Prognostic impact of the IASLC grading system of lung adenocarcinoma: a systematic review and meta-analysis.

AIMS: Tumour grading is an essential part of the pathologic assessment that promotes patient management. The International Association for the Study of Lung Cancer (IASLC) proposed a grading system for non-mucinous lung adenocarcinoma in 2020. We aimed to validate the prognostic impact of this novel grading system on overall survival (OS) and recurrence-free survival (RFS) based on literature data. METHODS AND RESULTS: The review protocol was registered in PROSPERO (CRD42023396059). We aimed to identify randomized or non-randomized controlled trials published after 2020 comparing different IASLC grade categories in Medline, Embase, and CENTRAL. Hazard ratios (HRs) with 95% confidence intervals (CIs) of OS and RFS were pooled and the Quality In Prognosis Studies (QUIPS) tool was used to assess the risk of bias in the included studies. Ten articles were eligible for this review. Regarding OS estimates, grade 1 lung adenocarcinomas were better than grade 3 both in univariate and multivariate analyses (HROSuni = 0.19, 95% CI: 0.05-0.66, p = 0.009; HROSmulti = 0.21, 95% CI: 0.12-0.38, p < 0.001). Regarding RFS estimates, grade 3 adenocarcinomas had a worse prognosis than grade 1 in multivariate analysis (HRRFSmulti: 0.22, 95% CI: 0.14-0.35, p < 0.001). CONCLUSION: The literature data and the result of our meta-analysis demonstrate the prognostic relevance of the IASLC grading system. This supports the inclusion of this prognostic parameter in daily routine worldwide.

The prognostic value of stem cell markers in triple-negative breast cancer.

Among the many consecutive theories of cancer, the stem cell theory is currently the most accepted one. Cancer stem cells are located in small niches with specific environment, renew themselves and are believed to be responsible for many recurrences. They can be highlighted with stem cell markers, but often these markers also label tumor cells, and this may represent a phenotypical change associated with prognosis. In this study, we attempted to match tumor outcomes with the expression of the following stem cell markers: ALDH1, AnnexinA1, CD44, CD117, CD166, Nanog and oct-4. Tissue microarray blocks from triple-negative breast cancers were immunostained for the listed markers, and their expression by the majority of tumor cells (diffuse positivity) was correlated with prognosis. Of the 106 tumors investigated, diffuse positivity was seen in 7 (ALDH1), 33 (AnnexinA1), 53 (CD44), 44 (CD117 membranous only), 49 (CD117), 72 (CD166), 19 (Nanog), and 11 (oct-4) cases. With a median follow-up of 83 months, ALDH1 and CD117 expression was associated with DFS, whereas CD44, CD117 and CD166 were associated with OS estimates, based on Kaplan-Meier analyses. In the multivariate Cox proportional hazard models (including the examined markers and clinicopathological data which had a statistical impact in the univariate analysis), the pN category and the lack of ALDH1 expression were independent prognosticators for DFS, and the pN category and diffuse CD44 staining were independent prognosticators for OS. In the multivariate analysis including all of the examined clinicopathological data and markers, only CD117 showed a statistical impact on OS. We failed to demonstrate a prognostic impact for most stem cell markers tested in triple-negative breast cancer, but lack of ALDH1 staining and CD44 expression appears as of prognostic value, requiring further examination in independent studies.

The impact of the COVID-19 pandemic on suicide rates in Hungary: an interrupted time-series analysis.

BACKGROUND: From 2010 to 2019, suicide mortality fell steadily and substantially in Hungary: the declining trend remained stable, and the suicide rate decreased by more than one-third which was remarkable even from an international perspective. However, despite the declining trend, regional inequalities have always characterised the distribution of suicide mortality in Hungary. Following these favourable trends, COVID-19 appeared in Hungary on the 4th of March 2020 which might lead to an increase in suicides. We aimed to investigate this hypothesis in Hungary by gender, age, educational attainment, and region, as well. METHODS: To test whether the pandemic changed the declining trend of Hungarian suicide rates, the observed number of suicides during March-December 2020 (pre-vaccination period) was compared with the expected numbers (without the appearance of COVID-19). An interrupted time-series analysis was conducted by negative binomial regression using monthly data from January 2010 to February 2020 (pre-pandemic period). RESULTS: Suicide mortality increased significantly compared to the trend during the pre-pandemic period: overall (by 16.7%), among males (18.5%), in the age group 35-49 years (32.8%), and among vocational school graduates (26.1%). Additionally, significant growths in suicide rates were detected in the two regions (Central Hungary and Central Transdanubia) with the lowest COVID mortality rates (by 27.3% and 22.2%, respectively). CONCLUSIONS: Our study revealed reversed trend in suicide mortality during the pre-vaccination period compared to the pre-pandemic period in Hungary. There were significant differences in the pattern of suicide rates by gender, age group, educational attainment, and region during the pre-vaccination period in Hungary, which might be attributed to the socio-economic effects of the COVID-19 pandemic. These findings could prove useful in preventive strategies as the identification of groups at higher risk may be important for suicide prevention; however, further investigations are needed to explore the reasons.

