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Simple Summary Brain metastases (BM) may affect a large portion of metastatic HER2-positive BC patients. Dual human epidermal growth factor receptor 2 (HER2) blockade with Pertuzumab and Trastuzumab (PT) in conjunction with chemotherapy represents the first line therapy of metastatic HER2- positive breast cancer (BC) and shows to prolong time to BM development as the first site of disease progression. When limited brain disease occurs with stable extracranial disease, current guidelines suggest to continue systemic therapies and add local brain treatment. However not data are available on the association between PT and stereotactic brain radiotherapy (SRT). This study aims to assess the safety and efficacy of fractionated SRT (fSRT) and PT in patients with breast cancer BM. Abstract (1) Background: This study aims to assess the safety and efficacy of fractionated SRT (fSRT) and pertuzumab–trastuzumab (PT) in patients with breast cancer brain metastases (BCBM). (2) Methods: Patients with HER2+ BCBM who received FSRT from 2015 to 2019 were identified. Patients were included if they were treated with fSRT within 21 days of receiving PT. All lesions were treated with LINAC-based fSRT to a total dose of 27 Gy delivered in three consecutive fractions. All patients received concurrent PT. Patients were evaluated 4–6 weeks after SRS and subsequently every 2–3 months with MRI re-imaging (3) Results: A total of 49 patients with HER2+ brain metastases were identified. Of these patients, a total of 10 patients with 32 HER2+ BCBM were treated with concurrent SRT and PT and included in the analysis. No local progression was observed. Overall response rate was 68.7%. Only one patient developed asymptomatic radionecrosis. Median time to BM occurrence was 15.6 (range: 1–40.5 months). Distant intracranial failure occurred in 4/10 patients (40.0%). Overall BCBM median survival was 33.9 months (95%CI 24.1–43.6). Mean duration of PT treatment was 27.9 months (range: 10.1–53.7 months). (4) Conclusions: In our single institution experience, fSRT and PT showed to be a safe treatment for patients with BCBM with an adequate overall response rate.

Rationale and Objective: Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFRcr-cys) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFRcr or eGFRcys, respectively), but the inclusion of creatinine in eGFRcr-cys requires specification of a person's race. beta 2-Microglobulin (B2M) and beta-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is.Study Design: Study of diagnostic test accuracy.Setting and Participants: Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants. Tests Compared: Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race. Outcomes: GFRmeasured as the urinary clearance of iothalamate, plasmaclearanceof iohexol, orplasma clearance of [Cr-51]EDTA.Results: Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m(2), and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFRcys (percentage of estimates greater than 30% different from measured GFR [1-P30] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFRcr-cys (1-P-30 of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups.Limitations: No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe.Conclusions: The 4-marker panel eGFR is as accurate as eGFRcr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance.

Preclinical studies have indicated that T-cell immunoglobulin and ITIM domain (TIGIT) can substantially attenuate anti-tumoral immune responses. Although multiple clinical studies have evaluated the significance of TIGIT in patients with solid cancers, their results remain inconclusive. Thus, we conducted the current systematic review and meta-analysis based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to determine its significance in patients with solid cancers. We systematically searched the Web of Science, Embase, PubMed, and Scopus databases to obtain peer-reviewed studies published before September 20, 2020. Our results have shown that increased TIGIT expression has been significantly associated with inferior overall survival (OS) (HR = 1.42, 95% CI: 1.11–1.82, and p-value = 0.01). Besides, the level of tumor-infiltrating TIGIT+CD8+ T-cells have been remarkably associated inferior OS and relapse-free survival (RFS) of affected patients (HR = 2.17, 95% CI: 1.43–3.29, and p-value < 0.001, and HR = 1.89, 95% CI: 1.36–2.63, and p-value < 0.001, respectively). Also, there is a strong positive association between TIGIT expression with programmed cell death-1 (PD-1) expression in these patients (OR = 1.71, 95% CI: 1.10–2.68, and p-value = 0.02). In summary, increased TIGIT expression and increased infiltration of TIGIT+CD8+ T-cells can substantially worsen the prognosis of patients with solid cancers. Besides, concerning the observed strong association between TIGIT and PD-1, ongoing clinical trials, and promising preclinical results, PD-1/TIGIT dual blockade can potentially help overcome the immune-resistance state seen following monotherapy with a single immune checkpoint inhibitor in patients with solid cancers.

