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Simple Summary: Ovarian cancer (OC) is the most lethal gynecological malignancy with a five-year survival rate of 47%, followed by cervical cancer (66%), and uterine cancer (81%). Despite the success of immunotherapies based on the programmed cell death pathway (PD-1/PD-L1) in other solid cancers, the response of OC patients is low. The promising approach in OC treatment seems to be a combined therapy, including other immune checkpoints such as the TIGIT/CD155/DNAM-1 axis. The approach may trigger the synergistic effect, break the immunosuppression in the ovarian cancer tumor microenvironment, and enhance the expression of tumor antigens. The dual blockade stimulates the effector activity of T cells and NK cells, and redirects the immune system activity against tumor cells. The current understanding of the activity of both pathways, TIGIT/CD155/DNAM-1 and PD-1/PD-L1, as well as their synergistic action in OC, remains unclear. The prognosis for ovarian cancer (OC) patients is poor and the five-year survival rate is only 47%. Immune checkpoints (ICPs) appear to be the potential targets in up-and-coming OC treatment. However, the response of OC patients to immunotherapy based on programmed cell death pathway (PD-1/PD-L1) inhibitors totals only 6–15%. The promising approach is a combined therapy, including other ICPs such as the T-cell immunoglobulin and ITIM domain/CD155/DNAX accessory molecule-1 (TIGIT/CD155/DNAM-1) axis. Preclinical studies in a murine model of colorectal cancer showed that the dual blockade of PD-1/PD-L1 and TIGIT led to remission in the whole studied group vs. the regression of the tumors with the blockade of a single pathway. The approach stimulates the effector activity of T cells and NK cells, and redirects the immune system activity against the tumor. The understanding of the synergistic action of the TIGIT and PD-1/PD-L1 blockade is, however, poor. Thus, the aim of this review is to summarize the current knowledge about the mode of action of the dual TIGIT and PD-1/PD-L1 blockade and its potential benefits for OC patients. Considering the positive impact of this combined therapy in malignancies, including lung and colorectal cancer, it appears to be a promising approach in OC treatment. [ABSTRACT FROM AUTHOR]

Purpose This study aimed to explore the genomic and transcriptomic landscape of bladder cancer (BC) and its implication for treatment with an immune checkpoint inhibitor (ICI). Materials and Methods We analyzed whole-exome and -transcriptome sequences of tumor samples from 64 BC patients who underwent surgical resection with either transurethral resection or radical cystectomy. For exploratory purposes, programmed death-ligand 1 (PD-L1) expression was evaluated in a subset of patients (n=57) including those treated with ICI (n=8). Results We identified frequent molecular dysregulations in chromatin regulatory genes (KDM6A, ARID1A, MLL2, and STAG2) and recurrent copy number alterations. Thirty-five samples (54.7%) were PD-L1–positive (PD-L1 combined positive score ≥ 1) with a significantly higher exonic tumor mutational burden (TMB) compared to PD-L1–negative BC samples (p=0.010). We observed that various immune-responsive pathways, including the PD-L1 signaling pathway, were enriched significantly in PD-L1–positive BCs. Interestingly, genes in the CTLA4 pathway were enriched significantly in PD-L1–positive BC as well. Among eight patients who received ICI, progressive disease was confirmed in one patient, whose tumor had low exonic TMB, negative PD-L1 status, and a relatively colder microenvironment. Conclusion Gaining new insights into the molecular landscape of BC will improve treatment strategies. Our analysis suggests a rationale for studying dual checkpoint inhibition against BC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a common cancer globally and a leading cause of cancer-related deaths. Although early-stage disease may be curable by resection, liver transplantation or ablation, many patients present with unresectable disease and have a poor prognosis. Combination treatment with atezolizumab (targeting PD-L1) and bevacizumab (targeting VEGF) in the recent IMbrave150 study was shown to be effective with an acceptable safety profile in patients with unresectable HCC. Herein, we discuss this novel combination in the context of the liver immune environment, summarize the mechanism and pharmacokinetics of atezolizumab and bevacizumab, and examine recent data on other immune checkpoint inhibitor combination strategies as well as future directions in the treatment of patients with advanced HCC. [ABSTRACT FROM AUTHOR]

Metabolic bone disorder is an abnormality of bones indicated by reduced bone mass and high risk of fractures. Several lines of evidence have demonstrated that the local bone tissue renin-angiotensin system (RAS) is directly involved in bone metabolism and influences the bone health. This review aimed to assess the role of RAS in bone metabolism and comparative effectiveness of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in reducing the bone fractures. In summary, the clinical trials, in vivo studies, and functional - pharmacological experiments suggested that the RAS regulates bone marrow metabolism and influences the bone health. Hence, it warrants further investigation on the role of ACEIs and ARBs in reducing risk fractures.

