR-β and IRS-1, whereas insulin significantly induced phosphorylation of ER-α. In addition, treatment with both insulin and estradiol together significantly increased the expression and phosphorylation of Akt, MAPK, and ERK. Notably, InsR-β inhibition had a limited effect on estradiol-dependent proliferation,cell cycle, and apoptosis, whereas ER-α inhibition had a limited insulin-dependent effect, in EC cell lines. Insulin and estradiol individually and synergistically promoted EC xenograft growth in mice.Conclusions: Estrogen and insulin play synergistic roles in EC carcinogenesis and progression by activating InsR-β and ER-α,promoting a crosstalk between them, and thereby resulting in the activation of downstream PI3K/Akt and MAPK/ERK signaling pathways.展开更多
The phosphatidylinositol-3 kinase(PI3K) pathway regulates a number of cellular processes, including cell survival, cell growth, and cell cycle progression. Consequently, this pathway is commonly deregulated in cancer....The phosphatidylinositol-3 kinase(PI3K) pathway regulates a number of cellular processes, including cell survival, cell growth, and cell cycle progression. Consequently, this pathway is commonly deregulated in cancer. In particular, mutations in the gene PIK3CA that encodes the p110α catalytic subunit of the PI3K enzymes result in cell proliferation and resistance to apoptosis in vitro and induce breast tumors in transgenic mice. These data underscore the role of this pathway during oncogenesis. Thus, an ongoing, large-scale effort is underway to develop clinically active drugs that target elements of the PI3K pathway. However, conflicting data suggest that gain-of-function PIK3CA mutations may be associated with either a favorable or a poor clinical outcome, compared with the wild-type PIK3CA gene. In the current study, we performed a systematic review of breast cancer clinical studies. Upon evaluation of 2587 breast cancer cases from 12 independent studies, we showed that patients with tumors harboring a PIK3CA mutation have a better clinical outcome than those with a wild-type PIK3CA gene. Importantly, this improved prognosis may pertain only to patients with mutations in the kinase domain of p110α and to postmenopausal women with estrogen receptor-positive breast cancer. We propose three potential explanations for this paradoxical observation. First, PIK3CA mutations may interfere with the metastasis process or may induce senescence, which results in a better outcome for patients with mutated tumors. Secondly, we speculate that PIK3CA mutations may increase early tumor diagnosis by modification of the actin cytoskeleton in tumor cells. Lastly, we propose that PIK3CA mutations may be a favorable predictive factor for response to hormonal therapy, giving a therapeutic advantage to these patients. Ultimately, an improved understanding of the clinical impact of PIK3CA mutations is critical for the development of optimally personalized therapeutics against breast cancer and other solid tumors. This effort will be important to prevent or explain therapeutic failures and select patients who are most likely to respond to new therapies that inhibit the PI3K pathway.展开更多
Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resul...Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease. Controversies remain, however, surrounding the optimal timing, duration and schedule of these hormonal approaches. Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer, This review highlights the various androgen-directed treatment options available to men with prostate cancer, their specific indications and the evidence supporting each approach, as well as patterns of use of hormonal therapies.展开更多
Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that constitutive overexpression of cyclooxygenase-2(COX-2) is a ubiquitous driver of mammary carcinogenesis, and r...Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that constitutive overexpression of cyclooxygenase-2(COX-2) is a ubiquitous driver of mammary carcinogenesis, and reciprocally, that COX-2 blockade has strong potential for breast cancer prevention and therapy. Key findings include the following:(1) COX-2 is constitutively expressed throughout breast cancer development and expression intensifies with stage at detection, cancer progression and metastasis;(2) essential features of mammary carcinogenesis(mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis and immunosuppression) are linked to COX-2-driven prostaglandin E2(PGE-2) biosynthesis;(3) upregulation of COX-2 and PGE-2 expression induces transcription of CYP-19 and aromatase-catalyzed estrogen biosynthesis which stimulates unbridled mitogenesis;(4) extrahe-patic CYP-1B1 in mammary adipose tissue converts paracrine estrogen to carcinogenic quinones with mutagenic impact; and(5) agents that inhibit COX-2 reduce the risk of breast cancer in women without disease and reduce recurrence risk and mortality in women with breast cancer. Recent sharp increases in global breast cancer incidence and mortality are likely driven by chronic inflammation of mammary adipose and upregulation of COX-2 associated with the obesity pandemic. The totality of evidence clearly supports the supposition that mammary carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive overexpression of COX-2 and the prostaglandin cascade in the "inflammogenesis of breast cancer".展开更多