Background: HER2-positive (HER2+) breast cancer (BC) is composed of 4 molecular subtypes: Luminal A and B, HER2-enriched (HER2-E) and Basal-like. Among them, the HER2-E is highly sensitive to anti-HER2 treatment. However, ˜60% of HER2-E tumors do not achieve a pathological complete response (pCR) following neoadjuvant dual HER2 blockade without chemotherapy. Here, we aimed to better understand the molecular changes of the HER2-E subtype during anti-HER2 treatment. Methods: Gene expression was evaluated in 101 patients with HER2-E tumors from the PAMELA neoadjuvant phase II trial (Lancet Oncol 2017). Briefly, women with HER2+ BC were treated with lapatinib and trastuzumab (and hormonal therapy if hormone receptor [HR]-positive) for 18 weeks. The median time between the last dose of treatment and surgery was 35 days (range=213; interquartile range=16). Expression of the PAM50 genes and 6 PAM50 signatures (Luminal A, Luminal B, HER2-E, Basal-like, normal-like and the PAM50 proliferation score) were determined using the nCounter platform at baseline (n=101), after 2 weeks of treatment (n=96) and in residual tumors (non-pCR) at surgery (n=57). Same analyses were done in 2 HER2+/HER2-E cell line models (BT474 [HR+] and SKBR3 [HR-]) following in vitro treatment with trastuzumab in combination with lapatinib. Biological changes between 2 time-points were determined by paired t-tests with a false discovery rate (FDR) Results: After 2 weeks of treatment, 85.7% and 94.6% of the 56 genes/signatures were found differentially expressed (FDR Conclusions: Dual HER2 blockade in the HER2-E subtype induces large biological changes that lead to a more low-proliferative Luminal A phenotype both in tumors and in vitro models, especially in HER2-E/HR+ disease. These phenotypic changes are reversible upon stopping anti-HER2 treatment. This finding supports the use of maintenance anti-HER2 treatment +/- endocrine therapy (if HR+) in advanced HER2+ BC. Citation Format: Brasó-Maristany F, Griguolo G, Llombart-Cussac A, Pascual T, Paré L, Bermejo B, Oliveira M, Morales S, Martinez N, Vidal M, Pernas S, Lopez R, Muñoz M, Galvan P, Garau I, Manso L, Alarcón J, Martínez E, Villagrasa P, Cortés J, Prat A. Gene signatures and subtype changes during HER2 dual blockade in PAM50 HER2-enriched HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-07.

© 2020 Elsevier Ltd. All rights reserved., Background: Skin rash and diarrhoea are known side-effects of pertuzumab. Studies with other anti-HER2 agents suggested that adverse events correlate with patient outcomes. In this exploratory cohort of patients with metastatic HER2-positive breast cancer included in the CLEOPATRA trial we evaluated the value of rash and diarrhoea as prognostic markers and as predictors of pertuzumab benefit. Methods: This is a retrospective analysis of the multicenter, prospective, randomised CLEOPATRA trial. We defined two analytic cohorts: cohort 1 (C1) included patients from treatment initiation, and cohort 2 (C2) included patients after discontinuation of docetaxel. A landmark analysis was introduced to deal with immortal-time bias. Study endpoints were progression-free survival (PFS) and overall survival (OS). Univariable and multivariable Cox proportional hazards models were used. Results: Of the 808 patients and after application of the landmark analysis, C1 and C2 included 777 and 518 patients, respectively. In C1, rash occurred in 271 patients (34.9%) and diarrhoea in 470 (60.5%). Rash was prognostic for PFS and OS (C1: adjusted hazard ratio [aHR] = 0.66 [95% CI = 0.48-0.91], p = 0.010]; C2: aHR 0.52 [95% CI = 0.30-0.89], p = 0.018) in both cohorts, while diarrhoea was only prognostic for PFS in cohort 2 (aHR = 0.65 [95% CI = 0.46-0.91], p = 0.011). Rash and diarrhoea were not predictive of pertuzumab benefit (in terms of PFS/OS) in the two cohorts. Conclusions: In patients treated with pertuzumab, trastuzumab, and docetaxel, rash is prognostic whenever it occurs during treatment, while diarrhoea only has prognostic value when occurring after docetaxel discontinuation. However, neither rash nor diarrhoea predict pertuzumab benefit.