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 < 0.001; log-rank test). Among radiologically re-assessed patients treated with TP as systemic first-line therapy after diagnosis of BM, 5/14 patients (35.7%) had complete intracranial remission (CR), 8/14 patients (57.1%) partial intracranial remission (PR), 1/14 patients (7.1%) stable intracranial disease (SD) and 0/14 patients (0.0%) progressive intracranial disease (PD) as best response resulting in an intracranial objective response rate (iORR) of 92.9% and an intracranial clinical benefit rate (iCBR) of 100.0%. 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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • First-line pertuzumab improves survival in metastatic HER2-positive breast cancer. • Rash and diarrhoea are common side-effects of pertuzumab. • Rash is prognostic independently of docetaxel use. • Diarrhoea is prognostic for PFS only after docetaxel use. • Both rash and diarrhoea are not predictive of PFS and/or OS. [ABSTRACT FROM AUTHOR]

The tumor necrosis factor (TNF) and IL-23/IL-17 axes are the main therapeutic targets in spondyloarthritis. Despite the clinical efficacy of blocking either pathway, monotherapy does not induce remission in all patients and its effect on new bone formation remains unclear. We aimed to study the effect of TNF and IL-17A dual inhibition on clinical disease and structural damage using the HLA-B27/human β2-microglobulin transgenic rat model of SpA. Immunized rats were randomized according to arthritis severity, 1 week after arthritis incidence reached 50%, to be treated twice weekly for a period of 5 weeks with either a dual blockade therapy of an anti-TNF antibody and an anti-IL-17A antibody, a single therapy of either antibody, or PBS as vehicle control. Treatment-blinded observers assessed inflammation and structural damage clinically, histologically and by micro-CT imaging. Both single therapies as well as TNF and IL-17A dual blockade therapy reduced clinical spondylitis and peripheral arthritis effectively and similarly. Clinical improvement was confirmed for all treatments by a reduction of histological inflammation and pannus formation (p < 0.05) at the caudal spine. All treatments showed an improvement of structural changes at the axial and peripheral joints on micro-CT imaging, with a significant decrease for roughness (p < 0.05), which reflects both erosion and new bone formation, at the level of the caudal spine. The effect of dual blockade therapy on new bone formation was more prominent at the axial than the peripheral level. Collectively, our study showed that dual blockade therapy significantly reduces inflammation and structural changes, including new bone formation. However, we could not confirm a more pronounced effect of dual inhibition compared to single inhibition.

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 EMAapproved indications and to agree on reimbursement, and doctors must optimize their use based on knowledge and discussion with patients. [ABSTRACT FROM AUTHOR]

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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.

The St. Gallen Consensus 2017 recommended neoadjuvant therapy as a standard of care in stage II-III HER2-positive (HER2+) early breast cancer (EBC). Today, the neoadjuvant approach has become even more clinically relevant, as pathological complete response (pCR) status can not only be used to predict patient outcome, but also to escalate anti-HER2 therapy after surgery, based on the recently published results from the KATHARINE trial. Based on the NEOSPHERE results, dual antibody blockade together with chemotherapy has become the neoadjuvant standard. The chemotherapy backbone consists either of an anthracycline-taxane sequence or of an anthracycline-free regimen such as docetaxel and carboplatin. Adjuvant anti-HER2 therapy is then chosen based on initial tumor burden and pCR status. A multidisciplinary approach right from the beginning guarantees optimal treatment results for patients with HER2+ EBC. Emerging strategies will include early response markers (e.g. biomarkers, molecular imaging) as well as novel targeted agents (e.g. immunotherapy) in order to individualize systemic therapy in HER2-positive EBC. Neoadjuvant and adjuvant therapy thus represent components of an integrated, continuous strategy in HER2+ EBC allowing therapy adaptation according to individual tumor response. Refining the treatment algorithm with further de-escalation and escalation approaches will hopefully lead to better chances for cure as well as reduced short- and long-term toxicities in HER2-positive early breast cancer. [ABSTRACT FROM AUTHOR]

