Pembrolizumab in patients from China with microsatellite instability-high/mismatch repair deficient tumors: KEYNOTE-158.

Aim: To evaluate pembrolizumab in patients of Chinese descent with microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) tumors enrolled in KEYNOTE-158 (Cohort L). Methods: Patients with MSI-H/dMMR advanced tumors received pembrolizumab 200 mg IV Q3W. Primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: 24 patients were enrolled (20 were evaluable for efficacy). With median follow-up of 12.4 months, the ORR was 70%. DOR, PFS and OS were all not reached. A total of 19 (79%) patients had a treatment-related adverse event (AE; grade ≥3 in 4 [17%]), and 8 (33%) had an immune-mediated AE (grade ≥3 in (4 [17%]). Conclusion: Pembrolizumab provided meaningful and durable responses with manageable safety. These results are consistent with those reported for the global trial.

Novel database for accA gene revealed a vertical variability pattern of autotrophic carbon fixation potential of ammonia oxidizing archaea in a permeable subterranean estuary.

The autotrophic carbon fixation pathway of ammonia-oxidizing archaea (AOA) was the 3-hydroxypropionate/4-hydroxybutyrate (3-HP/4-HB) cycle, of which the acetyl-CoA carboxylase α-submit (accA) gene is widely recognized as the indicator. To date, there is no reference database or suitable cut-off value for operational taxonomic unit (OTU) clustering to analyze the diversity of AOA based on the accA gene. In this study, a reference database with 489 sequences was constructed, all the accA gene sequences was obtained from the AOA enrichment culture, pure culture and environmental samples. Additionally, the 79% was determined as the cut-off value for OTU clustering by comparing the similarity between the accA gene and the 16S rRNA gene. The developed method was verified by analyzing samples from the subterranean estuary and a vertical variation pattern of autotrophic carbon fixation potential of AOA was revealed. This study provided an effective method to analyze the diversity and autotrophic carbon fixation potential of AOA based on accA gene.

A deep learning approach to track Arabidopsis seedlings' circumnutation from time-lapse videos.

BACKGROUND: Circumnutation (Darwin et al., Sci Rep 10(1):1-13, 2000) is the side-to-side movement common among growing plant appendages but the purpose of circumnutation is not always clear. Accurately tracking and quantifying circumnutation can help researchers to better study its underlying purpose. RESULTS: In this paper, a deep learning-based model is proposed to track the circumnutating flowering apices in the plant Arabidopsis thaliana from time-lapse videos. By utilizing U-Net to segment the apex, and combining it with the model update mechanism, pre- and post- processing steps, the proposed model significantly improves the tracking time and accuracy over other baseline tracking methods. Additionally, we evaluate the computational complexity of the proposed model and further develop a method to accelerate the inference speed of the model. The fast algorithm can track the apices in real-time on a computer without a dedicated GPU. CONCLUSION: We demonstrate that the accuracy of tracking the flowering apices in the plant Arabidopsis thaliana can be improved with our proposed deep learning-based model in terms of both the racking success rate and the tracking error. We also show that the improvement in the tracking accuracy is statistically significant. The time-lapse video dataset of Arabidopsis is also provided which can be used for future studies on Arabidopsis in various takes.

Effects of Sub-threshold Transcutaneous Auricular Vagus Nerve Stimulation on Cingulate Cortex and Insula Resting-state Functional Connectivity.

Transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive alternative to vagus nerve stimulation (VNS) with implantable devices, has shown promise in treating disorders such as depression, migraine, and insomnia. Studies of these disorders with resting-state functional magnetic resonance imaging (MRI) (rsfMRI) have found sustained changes in resting-state functional connectivity (rsFC) in patients treated with low frequency (1-20 Hz) taVNS. A recent study has reported reductions in pain scores in patients with rheumatoid arthritis after a 12-week treatment of high-frequency (20 kHz) sub-threshold taVNS. However, no studies to date have examined the effects of high-frequency sub-threshold taVNS on rsFC. The objective of this study was to determine whether high-frequency sub-threshold taVNS induces changes in rsFC using seed regions from the cingulate cortex and insula, brain regions that play a key role in interoception and processing of pain. With a single-blind placebo-controlled repeated measures experimental design, rsfMRI scans were acquired before and after 15 min of either sub-threshold taVNS treatment or a sham control. Significant taVNS-related changes in functional connections to the cingulate cortex were detected between the anterior cingulate cortex and right superior temporal gyrus and between the midcingulate cortex and right inferior parietal lobule. In addition, significant changes in functional connections to the insula were detected between the posterior insula and right precuneus and between the anterior insula and right cuneus gyrus. These results suggest that high-frequency sub-threshold taVNS can lead to sustained effects on the rsFC of brain regions involved in interoception and processing of pain in a cohort of healthy subjects. This study lays the foundation for future rsfMRI studies of high-frequency sub-threshold taVNS in clinical populations.

