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Simple Summary: Patients with HER2-positive metastatic breast cancer develop brain metastases in up to 30% of cases. The aim of this systematic review and meta-analysis was to determine the effect of different systemic therapies in patients with HER2-positive metastatic breast cancer and brain metastases, acknowledging the heterogeneity and sometimes low quality of 51 included studies. Tucatinib (combined with trastuzumab and capecitabine) and trastuzumab-deruxtecan appear to constitute the most effective systemic therapy, while pyrotinib might be an option in Asian patients. Preferably, future research will comprise of randomized controlled trials, including patients with active and/or inactive brain metastases. Aim: Patients with HER2-positive (HER2+) metastatic breast cancer (mBC) develop brain metastases (BM) in up to 30% of cases. Treatment of patients with BM can consist of local treatment (surgery and/or radiotherapy) and/or systemic treatment. We undertook a systematic review and meta-analysis to determine the effect of different systemic therapies in patients with HER2+ mBC and BM. Methods: A systematic search was performed in the databases PubMed, Embase.com, Clarivate Analytics/Web of Science Core Collection and the Wiley/Cochrane Library. Eligible articles included prospective or retrospective studies reporting on the effect of systemic therapy on objective response rate (ORR) and/or median progression free survival (mPFS) in patients with HER2+ mBC and BM. The timeframe within the databases was from inception to 19 January 2022. Fixed-effects meta-analyses were used. Quality appraisal was performed using the ROBINS-I tool. Results: Fifty-one studies were included, involving 3118 patients. Most studies, which contained the largest patient numbers, but also often carried a moderate-serious risk of bias, investigated lapatinib and capecitabine (LC), trastuzumab-emtansine (T-DM1) or pyrotinib. The best quality data and/or highest ORR were described with tucatinib (combined with trastuzumab and capecitabine, TTC) and trastuzumab-deruxtecan (T-DXd). TTC demonstrated an ORR of 47.3% in patients with asymptomatic and/or active BM. T-DXd achieved a pooled ORR of 64% (95% CI 43–85%, I2 0%) in a heavily pretreated population with asymptomatic BM (3 studies, n = 96). Conclusions: Though our meta-analysis should be interpreted with caution due to the heterogeneity of included studies and a related serious risk of bias, this review provides a comprehensive overview of all currently available systemic treatment options. T-Dxd and TTC that appear to constitute the most effective systemic therapy in patients with HER2+ mBC and BM, while pyrotinib might be an option in Asian patients. [ABSTRACT FROM AUTHOR]

The aim of this study is to provide an overview and understand the strength of evidence and the extent of potential biases and the validity of claimed associations between the use of statins and cancer mortality or survival. We performed a comprehensive umbrella review of meta-analyses and systematically appraised the relevant meta-analyses of observational studies on the associations between statin use and cancer mortality or survival in various kinds of cancer. We searched the PubMed database and screened the reference list of relevant articles. We obtained the summary effect, 95% confidence interval, heterogeneity, and also examined small study effects and 95% prediction intervals for effect sizes, and the level of evidence was determined from the criteria. Regarding cancer mortality, statin use showed convincing evidence for an association with a reduced cancer-specific mortality rate for colorectal cancer. Four associations with reduced all-cause mortality (for breast cancer, colorectal cancer, endocrine-related gynecological cancer, and ovarian cancer) had a suggestive evidence. Moreover, analyses in nine cancers showed a weak level of evidence, while the remaining 15 did not indicate significant changes in either direction. Although there was a preventive effect of statin on cancer mortality in some cancer types, the evidence supporting the use of statins to reduce cancer mortality or survival was low. [ABSTRACT FROM AUTHOR]

Tumor mutational burden (TMB) is a genomic biomarker that predicts favorable responses to immune checkpoint inhibitors (ICIs). Here, we set out to assess the predictive value of TMB on long-term survival outcomes in patients undergoing ICIs. We systematically searched PubMed, Embase, CENTRAL and clinicaltrials.gov from inception to 6 August 2019. We included retrospective studies or clinical trials of ICIs that reported hazard ratios (HRs) for overall survival (OS) and/or progression-free survival (PFS) according to TMB. Data on 5712 patients from 26 studies were included. Among patients who received ICIs, high TMB groups showed better OS (HR 0.53, 95% CI 0.42 to 0.67) and PFS (HR 0.52, 95% CI 0.40 to 0.67) compared to low TMB groups. In patients with high TMB, those who received ICIs had a better OS (HR 0.69, 95% CI 0.50 to 0.95) and PFS (HR = 0.66, 95% CI = 0.47 to 0.92) compared to those who received chemotherapy alone, while in patients with low TMB, such ICI benefits of OS or PFS were not statistically significant. In conclusion, TMB may be an effective biomarker to predict survival in patients undergoing ICI treatment. The role of TMB in identifying patient groups who may benefit from ICIs should be determined in future randomized controlled trials. [ABSTRACT FROM AUTHOR]