Background: Alterations in the human epidermal growth factor receptor‐2 (HER2) pathway have been identified in a subset of salivary duct carcinomas. Dual HER2 inhibition with trastuzumab and pertuzumab has superior antitumor efficacy to trastuzumab monotherapy in HER2‐positive breast cancer, yet its efficacy in HER2‐positive salivary duct carcinoma is unknown. Methods: We report 2 cases of exceptional responses of HER2‐positive salivary duct carcinomas to dual HER2 blockade and docetaxel combination and their molecular characteristics. Results: A 54‐year‐old man with recurrent metastatic HER2 expressing salivary duct carcinoma of the parotid gland after definitive concurrent chemoradiation achieved a complete response (CR) after 6 cycles of trastuzumab, pertuzumab, and docetaxel (TPH). A 42‐year‐old woman with HER2‐positive salivary duct carcinoma of the parotid gland with bone and liver metastases had CR with TPH and remains in remission on maintenance trastuzumab and pertuzumab. Conclusion: Dual HER2 blockage resulted in CR in patients with HER expressing salivary duct carcinoma and warrants further evaluation in this patient population. [ABSTRACT FROM AUTHOR]

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.

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. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase transmembrane receptor that is overexpressed on the surface of 15%-20% of breast tumors and has been associated with poor prognosis. Consistently improved pathologic response and survival rates have been demonstrated with use of trastuzumab in combination with standard chemotherapy in both early and advanced breast cancer. However, resistance to trastuzumab may pose a major problem in the effective treatment of HER2-positive breast cancer. Dual HER2 blockade, using agents that work in a complimentary fashion to trastuzumab, has more recently been explored to evade resistance in both the preoperative (neoadjuvant) and adjuvant settings. Increased effectiveness of dual anti-HER2 agents over single blockade has been recently reported in clinical studies. Pertuzumab in combination with trastuzumab and taxane is currently approved in the metastatic and neoadjuvant treatment of HER2-positive breast cancer. Various biomarkers have also been investigated to identify subsets of patients with HER2-positive tumors who would likely respond best to these targeted therapy combinations. In this article, available trial data regarding efficacy and toxicity of treatment with combination HER2 agents in the neoadjuvant and adjuvant setting have been reviewed, and relevant correlative biomarker data from these trials have been discussed. [ABSTRACT FROM AUTHOR]

The neoadjuvant strategy, initially developed to render primary inoperable tumors operable, is now increasingly being utilized for patients with triple-negative and HER2 positive breast cancer in clinical trials in order to assess for response and resistance with the incorporation of tissue biopsy studies. Pathological complete response (pCR) has been accepted as a primary endpoint in a number of neoadjuvant trials for operable HER2+ disease. This article provides a comprehensive summary of the knowledge gained from neoadjuvant trials conducted with HER2 directed agents to date, focuses on the concept of dual blockade of HER2, highlights the importance of predictive biomarkers, and finally puts them into perspective with current treatment recommendations and future research and trends. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to explore the genomic and transcriptomic landscape of bladder cancer (BC) and its implication for treatment with an immune checkpoint inhibitor (ICI)., Materials and Methods: We analyzed whole-exome and -transcriptome sequences of tumor samples from 64 BC patients who underwent surgical resection with either transurethral resection or radical cystectomy. For exploratory purposes, programmed death-ligand 1 (PD-L1) expression was evaluated in a subset of patients (n=57) including those treated with ICI (n=8)., Results: We identified frequent molecular dysregulations in chromatin regulatory genes (KDM6A, ARID1A, MLL2, and STAG2) and recurrent copy number alterations. Thirty-five samples (54.7%) were PD-L1-positive (PD-L1 combined positive score ≥ 1) with a significantly higher exonic tumor mutational burden (TMB) compared to PD-L1-negative BC samples (p=0.010). We observed that various immune-responsive pathways, including the PD-L1 signaling pathway, were enriched significantly in PD-L1-positive BCs. Interestingly, genes in the CTLA4 pathway were enriched significantly in PD-L1-positive BC as well. Among eight patients who received ICI, progressive disease was confirmed in one patient, whose tumor had low exonic TMB, negative PD-L1 status, and a relatively colder microenvironment., Conclusion: Gaining new insights into the molecular landscape of BC will improve treatment strategies. Our analysis suggests a rationale for studying dual checkpoint inhibition against BC.