Effects of sub-threshold transcutaneous auricular vagus nerve stimulation on cerebral blood flow.

Transcutaneous auricular vagus nerve stimulation (taVNS) has shown promise as a non-invasive alternative to vagus nerve stimulation (VNS) with implantable devices, which has been used to treat drug-resistant epilepsy and treatment-resistant depression. Prior work has used functional MRI to investigate the brain response to taVNS, and more recent work has also demonstrated potential therapeutic effects of high-frequency sub-threshold taVNS in rheumatoid arthritis. However, no studies to date have measured the effects of high-frequency sub-threshold taVNS on cerebral blood flow (CBF). The objective of this study was to determine whether high-frequency (20 kHz) sub-threshold taVNS induces significant changes in CBF, a promising metric for the assessment of the sustained effects of taVNS. Arterial spin labeling (ASL) MRI scans were performed on 20 healthy subjects in a single-blind placebo-controlled repeated measures experimental design. The ASL scans were performed before and after 15 min of either sub-threshold taVNS treatment or a sham control. taVNS induced significant changes in CBF in the superior posterior cerebellum that were largely localized to bilateral Crus I and Crus II. Post hoc analyses showed that the changes were driven by a treatment-related decrease in CBF. Fifteen minutes of high-frequency sub-threshold taVNS can induce sustained CBF decreases in the bilateral posterior cerebellum in a cohort of healthy subjects. This study lays the foundation for future studies in clinical populations, and also supports the use of ASL measures of CBF for the assessment of the sustained effects of taVNS.

Efficacy, Safety, and Tolerability of Pertuzumab, Trastuzumab, and Docetaxel for Patients With Early or Locally Advanced ERBB2-Positive Breast Cancer in Asia: The PEONY Phase 3 Randomized Clinical Trial.

Importance: Prospective assessment of treatments known to benefit patients in global clinical trials in specific racial groups is essential. Objective: To compare the efficacy, safety, and tolerability of adding pertuzumab to trastuzumab and docetaxel vs placebo, trastuzumab, and docetaxel in Asian patients with ERBB2-positive early or locally advanced breast cancer. Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled phase 3 trial enrolled 329 women with ERBB2-positive early (T2-3, N0-1, M0) or locally advanced breast cancer (T2-3, N2 or N3, M0; T4, any N, M0) and primary tumor larger than 2 cm from March 14, 2016, to March 13, 2017. Analysis of the primary end point was performed on an intention-to-treat basis. Interventions: Before surgery, patients received 4 cycles of intravenous pertuzumab (840-mg loading dose and 420-mg maintenance doses), trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance doses), and docetaxel (75 mg/m2) or intravenous placebo, trastuzumab, and docetaxel every 3 weeks. After surgery, patients received 3 cycles of intravenous fluorouracil, epirubicin, and cyclophosphamide followed by 13 cycles of the same intravenous anti-ERBB2 therapy (pertuzumab and trastuzumab or placebo and trastuzumab) for up to 1 year. Main Outcomes and Measures: The primary end point was independent review committee-assessed total pathologic complete response rate. The 2-sided Cochran-Mantel-Haenszel test, stratified by disease category and hormone receptor status, was used to compare rates between treatment groups. Results: In total, 329 female patients were randomized (pertuzumab, 219; and placebo, 110; mean [SD] age, 48.8 [9.5] years). In the intention-to-treat population, total pathologic complete response rates were 39.3% (86 of 219) in the pertuzumab group and 21.8% (24 of 110) in the placebo group (difference, 17.5% [95% CI, 6.9%-28.0%]; P = .001). Of the most common grade 3 or higher adverse events, there was a higher incidence of neutropenia in the pertuzumab group (83 of 218 [38.1%] vs 36 of 110 [32.7%]). Serious adverse events were reported in 10.1% of patients (22 of 218) in the pertuzumab group and 8.2% of patients (9 of 110) in the placebo group. Conclusions and Relevance: Treatment with pertuzumab, trastuzumab, and docetaxel resulted in a statistically significant improvement in the total pathologic complete response rate vs placebo, trastuzumab, and docetaxel for the neoadjuvant treatment of ERBB2-positive early or locally advanced breast cancer in Asian patients. Safety data were in line with the known pertuzumab safety profile and generally comparable between treatment groups. The PEONY trial adds to the totality of data showing the benefit of the pertuzumab regimen. Trial Registration: ClinicalTrials.gov identifier: NCT02586025.

