Metaplastic regeneration in the mouse stomach requires a reactive oxygen species pathway.

In pyloric metaplasia, mature gastric chief cells reprogram via an evolutionarily conserved process termed paligenosis to re-enter the cell cycle and become spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Here, we use single-cell RNA sequencing (scRNA-seq) following injury to the murine stomach to analyze mechanisms governing paligenosis at high resolution. Injury causes induced reactive oxygen species (ROS) with coordinated changes in mitochondrial activity and cellular metabolism, requiring the transcriptional mitochondrial regulator Ppargc1a (Pgc1α) and ROS regulator Nf2el2 (Nrf2). Loss of the ROS and mitochondrial control in Ppargc1a-/- mice causes the death of paligenotic cells through ferroptosis. Blocking the cystine transporter SLC7A11(xCT), which is critical in lipid radical detoxification through glutathione peroxidase 4 (GPX4), also increases ferroptosis. Finally, we show that PGC1α-mediated ROS and mitochondrial changes also underlie the paligenosis of pancreatic acinar cells. Altogether, the results detail how metabolic and mitochondrial changes are necessary for injury response, regeneration, and metaplasia in the stomach.

Gastric intestinal metaplasia: progress and remaining challenges.

Most gastric cancers arise in the setting of chronic inflammation which alters gland organization, such that acid-pumping parietal cells are lost, and remaining cells undergo metaplastic change in differentiation patterns. From a basic science perspective, recent progress has been made in understanding how atrophy and initial pyloric metaplasia occur. However, pathologists and cancer biologists have long been focused on the development of intestinal metaplasia patterns in this setting. Arguably, much less progress has been made in understanding the mechanisms that lead to the intestinalization seen in chronic atrophic gastritis and pyloric metaplasia. One plausible explanation for this disparity lies in the notable absence of reliable and reproducible small animal models within the field, which would facilitate the investigation of the mechanisms underlying the development of gastric intestinal metaplasia (GIM). This review offers an in-depth exploration of the current state of research in GIM, shedding light on its pivotal role in tumorigenesis. We delve into the histological subtypes of GIM and explore their respective associations with tumor formation. We present the current repertoire of biomarkers utilized to delineate the origins and progression of GIM and provide a comprehensive survey of the available, albeit limited, mouse lines employed for modeling GIM and engage in a discussion regarding potential cell lineages that serve as the origins of GIM. Finally, we expound upon the myriad signaling pathways recognized for their activity in GIM and posit on their potential overlap and interactions that contribute to the ultimate manifestation of the disease phenotype. Through our exhaustive review of the progression from gastric disease to GIM, we aim to establish the groundwork for future research endeavors dedicated to elucidating the etiology of GIM and developing strategies for its prevention and treatment, considering its potential precancerous nature.

The composition and roles of gastric stem cells in epithelial homeostasis, regeneration, and tumorigenesis.

The epithelial lining of the stomach undergoes rapid turnover to preserve its structural and functional integrity, a process driven by long-lived stem cells residing in the antral and corpus glands. Several subpopulations of gastric stem cells have been identified and their phenotypic and functional diversities linked to spatiotemporal specification of stem cells niches. Here, we review the biological features of gastric stem cells at various locations of the stomach under homeostatic conditions, as demonstrated by reporter mice, lineage tracing, and single cell sequencing. We also review the role of gastric stem cells in epithelial regeneration in response to injury. Moreover, we discuss emerging evidence demonstrating that accumulation of oncogenic drivers or alteration of stemness signaling pathways in gastric stem cells promotes gastric cancer. Given a fundamental role of the microenvironment, this review highlights the role reprogramming of niche components and signaling pathways under pathological conditions in dictating stem cell fate. Several outstanding issues are raised, such as the relevance of stem cell heterogeneity and plasticity, and epigenetic regulatory mechanisms, to Helicobacter pylori infection-initiated metaplasia-carcinogenesis cascades. With the development of spatiotemporal genomics, transcriptomics, and proteomics, as well as multiplexed screening and tracing approaches, we anticipate that more precise definition and characterization of gastric stem cells, and the crosstalk with their niche will be delineated in the near future. Rational exploitation and proper translation of these findings may bring forward novel modalities for epithelial rejuvenation and cancer therapeutics.