The clinical benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) are well established in chronic kidney disease (CKD) patients with diabetic and non-diabetic nephropathies. But despite appearance, the magnitude of this effect has been questioned particularly in mild, proteinuric nephropathies. Given that the single agents can achieve only partial and not durable suppression of the renin-angiotensin system (RAS), it has been hypothesized that dual blockage with ACE inhibitors and ARBs would be most beneficial in the management of progressive CKD than either agent alone. Available evidence indicates significant anti-proteinuric effect, but long-term data in CKD patients are lacking. Recently, the findings of the ONTARGET trial even questioned the safety of this therapeutic approach. Given that preventing cardiovascular complications is extremely important in CKD and RAS inhibition may be useful in this setting, benefits of RAS blockade must be weighed against its possible adverse effects particularly in elderly patients. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We evaluated the long-term changes on overt proteinuria induced by dual blockade of the renin–angiotensin system (RAS). Dual blockade was produced by adding an angiotensin II receptor blocker (ARB) to treatment with maximal recommended doses of an angiotensin converting enzyme (ACE) inhibitor in proteinuric patients. A total of 28 patients (19 men and 9 women) with proteinuria higher than 1 g/24 h were enrolled in this trial of treatment with the ARB candesartan (from 4 up to 32 mg daily) added to existing treatment with an ACE inhibitor. At 6, 12, 24, and 36 months, we evaluated proteinuria in 24-h urinary collections, office blood pressure (BP), plasmatic creatinine (Cr), serum potassium (K), and 24 h urine collection creatinine clearance (CrC). During monoblockade of the RAS by ACE inhibitor treatment, albuminuria was 2.94 ± 1.92 mg/24 h; BP was 137/76 mmHg; K+ was 4.8 ± 0.5 mmol/l, Cr was 1.76 ± 0.67 mg/dL, and CrC was 62 ± 31.9 mL/min. After 6 months, dual blockade of the RAS albuminuria was 2.18 ± 2.29 mg/24 h ( P < 0.01 vs. baseline) and BP was 133/75 mmHg (not significant). At 36 months, albuminuria was 2.21 ± 2.20 mg/24 h ( P < 0.05 vs. baseline); BP was 133/73 mmHg (not significant). CrC was not changed along the follow up. A small increment of Cr was detected at 24 months (2.11 ± 1.06 mg/mL, P < 0.05). The antiproteinuric effect of dual renin–angiotensin system blockade combining candesartan and ACE inhibitors remain after 36 months without losing its initial effect. Blood pressure changes seem not to explain this long-term antiproteinuric effect. [ABSTRACT FROM AUTHOR]

Summary: Aim: Dual blockade of renin–angiotensin system (RAS) has increased antiproteinuric effects and it has been increasingly used on patients with proteinuria, but could have secondary effects when this kind of treatment is administered to patients with single functioning kidney. The aim of this study has been to assess the efficacy and safety of dual blockade of RAS in this group of patients. Design and methods: Sixteen patients with a single functioning kidney have been treated in our unit with dual RAS blockade due to proteinuria higher than 1 g/24 h. Mean age was 54.7±12.1 years, they were 12 males and 4 females. Analytical data of six months visit and last follow up visit have been retrospectively registered. Several different angiotensin conversor enzyme (ACE) inhibitors and angiotensin receptor blocking (ARB) drugs were used at the maximal dose tolerated by the patient. Results: A small but not significant reduction of SBP and DBP were was observed throughout the study. Mean K+ increase in the second visit (from 4.65±0.67 to 5.01±1.02 mmol/l, not significant). There were no changes neither in plasmatic creatinine (baseline 1.86±0.67, 6 months 1.96±0.85) nor in creatinine clearance (baseline 65.2±26.9, 6 months 61.6±23.8 ml/min). Proteinuria was not reduced by dual RAS blockade (baseline 4.26±0.24, 6 months 4.25±0.39). Conclusions: Dual RAS blockade seems to be safe but unhelpful in renal patients with proteinuria associated to single functioning kidney. [Copyright &y& Elsevier]

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. (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. [ABSTRACT FROM AUTHOR]

