Chloroquine Potentiates the Anticancer Effect of Pterostilbene on Pancreatic Cancer by Inhibiting Autophagy and Downregulating the RAGE/STAT3 Pathway.

The treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, because pro-survival signaling pathways-such as the receptor for advanced glycation end products (RAGE)/signal transducer and activator of transcription 3 (STAT3) pathway-are overexpressed in PDAC cells. Moreover, PDAC cells are highly resistant to chemotherapeutic agents because of autophagy induction. Therefore, autophagy and its modulated signaling pathways are attractive targets for developing novel therapeutic strategies for PDAC. Pterostilbene is a stilbenoid chemically related to resveratrol, and has potential for the treatment of cancers. Accordingly, we investigated whether the autophagy inhibitor chloroquine could potentiate the anticancer effect of pterostilbene in the PDAC cell lines MIA PaCa-2 and BxPC-3, as well as in an orthotopic animal model. The results indicated that pterostilbene combined with chloroquine significantly inhibited autophagy, decreased cell viability, and sensitized the cells to pterostilbene-induced apoptosis via downregulation of the RAGE/STAT3 and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways in PDAC cells. The results of the orthotopic animal model showed that pterostilbene combined with chloroquine significantly inhibited pancreatic cancer growth, delayed tumor quadrupling times, and inhibited autophagy and STAT3 in pancreatic tumors. In summary, the present study suggested the novel therapeutic strategy of pterostilbene combined with chloroquine against the growth of pancreatic ductal adenocarcinoma by inhibiting autophagy and downregulating the RAGE/STAT3 signaling pathways.

BRCA Genes and Related Cancers: A Meta-Analysis from Epidemiological Cohort Studies.

Background and Objectives:BRCA1 and BRCA2 are genes located in different chromosomes that are disproportionately associated with hereditary breast and ovarian cancer syndrome. Their association with other cancers remains to be explored. Materials and Methods: We systematically reviewed cohort studies to explore the association of BRCA 1 and BRCA2 with various cancers except lung cancer. We searched PubMed, Medline (EBSCOhost) and relevant articles published up to 10 May 2021. The odds ratio, standardised morbidity rate and cancer-specific standardised incidence ratio were pooled together as relative risk (RR) estimates. Results: Twelve studies were included for analysis. BRCA mutation increased pancreatic and uterine cancers by around 3-5- and 1.5-fold, respectively. BRCA mutation did not increase brain cancer; colorectal cancer; prostate, bladder and kidney cancer; cervical cancer; or malignant melanoma. BRCA2 increased gastric cancer with RR = 2.15 (1.98-2.33). Conclusion: The meta-analysis results can provide clinicians and relevant families with information regarding increased specific cancer risk in BRCA1 and BRCA2 mutation carriers.

BRCA1 and BRCA2 Gene Mutations and Lung Cancer Sisk: A Meta-Analysis.

Background and objective: BRCA1 and BRCA2 are associated with many cancer types in addition to hereditary breast and ovarian cancers. However, their relation to lung cancer remains to be explored. Materials and Methods: Observation studies were systematically reviewed to explore the association of BRCA1 or BRCA2 with lung cancer. PubMed, MEDLINE [EBSCOhost], and relevant articles published up to 7 January 2020 were searched. Odd ratio (OR), standardized morbidity rate (SMR), and cancer-specific standardized incidence ratios (SIRs) were pooled together as relative risk (RR) estimates (95% confidence interval [CI], 0.66-1.40). Results: Thirteen studies were included for analysis. Results showed that the RR of BRCA2 is 0.76 (95% CI, 0.48-1.19), the overall RR is 0.96 (95% CI, 0.66-1.40), and that of BRCA1 is 0.66 (95% CI, 0.41-1.05), indicating that it was not associated with lung cancer. Conclusion: With the limitation of the retrospective study design and severe heterogeneity, these results inform clinicians and relevant families that BRCA1 and BRCA2 mutation carriers have no increased risk of lung cancer.