Patterns of suicide deaths in Hungary between 1995 and 2017.

Hungary has had one of the highest suicide mortality rates in the world for decades. Investigating seasonality of suicide deaths is essential as its findings could be key elements in the prevention. In our study we have analyzed the seasonal effect in suicide mortality in relation to possible risk factors in Hungary during 1995-2017. Data on the numbers of suicide deaths were obtained from a published online database. Negative binomial regression was employed to investigate the effect of possible risk factors and seasonal and annual trends in suicide rates. The seasonal effect was further investigated, adding a significant risk factor from the "initial" negative binomial regression. The suicide risk was significantly (p < 0.001) higher in men than in women (incidence rate ratio: 3.48), and it increased with age and decreased with education level. Marriage was a protective factor against suicide. Annual suicide mortality declined significantly (p < 0.001 for trend) from 36.7 (95% confidence interval: 35.5-37.9) to 16.5 (15.7-17.3) per 100,000 persons per year during the study period. Significant seasonality was found in suicide rates with a peak in late June. Similar peaks were observed at each level of each risk factor. There were differences in peaks by suicide method. The peak of non-violent suicides was in early June; suicides committed by violent methods peaked half a month later. This study suggests that there was a significant seasonal effect on suicide deaths between 1995 and 2017, which remained significant even in the presence of each risk factor. To our knowledge, this has been the first study to investigate the seasonal pattern so extensively in Hungary. Our findings confirm that the environmental effects are involved in the etiology of suicide mortality.

Vitex agnus-castus in premenstrual syndrome: A meta-analysis of double-blind randomised controlled trials.

Although chasteberry (Vitex agnus-castus, VAC) has been studied in several clinical trials and available as medicine for the alleviation of premenstrual syndrome (PMS) symptoms, the efficacy of properly characterised preparations has not been assessed in meta-analyses. The aim of our work was to evaluate the efficacy of VAC in PMS. The meta-analysis was performed following the PRISMA guidelines using the PICOS format, taking into account the CONSORT recommendations. PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched for studies on VAC. The analysis assessed the efficacy of properly characterised products VAC compared to a placebo for the alleviation of PMS symptoms in terms of responder rate, considering the decrease of Total Symptom Score or PMS Diary score. The random effects model was used to calculate summary relative risk (RR) and 95% confidence interval (CI). Only those randomised, double-blind, placebo-controlled trials were included that fulfilled the criteria of the CONSORT recommendations aiming at the proper characterization of herbal products. Out of the 21 clinical trials, three studies (520 females) fulfilled the inclusion criteria, comparing the efficacy of special extracts Ze 440 and BNO 1095 to a placebo for the treatment of PMS. VAC preparations were confirmed to be effective in the reduction of PMS symptoms: women taking VAC were 2.57 (95% CI 1.52-4.35) times more likely to experience a remission in their symptoms compared to those taking the placebo. Although several clinical trials have been carried out with VAC, the majority of the studies cannot be used as evidence for efficacy due to incomplete reporting, especially concerning the description of the used medication. More trials following the CONSORT recommendations are needed to assess the efficacy of VAC extracts.

The combination of hawthorn extract and camphor significantly increases blood pressure: A meta-analysis and systematic review.

BACKGROUND: A fixed combination of hawthorn and camphor (Korodin Herz-Kreislauf-Tropfen®) has been used in the therapy of hypotension for decades. Although its efficacy was evaluated in clinical trials, these studies have not been critically assessed in meta-analyses. PURPOSE: To systematically evaluate the efficacy of a fix combination of camphor and hawthorn extract (Korodin®) on blood pressure and cognition compared to placebo, in a meta-analysis based on randomized controlled trials (RCTs). STUDY DESIGN: The meta-analysis was carried out following the PRISMA guidelines, using the PICO format, and it was registered in the PROSPERO register. METHODS: The Cochrane Central Register of Controlled Trials, PubMed, Embase, and Web of Science databases were searched for relevant studies. Placebo-controlled clinical studies involving adult patients receiving a fix combination of hawthorn extract and camphor were included. No language or publication year restrictions were applied. RESULTS: Four randomized trials including a total of 221 patients were pooled for statistical analysis. According to the present meta-analysis, the fixed combination of hawthorn and camphor significantly increases systolic and diastolic blood pressure compared to placebo (p-values: 0.017 and 0.049, respectively) and had a beneficial, but not statistically significant effect on the cognitive performance in the connect-the-numbers test (p-value: 0.071). CONCLUSION: Korodin® is an effective and presumably safe complementary therapy for the treatment of hypotension. Its blood pressure increasing effect is confirmed; however, the evidence supporting its use is very limited. The optimum dose and duration of treatment is still unclear. The comprehensive evaluation of efficacy and safety is required in further, high-quality clinical studies, involving larger patient populations and comparable endpoints.