Pharmacokinetics of pertuzumab administered concurrently with trastuzumab in Chinese patients with HER2-positive early breast cancer.

In the APHINITY study (NCT01358877, BIG 4-11/BO25126/TOC4939G), pertuzumab added to trastuzumab and chemotherapy significantly improved invasive disease-free survival as adjuvant treatment for patients with HER2-positive early breast cancer. The objective of this analysis was to assess the pharmacokinetics of pertuzumab in combination with trastuzumab in Chinese patients with early breast cancer. Samples for pertuzumab and trastuzumab pharmacokinetic analysis were taken from Chinese patients during cycle 1 of treatment and at steady-state in cycle 10. Noncompartmental analysis was used to estimate minimum and maximum serum concentrations (Cmax and Cmin), area under the concentration-time curve, clearance, and other pharmacokinetic parameters. In 15 patients, mean steady-state Cmax and Cmin pertuzumab serum concentrations (368 ± 177 µg/ml, and 122 ± 47 µg/ml, respectively) were numerically higher than observed previously in a pharmacokinetic analysis of the global population in APHINITY and in patients treated in the metastatic setting. The geometric mean ratio and corresponding 90% confidence interval for trastuzumab Cmax and Cmin in the presence (n = 15) or absence (n = 17) of pertuzumab were 104.6 (91.09-120) and 98.23 (84.58-114), respectively, indicating no apparent impact of pertuzumab on the pharmacokinetics of trastuzumab. Increases in pertuzumab Cmax and Cmin were not associated with an increase in adverse events. The APHINITY Chinese pharmacokinetic substudy analysis supports the dosing regimen for pertuzumab (840 mg loading dose followed by 420 mg maintenance doses every 3 weeks administered by intravenous infusion) in a Chinese HER2-positive early breast cancer patient population.

Pertuzumab in combination with trastuzumab and chemotherapy for Chinese patients with HER2-positive metastatic gastric or gastroesophageal junction cancer: a subpopulation analysis of the JACOB trial.

BACKGROUND: The JACOB trial (NCT01774786) was a double-blinded, placebo-controlled, randomized, multicenter, international, phase III trial evaluating the efficacy and safety of adding pertuzumab to trastuzumab and chemotherapy in first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric cancer/gastroesophageal junction cancer (GEJC). The aim of this analysis was to investigate efficacy and safety outcomes in the Chinese subpopulation from the JACOB trial. METHODS: This post hoc subpopulation analysis included all patients recruited in mainland China (n = 163; 20.9%) between June 2013 and January 2016. The patients were randomly assigned in a 1:1 ratio to receive pertuzumab plus trastuzumab and chemotherapy (pertuzumab group; n = 82) or placebo plus trastuzumab and chemotherapy (control group; n = 81). Intravenous pertuzumab (840 mg) and trastuzumab (8 mg/kg loading and 6 mg/kg maintenance doses) were given every 3 weeks until disease progression or unacceptable toxicity. Chemotherapy was given as per standard regimens/doses of capecitabine or 5-fluorouracil plus cisplatin. The primary endpoint was overall survival (OS); secondary efficacy endpoints included progression-free survival (PFS), and overall objective response rate (ORR). RESULTS: The median OS was 18.7 months in the pertuzumab group and 16.1 months in the control group (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.49 to 1.14). The median PFS was 10.5 and 8.6 months in the pertuzumab and control groups, respectively (HR 0.85; 95% CI 0.60 to 1.21), and the median ORRs were 68.9% and 55.7%, respectively. The treatment effect in this Chinese subpopulation showed consistency with that in the global ITT population with numerically lower HR for OS and PFS compared with the control group. The safety profiles of the pertuzumab and control groups in this Chinese subpopulation analysis were generally comparable. The most common grade 3-5 adverse events were neutropenia, anemia, and leukopenia. However, due to the nature of being a post hoc subgroup analysis, the results presented here are descriptive only and need to be interpreted with caution. CONCLUSIONS: OS and PFS were numerically improved by adding pertuzumab to trastuzumab and chemotherapy as first-line treatment in Chinese HER2-positive gastric cancer/GEJC patients, and this regimen demonstrated an acceptable safety profile. Trial registration ClinicalTrials.gov. NCT01774786. Registered on 24 January 2013, https://clinicaltrials.gov/ct2/show/NCT01774786.