Blockade of the programmed death ligand 1(PD-L1) and programmed cell death 1(PD-1) receptor axis represents an effective form of cancer immunotherapy. Preclinical evidence initially suggested that gastric and gastroes...Blockade of the programmed death ligand 1(PD-L1) and programmed cell death 1(PD-1) receptor axis represents an effective form of cancer immunotherapy. Preclinical evidence initially suggested that gastric and gastroesophageal junction(GEJ) cancers are potentially immunotherapy-sensitive tumors. Early phase clinical trials have demonstrated promising antitumor activity with PD-1/PD-L1 blockade in advanced or metastatic gastric/GEJ cancer. Microsatellite instability(MSI) and PD-L1 expression have been shown to predict higher response to PD-1 inhibitors as highlighted by the recent approvals of pembrolizumab in treatmentrefractory solid tumors with MSI status and the thirdline or greater treatment of PD-L1 positive advanced gastric/GEJ cancers. However, predictive and prognostic biomarkers remain an ongoing need. In this review, we detail the preclinical evidence and early tissue biomarker analyses illustrating potential predictive biomarkers to PD-1/PD-L1 blockade in gastric/GEJ cancer. We also review the clinical development of PD-1/PD-L1 inhibitors in gastric/GEJ cancer and highlight several areas in need of future investigation in order to optimize the efficacy of PD-1/PD-L1 blockade in gastric/GEJ cancer.展开更多
In spite of the well-established understanding of the phenotypic lesions occurring in the shift from native epithelia to invasive （adeno） carcinoma, the molecular b/ping of the precancerous changes in the gastrointe...In spite of the well-established understanding of the phenotypic lesions occurring in the shift from native epithelia to invasive （adeno） carcinoma, the molecular b/ping of the precancerous changes in the gastrointes- tinal tract remains unreliable. In recent years, no biomarkers have aroused as much interest as the miRNAs, a class of non-coding RNA molecules that function as endogenous silencers of numerous target genes. Aberrant miRNA expression is a hallmark of human disease, including cancer. Unlike most mRNAs, miRNAs are both long-living in vivo and very stable in vitro. Such charac- teristics allow their testing in paraffin-embedded tissue samples, which is essential in the biological profiling of small （phenotypically characterized） preneoplastic lesions of the gastrointestinal tract （as well as in other fields of human pathology）. The upcoming challenge lies in the reliable identification of disease-specific targets of dysregulated miRNAs, to enable miRNA testing in the clinical management of the secondary prevention of gastrointestinal cancer.展开更多
In recent years, it has become increasingly apparent that noncoding RNAs(ncRNA) are of crucial importance for human cancer. The functional relevance of ncRNAs is particularly evident for microRNAs(miRNAs) and long non...In recent years, it has become increasingly apparent that noncoding RNAs(ncRNA) are of crucial importance for human cancer. The functional relevance of ncRNAs is particularly evident for microRNAs(miRNAs) and long noncoding RNAs(lncRNAs). miRNAs are endogenously expressed small RNA sequences that act as post-transcriptional regulators of gene expression and have been extensively studied for their roles in cancers, whereas lncRNAs are emerging as important players in the cancer paradigm in recent years. These noncoding genes are often aberrantly expressed in a variety of human cancers. However, the biological functions of most ncRNAs remain largely unknown. Recently, evidence has begun to accumulate describing how ncRNAs are dysregulated in cancer and cancer stem cells, a subset of cancer cells harboring self-renewal and differentiation capacities. These studies provide insight into the functional roles that ncRNAs play in tumor initiation, progression, and resistance to therapies, and they suggest ncRNAs as attractive therapeutic targets and potentially useful diagnostic tools.展开更多
文摘Recently, a novel comprehensive treatment consisting of cytoreductive surgery(CRS) and perioperative chemotherapy(POC) was developed for the treatment of peritoneal metastasis(PM) with a curative intent. In the treatment, the macroscopic disease is completely removed by the peritonectomy techniques in combination with POC. This article reviews the results of the comprehensive treatment for PM from gastric cancer, and verifies the effects of CRS and POC, including neoadjuvant chemotherapy(NAC) and hyperthermic intraoperative intraperitoneal chemotherapy(HIPEC). Completeness of cytoreduction, peritoneal carcinomatosis index(PCI) less than the threshold levels after NAC,absence of ascites, cytologic status, pathologic response after NAC are the independent prognostic factors. Among these prognostic factors, PCI threshold level is the most valuable independent prognostic factor. After staging laparoscopy, patients with PM from gastric cancer are recommended to treat with NAC before CRS. After NAC, indication for CRS is determined by laparoscopy. The indications of the comprehensive treatment are patients with PCI less than the threshold levels, negative cytology, and responders after NAC. Patients satisfy these factors are the candidates for the CRS and HIPEC.