Background: Dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab (TP) is a standard therapy of metastatic and localized HER2-positive breast cancer (BC), but its activity in breast cancer brain metastases (BCBM) is unknown. Methods: Patients with HER2-positive BCBM were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, therapies and overall survival (OS) were obtained. Patients were grouped into ‘TP’, ‘other-HER2-targeted therapy’ and ‘no-HER2-targeted therapy’ according to received first-line systemic therapy after diagnosis of BCBM. Radiological re-assessment of intracranial lesions was performed in patients treated with TP as systemic first-line therapy according to RANO response criteria for brain metastases (BM). Results: A total of 252 HER2-positive BC patients with BM were available for this analysis. Patients treated with TP as systemic first-line therapy after diagnosis of BM had a significantly longer OS compared with treatment with other-HER2-targeted therapy and no-HER2-targeted therapy (44 versus 17 versus 3 months, p Conclusion: First-line therapy with dual HER2-inhibition of TP after BM diagnosis was associated with the longest median OS times in patients with BCBM.

The use of adjuvant pertuzumab in HER2-positive early-stage breast cancer has recently been approved by the EMA on the basis of data from the APHINITY trial. Accordingly, we have produced this opinion article with the aim of putting the study data in perspective against other add-on therapeutic strategies, to clarify methodological or statistical doubts about the study, and to define the population of high-risk patients with hormone receptor-negative breast cancer that we agree, in general, should be treated. With this approval, physicians must be well prepared to place the APHINITY study data in context. It is now up to each country to ratify the EMA-approved indications and to agree on reimbursement, and doctors must optimize their use based on knowledge and discussion with patients.

Objective: The effect of dual renin–angiotensin system (RAS) inhibition in heart failure (HF) is still controversial. Systematic reviews have shown that dual RAS blockade may reduce mortality and hospitalizations, yet it has been associated with the increased risk of renal dysfunction (RD). Surprisingly, although RD in patients with HF is frequent, the effect of combining RAS inhibitors in HF patients with RD has never been studied in a meta-analysis. Methods: A systematic review and meta-analysis of randomized clinical trials involving HF patients with RD who received dual blockade analyzing death, cardiovascular (CV) death or HF hospitalization, and adverse events. Results: Out of 2258 screened articles, 12 studies were included (34,131 patients). Compared with monotherapy, dual RAS inhibition reduced hazard ratio of death to 0.94 ( p=0.07) and significantly reduced CV death or HF hospitalization to 0.89 ( p=0.0006) in all individuals, and to 0.86 ( p=0.005) in patients with RD and to 0.91 ( p=0.04) without RD. Nevertheless, dual RAS blockade significantly increased the risk of renal impairment (40%), hyperkalemia (44%), and hypotension (42%), although discontinuation of treatment occurs only in 3.68% versus 2.19% ( p=0.00001). Conclusions: Dual RAS inhibition therapy reduces the risk of CV death or HF hospitalization. However, cautions monitoring for specific adverse events may be warranted.

Patients with positive Her-2/neu breast cancer and a high risk of recurrence are known to benefit from the addition of the dual blockade of Her-2/neu with Trastuzumab and Pertuzumab to the neoadjuvant chemotherapy, a combination which has been demonstrated to give a higher rate of a complete pathologic response in the breast and in the axilla. The purpose of this review is to outline the efficacy of the dual blockade with Trastuzumab and Pertuzumab in the neoadjuvant treatment of high-risk Her-2 positive breast cancer. Electronic databases (Pubmed, Medline, and Cochrane Database of Systematic Reviews) were searched for English- and German-language studies, which were published in the last ten years. The search has been focused on neoadjuvant clinical trials as well as on the data presented in the abstracts published at the San Antonio Breast Cancer Symposium as well as at the annual meeting of the American Society of Clinical Oncology. The results reported in the published clinical trials demonstrated a higher pathologic complete response rate in breast and lymph nodes after using targeted therapy with two anti-Her-2/neu agents - Trastuzumab and Pertuzumab in combination with neoadjuvant chemotherapy for early-stage Her-2/neu positive breast cancers. The pathologic complete response rate is the most important prognostic marker in Her-2/neu positive tumors, a higher pathologic complete response rate being demonstrated to be associated with a better survival outcome in terms of higher overall survival and disease-free survival rates.