BLACAT1 predicts poor prognosis and serves as oncogenic lncRNA in small-cell lung cancer.

Bladder cancer-associated transcript 1 (BLACAT1) is a novel identified long noncoding RNA (lncRNA) in bladder cancer, and has been suggested to function as an oncogenic lncRNA in several types of human cancer. However, its involvement in the progression of small-cell lung cancer (SCLC) remained unknown. The aim of our study was to investigate the clinical value and biological function in SCLC. In our results, BLACAT1 expression was increased in SCLC tissues and cell lines compared with paired adjacent normal tissues and bronchial epithelial cell lines, respectively. In addition, BLACAT1 high-expression was obviously associated with advanced clinical stage, large tumor size, more lymph node metastasis, present distant metastasis, and poor prognosis. Furthermore, multivariate analysis indicated that high-expression of BLACAT1 acted as an independent poor prognostic factor for overall survival in SCLC cases. The loss-of-function studies suggested that of BLACAT1 suppressed SCLC cell proliferation, migration, and invasion, and induced G0/G1 phase arrest. In conclusion, BLACAT1 is associated with the malignant status and prognosis in patients with SCLC, and functions as an oncogenic lncRNA in regulating cell proliferation and motility, suggesting BLACAT1 may act as a potential target for SCLC prevention and treatment.

RNA sequencing analyses reveal novel differentially expressed genes and pathways in pancreatic cancer.

Gene expression microarrays have identified many tumor markers and therapeutic targets for pancreatic ductal adenocarcinoma (PDAC). However, microarray profilings have limited sensitivity and are prone to cross-hybridization between homologous DNA fragments. Here, we perform a transcriptome analysis of paired tumor and adjacent benign pancreatic tissues from 10 patients who underwent resection for PDAC. We identify a total of 2736 differentially expressed genes (DEGs) with false discovery rate less than 0.05, including 1554 upregulated, 1182 downregulated, and 6 microRNAs (miR-614, miR-217, miR-27b, miR-4451, miR-3609, and miR-612). Overexpression of five DEGs, i.e. KRT16, HOXA10, CDX1, SI, and SERPINB5 in tumors is confirmed by RT-PCR in 20 additional tissues. Overexpression of KRT16 in PDAC is also verified on protein level. In addition, top canonical pathways such as granulocyte adhesion and diapedesis pathway have been identified. Our study represents a comprehensive characterization of the PDAC transcriptome and provides insight to the mechanisms of pancreatic carcinogenesis and potential biomarkers and novel therapeutic targets for pancreatic cancer.

Serum exosomal miR-4772-3p is a predictor of tumor recurrence in stage II and III colon cancer.

PURPOSE: The study was aimed to evaluate the prognostic or predictive value of serum exosomal microRNAs (miRNAs) for tumor recurrence and response to adjuvant therapy in stage II and stage III colon cancer. RESULTS: 145 differentially expressed mature miRNAs were identified (P<0.05) and 10 top hits were carried forward in validation test. MiR-4772-3p was significantly under-expressed in 27 patients with recurrence compared to in 57 patients without recurrence (P=0.002). The reduced expression was significantly related to increased risk of tumor recurrence and risk of death. As a predictor for tumor recurrence, ROC analysis revealed the AUC (95% CI) was 0.72 (0.59-0.85, P=0.001) for lower level of miR-4772-3p compared to 0.63 (0.51-0.75, P=0.062) for tumor site and 0.65 (0.51-0.78,P=0.034) for lymph node status. Among 66/84 patients who received FOLFOX adjuvant therapy, 9/10 (90%) patients with a lower level and 10/56 (18%) patients with a higher level of miR-4772-3p had tumor recurrence (P<0.001). MATERIALS AND METHODS: Blood samples were prospectively collected from84 patients with stage II/III colon cancer after tumor resection and before adjuvant therapy. Serum exosomal miRNA profiles were determined by RNA sequencing. Differentially expressed mature miRNAs were identified between patients with or without tumor recurrence. The top hits were validated in individual RNA samples using quantitative real-time reverse transcription PCR. CONCLUSIONS: Reduced expression of serum exosomal miR-4772-3p is a prognostic biomarker for tumor recurrence in stage II and stage III colon cancer patients. The predictive value of this marker for response to FOLFOX adjuvant therapy needs further investigation.