文摘Rarely,scientific developments centered around the patient as a whole arepublished.Our multidisciplinary group,headed by gastrointestinal surgeons,applied this research philosophy considering the most important aspects of thediseases“colon-and rectal cancer”in the long-term developments.Good expertcooperation/knowledge at the Comprehensive Cancer Center Ulm(CCCU)wereapplied in several phase III trials for multimodal treatments of primary tumors(MMT)and metastatic diseases(involving nearly 2000 patients and 64 centers),fortreatment individualization of MMT and of metastatic disease,for psychooncology/quality of life involving the patients’wishes,and for disease prevention.Most of the targets initially were heavily rejected/discussed in thescientific communities,but now have become standards in treatments andnational guidelines or are topics in modern translational research protocolsinvolving molecular biology for e.g.,“patient centered individualized treatment”.In this context we also describe the paths we had to tread in order to realize ournew goals,which at the end were highly beneficial for the patients from manypoints of view.This description is also important for students and youngresearchers who,with an actual view on our recent developments,might want toknow how medical progress was achieved.
基金supported by the VA Merit Award(grant number:I01BX003895)National Cancer Institute R01(grant num-ber:AI154722)Personalized Cancer Therapy Gift Fund(T.L.).
文摘Immune checkpoint inhibitors(ICIs)and cellular immunotherapy have revolutionized cancer treatment.Although these therapies have significantly improved cancer patients’survival,they are associated with a range of immunerelated adverse events(irAEs)that can affect patients’quality of life.Neuromuscular complications related to cancer immunotherapy are rare(<5%with monotherapy and up to 14%with combination therapy),but they can be fatal if not addressed promptly.Early diagnosis and intervention are crucial to improving the quality of life and survival of cancer patients affected by neuromuscular complications associated with immunotherapy.However,symptoms can be diverse and nonspecific,including weakness,numbness,imbalance,dysarthria,dysphagia,and even difficulty in breathing,which presents significant challenges for diagnosis and management.This review summarizes the current understanding of the mechanisms,clinical features,diagnostic challenges,and management strategies for neuromuscular complications related to cancer immunotherapy.Understanding the complex interplay between T cells,B cells,and cytokines in the pathogenesis of neuromuscular irAEs is essential for guiding their management.It is important for healthcare providers,including oncologists,neurologists,primary care physicians,and other practitioners,to be familiar with the multidisciplinary clinical management of neuromuscular irAEs.This knowledge will help reduce the mortality and morbidity associated with these complications.
文摘Rational design of multifunctional nanoplatforms capable of combining therapeutic effects with real-time monitoring of drug distribution and tumor status is emerging as a promising approach in cancer nanomedicine.Here,we introduce pyropheophorbide a-bisaminoquinoline conjugate lipid nanoparticles(PPBC LNPs)as a bimodal system for image-guided phototherapy in bladder cancer treatment.PPBC LNPs not only demonstrate both powerful photodynamic and photothermal effects upon light activation,but also exhibit potent autophagy blockage,effectively inducing bladder cancer cell death.Furthermore,PPBC LNPs possess remarkable photoacoustic(PA)and fluorescence(FL)imaging capabilities,enabling imaging with high-resolution,deep tissue penetration and high sensitivity for tracking drug biodistribution and phototherapy efficacy.Specifically,PA imaging confirms the efficient accumulation of PPBC LNPs within tumor and predicts therapeutic outcomes of photodynamic therapy,while FL imaging confirms their prolonged retention at the tumor site for up to 6 days.PPBC LNPs significantly suppress bladder tumor growth,with several tumors completely ablated following just two doses of the nanoparticles and laser treatment.Additionally,PPBC LNPs were formulated with lipid-based excipients and assembled using microfluidic technology to enhance biocompatibility,stability,and scalability,showing potential for clinical translation.This versatile nanoparticle represents a promising candidate for further development in bladder cancer therapy.