Contrast-Induced Acute Kidney Injury Among Patients With Chronic Kidney Disease Undergoing Imaging Studies: A Meta-Analysis.

OBJECTIVE. Contrast-induced nephropathy (CIN) generally is the main concern for patients with chronic kidney disease (CKD) undergoing contrast-enhanced imaging. To evaluate the risk of nephropathy induced by IV contrast medium (CM) in patients with CKD, we performed a meta-analysis. MATERIALS AND METHODS. We searched for PubMed and MEDLINE articles that were published up to October 3, 2018, contained the phrase "contrast medium" or "contrast media" and the word "renal," and included patients with CKD and a proper control group. The publications that were identified were reviewed, and only studies that used an IV route of CM administration were selected. Subgroup analysis was performed according to the estimated glomerular filtration rate. RESULTS. Six studies including 55,963 participants were selected. The Peto method and random-effects model were applied. IV infusion of CM did not lead to the deterioration of renal function in patients with CKD compared with those without CKD (odds ratio [OR], 1.07; 95% CI, 0.98-1.17; I2, 35.3%). As the estimated glomerular filtration rate decreased, fewer patients received IV CM. The ORs for CIN on the basis of CKD stage were as follows: 1.11 (95% CI, 0.95-1.30; I2, 4.0%) for stage 2 CKD, 1.05 (95% CI, 0.93-1.18, I2, 48.3%) for CKD lower than stage 3, 1.06 (95% CI, 0.94-1.19; I2, 32.0%) for stage 3 CKD, 1.08 (95% CI, 0.84-1.39; I2, 44.6%) for CKD lower than stage 4, 0.86 (95% CI, 0.37-2.00) for stage 4 CKD, and 0.26 (95% CI, 0.02-3.4) for stage 5 CKD in one study only. All analyses showed the lack of difference in the ORs for CIN between participants who received IV injection of CM and those who did not. CONCLUSION. Retrospective cohort studies of IV radiographic CM have failed to show renal damage in patients with CKD. This retrospective study is limited, and other risk factors for CIN might not be distributed evenly.

A Population-Based Study of Secondary Prostate Cancer Risk after Radiotherapy in Male Patients with Rectal Cancer: A Retrospective Cohort Study.

Background and objective: Risk of secondary prostate cancer after radiation therapy among patients with rectal cancer remains undetermined. Given an increased incidence of rectal cancer in younger people and improved survival for rectal cancer patients who received radiation therapy, the potential risk of secondary prostate cancer needs to be further investigated. Materials and Methods: Male patients (n = 11,367) newly diagnosed rectal cancer and who underwent abdominoperineal resection (APR) or low anterior resection (LAR) from 1 January, 1998 to 31 December, 2010 were identified from Taiwan National Health Insurance Research Database. The incidence and relative risk of secondary prostate cancer in study patients with (n = 1586) and without (n = 9781) radiotherapy within one year after rectal cancer diagnosis were compared using a competing-risks analysis. Results: Rectal cancer patients with radiotherapy were at a significantly decreased risk of developing prostate cancer, with a hazard ratio (HR) of 0.41 (95% confidence interval = 0.20⁻0.83) after adjustment for age. Analysis of the risk estimated for various follow-up lengths suggested that a decreasing HR was seen through the period followed-up and that there was a trend of decreasing prostate cancer risk with time after radiotherapy. Conclusions: Radiotherapy was significantly associated with decreased risk of secondary prostate cancer among rectal cancer patients, by a magnitude of 59%.

Which Should Be Used First for ALK-Positive Non-Small-Cell Lung Cancer: Chemotherapy or Targeted Therapy? A Meta-Analysis of Five Randomized Trials.