Survival benefits from postoperative radiation therapy on lymph node positive patients with pancreatic adenocarcinoma.

The benefit of combining postoperative radiation therapy (PORT) with chemotherapy for resected patients with pancreatic adenocarcinoma is controversial. We sought to determine the effects of PORT on survival in patients with pancreatic adenocarcinoma who underwent primary site surgery. Patients with pancreatic adenocarcinoma receiving primary tumor surgery between 1988 and 2012 were identified from the Surveillance, Epidemiology and End Results (SEER) database. We estimated the association between PORT and other clinicopathologic factors and survival. In total, 5304 patients were identified who underwent pancreatic resection including 2093 patients who had PORT and 3211 patients who had no PORT. Median overall, cancer-specific, and other-cause survival were 19.0, 20.0, and 196.0 months, respectively, with PORT versus 14.0, 15.0, and 163.0 months, respectively, without PORT (all P < 0.001). Subset analysis revealed that the benefit of PORT was limited to patients with N1 disease. Median overall, cancer-specific, and other-cause survival for patients with N1 disease were 18.0, 18.0, and NA months, respectively, with PORT versus 12.0, 13.0, and 154.0 months, respectively, without PORT (all P < 0.001). Regardless the number of positive lymph node count (PLN) and lymph node ratio (LNR), PORT was always associated with increased survival on multivariate analysis in patients with N1 disease (all P < 0.001). In summary, survival benefits might be obtained from PORT on lymph node positive patients with pancreatic adenocarcinoma.

B7-H3 and B7-H4 are independent predictors of a poor prognosis in patients with pancreatic cancer.

B7-H3 and B7-H4 belong to the peripheral membrane protein B7 family and are hypothesized to regulate immunity. These proteins are expressed in human pancreatic cancer (PC), but their prognostic significance is poorly understood. The present study examined the association between B7-H3 and B7-H4 expression and the overall survival time in patients with PC that underwent surgery at the Second Affiliated Hospital to Zhengzhou University between April 2000 and January 2009. Immunohistochemical analysis demonstrated that B7-H3 and B7-H4 were expressed in 35 (88%) and 30 (75%) tumor tissue samples, respectively, which were obtained from 40 patients with PC. Statistical analysis revealed that B7-H3 expression was associated with an early tumor-node-metastasis stage (stage I and II; P<0.01), and B7-H4 expression was associated with tumors located in the body and tail of the pancreas (P<0.01) and lymph node metastasis (P=0.02). In addition, using Spearman's rank correlation coefficient, the present study demonstrated a positive correlation between B7-H3 expression and B7-H4 expression (r=0.37; P=0.02) in tumor samples. B7-H4 expression (P=0.01), tumors located in the pancreatic body and tail (P<0.01), lymph node metastasis (P=0.02) and combined B7-H3 and B7-H4 expression (P<0.01) were indicators of a poor overall survival time. However, solitary B7-H4 expression (P=0.03) and combined B7-H3 and B7-H4 expression (P=0.04) remained significant prognostic factors following adjustment for other prognostic factors in a multivariate Cox's proportional hazards regression model. Therefore, the present results indicate that solitary B7-H4 expression and a combination of B7-H3 and B7-H4 expression are independent predictors of a poor prognosis in patients with PC.

Impacts of new-onset and long-term diabetes on clinical outcome of pancreatic cancer.