Single-cell sequencing of ascites fluid illustrates heterogeneity and therapy-induced evolution during gastric cancer peritoneal metastasis.

Peritoneal metastasis is the leading cause of death for gastrointestinal cancers. The native and therapy-induced ascites ecosystems are not fully understood. Here, we characterize single-cell transcriptomes of 191,987 ascites cancer/immune cells from 35 patients with/without gastric cancer peritoneal metastasis (GCPM). During GCPM progression, an increase is seen of monocyte-like dendritic cells (DCs) that are pro-angiogenic with reduced antigen-presenting capacity and correlate with poor gastric cancer (GC) prognosis. We also describe the evolution of monocyte-like DCs and regulatory and proliferative T cells following therapy. Moreover, we track GC evolution, identifying high-plasticity GC clusters that exhibit a propensity to shift to a high-proliferative phenotype. Transitions occur via the recently described, autophagy-dependent plasticity program, paligenosis. Two autophagy-related genes (MARCKS and TXNIP) mark high-plasticity GC with poorer prognosis, and autophagy inhibitors induce apoptosis in patient-derived organoids. Our findings provide insights into the developmental trajectories of cancer/immune cells underlying GCPM progression and therapy resistance.

Gut microbiota composition in chemotherapy and targeted therapy of patients with metastatic colorectal cancer.

Studies have reported the effects of the gut microbiota on colorectal cancer (CRC) chemotherapy, but few studies have investigated the association between gut microbiota and targeted therapy. This study investigated the role of the gut microbiota in the treatment outcomes of patients with metastatic CRC (mCRC). We enrolled 110 patients with mCRC and treated them with standard cancer therapy. Stool samples were collected before administering a combination of chemotherapy and targeted therapy. Patients who had a progressive disease (PD) or partial response (PR) for at least 12 cycles of therapy were included in the study. We further divided these patients into anti-epidermal growth factor receptor (cetuximab) and anti-vascular endothelial growth factor (bevacizumab) subgroups. The gut microbiota of the PR group and bevacizumab-PR subgroup exhibited significantly higher α-diversity. The ß-diversity of bacterial species significantly differed between the bevacizumab-PR and bevacizumab-PD groups (P = 0.029). Klebsiella quasipneumoniae exhibited the greatest fold change in abundance in the PD group than in the PR group. Lactobacillus and Bifidobacterium species exhibited higher abundance in the PD group. The abundance of Fusobacterium nucleatum was approximately 32 times higher in the PD group than in the PR group. A higher gut microbiota diversity was associated with more favorable treatment outcomes in the patients with mCRC. Bacterial species analysis of stool samples yielded heterogenous results. K. quasipneumoniae exhibited the greatest fold change in abundance among all bacterial species in the PD group. This result warrants further investigation especially in a Taiwanese population.

Metformin Enhancement of Therapeutic Effects of 5-Fluorouracil and Oxaliplatin in Colon Cancer Cells and Nude Mice.