Seasonal variation of mortality from external causes in Hungary between 1995 and 2014.

OBJECTIVE: To analyze trends in external mortality in Hungary between 1995 and 2014 by sex. METHODS: Data on the numbers of deaths due to external causes were obtained from the published nationwide population register. Negative binomial regression was applied to investigate the yearly trends in external-cause mortality rates. Cyclic trends were investigated using the Walter-Elwood method. RESULTS: Suicide and accidents accounted for approximately 84% of the all-external-cause of deaths in Hungary. Annual suicide, unintentional falls and traffic accidents mortality declined significantly (p-value for annual trend: p < 0.001) from 30.5 (95% CI: 29.5-31.5) to 15.8 (15.1-16.5), from 31.2 (30.2-32.2) to 12.2 (11.7-12.8) and from 17.2 (16.4-18) to 5.4 (5-5.8) per 100 000 persons per year, respectively, during the study period. A significant declining trend in annual mortality was also found for assault, cold/heating-related accidents and accidents caused by electric current. However, the declining trend for drowning-related accidents was significant only for males. Significant winter-peak seasonality was found in the mortality rates from accidental falls, cold/heat-related accidents, other accidents caused by submersion/obstruction and other causes. Seasonal trends with a peak from June to July were observed in death rates from suicide/self-harm, accidental drowning/submersion and accidents caused by electric current. A significant seasonal variation with a peak in September was revealed in the mortality due to traffic accidents. CONCLUSIONS: This Hungarian study suggests that there was a significant seasonal effect on almost all kinds of deaths from external causes between 1995 and 2014. Environmental effects are involved in the aetiology of suicide and accidents.

Antibiotic therapy in acute pancreatitis: From global overuse to evidence based recommendations.

BACKGROUND: Unwarranted administration of antibiotics in acute pancreatitis presents a global challenge. The clinical reasoning behind the misuse is poorly understood. Our aim was to investigate current clinical practices and develop recommendations that guide clinicians in prescribing antibiotic treatment in acute pancreatitis. METHODS: Four methods were used. 1) Systematic data collection was performed to summarize current evidence; 2) a retrospective questionnaire was developed to understand the current global clinical practice; 3) five years of prospectively collected data were analysed to identify the clinical parameters used by medical teams in the decision making process, and finally; 4) the UpToDate Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system was applied to provide evidence based recommendations for healthcare professionals. RESULTS: The systematic literature search revealed no consensus on the start of AB therapy in patients with no bacterial culture test. Retrospective data collection on 9728 patients from 22 countries indicated a wide range (31-82%) of antibiotic use frequency in AP. Analysis of 56 variables from 962 patients showed that clinicians initiate antibiotic therapy based on increased WBC and/or elevated CRP, lipase and amylase levels. The above mentioned four laboratory parameters showed no association with infection in the early phase of acute pancreatitis. Instead, procalcitonin levels proved to be a better biomarker of early infection. Patients with suspected infection because of fever had no benefit from antibiotic therapy. CONCLUSIONS: The authors formulated four consensus statements to urge reduction of unjustified antibiotic treatment in acute pancreatitis and to use procalcitonin rather than WBC or CRP as biomarkers to guide decision-making.

The Efficacy of Saffron in the Treatment of Mild to Moderate Depression: A Meta-analysis.