Patients with pancreatic cancer have a high frequency of concurrent diabetes. This study is aimed to demonstrate the impact of diabetes on clinical outcome of pancreatic cancer. Clinical and epidemiological information was collected from medical records or by personal interview in 1328 patients with pancreatic ductal adenocarcinoma. Diabetes was defined by a known medical history, or abnormal fasting blood glucose (FBG) and HbA1c levels within three months of the cancer diagnosis. Duration of ≤3 years was used as the cutoff to arbitrarily define the new-onset and long-term diabetes. Logistic regression, Kaplan-Meier plot, log-rank test and Cox regression models were employed in the data analysis. Elevated level of FBG or HbA1c was observed in 24.7% and 11.5% of the patients without a known diabetes history, respectively. The prevalence of DM was 44.4% and was comparable by strata of tumor stage. New-onset diabetes was a significant independent predictor for risk of death in metastatic patients (HR=1.35, 95% CI=1.11-1.63, P=0.002) and in all patients (HR=1.23, 95% CI=1.09-1.40, P=0.001). Both new-onset and long term diabetes were significantly associated with older age, obesity, hypertension and coronary artery disease as well as weight loss. New-onset diabetes was also significantly related to larger tumors and elevated level of CA19-9 but not to tumor site and presence of biliary obstruction. Diabetes in general and new-onset diabetes in particular, is associated with poor outcome of pancreatic cancer. New-onset and long-term diabetes share common risk factors for type 2 diabetes.

Effect of Diabetes Mellitus on Survival in Patients with Pancreatic Cancer: A Systematic Review and Meta-analysis.

Concurrent diabetes has been linked with an increased risk of death in many cancers, but findings in pancreatic cancer have been inconsistent. We performed a systematic review and meta-analysis to assess the effect of diabetes on survival in patients with pancreatic cancer. Of 4, 463 original articles, 41 were included in the review; 29 studies with 33 risk estimates were included in the meta-analysis. In the overall comparison of patients with pancreatic cancer and diabetes with their nondiabetic counterparts, the former had significantly higher all-cause mortality (pooled HR: 1.13; 95% CI: 1.04-1.22). Subgroup analyses showed that diabetes was associated with poor survival in patients with resectable disease (HR: 1.37; 95% CI: 1.15-1.63) but not in those with unresectable disease (HR: 1.07; 95% CI: 0.89-1.29). The HR (95% CI) was 1.52 (1.20-1.93) for patients with new-onset diabetes (≤ 2 years of diabetes duration) and 1.22 (0.83-1.80) for those with longstanding diabetes (> 2 years). Diabetes was associated with higher mortality overall in patients with pancreatic cancer. The effect of diabetes on overall survival was associated with the stages of tumor and the duration of diabetes.

Primary Tumor Resection Is Associated with Improved Survival in Stage IV Colorectal Cancer: An Instrumental Variable Analysis.

Primary tumor resection (PTR) is recommended for patients with unresectable stage IV colorectal cancer (CRC) who present with symptoms related to their primary tumor. However, the survival benefit of PTR for asymptomatic patients is controversial. We investigated the change in PTR rates and the contribution of PTR to survival in patients with unresectable stage IV CRC over the past two decades in the United States. Clinicopathological factors and long-term survival were compared for 44 514 patients diagnosed with unresectable stage IV CRC from January 1, 1988, through December 31, 2010, who had or had not undergone PTR. Multivariable Cox regression and the instrumental variable method were used to identify independent factors for survival. Of the 44 514 patients with unresectable stage IV CRC, 27 931 (62.7%) had undergone PTR. The annual rate of PTR decreased from 74.4% to 50.2% diagnosed in 1988 and 2010, and the median overall survival increased for both PTR and non-PTR patients. Instrumental variable analyses revealed that PTR was associated with better overall, cancer-specific, and other-cause survival of patients with unresectable stage IV CRC.

Metformin Use Is Associated With Better Survival of Breast Cancer Patients With Diabetes: A Meta-Analysis.