Studies have demonstrated that metformin has antitumor effects in addition to therapeutic effects on hyperglycemia; however, few studies have explored the effects of metformin in chemotherapy. Therefore, we hypothesized that the administration of metformin would enhance the therapeutic effects of 5-fluorouracil and oxaliplatin (FuOx) to inhibit the growth of colorectal cancer (CRC) cells in vitro and in vivo. The results of our in vitro experiments demonstrated that metformin significantly increased the effects of FuOx with respect to cell proliferation (p < 0.05), colony formation (p < 0.05), and migration (p < 0.01) and induced cell cycle arrest in the G0/G1 phase in HT29 cells and the S phase in SW480 and SW620 cells (p < 0.05). Flow cytometry analysis revealed that metformin combined with FuOx induced late apoptosis (p < 0.05) by mediating mitochondria-related Mcl-1 and Bim protein expression. Furthermore, in vivo, metformin combined with FuOx more notably reduced tumor volume than FuOx or metformin alone did in BALB/c mice (p < 0.05). These findings demonstrate that metformin may act as an adjunctive agent to enhance the chemosensitivity of CRC cells to FuOx. However, further clinical trials are warranted to validate the clinical implications of the findings.

Gastric Organoids: Progress and Remaining Challenges.

The stomach is a complex and physiologically necessary organ, yet large differences in physiology between mouse and human stomachs have impeded translation of physiological discoveries and drug screens performed using murine gastric tissues. Gastric cancer (GC) is a global health threat, with a high mortality rate and limited treatment options. The heterogeneous nature of GC makes it poorly suited for current "one size fits all" standard treatments. In this review, we discuss the rapidly evolving field of gastric organoids, with a focus on studies expanding cultures from primary human tissues and describing the benefits of mouse organoid models. We introduce the differing methods for culturing healthy gastric tissue from adult tissues or pluripotent stem cells, discuss the promise these systems have for preclinical drug screens, and highlight applications of organoids for precision medicine. Finally, we discuss the limitations of these models and look to the future to present potential ways gastric organoids will advance treatment options for patients with GC.

CD36 maintains the gastric mucosa and associates with gastric disease.

The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd36-/-), with Cd36 deletion in parietal cells (PC-Cd36-/-) or in endothelial cells (EC-Cd36-/-). CD36 expresses on corpus ECs, on PC basolateral membranes, and in gastrin and ghrelin cells. Stomachs of Cd36-/- mice have altered gland organization and secretion, more fibronectin, and inflammation. Tissue respiration and mitochondrial efficiency are reduced. Phospholipids increased and triglycerides decreased. Mucosal repair after injury is impaired in Cd36-/- and EC-Cd36-/-, not in PC-Cd36-/- mice, and is due to defect of progenitor differentiation to PCs, not of progenitor proliferation or mature PC dysfunction. Relevance to humans is explored in the Vanderbilt BioVu using PrediXcan that links genetically-determined gene expression to clinical phenotypes, which associates low CD36 mRNA with gastritis, gastric ulcer, and gastro-intestinal hemorrhage. A CD36 variant predicted to disrupt an enhancer site associates (p < 10-17) to death from gastro-intestinal hemorrhage in the UK Biobank. The findings support role of CD36 in gastric tissue repair, and its deletion associated with chronic diseases that can predispose to malignancy.

DDIT4 Licenses Only Healthy Cells to Proliferate During Injury-induced Metaplasia.

BACKGROUND AND AIMS: In stomach, metaplasia can arise from differentiated chief cells that become mitotic via paligenosis, a stepwise program. In paligenosis, mitosis initiation requires reactivation of the cellular energy hub mTORC1 after initial mTORC1 suppression by DNA damage induced transcript 4 (DDIT4 aka REDD1). Here, we use DDIT4-deficient mice and human cells to study how metaplasia increases tumorigenesis risk. METHODS: A tissue microarray of human gastric tissue specimens was analyzed by immunohistochemistry for DDIT4. C57BL/6 mice were administered combinations of intraperitoneal injections of high-dose tamoxifen (TAM) to induce spasmolytic polypeptide-expressing metaplasia (SPEM) and rapamycin to block mTORC1 activity, and N-methyl-N-nitrosourea (MNU) in drinking water to induce spontaneous gastric tumors. Stomachs were analyzed for proliferation, DNA damage, and tumor formation. CRISPR/Cas9-generated DDIT4-/- and control human gastric cells were analyzed for growth in vitro and in xenografts with and without 5-fluorouracil (5-FU) treatment. RESULTS: DDIT4 was expressed in normal gastric chief cells in mice and humans and decreased as chief cells became metaplastic. Paligenotic Ddit4-/- chief cells maintained constitutively high mTORC1, causing increased mitosis of metaplastic cells despite DNA damage. Lower DDIT4 expression correlated with longer survival of patients with gastric cancer. 5-FU-treated DDIT4-/- human gastric epithelial cells had significantly increased cells entering mitosis despite DNA damage and increased proliferation in vitro and in xenografts. MNU-treated Ddit4-/- mice had increased spontaneous tumorigenesis after multiple rounds of paligenosis induced by TAM. CONCLUSIONS: During injury-induced metaplastic proliferation, failure of licensing mTORC1 reactivation correlates with increased proliferation of cells harboring DNA damage, as well as increased tumor formation and growth in mice and humans.