基金Supported by Funding for Clinical Trials from the Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,No.2021-LCYJ-MS-11.
文摘Esophageal cancer(EC),a common malignant tumor of the digestive tract,requires early diagnosis and timely treatment to improve patient prognosis.Automated detection of EC using medical imaging has the potential to increase screening efficiency and diagnostic accuracy,thereby significantly improving long-term survival rates and the quality of life of patients.Recent advances in deep learning(DL),particularly convolutional neural networks,have demons-trated remarkable performance in medical imaging analysis.These techniques have shown significant progress in the automated identification of malignant tumors,quantitative analysis of lesions,and improvement in diagnostic accuracy and efficiency.This article comprehensively examines the research progress of DL in medical imaging for EC,covering various imaging modalities such as digital pathology,endoscopy,computed tomography,etc.It explores the clinical value and application prospects of DL in EC screening and diagnosis.Additionally,the article addresses several critical challenges that must be overcome for the clinical translation of DL techniques,including constructing high-quality datasets,promoting multimodal feature fusion,and optimizing artificial intelligence-clinical workflow integration.By providing a detailed overview of the current state of DL in EC imaging and highlighting the key challenges and future directions,this article aims to guide future research and facilitate the clinical implementation of DL technologies in EC management,ultimately contributing to better patient outcomes.
基金National Council for Scientific and Technological Development,CNPq,Research Productivity,grant numbers:304747/2018-1/310135/2022-2(Reis LO).
文摘Objective:To determine the safety and the role of modulating cytokines and proteases in the immune response to intravesical Bacillus Calmette-Guérin(BCG)when primed with systemic intradermal BCG.Methods:Phase 1 and mechanistic longitudinal,prospective,single-blind randomized study(NCT04806178).Twenty-one non-muscle invasive urothelial bladder cancer patients undergoing intravesical adjuvant BCG after transurethral resection of bladder tumor(TURBT)in a teaching hospital between September 2021 and April 2023 were randomized to 0.1 mL of intradermal BCG vaccine or placebo(0.9%saline)administered 15 days before the start of intravesical BCG therapy.Blood samples were evaluated mechanistically regarding eight cytokines serum levels interferon-induced transmembrane protein 3 Gene(IFITM3),Interleukin 1 beta(IL1-BETA),interleukin-2 receptor alpha chain(IL2 RA),Interleukin 6(IL 6),Interleukin 10(IL 10),Tumor necrosis factor alpha(TNF-α),Interferon-β,AXL,and one protease CASPASE 8.Results:After 1 exclusion,twenty patients were randomized to intradermal BCG(n=11)and intradermal placebo(n=9).There was no difference in adverse effects emerging from the intravesical Onco-BCG therapy,and no difference in the expression of the cytokines and proteases analyzed between control and intervention,and over time.Conclusions:Intradermal BCG administration before intravesical application was safe,with no increase in adverse effects.It also does not seem to change the analyzed targets during the intravesical induction-phase BCG.Other immune targets should be explored in the future.The Brazilian tuberculosis-endemic status,where BCG vaccination is mandatory,might have affected the results.
文摘In spite of advances made in the management of the other more common cancers of the gastrointestinal tract,significant progress in the treatment of pancreatic cancer remains elusive.Nearly as many deaths occur from pancreatic cancer as are diagnosed each year reflecting the poor prognosis typically associated with this disease.Until recently,the only treatment with an impact on survival was surgery.In the palliative setting,gemcitabine(Gem) has been a standard treatment for advanced pancreatic cancer since it was shown a decade ago to result in a superior clinical benefit response and survival compared with bolus 5-fluorouracil.Since then,clinical trials have explored the pharmacokinetic modulation of Gem by fixed dose administration and the combination of Gem with other cytotoxic or the biologically"targeted"agents.However,promising trial results in small phaseⅡtrials have not translated into survival improvements in larger phaseⅢrandomized trials in the advanced disease setting.Two trials have recently reported modest survival improvements with the use of combination treatment with Gem and capecitabine(United Kingdom National Cancer Research GEMCAP trial) or erlotinib(National Cancer Institute of CanadaClinical Trials Group PA.3 trial) .This review will focus on the use of systemic therapy for advanced and metastatic pancreatic cancer,summarizing the results of several recent clinical trials and discuss their implications for clinical practice.We will also discuss briefly the second-line chemotherapy options for advanced pancreatic cancer.