BackgroundTIGIT and LAG3 are inhibitory receptors expressed on cytotoxic CD8+ T cells and NK cells and directly inhibit the activation and proliferation of these cells. We proposed that blockade of TIGIT and LAG3 could improve antitumor immune response in a mouse model of anti-PD1 (aPD1)-resistant mice.Methods129Sv/Ev mice were inoculated with 50,000 aPD1-resistant 344SQR cells in the right leg on day 0 (primary tumor) and with 50,000 cells in the left leg on day 4 (secondary tumor). Primary tumors were injected with NBTXR3 radioenhancer nanoparticles on day 7 and irradiated with 12 Gy on days 8, 9, and 10. Anti-PD1, aLAG3, and aTIGIT were given to mice by intraperitoneal injections on days 5, 8, 11, 14, 21, 28, 35, and 42. On day 21, primary tumors, secondary tumors, and blood samples were harvested and analyzed with flow cytometry to evaluate changes in immune cell populations. The RNA extracted from the tumors were also analyzed by Nanostring. Mice in which tumors were completely eradicated were re-challenged with another 50,000 344SQR cells in the right flank at least two months post radiation; no further treatment was given to these mice, and tumor growth was monitored.ResultsThe addition of aTIGIT, aLAG3, or aTIGIT+aLAG3 to NBTXR3+XRT+aPD1 therapy significantly improved control of tumors, and the addition of aTIGIT+aLAG3 also led to fewer spontaneous lung metastases. The addition of either aTIGIT or aLAG3 to NBTXR3+XRT+aPD1 extended mouse survival time relative to NBTXR3+XRT+aPD1. None of the 8 mice in either the NBTXR3+XRT+aPD1+aTIGIT group or the NBTXR3+XRT+aPD1+aLAG3 group survived more than 32 days; in contrast, 3 of the 8 mice that received NBTXR3+XRT+aPD1+aTIGIT+aLAG3 survived until the end of the experiment. These surviving mice were found to have developed memory against 344SQR cells, and no further tumor growth was observed after re-challenge. Flow cytometry analysis showed that adding aTIGIT+aLAG3 to NBTXR3+XRT+aPD1 increased the percentages of proliferating CD8+ T cells in primary tumors, secondary tumors, and blood. Furthermore, Nanostring transcriptomic analysis of cells isolated from the tumors of mice thus treated showed evidence of classical two-step immunological priming, with an elevation of innate immune genes at the primary tumor and full-blown activation of the immune system within the secondary tumor.ConclusionsBlockade of TIGIT and LAG3 with NBTXR3+XRT+aPD1 improved CD8+ T-cell proliferation, augmented the antitumor response at both irradiated and unirradiated (abscopal) tumors, and induced potent long-term antitumor memory in mice.AcknowledgementsThis work was supported by Cancer Center Support (Core) Grant CA016672 to The University of Texas MD Anderson Cancer Center; the Goodwin family research fund; the family of M. Adnan Hamed and the Orr Family Foundation to MD Anderson Cancer Center‘s Thoracic Radiation Oncology program; an MD Anderson Knowledge Gap award; Nanobiotix.