The tumor necrosis factor (TNF) and IL-23/IL-17 axes are the main therapeutic targets in spondyloarthritis. Despite the clinical efficacy of blocking either pathway, monotherapy does not induce remission in all patients and its effect on new bone formation remains unclear. We aimed to study the effect of TNF and IL-17A dual inhibition on clinical disease and structural damage using the HLA-B27/human β2-microglobulin transgenic rat model of SpA. Immunized rats were randomized according to arthritis severity, 1 week after arthritis incidence reached 50%, to be treated twice weekly for a period of 5 weeks with either a dual blockade therapy of an anti-TNF antibody and an anti-IL-17A antibody, a single therapy of either antibody, or PBS as vehicle control. Treatment-blinded observers assessed inflammation and structural damage clinically, histologically and by micro-CT imaging. Both single therapies as well as TNF and IL-17A dual blockade therapy reduced clinical spondylitis and peripheral arthritis effectively and similarly. Clinical improvement was confirmed for all treatments by a reduction of histological inflammation and pannus formation (p < 0.05) at the caudal spine. All treatments showed an improvement of structural changes at the axial and peripheral joints on micro-CT imaging, with a significant decrease for roughness (p < 0.05), which reflects both erosion and new bone formation, at the level of the caudal spine. The effect of dual blockade therapy on new bone formation was more prominent at the axial than the peripheral level. Collectively, our study showed that dual blockade therapy significantly reduces inflammation and structural changes, including new bone formation. However, we could not confirm a more pronounced effect of dual inhibition compared to single inhibition. [ABSTRACT FROM AUTHOR]

Proteinuria and hypertension are predictors of poor renal outcome in chronic glomerulonephritis (CGN). At the same level of blood pressure (BP) control, we evaluated which is superior, dual blockade of the rennin–angiotensin system (RAS) with both angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II type 1 (AT-1) receptor blockade (ARB) or single blockade of ARB to reduce proteinuria and to preserve renal function in patients with CGN. In this prospective, parallel, open study of 86 patients with CGN, we compared the effects on proteinuria and renal functions of 36 months with comparable blood pressure (BP) control achieved by candesartan cilexetil (candesartan, 4–12 mg/day) or benazepril hydrochrolide (benazepril, 2.5–10 mg/day) with candesartan (4 mg/day). Aiming at BP 125/75 mmHg or less, the dose of candesartan (single blockade) or benazepril (dual blockade) was increased. Dual blockade decreased proteinuria more than single blockade with ARB (−42.3 vs. −60.5%, P < 0.01). Renal plasma flow (RPF) and glomerular filtration fraction (GFR) did not change significantly in either group. The filtration fraction (FF) decreased dual blockade more than single blockade (−1.7 vs. −19.0%, P < 0.05). Decreased FF was associated with the reduction of proteinuria ( P < 0.05). Six percent of patients with dual blockade were not able to continue the study because of a dry cough. Long-term dual blockade decreased proteinuria more than single blockade with ARB. Although ARB and ACEI have a glomerular size-selective function for proteinuria, a greater antiproteinuric effect may depend on renal hemodynamics, especially FF. Increased levels of bradykinin after ACEI can decrease FF and ameliorate proteinuria. Dry cough is a significant adverse effect of ACE inhibitor. [ABSTRACT FROM AUTHOR]

Dual blockade of the renin–angiotensin system (RAS) has increased antiproteinuric effects and so a higher incidence of secondary effects can be expected when this kind of treatment is administered. The aim of this study was to assess the safety of dual blockade of RAS. Seventy-five (54 men and 21 women) patients has been treated in our unit with dual RAS blockade due to proteinuria higher than 1 g/24 h. Mean age was 57.1 ± 14.0 years. Fifty-three patients had chronic renal failure (CRF) at baseline. Analytical data of 6 months visit and last follow-up visit were recorded. A small reduction of systolic blood pressure and diastolic blood pressure was observed in both treatment groups throughout the study. Neither the CRF patients nor those with normal renal function showed any reduction in mean plasma haemoglobin levels, but differences between groups were significant at the second and third visits (anova). No change was detected in haematocrit. Mean K+ significantly increase at the second visit in the CRF group (from 4.80 ± 0.64 to 5.23 ± 0.81 mmol/l, p < 0.001, Student's t-test). There were no changes in normal kidney function group (4.58 ± 0.37 vs. 4.63 ± 0.44). At baseline plasmatic creatinine was higher in the CRF group (2.09 ± 0.60 0.20 mg/dl vs. 0.99 ± 0.20 mg/dl, p < 0.001, Student's t-test) and creatinine clearance was lower (48.6 ± 20.7 ml/min vs. 107.0 ± 0.30 ml/min, p < 0.001, Student's t-test). There was a small increase in creatinine along the follow-up when compared with the normal renal function group (p < 0.001,anova). Conversely, creatinine clearance remain unchanged in the normal renal function group, and there was a decrease in creatinine in CRF patients (p < 0.001). Dual RAS blockade seems to be safe in renal patients even when mild to moderate renal failure is present. Severe hyperkalaemia is uncommon. Small increments in plasmatic creatinine can be seen but they are hardly dangerous. Combined treatment does not significantly influence erythropoiesis. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is a major problem for patients and health care systems. The costs of treatment remain high. To confront the ongoing challenge, we need to identify individuals at high risk for initiation and progression of this devastating complication. Risk factors include genetic markers; constitutional factors such as low birthweight; haemodynamic factors, including activation of the RAS system and hypertension; metabolic factors such as glycaemia; and additional factors such as urinary AER and smoking. Modifiable risk factors should be treated aggressively. Potential new markers of risk include indices of increased inflammation, changes in coagulation, endothelial dysfunction, growth factors and cytokines. Application of such markers may in time improve risk assessment and allow new treatment targets to be identified. Interventions that aim to achieve strict glycaemic control and blockade of the renin-angiotensin system have been shown to be effective in clinical trials and are feasible in clinical practice. The ‘natural history’ of diabetic nephropathy can be transformed if these strategies of intensive screening and care are applied, leading both to a lower incidence of diabetic nephropathy and to an improved outcome, with survival exceeding 20 years from onset of overt proteinuria. [ABSTRACT FROM AUTHOR]

Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in patients with diabetic nephropathy (DN). Intensive treatment requires blockade of the renin-angiotensin system (RAS) by either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), which reduce blood pressure and proteinuria. Combining the two therapies has shown greater benefits than either drug alone to reduce progression of DN. Although treatment goals are more likely to be achieved with the combination, this requires close monitoring of serum creatinine and potassium which invariably rise on such therapy. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM PUBLISHER]

Diabetic nephropathy is the most common cause of end stage renal failure (ESRF) in the developedof world and as the incidence of diabetes increases this trend will continue, although most of these patients will die of cardiovascular diseases. The renin-angiotensin system (RAS) is believed to play a central role in the development and progression of both micro- and macrovascular complications of diabetes and blocking this system in diabetic patients is critically important. Two widely used inhibitors of RAS are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). These drugs affect the system at different levels and thus may have an additive effect. Use of drugs from one class may not be completely effective in blocking this system for several reasons. In this article we discuss issues surrounding the use of dual blockade (i.e. the use of ARB and ACE inhibitors together in patients with diabetic nephropathy responding insufficiently to previous antihypertensive treatment including either ARB or ACE inhibitors) in patients with diabet [ABSTRACT FROM PUBLISHER]

Diabetic nephropathy is a major cause of diabetes related morbidity and mortality. The first part of the current review was published in the last issue of this journal and discussed the impotant role of the renin-angiotensin system (RAS) in diabetic nephropathy and the genetic influence on development of end-stage renal disease (ESRD) in diabetic patients. This second part of the review focus on the potential improvement of the current treatment strategy to slow down the loss of kidney function using dual blockade of the RAS with both ACE-inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs). Substantial evidence from short-term studies using surrogate endpoints indicates a beneficial impact of dual blockade of the RAS, not obtainable with single agent blockade alone, both in diabetic and non-diabetic renal disease. This conclusion has been confirmed and extended in a longterm trial with regard to prevention of ESRD in non-diabetic renal disease. Results indicate that dual blockade of the RAS may further slow down, but not arrest progressive loss of renal function. However, studies defining the optimal dose of ACE-I / ARBs without additional adverse effects are essential to ensure relevant comparison with dual blockade therapy. Trials using primary renal endpoints in diabetic nephropathy are still needed, and will finally establish the role of dual blockade of the RAS in a clinical setting. [ABSTRACT FROM PUBLISHER]

The renin-angiotensin-aldosterone system has an important role in the progression of both diabetic and nondiabetic nephropathy. Angiotensin-converting enzyme inhibitors and angiotensin-II receptor blocker can effectively retard or halt this progression. However, their renoprotective effect is not enough, because approximately 20% of patients have a progressive course to endstage renal disease. There is now clear evidence that combination therapy of two agents is more antiproteinuric and, likely renoprotective, than each agent alone. However, several critical issues should be addressed before recommending it as standard treatment in chronic renal disease. [ABSTRACT FROM AUTHOR]