文摘The incidence and mortality of gastric cancer have fallen dramatically in US and elsewhere over the past several decades. Nonetheless, gastric cancer remains a major public health issue as the fourth most common cancer and the second leading cause of cancer death worldwide. Demographic trends differ by tumor location and histology. While there has been a marked decline in distal, intestinal type gastric cancers, the incidence of proximal, diffuse type adenocarcinomas of the gastric cardia has been increasing, particularly in the Western countries. Incidence by tumor sub-site also varies widely based on geographic location, race, and socioeconomic status. Distal gastric cancer predominates in developing countries, among blacks, and in lower socioeconomic groups, whereas proximal tumors are more common in developed countries, among whites, and in higher socio-economic classes. Diverging trends in the incidence of gastric cancer by tumor location suggest that they may represent two diseases with different etiologies. The main risk factors for distal gastric cancer include Helicobacter pylori （H pylori） infection and dietary factors, whereas gastroesophageal reflux disease and obesity play important roles in the development of proximal stomach cancer. The purpose of this review is to examine the epidemiology and risk factors of gastric cancer, and to discuss strategies for primary prevention.
文摘The estrogen receptor(ER) pathway plays a critical role in breast cancer development and progression. Endocrine therapy targeting estrogen action is the most important systemic therapy for ER positive breast cancer. However its efficacy is limited by intrinsic and acquired resistance. Mechanisms responsible for endocrine resistance include deregulation of the ER pathway itself, including loss of ER expression, posttranslational modification of ER, deregulation of ER coactivators; increased receptor tyrosine kinase signaling leading to activation of various intracellular pathways involved in signal transduction, proliferation and cell survival, including growth factor receptor tyrosine kinases human epidermal growth factor receptor-2, epidermal growth factor receptor, PI3K/AKT/mammalian target of rapamycin(m TOR), Mitogen activated kinase(MAPK)/ERK, fibroblast growth factor receptor, insulin-like growth factor-1 receptor; alterations in cell cycle and apoptotic machinery; Epigenetic modificationincluding dysregulation of DNA methylation, histone modification, and nucleosome remodeling; and altered expression of specific micro RNAs. Functional genomics has helped us identify a catalog of genetic and epigenetic alterations that may be exploited as potential therapeutic targets and biomarkers of response. New treatment combinations targeting ER and such oncogenic signaling pathways which block the crosstalk between these pathways have been proven effective in preclinical models. Results of recent clinical studies suggest that subsets of patients benefit from the combination of inhibitor targeting certain oncogenic signaling pathway with endocrine therapy. Especially, inhibition of the m TOR signaling pathway, a key component implicated in mediating multiple signaling cascades, offers a promising approach to restore sensitivity to endocrine therapy in breast cancer. We systematically reviewed important publications cited in Pub Med, recent abstracts from ASCO annual meetings and San Antonio Breast Cancer Symposium, and relevant trials registered at Clinical Trials.gov. We present the molecular mechanisms contributing to endocrine resistance, in particular focusing on the biological rationale for the clinical development of novel targeted agents in endocrine resistant breast cancer. We summarize clinical trials utilizing novel strategies to overcome therapeutic resistance, highlighting the need to better identify the appropriate patients whose diseases are most likely to benefit from these specific strategies.