Background M9241 is a tumor-targeting immunocytokine composed of IL-12 heterodimers fused to a monoclonal antibody targeting DNA in necrotic tumor regions. Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody with clinical activity in various tumor types. Preclinical data predicted a potential drug-drug interaction (DDI) between M9241 and avelumab. We report an interim analysis of safety and PK/PD from the dose-escalation part of JAVELIN IL-12 (NCT02994953), a phase Ib study of M9241 and avelumab in pts with locally advanced, unresectable, or metastatic solid tumors. Methods At data cutoff (20 Aug 2018), 29 pts in dose levels (DLs) 1-4 received M9241 4, 8, 12, or 16.8 μg/kg SC every 4 weeks (Q4W) and avelumab 10 mg/kg IV every 2 weeks (Q2W). Three pts in DL5 received 12-week induction with avelumab 800 mg IV once weekly (Q1W) and M9241 16.8 μg/kg SC Q4W and then continuation treatment with avelumab 800 mg IV Q2W and M9241 16.8 μg/kg SC Q4W. The primary endpoint was overall safety and dose-limiting toxicities (DLTs). Results DLs 1-4 were well tolerated. One DLT occurred at DL3 (grade 3 autoimmune hepatitis), but no DLTs occurred at other DLs. Maximum tolerated dose was not reached. PK analyses suggested a DDI at DLs 1-4, evidenced by decreased avelumab exposure concurrent with increased IFN-γ levels; therefore, DL5 was introduced. At DL5, PK data showed no evidence of a DDI. DL5 was also well tolerated and showed a similar safety profile to DL4, with treatment-emergent adverse events limited to grade 1/2. Prolonged clinical responses (CR/PR) were seen, including in a checkpoint inhibitor–refractory pt. Conclusions Combining avelumab 800 mg IV Q1W and M9241 16.8 μg/kg SC Q4W as 12-week induction followed by avelumab 800 mg IV Q2W and M9241 16.8 μg/kg SC Q4W as continuation treatment had an acceptable safety and tolerability profile and was therefore declared as recommended phase II dose (RP2D). The observed DDI is likely driven by M9241-mediated IFN-γ induction, causing PD-L1 upregulation in the periphery and tumor and target-mediated clearance of avelumab. Based on available data, this DDI mechanism is likely saturated at the RP2D. This trial continues recruitment into expansion cohorts at the RP2D. Clinical trial identification NCT02994953. Editorial acknowledgement ClinicalThinking, funded by Merck Healthcare KGaA and Pfizer Inc. Legal entity responsible for the study Merck Healthcare KGaA. Funding Merck Healthcare KGaA and Pfizer Inc. Disclosure J. Strauss: Research grant / Funding (institution): EMD Serono; Licensing / Royalties, Patent: dual blockade of PD-L1 and TGF beta for HPV+ cancer: Not applicable. Y. Vugmeyster: Full / Part-time employment: EMD Serono; Shareholder / Stockholder / Stock options: EMD Serono; Shareholder / Stockholder / Stock options: Alexion; Licensing / Royalties: EMD Serono; Licensing / Royalties: Wyeth; Licensing / Royalties: Pfizer. M. Sznol: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Genentech/Roche ; Advisory / Consultancy: AstraZeneca/MedImmune ; Advisory / Consultancy: Kyowa Hakko Kirin ; Advisory / Consultancy: Nektar; Advisory / Consultancy: Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Theravance; Advisory / Consultancy: Modulate Pharma; Advisory / Consultancy: Omniox; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Inovio Pharmaceuticals; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Torque; Shareholder / Stockholder / Stock options: Amphivena Therapeutics; Shareholder / Stockholder / Stock options: Intensity Therapeutics; Shareholder / Stockholder / Stock options: Adaptive Biotechnologies ; Shareholder / Stockholder / Stock options: Actym Therapeutics; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Newlink Genetics; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy: Genmab; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Allakos; Advisory / Consultancy: Hinge; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Pieris Pharmaceuticals; Advisory / Consultancy: Gritstone Oncology; Advisory / Consultancy: Innate Pharma; Advisory / Consultancy: Celldex; Advisory / Consultancy: Incyte; Advisory / Consultancy: Almac Diagnostics; Advisory / Consultancy: immunocore; Advisory / Consultancy: Array BioPharma. R.K. Pachynski: Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Jounce Therapeutics; Speaker Bureau / Expert testimony: Dendreon; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Genentech/Roche; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Genomic Health; Research grant / Funding (institution): Janssen Oncology. K. Trang: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck KGaA/EMD Serono. S. Chennoufi: Full / Part-time employment: Merck KGaA. J.L. Gulley: Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Astellas Medivation; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): NantBioScience, Inc.; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck.

Purpose The study evaluated whether the dual blockade of the renin–angiotensin system may influence the sodium balance in hemodialysis. Methods The study involved 148 hemodialysis patients (male 85, female 63), mean age 59.6 ± 12.9 years. Participants were randomly selected to receive either angiotensin-converting enzyme inhibitor (ACEI)—subgroup A—or dual blockade ACEI and angiotensin receptor blocker (ARB)—subgroup AA. Results At baseline, in the A versus AA subgroups, the pre-dialysis sodium concentrations (mmol/l) were 137.7 ± 0.5 versus 137.9 ± 0.8, the sodium gradients 2.6 ± 0.5 versus 2.9 ± 0.4, interdialytic weight gain (IWG) (kg) 3.1 ± 0.2 versus 3.0 ± 0.3, and thirst inventory score (points) 18.1 ± 1.0 versus 19.0 ± 1.7, respectively. After 3 months of therapy, a decrease in sodium concentration to 134.5 ± 0.5 and the increase of its gradient to 5.5 ± 0.5 were noted in the AA subgroup. An elevation of mean interdialytic weight gain to 3.47 ± 0.2 and thirst score to 21.3 ± 2.1 was observed. No significant changes in subgroup A were found. One month of the dialysate sodium concentration being lowered from 140 mmol/l to 138 mmol/l was associated with reduced serum sodium concentration and gradient, decreased IWG and restored moderate thirst score in the AA subgroup (137.5 ± 0.6 and 2.9 ± 0.6, 3.0 ± 0.5 and 19.2 ± 1.3, respectively). Conclusions The dual blockade of the renin–angiotensin system affects sodium balance, increasing the sodium gradient, thus elevating thirst sensation and enhancing interdialytic weight gain. In maintenance hemodialysis patients treated with both ACEI and ARB, lowered dialysate sodium levels should be prescribed.