Autophagy repurposes cells during paligenosis.

Differentiated cells have evolved paligenosis, a conserved program to return to a stem or progenitor state and reenter the cell cycle to fuel tissue repair. Paligenosis comprises three sequential stages: 1) quenching of MTORC1 activity with induction of massive macroautophagy/autophagy that remodels differentiated cell architecture; 2) induced expression of progenitor/repair-associated genes; 3) MTORC1 reactivation with cell cycle reentry. Here, we summarize work showing that evolutionarily conserved genes - Ddit4 and Ifrd1 - are critical regulators of paligenosis. DDIT4 suppresses MTORC1 function to induce lysosomes and autophagosomes in paligenosis stage 1. As DDIT4 decreases during paligenosis, TRP53 continues MTORC1 suppression until cells are licensed to reenter the cell cycle by IFRD1 suppression of TRP53. Cells with DNA damage maintain TRP53 until either the damage is repaired, or they undergo apoptosis. The concept of paligenosis and identification of paligenosis-dedicated genes may provide new angles to harness tissue regeneration and specifically target tumor cells.

Gut Fecal Microbiota Transplant in a Mouse Model of Orthotopic Rectal Cancer.

The gut microbiota is reported to play an important role in carcinogenesis and the treatment of CRC. SW480 and SW620 colon cancer cells integrated with infrared fluorescent proteins were injected into the rectal submucosa of nude mice. In the subsequent 30 days, we observed tumor growth weekly using an in vivo imaging system. The bacterial solution was infused anally into the mice to perform bacterial transplant. Phosphate-buffered saline, Acinetobacter lwoffii, and Bifidobacterium longum solutions were infused individually. The 16S ribosomal DNA (rDNA) and polymerase chain reaction of murine feces were investigated to confirm the colonization of target bacteria. In the SW620 orthotopic xenograft rectal cancer model, 4 of 5 mice developed rectal cancer by 30 days after submucosal injection. In the SW480 orthotopic xenograft rectal cancer model, 2 of 6 mice developed rectal cancer by 30 days after submucosal injection. For the 16S rDNA analysis, the mice receiving the bacterial solution infusion demonstrated positive findings for A. lwoffii and B. longum. With the successful establishment of a mouse model of orthotopic rectal cancer and transplant of target bacteria, we can further explore the relationship between gut microbiota and CRC. The role of fecal microbiota transplant in the treatment and alleviation of adverse events of chemotherapy in CRC could be clarified in subsequent studies.

Racial and ethnic disparities in 21-gene recurrence scores, chemotherapy, and survival among women with hormone receptor-positive, node-negative breast cancer.