文摘The interplay between inflammation and cancer progression is a growing area of research. A combination of clinical, epidemiological, and basic science investigations indicate that there is a relationship between inflammatory changes in the pancreas and neoplastic progression. Diets high in ω-6 polyunsaturated fatty acids provide increased substrate for arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) to form eicosanoids. These eicosanoids directly contribute to pancreatic cancer cell proliferation. Both COX-2 and 5-LOX are upregulated in multiple cancer types, including pancreatic cancer. In vitro studies using pancreatic cancer cell lines have demonstrated upregulation of COX-2 and 5-LOX at both the mRNA and protein levels. When COX-2 and 5-LOX are blocked via a variety of mechanisms, cancer cell proliferation is abrogated both in vitro and in vivo. The mechanism of COX-2 has been shown to include effects on apoptosis as well as angiogenesis. 5-LOX has been implicated in apoptosis. The use of COX-2 and 5-LOX inhibitors in clinical studies in patients with pancreatic cancer has been limited. Patient enrollment has been restricted to those with advanced disease which makes evaluation of these drugs as chemopreventive agents difficult. COX-2 and 5-LOX expression have been shown to be present during the early neoplastic changes of pancreatic cancer, well before progression to invasive disease. This indicates that the ideal role for these interventions is early in the disease process as preventive agents, perhaps in patients with chronic pancreatitis or hereditary pancreatitis.
文摘Stereotactic body radiation therapy(SBRT) is the treatment of choice for medically inoperable patients with early stage non-small cell lung cancer(NSCLC). A literature search primarily based on PubMed electronic databases was completed in July 2018. Inclusion and exclusion criteria were determined prior to the search, and only prospective clinical trials were included. Nineteen trials from 2005 to 2018 met the inclusion criteria, reporting the outcomes of 1434 patients with central and peripheral early stage NSCLC. Patient eligibility,prescription dose and delivery, and follow up duration varied widely. Threeyears overall survival ranged from 43% to 95% with loco-regional control of up to 98% at 3 years. Up to 33% of patients failed distantly after SBRT at 3 years. SBRT was generally well tolerated with 10%-30% grade 3-4 toxicities and a few treatment-related deaths. No differences in outcomes were observed between conventionally fractionated radiation therapy and SBRT, central and peripheral lung tumors, or inoperable and operable patients. SBRT remains a reasonable treatment option for medically inoperable and select operable patients with early stage NSCLC. SBRT has shown excellent local and regional control with toxicity rates equivalent to surgery. Decreasing fractionation schedules have been consistently shown to be both safe and effective. Distant failure is common, and chemotherapy may be considered for select patients. However, the survival benefit of additional interventions, such as chemotherapy, for early stage NSCLC treated with SBRT remains unclear.
基金Supported by United States Public Health Service,Nos.DK067287,CA162147 and CA206010the A.Alfred Taubman Medical Research Institute of the University of Michigan
文摘Microsatellite alterations within genomic DNA frameshift as a result of defective DNA mismatch repair(MMR). About 15% of sporadic colorectal cancers(CRCs) manifest hypermethylation of the DNA MMR gene MLH1, resulting in mono-and di-nucleotide frameshifts to classify it as microsatellite instability-high(MSI-H) and hypermutated, and due to frameshifts at coding microsatellites generating neo-antigens, produce a robust protective immune response that can be enhanced with immune checkpoint blockade. More commonly, approximately 50% of sporadic nonMSI-H CRCs demonstrate frameshifts at di-and tetra-nucleotide microsatellites to classify it as MSIlow/elevated microsatellite alterations at selected tetranucleotide repeats(EMAST) as a result of functional somatic inactivation of the DNA MMR protein MSH3 via a nuclear-to-cytosolic displacement. The trigger for MSH3 displacement appears to be inflammation and/or oxidative stress, and unlike MSI-H CRC patients, patients with MSI-L/EMAST CRCs show poor prognosis. These inflammatory-associated microsatellite alterations are a consequence of the local tumor microenvironment, and in theory, if the microenvironment is manipulated to lower inflammation, the microsatellite alterations and MSH3 dysfunction should be corrected. Here we describe the mechanisms and significance of inflammatory-associated microsatellite alterations, and propose three areas to deeply explore the consequences and prevention of inflammation's effect upon the DNA MMR system.
文摘Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer （CRPC）. Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing ＇level-1 evidence＇ that docetaxel-based chemotherapy led to prolongation in overall survival （OS）. This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents （e.g. abiraterone and enzalutamide） have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include： how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.