Objective: To examine the efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system (RAAS) among patients with type 2 diabetic kidney disease. Data Sources: We searched the major literature repositories, including the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE, for randomized clinical trials published between January 1990 and October 2015 that compared the efficacy and safety of the use of dual blockade of the RAAS versus the use of monotherapy, without applying any language restrictions. Keywords for the searches included "diabetic nephropathy," "chronic kidney disease," "chronic renal insufficiency," "diabetes mellitus," "dual therapy," "combined therapy," "dual blockade," "renin-angiotensin system," "angiotensin-converting enzyme inhibitor," "angiotensin-receptor blocker," "aldosterone blockade," "selective aldosterone blockade," "renin inhibitor," "direct renin inhibitor," "mineralocorticoid receptor blocker," etc. Study Selection: The selected articles were carefully reviewed. We excluded randomized clinical trials in which the kidney damage of patients was related to diseases other than diabetes mellitus. Results: Combination treatment with an angiotensin-converting enzyme inhibitor supplemented by an angiotensin II receptor blocking agent is expected to provide a more complete blockade of the RAAS and a better control of hypertension. However, existing literature has presented mixed results, in particular, related to patient safety. In view of this, we conducted a comprehensive literature review in order to explain the rationale for dual blockade of the RAAS, and to discuss the pros and cons. Conclusions: Despite the negative results of some recent large-scale studies, it may be immature to declare that the dual blockade is a failure because of the complex nature of the RAAS surrounding its diversified functions and utility. Further trials are warranted to study the combination therapy as an evidence-based practice.

Aim: Aim of the study was the evaluation of the effect of dual blockade of the renin-angiotensin system (RAS) on proteinuria. Material and Methods: Sixty patients, included in the study, were treated with angiotensin-converting enzyme inhibitor and angiotensin receptor blocker for a period of 3 months. Results: The dual blockade of RAS resulted with decrease of proteinuria, a slight increase of serum creatinine and was not associated with a lowering of blood pressure.Conclusion: Combined therapy with ACE-I and ARB results in a more complete blockade of the RAS than monotherapy. In proteinuric nephropathies it reduces significantly baseline proteinuria.

The effects of 24 weeks losartan and ramipril treatment, both alone and in combination, on left ventricular mass (LVM), circulating transforming growth factor beta1 (TGFbeta1), procollagen type I (PIP) and III (PIIIP), have been evaluated in hypertensive (HT) patients. A total of 57 HT with stage 1 and 2 essential hypertension were included. After 4 weeks run in, a randomized double-blind, three arms, double dummy, independent trial was used. All HT patients were randomly allocated to three treatment arms consisting of losartan (50 mg/daily), ramipril (5 mg/ daily) and combined (losartan 50 mg/daily + ramipril 5 mg/daily) for 24 weeks. TGFbeta1, PIP and PIIIP, LVM, LVM/h(2.7) and other echocardiographic measurements, blood urea nitrogen, creatinine and clearance and potassium were determined after run in and after 24 weeks. All groups were comparable for gender, age, body mass index, blood pressure and LVM. The prevalence of baseline left ventricular hypertrophy (LVH) was not significantly different among three groups. At the end of treatment, a significant (P0.05) reduction in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), TGFbeta1, PIP, PIIIP, LVM and LVM/h(2.7) was observed in all groups. The absolute and percent reduction in TGFbeta1 and LVM/h(2.7) were significantly higher in combined than losartan or ramipril groups and also in HT patients with LVH. No significant change in absolute and percent reduction of SBP, DBP and MBP were found. Our data indicate an additional cardioprotective effect of dual blockade of renin-angiotensin in HT patients.