PURPOSE: Cutoffs of the 21-gene recurrence score (RS), a commonly used genomic assay for hormone receptor-positive breast cancer, have been updated. Little is known about racial/ethnic differences in RS results, RS-guided chemotherapy use, and outcomes on updated cutoff (RS ≥ 31 defined as high-risk) in the real-world setting. METHODS: A total of 81,937 women [75.0% whites, 7.7% blacks, 8.3% Asian American/Pacific Islanders (AAPIs), and 9.0% Hispanics] diagnosed with hormone receptor-positive breast cancer between 2004 and 2015, who received the 21-gene assay, were identified from the Surveillance, Epidemiology, and End Results. Logistic regressions estimated the race-associated odds ratios (ORs) of RS and chemotherapy use. Cox regressions estimated the race-associated hazard ratios (HRs) of breast cancer-specific and all-cause mortality. RESULTS: Compared with white women, black women were more likely to have RS-defined high-risk tumors (adjusted OR [aOR] 1.29; 95% CI 1.16-1.42). In high RS, blacks had lower odds of chemotherapy use (aOR 0.76; 95% CI 0.62-0.94) than whites, particularly among women ≥ 65 years (aOR 0.51; 95% CI 0.35-0.76), while AAPI and Hispanic women had no variation in chemotherapy use compared with whites in high RS. Black women had a higher risk of breast cancer-specific mortality (HR 1.37; 95% CI 1.12-1.67) and all-cause mortality compared with white women after adjusting for demographic and pathological factors, county-level socioeconomic deprivation, treatments and RS; AAPIs had lower mortality and Hispanics had similar mortality. CONCLUSIONS: Black women were more likely to have a high-risk RS tumor and less likely to receive chemotherapy in the group of high RS, especially those ≥ 65 years. Further studies are needed to identify barriers to chemotherapy in black patients with high RS scores.

A Dedicated Evolutionarily Conserved Molecular Network Licenses Differentiated Cells to Return to the Cell Cycle.

Differentiated cells can re-enter the cell cycle to repair tissue damage via a series of discrete morphological and molecular stages coordinated by the cellular energetics regulator mTORC1. We previously proposed the term "paligenosis" to describe this conserved cellular regeneration program. Here, we detail a molecular network regulating mTORC1 during paligenosis in both mouse pancreatic acinar and gastric chief cells. DDIT4 initially suppresses mTORC1 to induce autodegradation of differentiated cell components and damaged organelles. Later in paligenosis, IFRD1 suppresses p53 accumulation. Ifrd1-/- cells do not complete paligenosis because persistent p53 prevents mTORC1 reactivation and cell proliferation. Ddit4-/- cells never suppress mTORC1 and bypass the IFRD1 checkpoint on proliferation. Previous reports and our current data implicate DDIT4/IFRD1 in governing paligenosis in multiple organs and species. Thus, we propose that an evolutionarily conserved, dedicated molecular network has evolved to allow differentiated cells to re-enter the cell cycle (i.e., undergo paligenosis) after tissue injury. VIDEO ABSTRACT.

A Metformin-Responsive Metabolic Pathway Controls Distinct Steps in Gastric Progenitor Fate Decisions and Maturation.

Cellular metabolism plays important functions in dictating stem cell behaviors, although its role in stomach epithelial homeostasis has not been evaluated in depth. Here, we show that the energy sensor AMP kinase (AMPK) governs gastric epithelial progenitor differentiation. Administering the AMPK activator metformin decreases epithelial progenitor proliferation and increases acid-secreting parietal cells (PCs) in mice and organoids. AMPK activation targets Krüppel-like factor 4 (KLF4), known to govern progenitor proliferation and PC fate choice, and PGC1α, which we show controls PC maturation after their specification. PC-specific deletion of AMPKα or PGC1α causes defective PC maturation, which could not be rescued by metformin. However, metformin treatment still increases KLF4 levels and suppresses progenitor proliferation. Thus, AMPK activates KLF4 in progenitors to reduce self-renewal and promote PC fate, whereas AMPK-PGC1α activation within the PC lineage promotes maturation, providing a potential suggestion for why metformin increases acid secretion and reduces gastric cancer risk in humans.