Background and objectives: Targeted therapy is widely used in the era of precision medicine. Whether the sequence in which targeted therapy and chemotherapy are performed matters, is however not known. We examined the impact of the sequential treatment of targeted therapy and chemotherapy among advanced anaplastic lymphoma kinase (ALK), non-small cell lung cancer (NSCLC) patients. Materials and Methods: Randomized controlled trials comparing the use of ALK inhibitors with chemotherapy were included in this meta-analysis. We estimated the hazard ratios (HRs) and 95% confidence intervals (CI), for progression-free survival (PFS) and overall survival (OS) from a random effects model. Two-sided statistical tests were used to determine the significance of these estimates. Results: In five eligible studies (1404 patients), ALK targeted therapy, in comparison with chemotherapy, had a significantly higher PFS (HR = 0.48; 95% CI, 0.42⁻0.55), but not significantly higher OS (HR = 0.88; 95% CI, 0.72⁻1.07). Crossover from chemotherapy to ALK inhibitors was allowed after progression in all trials. The sensitivity analysis of the use of ALK inhibitors as either the first- or second-line treatment, showed improvements in PFS but not in OS. Conclusions: Our results indicate that using targeted therapy first improved PFS, but that the sequence in which the treatments were performed did not cause a significant difference in overall survival.

Molecular Markers and Prognosis of Myelofibrosis in the Genomic Era: A Meta-analysis.

Molecular markers are important in guiding treatment and predicting outcome in the genomic era. Meta-analysis of molecular markers in myelofibrosis through a search of PubMed and Medline through October 31, 2017 was performed. Markers with more than 3 studies that compared overall survival (OS) and leukemia-free survival (LFS) were analyzed. A total of 16 studies were included. Hazard ratios (HRs) for OS were as follows: IDH 2.65 (95% confidence interval [CI], 1.66-4.21), SRSF2 2.12 (95% CI, 1.18-3.79), high-risk myeloma 2.11 (95% CI, 1.70-2.61), ASXL1 1.92 (95% CI, 1.60-2.32), EZH2 1.88 (95% CI, 1.32-2.67), JAK2 1.41 (95% CI, 1.04-1.93) in the univariate analysis and 1.49 (95% CI, 0.42-5.30) in the multivariate analysis. LFS of JAK2 and SRSF2 had HRs of 1.81 (95% CI, 0.42-5.30) and 0.36 (95% CI, 0.02-6.48), respectively. In conclusion, mutations in IDH, SRSF2, and ASXL1 had worse prognosis in OS with HRs around 2. JAK2 and SRSF2 mutation were not associated with increased leukemia transformation. The adverse effect of triple-negative, which was often compared with CALR mutation, needs to be explored.

The necessity of intrathecal chemotherapy for the treatment of breast cancer patients with leptomeningeal metastasis: A systematic review and pooled analysis.

Leptomeningeal carcinomatosis is a devastating disease. Despite its numerous complications, intrathecal (IT) chemotherapy remains a longstanding treatment for leptomeningeal carcinomatosis. Using case studies with internationally reported results, we attempted to determine the necessity of IT chemotherapy in treating leptomeningeal carcinomatosis. We conducted a systematic review and pooled analysis to compare hormone therapy, chemotherapy, and IT therapy. We excluded articles on IT trastuzumab therapy. We performed our literature search without language restriction. We retrieved articles that were published by as late as July 19, 2016. The present study was performed in accordance with the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis. The Cox proportional hazard regression model was performed to examine the effects of prognostic variables. A total of 34 patients from 32 studies were considered eligible. The median age of the patients in the hormone treatment, chemotherapy, and IT therapy groups was 46, 51.5, and 51 years, respectively. The median overall survival (OS) of the patients in the hormone treatment, chemotherapy, and IT therapy groups was 65, 52, and 41 weeks, respectively. One patient who received hormone therapy exhibited the longest survival of approximately 8.5 years. Only magnetic resonance imaging response was associated with OS (hazard ratio = 0.05, 95% confidence interval 0.00-0.74; p = 0.03). Hormone status, HER2 status, age, central nervous system radiation therapy, IT therapy, metastasis sites (central nervous system only vs. others), and cerebrospinal fluid responses were all not associated with OS. Given its obvious side effects and lack of evidence of effectiveness from prospective randomized clinical trials, IT chemotherapy should be used with caution in the treatment of leptomeningeal metastasis breast cancer patients.