Herbal products, especially Hypericum perforatum extracts, have been widely used as first-line treatments for mild to moderate depression. Recently, several randomized, controlled clinical trials have been conducted to evaluate the efficacy of another plant, saffron (Crocus sativus), in mild to moderate depression. We have carried out a literature review of currently available published randomized, controlled clinical trials to give an up-to-date evaluation of the efficacy of saffron in mild to moderate depression, compared to placebo or routinely used antidepressants. The meta-analysis is reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines using the PICO (patients, intervention, comparison, outcome) format and was conducted using the statistical programs Comprehensive Meta-analysis and RevMan. PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science databases were searched for relevant studies. Only placebo or active controlled, randomized clinical studies involving patients suffering from mild to moderate depression and using pharmacological doses of saffron per os were included. Hedges' g was used to calculate effect sizes. Risk of bias was assessed using the Cochrane Collaboration tool, and heterogeneity was tested by both performing the Cochran's Q test and calculating Higgins' I2 indicator. Eleven randomized trials were included in the qualitative analysis, and nine were pooled for statistical analysis. According to the present meta-analysis, saffron has a significant effect on the severity of depression. Available data from randomized, controlled clinical trials support that saffron is significantly more effective than placebo (g = 0.891; 95% CI: 0.369 - 1.412, p = 0.001), and non-inferior to tested antidepressant drugs (g = - 0.246; 95% CI: - 0.495 - 0.004, p = 0.053).

PPIs Are Not Responsible for Elevating Cardiovascular Risk in Patients on Clopidogrel-A Systematic Review and Meta-Analysis.

Background: Clopidogrel and proton pump inhibitors (PPIs) are metabolized by cytochrome P450 enzymes. Contradictory results have been reported on possible complications of simultaneous PPI and clopidogrel use. Our aim was to investigate the clinical relevance of this debate with a systematic review and meta-analysis. Methods: The PubMed, Embase, and Cochrane Central Register of Controlled Trials electronic databases were searched for human studies [randomized controlled trials (RCTs) and observational studies] using the PICO format (P: patients on clopidogrel; I: patients treated with PPI; C: patients without PPI treatment; O: cardiovascular risk). We screened eligible studies from 2009 to 2016. After study exclusions, we extracted data from 27 articles for three outcomes: major adverse cardiac event (MACE), myocardial infarction (MI) and cardiovascular (CV) death. The meta-analysis was registered on PROSPERO (CRD42017054316). Results: Data were extracted on 156,823 patients from the 27 trials included (MACE: 23, CV death: 10, MI: 14). The risks of MACE (RR = 1.22, 95% CI = 1.06-1.396, p = 0.004) and MI (RR = 1.43, 95% CI = 1.24-1.66, p < 0.001) were significantly higher in the PPI plus clopidogrel group. However, subgroup analysis demonstrated that this significance disappeared in RCTs (RR = 0.99, 95% CI = 0.76-1.28, p = 0.93) in the MACE outcome group. There was no effect of combined PPI and clopidogrel therapy on CV death outcome (RR = 1.21, 95% CI = 0.97-1.50, p = 0.09). Conclusion: Concomitant use of PPIs and clopidogrel has been proved not to be associated with elevated cardiovascular risks according to RCTs. Based on our results, no restrictions should be applied whenever PPIs and clopidogrel are administered simultaneously.

Ginger (Zingiber officinale): An alternative for the prevention of postoperative nausea and vomiting. A meta-analysis.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a distressing outcome related to surgeries. Traditionally, ginger has been used in the treatment of nausea and vomiting for thousands of years. Recently, several randomized, placebo-controlled clinical trials (RCTs) have been conducted to evaluate the efficacy of ginger in PONV. PURPOSE: To systematically evaluate the efficacy of ginger on postoperative nausea and vomiting (PONV) compared to placebo, based on RCTs. STUDY DESIGN: The meta-analysis was reported following the PRISMA guidelines using the PICO format, and it was registered with the PROSPERO register. METHODS: PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched for relevant studies. Human, placebo-controlled clinical studies of patients undergoing any types of surgery, receiving pharmacological doses of ginger per os were included. Only clinical trials with explicit description of the ginger preparation used were analysed. No language or publication year restrictions was applied. RESULTS: Ten randomized trials including a total of 918 patients were pooled for the statistical analysis. The present meta-analysis supports that ginger has a significant effect on the severity of PONV based on visual analogue scale (VAS) results: in a fixed effects model the pooled standardized mean difference (SMD) was -0.247 (favouring ginger; [LL]: -0.455, [UL]: -0.040, p-value: 0.019). Moreover, our results suggest that ginger reduces the incidence of postoperative nausea and vomiting, as well antiemetic drug demand; however, these effects are not statistically significant compared to placebo, which may be explained by underdosing. CONCLUSIONS: According to our thorough meta-analysis ginger is safe and well tolerated, and decreases the severity of PONV, and may lower the incidence of postoperative nausea and vomiting, which in turn may reduce antiemetic drug demand, suggesting that ginger may be a useful alternative to antiemetic medications to alleviate PONV.