High blood sugar levels but not diabetes mellitus significantly enhance oxaliplatin chemoresistance in patients with stage III colorectal cancer receiving adjuvant FOLFOX6 chemotherapy.

BACKGROUND: The high prevalence of type 2 diabetes mellitus (DM) among patients with colorectal cancer (CRC) is becoming a serious public health concern worldwide. FOLFOX4 chemotherapy is one of the most widely used adjuvant therapies in patients with stage III colon cancer after surgical resection. However, chemotherapy resistance is associated with a poor prognosis. The prognostic impact of high blood sugar levels on oxaliplatin resistance in CRC patients is an unexplored topic. METHODS: In total, 157 patients with stage III CRC were classified according to their fasting blood sugar level (⩾126 or <126 mg/dl). Clinicopathological features and oxaliplatin chemoresistance/survival outcome of the two groups were compared. In vitro cell proliferation assay was performed through d-(+)-glucose administration. RESULTS: Multivariate analysis results revealed that high blood sugar level was a significantly independent prognostic factor of disease-free survival and overall survival (both p < 0.05), but not DM history. After metformin administration, enhanced proliferation of CRC cells (HT-29, HCT-116, SW480, and SW620) with d-(+)-glucose administration could be reversed and oxaliplatin chemosensitivity considerably increased (p < 0.05). Furthermore, phosphorylation of two glycolysis-related target proteins, SMAD3 and MYC, notably increased under high glucose concentration. CONCLUSIONS: Hyperglycemia can affect clinical outcomes in stage III CRC patients receiving adjuvant chemotherapy, and the mechanism underlying oxaliplatin resistance is possibly associated with increased phosphorylation of SMAD3 and MYC and upregulation of EHMT2 expression.

Smoking status and subsequent gastric cancer risk in men compared with women: a meta-analysis of prospective observational studies.

BACKGROUND: Smoking is one of the well-established risk factors for gastric cancer incidence, yet whether men are more or equally susceptible to gastric cancer due to smoking compared with women is a matter of controversy. The aim of this study was to investigate and compare the effect of sex on gastric cancer risk associated with smoking. METHODS: We conducted a systemic literature search in MEDLINE, EMBASE, and the Cochrane CENTRAL databases to identify studies published from inception to December 2018. We included prospective observational studies which reported effect estimates with 95% confidence intervals (CIs) for associations of current or former smokers with the incidence of gastric cancer by sex. We calculated the ratio of relative risk (RRR) with corresponding 95% CI based on sex-specific effect estimates for current or former smokers versus non-smokers on the risk of gastric cancer. RESULTS: We included 10 prospective studies with 3,381,345 participants in our analysis. Overall, the summary RRR (male to female) for gastric cancer risk in current smokers was significantly increased compared with non-smokers (RRR: 1.30; 95% CI: 1.05-1.63; P = 0.019). Furthermore, there was no significant sex difference for the association between former smokers and gastric cancer risk (RRR: 1.20; 95% CI: 0.92-1.55; P = 0.178). However, the result of sensitivity analysis indicated the pooled result was not stable, which was altered by excluding a nested case-control study (RRR: 1.31; 95% CI: 1.10-1.57; P = 0.002). CONCLUSION: This systematic review showed a potential sex difference association between current smokers and the risk of gastric cancer. The sex differential in smokers can give important clues for the etiology of gastric cancers and should be examined in further studies.

miR-148a inhibits early relapsed colorectal cancers and the secretion of VEGF by indirectly targeting HIF-1α under non-hypoxia/hypoxia conditions.