We conducted a systematic review for evidence of the clinical efficacy of cancer immunotherapies. We searched PubMed from inception to 14 February 2018 for meta-analyses of randomized controlled trials (RCTs) of cancer immunotherapies. Re-analyses were performed to estimate the summary effect size under random-effects, the 95% confidence interval (CI), heterogeneity, and the 95% prediction interval, and we determined the strength of the evidence. We examined publication bias and excess significance bias. 63 articles corresponding to 247 meta-analyses were eligible. Nine meta-analyses were classified to have convincing evidence, and 75 were classified as suggestive evidence. The clinical benefit of immunotherapy was supported by convincing evidence in the following settings: anti-PD-1/PD-L1 monoclonal antibody (mAb) therapy for treating advanced melanoma and non-small cell lung cancer (NSCLC), the combination of rituximab and chemotherapy for treating chronic lymphocytic leukemia and B-cell non-Hodgkin's lymphoma, adoptive cell immunotherapy for NSCLC, and the combination of interferon α and chemotherapy for metastatic melanoma. A further meta-analysis of 16 RCTs showed that anti-PD-1/PD-L1 mAb therapy had a benefit in patients with solid tumors (overall survival; hazard ratio = 0.73, 95% CI: 0.68–0.79; p < 0.001), supported by convincing evidence. In the future, rigorous approaches are needed when interpreting meta-analyses to gain better insight into the true efficacy of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Hyperprogressive disease (HPD) is a recently acknowledged pattern of rapid tumor progression after the initiation of immune checkpoint inhibitors. HPD has been observed across various types of tumors and has been associated with poor survival. We performed a meta-analysis to identify baseline (i.e., prior to programmed cell death 1 [PD-1, PDCD1] / programmed cell death 1 ligand 1 [PD-L1, CD274] inhibitor therapy) patient factors associated with risks of developing HPD during PD-1/PD-L1 inhibitor therapy. We searched eight databases until 6 June 2019. We calculated the summary odds ratio (OR) and its 95% confidence interval (CI) using the random-effects model and explored between-study heterogeneity and small-study effects. A total of nine articles was eligible (217 HPD cases, 1519 cancer patients) for meta-analysis. There was no standard definition of HPD, and the incidence of HPD ranged from 1 to 30%. We identified twenty-three baseline patient factors, of which five factors were statistically significantly associated with HPD. These were serum lactate dehydrogenase (LDH) above the upper normal limit (OR = 1.89, 95% CI = 1.02–3.49, p = 0.043), more than two metastatic sites (OR = 1.86, 1.34–2.57, p < 0.001), liver metastases (OR = 3.33, 2.07–5.34, p < 0.001), Royal Marsden Hospital prognostic score of 2 or above (OR = 3.33, 1.96–5.66, p < 0.001), and positive PD-L1 expression status that was inversely correlated with HPD (OR = 0.60, 0.36–0.99, p = 0.044). Between-study heterogeneity was low. Evidence of small-study effect was found in one association (PD-L1 expression). Subset analyses of patients with non-small cell lung cancer showed similar results. Future studies are warranted to identify underlying molecular mechanisms and to test their roles as predictive biomarkers of HPD. [ABSTRACT FROM AUTHOR]

Statins are reported to reduce the risk of cancer, but the results of various published studies have been contradictory. We carried out an umbrella review to provide an overview and understand the strength of evidence, extent of potential biases, and validity of claimed associations between the use of statins and cancer incidence. We comprehensively re-analyzed the data of meta-analyses of randomized controlled trials (RCTs) and observational studies on associations between statin use and cancer incidence. We also assessed the strength of evidence of the re-analyzed outcomes, which were determined from the criteria including statistical significance of the p-value of random-effects, as well as fixed-effects meta-analyses, small study effects, between-study heterogeneity, and a 95% prediction interval. Using a conventional method to assess the significance of meta-analysis (p-value < 0.05), statins had a statistically significant effect on reducing cancer incidence in 10 of 18 types of cancer. When we graded the level of evidence, no cancer type showed convincing evidence, and four cancers (esophageal cancer, hematological cancer, leukemia, and liver cancer) showed suggestive evidence of a preventive effect. There was weak evidence of an association with six cancers, and no significance for the remaining eight cancers. None of the meta-analyses of RCTs on the association of statin and cancer incidence showed a statistical significance. Although there was a preventive effect of statin on cancer incidence in 10 of the 18 cancer types, the evidence supporting the use of statins to reduce cancer incidence was low. Therefore, the associations between statin use and cancer incidence should be carefully considered by clinicians. [ABSTRACT FROM AUTHOR]