基金supported by grants from the National Natural Science Foundation of China (Grant No. 30772316 and 81572568)
文摘Objective: Despite evidence that estrogens and insulin are involved in the development and progression of many cancers, their synergistic role in endometrial carcinoma(EC) has not been analyzed yet.Methods: Here, we investigated how estrogens act synergistically with insulin to promote EC progression. Cell growth in vitro and in vivo, effects of estradiol and insulin on apoptosis and cell cycle distribution, and expression and activation of estrogen receptor(ER), insulin receptor(InsR), and key proteins in the PI3K and MAPK pathways were examined after combined stimulation with estradiol and insulin.Results: Compared to EC cells treated with estradiol or insulin alone, those treated with both estradiol and insulin exhibited stronger stimulation. Estradiol significantly induced phosphorylation of InsR-β and IRS-1, whereas insulin significantly induced phosphorylation of ER-α. In addition, treatment with both insulin and estradiol together significantly increased the expression and phosphorylation of Akt, MAPK, and ERK. Notably, InsR-β inhibition had a limited effect on estradiol-dependent proliferation,cell cycle, and apoptosis, whereas ER-α inhibition had a limited insulin-dependent effect, in EC cell lines. Insulin and estradiol individually and synergistically promoted EC xenograft growth in mice.Conclusions: Estrogen and insulin play synergistic roles in EC carcinogenesis and progression by activating InsR-β and ER-α,promoting a crosstalk between them, and thereby resulting in the activation of downstream PI3K/Akt and MAPK/ERK signaling pathways.
基金supported by the University of Texas-Graduate School of Biomedical Sciences at Houston(A.G.D)the French Association for Research against Cancer(S.N.D)
文摘The phosphatidylinositol-3 kinase(PI3K) pathway regulates a number of cellular processes, including cell survival, cell growth, and cell cycle progression. Consequently, this pathway is commonly deregulated in cancer. In particular, mutations in the gene PIK3CA that encodes the p110α catalytic subunit of the PI3K enzymes result in cell proliferation and resistance to apoptosis in vitro and induce breast tumors in transgenic mice. These data underscore the role of this pathway during oncogenesis. Thus, an ongoing, large-scale effort is underway to develop clinically active drugs that target elements of the PI3K pathway. However, conflicting data suggest that gain-of-function PIK3CA mutations may be associated with either a favorable or a poor clinical outcome, compared with the wild-type PIK3CA gene. In the current study, we performed a systematic review of breast cancer clinical studies. Upon evaluation of 2587 breast cancer cases from 12 independent studies, we showed that patients with tumors harboring a PIK3CA mutation have a better clinical outcome than those with a wild-type PIK3CA gene. Importantly, this improved prognosis may pertain only to patients with mutations in the kinase domain of p110α and to postmenopausal women with estrogen receptor-positive breast cancer. We propose three potential explanations for this paradoxical observation. First, PIK3CA mutations may interfere with the metastasis process or may induce senescence, which results in a better outcome for patients with mutated tumors. Secondly, we speculate that PIK3CA mutations may increase early tumor diagnosis by modification of the actin cytoskeleton in tumor cells. Lastly, we propose that PIK3CA mutations may be a favorable predictive factor for response to hormonal therapy, giving a therapeutic advantage to these patients. Ultimately, an improved understanding of the clinical impact of PIK3CA mutations is critical for the development of optimally personalized therapeutics against breast cancer and other solid tumors. This effort will be important to prevent or explain therapeutic failures and select patients who are most likely to respond to new therapies that inhibit the PI3K pathway.
文摘Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease. Controversies remain, however, surrounding the optimal timing, duration and schedule of these hormonal approaches. Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer, This review highlights the various androgen-directed treatment options available to men with prostate cancer, their specific indications and the evidence supporting each approach, as well as patterns of use of hormonal therapies.