Vascular endothelial growth factor (VEGF) is correlated with angiogenesis and early relapse of colorectal cancer (CRC). This study investigated the role of miR-148a in the regulation of VEGF/angiogenesis and early relapse of CRC. We established a stable clone with miR-148a expression in HCT116 and HT29 cell lines and created a hypoxic condition by using CoCl2 to determine the underlying mechanism of miR-148a. The effects of miR-148a on the phosphoryl-ERK (pERK)/hypoxia-inducible factor-1α (HIF-1α)/VEGF pathway were evaluated through Western blotting and the inhibitory effect of miR-148a on angiogenesis was demonstrated through a tube formation assay. Sixty-three CRC tissues (28 early relapse and 35 non-early relapse) were analysed to assess the relationship between miR-148a and HIF-1α/VEGF. The protein expression of pERK/HIF-1α/VEGF in HCT116 and HT29 cells was significantly decreased by miR-148a (all P < 0.05). The protein expression of VEGF/HIF-1α was strongly inversely associated with the expression of miR-148a in the 63 CRC tissue samples (all P < 0.05). Tube formation assay demonstrated that miR-148a significantly obliterated angiogenesis. miR-148a suppresses VEGF through down-regulation of the pERK/HIF-1α/VEGF pathway and might lead to the inhibition of angiogenesis; miR-148a down-regulation increased the early relapse rate of CRC. This demonstrates that miR-148a is a potential diagnostic and therapeutic target.

The role of EGFR mutation as a prognostic factor in survival after diagnosis of brain metastasis in non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: The brain is a common site for metastasis in non-small-cell lung cancer (NSCLC). This study was designed to evaluate the relationship between the mutational of the epidermal growth factor receptor (EGFR) and overall survival (OS) in NSCLC patients with brain metastases. METHODS: Searches were performed in PubMed, EmBase, and the Cochrane Library to identify studies evaluating the association of EGFR mutation with OS in NSCLC patients through September 2017. RESULTS: 4373 NSCLC patients with brain metastases in 18 studies were involved. Mutated EGFR associated with significantly improved OS compared with wild type. Subgroup analyses suggested that this relationship persisted in studies conducted in Eastern, with retrospective design, with sample size ≥500, mean age of patients ≥65.0 years, percentage male < 50.0%, percentage of patients receiving tyrosine kinase inhibitor ≥30.0%. Finally, although significant publication bias was observed using the Egger test, the results were not changed after adjustment using the trim and fill method. CONCLUSIONS: This meta-analysis suggests that EGFR mutation is an important predictive factor linked to improved OS for NSCLC patients with brain metastases. It can serve as a useful index in the prognostic assessment of NSCLC patients with brain metastases.

Dietary isoflavones or isoflavone-rich food intake and breast cancer risk: A meta-analysis of prospective cohort studies.

BACKGROUND & AIMS: Previous studies implied that dietary isoflavone intake may reduce the risk of developing breast cancer, but some have shown ambiguous results. This study aimed to systematically evaluate and summarize available evidence on the effect dietary isoflavone intake has on the risk of developing breast cancer. METHODS: PubMed, Embase, and the Cochrane Library were searched for prospective cohort studies published through April 2017 that evaluated the effect of dietary isoflavone intake on the development of breast cancer. RESULTS: Sixteen prospective cohort studies, involving 11,169 breast cancer cases and 648,913 participants, were identified and included in our data analysis. The pooled relative risk (RR) of breast cancer was 0.99 for high versus low intake of isoflavones (95% confidence interval [CI], 0.91-1.09; P = 0.876) and 0.99 for moderate versus low intake of isoflavones (95%CI, 0.92-1.05; P = 0.653), with insignificant heterogeneity (P = 0.187 for high versus low, and P = 0.192 for moderate versus low). While a moderate consumption of soy-based foods did not significantly affect breast cancer risk, a high intake of soy-based foods associated with a lower risk of developing breast cancer. Considering specific foods, an increased the risk of developing breast cancer was seen with a moderate intake of formononetin, but no significant associations were found between breast cancer risk and other isoflavone-rich diets. CONCLUSIONS: The present meta-analysis indicates that women with a high dietary intake of soy foods may experience a statistically significant reduction in breast cancer risk. However, moderate formononetin consumption may increase the risk of developing breast cancer.