BACKGROUND: Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pathologic complete response rate than do diabetic patients not receiving metformin, but findings on salvage treatment have been inconsistent. We performed a meta-analysis to assess the effect of adding metformin to standard therapy on the prognosis of breast cancer patients with diabetes. METHODS: We searched PubMed, Embase, Web of Science (Thomson Scientific), China Knowledge Resource Integrated Database, VIP journal integration platform, and Chinese BioMedical Literature Database from inception to January 10, 2015, without language restrictions, including references related to metformin, breast cancer, and prognosis. We performed the meta-analysis using a random-effects model, with hazard ratios (HRs) and 95% confidence intervals (95% CIs) as effect measures. RESULTS: A total of 11 studies consisting of 5,464 breast cancer patients with diabetes were included, comprising 2,760 patients who had received metformin and 2,704 patients who had not. The meta-analysis showed that metformin was associated with better overall survival times (HR: 0.53; 95% CI: 0.39-0.71) and cancer-specific survival times (HR: 0.89; 95% CI: 0.79-1.00). Subgroup analysis revealed that metformin improved the overall survival by 65% after adjusting for hormone receptor expression (HR: 0.35; 95% CI: 0.15-0.84). Taking metformin after the diagnosis of breast cancer was still associated with prolonged overall survival. CONCLUSION: The use of metformin in standard cancer therapy might improve both overall and cancer-specific survivals of diabetic patients with breast cancer. IMPLICATIONS FOR PRACTICE: Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pathologic complete response rate than diabetic patients not receiving metformin, but findings on salvage treatment have been inconsistent. The meta-analysis showed that metformin was associated with better overall survival times and cancer-specific survival times. Subgroup analysis revealed that metformin improved the overall survival by 65% after adjusting for hormone receptor expression. Taking metformin after the diagnosis of breast cancer was still associated with prolonged overall survival. The findings of this study highlight the potential usage of metformin in diabetic patients with breast cancer.

Tamoxifen enhances the anticancer effect of cantharidin and norcantharidin in pancreatic cancer cell lines through inhibition of the protein kinase C signaling pathway.

Cantharidin is an active constituent of mylabris, a traditional Chinese therapeutic agent. Cantharidin is a potent and selective inhibitor of protein phosphatase 2A (PP2A). Cantharidin has been previously reported to efficiently repress the growth of pancreatic cancer cells. However, excessively activated protein kinase C (PKC) has been shown to improve cell survival following the adminstration of cantharidin. Tamoxifen is widely used in the treatment of estrogen receptor-positive breast cancer. In addition, an increasing number of studies have found that tamoxifen selectively inhibits PKC and represses growth in estrogen receptor-negative cancer cells. Administration of a combination of PKC inhibitor and PP2A inhibitors has been demonstrated to exert a synergistic anticancer effect. The proliferation of pancreatic cancer cells was analyzed by 3-(4,5-dimethyltiazol-2-yl]2, 5-diphenyltetrazo-lium bromide assay. The expression levels of ERα and ERß in various pancreatic cancer cell lines were determined by reverse transcription polymerase chain reaction. In addition, the protein levels of PKCα and phosphorylated PKCα in pancreatic cell lines were analyzed by western blot analysis. In the present study, tamoxifen was found to exert a cytotoxic effect against pancreatic cancer cells independent of the hormone receptor status. Tamoxifen repressed the phosphorylation of PKC, and amplified the anticancer effect induced by cantharidin and norcantharidin. The findings reveal a novel potential strategy against pancreatic cancer using co-treatment with tamoxifen plus cantharidin or cantharidin derivatives.

B7-H1 and B7-H3 are independent predictors of poor prognosis in patients with non-small cell lung cancer.

B7-H1 and B7-H3, two members of the B7 family that are thought to regulate T-cell activation, are expressed in human non-small cell lung cancer (NSCLC). However, their prognostic significance is poorly understood. In the present study we reported that B7-H1 and B7-H3 were expressed in 96/128 (72.7%) and 89/128 (69.5%) samples, respectively. B7-H1 and B7-H3 expression and the number of infiltrating T-cell intracellular antigen-1+ and interferon-γ+ cells in NSCLC tissues were significantly higher than those in the adjacent tissues (p<0.01). High B7-H1 or B7-H3 expression was associated with lymph node metastasis and TNM stage (p<0.05, respectively). Sex, TNM stage, B7-H1, B7-H3, and T-cell intracellular antigen-1 expression remained significant prognostic factors after adjusting for other prognostic factors in a multivariate Cox proportional hazards regression model. In vitro studies revealed that knockdown of B7-H3 on tumor cells enhanced T-cell growth and interferon-γ secretion when stimulated by anti-CD3 and anti-CD28 monoclonal antibodies. Interferon-γ reduced CXCR4 expression on cancer cells and inhibited the CXCL12-induced cell migration.B7-H1 and B7-H3 are independent predictors of poorer survival in patients with NSCLC. Interference of the signal pathways of these negative regulatory molecules might be a new strategy for treating NSCLC.