Hepatocellular carcinoma-associated single-nucleotide variants and deletions identified by the use of genome-wide high-throughput analysis of hepatitis B virus.

This study investigated hepatitis B virus (HBV) single-nucleotide variants (SNVs) and deletion mutations linked with hepatocellular carcinoma (HCC). Ninety-three HCC patients and 108 non-HCC patients were enrolled for HBV genome-wide next-generation sequencing (NGS) analysis. A systematic literature review and a meta-analysis were performed to validate NGS-defined HCC-associated SNVs and deletions. The experimental results identified 60 NGS-defined HCC-associated SNVs, including 41 novel SNVs, and their pathogenic frequencies. Each SNV was specific for either genotype B (n = 24) or genotype C (n = 34), except for nt53C, which was present in both genotypes. The pathogenic frequencies of these HCC-associated SNVs showed a distinct U-shaped distribution pattern. According to the meta-analysis and literature review, 167 HBV variants from 109 publications were categorized into four levels (A-D) of supporting evidence that they are associated with HCC. The proportion of NGS-defined HCC-associated SNVs among these HBV variants declined significantly from 75% of 12 HCC-associated variants by meta-analysis (Level A) to 0% of 10 HCC-unassociated variants by meta-analysis (Level D) (P < 0.0001). PreS deletions were significantly associated with HCC, in terms of deletion index, for both genotypes B (P = 0.030) and C (P = 0.049). For genotype C, preS deletions involving a specific fragment (nt2977-3013) were significantly associated with HCC (HCC versus non-HCC, 6/34 versus 0/32, P = 0.025). Meta-analysis of preS deletions showed significant association with HCC (summary odds ratio 3.0; 95% confidence interval 2.3-3.9). Transfection of Huh7 cells showed that all of the five novel NGS-defined HCC-associated SNVs in the small surface region influenced hepatocarcinogenesis pathways, including endoplasmic reticulum-stress and DNA repair systems, as shown by microarray, real-time polymerase chain reaction and western blot analysis. Their carcinogenic mechanisms are worthy of further research. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Secondary Cancers After Radiation Therapy for Primary Prostate or Rectal Cancer.

Literature about the risk of secondary cancer after radiation therapy (RT) of prostate and rectal cancer reveals contradictory results. We conducted a meta-analysis to examine whether the RT induces secondary rectal or prostate cancer in patients, respectively, with prostate or rectal cancer. All studies published in Medline or Pubmed up to March 3, 2015, containing RT of primary rectal or prostate cancer, and providing risk estimates of secondary prostate or rectal cancer were considered as eligible. Relative risk (RR) and standardized incidence ratios (SIR) were calculated using the random-effects model. Twenty studies met the inclusion criteria. 12 of them were from the Surveillance, Epidemiology, and End Results (SEER) database. For prostate cancer patients, pooled adjusted RRs or SIRs did not show an effect on the risk of secondary rectal cancer. However, notwithstanding the limitations of SEER-based studies, the subgroup of prostate cancer patients receiving external beam radiation therapy (EBRT) showed an increased risk of rectal cancer. For rectal cancer patients, pooled adjusted RR of prostate cancer was 1.12 (95 % CI, 0.44-2.8) and SIR was 0.40 (95 % CI, 0.29-0.55). All studies included in the SIR analysis of rectal cancer were derived from the SEER data source. Based on current evidence, RT for prostate cancer patients had no effect on rectal cancer incidence, except for patients who received EBRT therapy. However, compared with the general population, RT for rectal cancer is associated with a decreased prostate cancer risk as found in SEER-based studies.

A higher incidence rate of acute coronary syndrome following radiation therapy in patients with breast cancer and a history of coronary artery diseases.