文摘Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that constitutive overexpression of cyclooxygenase-2(COX-2) is a ubiquitous driver of mammary carcinogenesis, and reciprocally, that COX-2 blockade has strong potential for breast cancer prevention and therapy. Key findings include the following:(1) COX-2 is constitutively expressed throughout breast cancer development and expression intensifies with stage at detection, cancer progression and metastasis;(2) essential features of mammary carcinogenesis(mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis and immunosuppression) are linked to COX-2-driven prostaglandin E2(PGE-2) biosynthesis;(3) upregulation of COX-2 and PGE-2 expression induces transcription of CYP-19 and aromatase-catalyzed estrogen biosynthesis which stimulates unbridled mitogenesis;(4) extrahe-patic CYP-1B1 in mammary adipose tissue converts paracrine estrogen to carcinogenic quinones with mutagenic impact; and(5) agents that inhibit COX-2 reduce the risk of breast cancer in women without disease and reduce recurrence risk and mortality in women with breast cancer. Recent sharp increases in global breast cancer incidence and mortality are likely driven by chronic inflammation of mammary adipose and upregulation of COX-2 associated with the obesity pandemic. The totality of evidence clearly supports the supposition that mammary carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive overexpression of COX-2 and the prostaglandin cascade in the "inflammogenesis of breast cancer".
文摘Blockade of the programmed death ligand 1(PD-L1) and programmed cell death 1(PD-1) receptor axis represents an effective form of cancer immunotherapy. Preclinical evidence initially suggested that gastric and gastroesophageal junction(GEJ) cancers are potentially immunotherapy-sensitive tumors. Early phase clinical trials have demonstrated promising antitumor activity with PD-1/PD-L1 blockade in advanced or metastatic gastric/GEJ cancer. Microsatellite instability(MSI) and PD-L1 expression have been shown to predict higher response to PD-1 inhibitors as highlighted by the recent approvals of pembrolizumab in treatmentrefractory solid tumors with MSI status and the thirdline or greater treatment of PD-L1 positive advanced gastric/GEJ cancers. However, predictive and prognostic biomarkers remain an ongoing need. In this review, we detail the preclinical evidence and early tissue biomarker analyses illustrating potential predictive biomarkers to PD-1/PD-L1 blockade in gastric/GEJ cancer. We also review the clinical development of PD-1/PD-L1 inhibitors in gastric/GEJ cancer and highlight several areas in need of future investigation in order to optimize the efficacy of PD-1/PD-L1 blockade in gastric/GEJ cancer.
基金Supported by The AIRC grant Veneto Region 2009the "G.Berlucchi" and "G.B. Morgagni" Foundations
文摘In spite of the well-established understanding of the phenotypic lesions occurring in the shift from native epithelia to invasive （adeno） carcinoma, the molecular b/ping of the precancerous changes in the gastrointes- tinal tract remains unreliable. In recent years, no biomarkers have aroused as much interest as the miRNAs, a class of non-coding RNA molecules that function as endogenous silencers of numerous target genes. Aberrant miRNA expression is a hallmark of human disease, including cancer. Unlike most mRNAs, miRNAs are both long-living in vivo and very stable in vitro. Such charac- teristics allow their testing in paraffin-embedded tissue samples, which is essential in the biological profiling of small （phenotypically characterized） preneoplastic lesions of the gastrointestinal tract （as well as in other fields of human pathology）. The upcoming challenge lies in the reliable identification of disease-specific targets of dysregulated miRNAs, to enable miRNA testing in the clinical management of the secondary prevention of gastrointestinal cancer.
基金supported in part by grants from the US NIH grant CA130966, CA158911 to S. Y. Chengthe Zell Scholar Award from the Zell Family Foundation and funds from Northwestern Brain Tumor Institute and Department of Neurology at Northwestern University Feinberg School of Medicine to S. Y. Chengthe Brain Cancer Research Award from the James S. McDonnell Foundation to B. Hu
文摘In recent years, it has become increasingly apparent that noncoding RNAs(ncRNA) are of crucial importance for human cancer. The functional relevance of ncRNAs is particularly evident for microRNAs(miRNAs) and long noncoding RNAs(lncRNAs). miRNAs are endogenously expressed small RNA sequences that act as post-transcriptional regulators of gene expression and have been extensively studied for their roles in cancers, whereas lncRNAs are emerging as important players in the cancer paradigm in recent years. These noncoding genes are often aberrantly expressed in a variety of human cancers. However, the biological functions of most ncRNAs remain largely unknown. Recently, evidence has begun to accumulate describing how ncRNAs are dysregulated in cancer and cancer stem cells, a subset of cancer cells harboring self-renewal and differentiation capacities. These studies provide insight into the functional roles that ncRNAs play in tumor initiation, progression, and resistance to therapies, and they suggest ncRNAs as attractive therapeutic targets and potentially useful diagnostic tools.