Both angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) interfere with the activity of the renin-angiotensin system (RAS) in a different way. Theoretically, one might expect beneficial effects when they are used in combination, as a more complete suppression of the RAS can be achieved. But can this additional effect still be seen in patients on full-dose ACE-inhibition? Several controlled trials demonstrated that combination therapy can have additional benefits in hypertensive patients, in chronic heart failure patients, and in both diabetic and non-diabetic nephropathy patients. However, the clinical benefit was not always as pronounced as expected and not every patient will benefit from dual blockade of the RAS. There is some evidence of a less pronounced effect of combination therapy when a full dose of the ACE-inhibitor is given. However, it is well known that ACE-inhibitors cannot completely suppress the formation of angiotensin II, in particular, when the RAS is activated. Indeed, clinical trials indicated that add-on therapy with an ARB was especially of use when the RAS remained activated despite full-dose ACE-inhibitor treatment. In summary, combination of a full-dose ACE-inhibitor and an ARB can be a rational choice in selected patients.

OBJECTIVE—To assess and compare the long-term effects of the combination of candesartan and lisinopril with high-dose lisinopril on systolic blood pressure in patients with hypertension and diabetes. RESEARCH DESIGN AND METHODS—This was a prospective, randomized, parallel-group, double-blind, double-dummy study with a 12-month follow-up. Drug therapy was either lisinopril 40 mg once daily or dual-blockade treatment with candesartan 16 mg once daily and lisinopril 20 mg once daily. The study comprised 75 type 1 and type 2 diabetic patients aged 35–74 years. The main outcome measures were seated and 24-h ambulatory systolic blood pressure. RESULTS—Reduction in systolic blood pressure (24-h systolic blood pressure) reduction was obtained in both treatment arms (mean reduction at final follow-up: dual blockade 6 mmHg vs. lisinopril 2 mmHg), but no significant difference was found between dual-blockade and lisinopril 40 mg once daily (P = 0.10). Both treatments were generally well tolerated, and similar low rates of side effects were found in the two groups. CONCLUSIONS—There was no statistically significant difference between lisinopril 40 mg once daily and lisinopril 20 mg in combination with candesartan 16 mg once daily in reducing systolic blood pressure in hypertensive patients with diabetes.

There is much effort to develop new therapeutic approaches to rescue dysfunctional T cells in patients with cancer. In the June issue of Cancer Research , Duraiswamy and colleagues demonstrate that a triple therapy consisting of anti-PD-1, anti-CTLA-4, and therapeutic vaccination provides consistent

We have recently reported that the PD-1 and CTLA4 signaling pathways are active in both effector and regulatory T cells, causing profound immune dysfunctions in the tumor microenvironment. In line with this notion, the dual blockade of PD-1- and CTLA4-conveyed signals may exert robust therapeutic effects. Here, we discuss the mechanisms possibly underlying such a synergic interaction.

Beneficial impact on cardiovascular risk factors by dual blockade of the rennin-angiotensin system in diabetic nephropathy.BackgroundPatients with diabetic nephropathy have a high risk of cardiovascular disease and end-stage renal disease. Dual blockade of the renin-angiotensin system (RAS) with both ACE inhibitors (ACE-I) and angiotensin II receptor blockers may offer therapeutic advantages.MethodsBased on three double-blind randomized cross-over trials, we analyzed the short-term effects of dual blockade of the RAS on cardiovascular surrogate end points in 51 type 1 diabetic patients with diabetic nephropathy.ResultsCompared to ACE-I, dual blockade of the RAS decreased albuminuria 37% from 558 mg/24 hour, and lowered 24-hour blood pressure 7/5 mm Hg from 137/76 mm Hg (P < 0.01). In addition, dual blockade lowered total and LDL-cholesterol 0.3 from 5.4 mmol/L and 3.1 mmol/L, respectively (P≤ 0.01). The antialbuminuric response to dual blockade of the RAS was influenced by the insertion (I)/deletion (D) polymorphism in the ACE gene.ConclusionDual blockade of the RAS may offer additional cardiovascular and renal protection in type 1 diabetic patients with diabetic nephropathy. Determination of the ACE/ID genotype may help identify patients particularly sensitive to such therapy.