This study aims to investigate whether patients with breast cancer and a history of cardiovascular diseases (CADs) are at an increased incidence of acute coronary syndrome (ACS) after receiving radiation therapy (RT). In Taiwan, 5828 patients who had a history of CAD were newly diagnosed of breast cancer and received mastectomy between 1999 and 2009. Among these patients, 1851 also received RT. The study cohort was prospectively followed to the end of 2010 for estimating the incidence of ACS in association with exposure to RT. A Cox proportional hazard model that was adjusted for covariates was used to estimate the hazard ratio (HR) of ACS. Over the study period, the incident rates of ACS for RT and control patients were estimated at 1.51 and 1.77 per 100 person-years, respectively. Covariate-adjusted regression analysis indicated that the hazard of ACS significantly increased in RT patients at an adjusted HR of 1.48 [95% confidence interval (CI) 1.18-1.87]. Both hypertension and diabetes significantly increased the hazard of ACS in this patient cohort, with adjusted HRs of 3.31 (95% CI 1.94-5.66) and 1.50 (95% CI 1.19-1.89), respectively. This 12-year follow-up study suggested excess of ACS events in association with RT exposure in patients with breast cancer who had a higher cardiovascular risk. In consideration of the benefit associated with RT, intensive cardiac care should be given to patients with breast cancer and high cardiovascular risk.

Differences in survival between colon and rectal cancer from SEER data.

BACKGROUND: Little is known about colorectal cancer or colon and rectal cancer. Are they the same disease or different diseases? OBJECTIVES: The aim of this epidemiology study was to compare the features of colon and rectal cancer by using recent national cancer surveillance data. DESIGN AND SETTING: Data included colorectal cancer (1995-2008) from the Surveillance, Epidemiology, and End Results Program (SEER) database. Only adenocarcinoma was included for analysis. PATIENTS: A total of 372,130 patients with a median follow-up of 32 months were analyzed. MAIN OUTCOME MEASURES: Mean survival of patients with the same stage of colon and rectal cancer was evaluated. RESULTS: Around 35% of patients had stage information. Among them, colon cancer patients had better survival than those with rectal cancer, by a margin of 4 months in stage IIB. In stage IIIC and stage IV, rectal cancer patients had better survival than colon cancer patients, by about 3 months. Stage IIB colorectal cancer patients had a poorer prognosis than those with stage IIIA and IIIB colorectal cancer. After adjustment of age, sex and race, colon cancer patients had better survival than rectal cancer of stage IIB, but in stage IIIC and IV, rectal cancer patients had better survival than colon cancer. LIMITATIONS: The study is limited by its retrospective nature. CONCLUSION: This was a population-based study. The prognosis of rectal cancer was not worse than that of colon cancer. Local advanced colorectal cancer had a poorer prognosis than local regional lymph node metastasis. Stage IIB might require more aggressive chemotherapy, and no less than that for stage III.

Prognostic significance of partial tumor regression after preoperative chemoradiotherapy for rectal cancer: a meta-analysis.

BACKGROUND: Complete tumor regression after preoperative chemoradiotherapy for rectal cancer has been associated with better disease-free and overall survival. The survival experience for patients with partial tumor regression is less clear. OBJECTIVE: The aim of this meta-analysis was to evaluate the prognostic significance of partial response after preoperative chemotherapy on disease-free survival in rectal cancer patients. DATA SOURCES: Relevant studies were identified by a search of MEDLINE and EMBASE databases with no restrictions to October 31, 2012. STUDY SELECTION: We included long-course radiotherapy that reported the association between degree of tumor regression and disease-free survival of rectal cancer. INTERVENTIONS: Direct, indirect, and graph methods were used to extract HRs. MAIN OUTCOME MEASURES: Study-specific HRs on the disease-free survival were pooled using a random-effects model. Eleven articles in total were selected. Analysis was performed first among the 6 studies that separated partial response from the complete response and later among all 11 of the studies. RESULTS: Pooled HR was 0.49 (95% CI, 0.28-0.85) for the 6 studies that compared partial response with poor response. It was 0.41 (95% CI, 0.25-0.67) when all 11 of the studies were analyzed together. LIMITATIONS: The studies were limited by not being prospective, randomized trials, and the tumor regression grades were not uniform. CONCLUSIONS: Partial tumor response is associated with a 50% improvement in disease-free survival and should be considered as a favorable prognostic factor.