Capillary leak syndrome (CLS) is a rare disease with profound vascular leakage, which can be associated with a high mortality. There have been several reports on CLS as an adverse effect of anti-cancer agents and therapy, but the incidence of CLS according to the kinds of anti-cancer drugs has not been systemically evaluated. Thus, the aim of our study was to comprehensively meta-analyze the incidence of CLS by different types of cancer treatment or after bone marrow transplantation (BMT). We searched the literatures (inception to July 2018) and among 4612 articles, 62 clinical trials (studies) were eligible. We extracted the number of patients with CLS, total cancer patients, name of therapeutic agent and dose, and type of cancer. We performed a meta-analysis to estimate the summary effects with 95% confidence interval and between-study heterogeneity. The reported incidence of CLS was categorized by causative drugs and BMT. The largest number of studies reported on CLS incidence during interleukin-2 (IL-2) treatment (n = 18), which yielded a pooled incidence of 34.7% by overall estimation and 43.9% by meta-analysis. The second largest number of studies reported on anti-cluster of differentiation (anti-CD) agents (n = 13) (incidence of 33.9% by overall estimation and 35.6% by meta-analysis) or undergoing BMT (n = 7 (21.1% by overall estimation and 21.7% by meta-analysis). Also, anti-cancer agents, including IL-2 + imatinib mesylate (three studies) and anti-CD22 monoclinal antibodies (mAb) (four studies), showed a dose-dependent increase in the incidence of CLS. Our study is the first to provide an informative overview on the incidence rate of reported CLS patients as an adverse event of anti-cancer treatment. This meta-analysis can lead to a better understanding of CLS and assist physicians in identifying the presence of CLS early in the disease course to improve the outcome and optimize management. [ABSTRACT FROM AUTHOR]

Systemic capillary leak syndrome (SCLS) is a rare disease characterized by shock caused by capillary hyperpermeability. The disease can occur in cancer patients and effective therapeutic strategies have not been established yet. The aim of the study was to analyze the clinical and laboratory data, treatment modalities, and mortality rate of patients and to identify contributing factors leading to mortality of SCLS in cancer. We searched MEDLINE (inception to July 2018) and of 4612 articles, we identified 62 case reports on SCLS associated with cancer or cancer-related drugs in a total of 53 articles. SCLS was associated with cancer itself in 43.6%, with anti-cancer agents in 51.6% and bone marrow transplantation (BMT) in 4.8%. Among anti-cancer agents, granulocyte-colony stimulating factor (G-CSF) was the most frequently associated drug (14.6%), followed by interleukin (IL)-2 (11.4%). The most common associated malignancies were hematologic (61.3%) with non-Hodgkin lymphoma (22.7%) and multiple myeloma (12.9%) being the leading causes. Common symptoms and signs included dyspnea (27.4%), edema (67.7%), hypotension (32.2%), pleural effusion (29.0%), ascites (22.7%), oliguria (22.7%), and weight gain (21.0%). Patients with SCLS were treated with steroids (59.7%), volume replacement (33.8%), diuretics (24.2%), inotropes (9.6%), methylxanthines (12.8%), β2 agonists (4.8%), while intravenous immunoglobulins (IVIG) were administered in 2 patients (3.2%) only. Among sixteen deaths during follow-up, four were directly attributed to SCLS. Hematologic malignancies were associated with an increased risk for mortality (hazard ratio (HR) 8.820, 95% confidence interval (CI) 1.126–69.063, p = 0.038). Taken together, SCLS can be one important adverse event in cancer patients and careful monitoring of fluid volume is required in the management of SCLS. [ABSTRACT FROM AUTHOR]

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder characterized by early onset fatal multi-system autoimmunity due to loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor which is crucial for the development, maturation, and maintenance of CD4+ regulatory T (T-reg) cells. Various autoimmune phenomena such as enteropathy, endocrinopathies, cytopenias, renal disease, and skin manifestations are characteristic findings in patients affected by IPEX syndrome. In this systematic review, we focus on both clinical and demographic characteristics of IPEX patients, highlighting possible genotype-phenotype correlations and address prognostic factors for disease outcome. We performed a literature search to systematically investigate the case reports of IPEX which were published before August 7th, 2017. A total of 75 articles (195 patients) were identified. All IPEX patients included had FOXP3 mutations which were most frequently located in the forkhead domain (n = 68, 34.9%) followed by the leucine-zipper domain (n = 30, 15.4%) and repressor domain (n = 36, 18.4%). Clinical manifestations were as follows: enteropathy (n = 191, 97.9%), skin manifestations (n = 121, 62.1%), endocrinopathy (n = 104, 53.3%), hematologic abnormalities (n = 75, 38.5%), infections (n = 78, 40.0%), other immune-related complications (n = 43, 22.1%), and renal involvement (n = 32, 16.4%). Enteropathic presentations (P = 0.017), eczema (P = 0.030), autoimmune hemolytic anemia (P = 0.022) and food allergy (P = 0.009) were associated with better survival, while thrombocytopenia (P = 0.034), septic shock (P = 0.045) and mutations affecting the repressor domain (P = 0.021), intron 7 (P = 0.033) or poly A sequence (P = 0.025) were associated with increased risk of death. Immunosuppressive therapy alone was significantly associated with increased cumulative survival compared to patients who received no treatment (P = 0.041). We report the most comprehensive summary of demographic and clinical profiles derived from a total of 195 IPEX patients with deleterious mutations in FOXP3. Analysis of our findings provides new insights into genotype/phenotype correlations, and clinical and genetic factors associated with increased risk of death and response to treatment strategies. [ABSTRACT FROM AUTHOR]