Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype arising from renal cell carcinomas. This tumor is characterized by a predominant angiogenic and immunogenic ...microenvironment that interplay with stromal, immune cells, and tumoral cells. Despite the obscure prognosis traditionally related to this entity, strategies including angiogenesis inhibition with tyrosine kinase inhibitors (TKIs), as well as the enhancement of the immune system with the inhibition of immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. This approach has achieved a substantial improvement in life expectancy and quality of life from patients with advanced ccRCC. Unfortunately, not all patients benefit from this success as most patients will finally progress to these therapies and, even worse, approximately 5 to 30% of patients will primarily progress. In the last few years, preclinical and clinical research have been conducted to decode the biological basis underlying the resistance mechanisms regarding angiogenic and immune-based therapy. In this review, we summarize the insights of these molecular alterations to understand the resistance pathways related to the treatment with TKI and immune checkpoint inhibitors (ICIs). Moreover, we include additional information on novel approaches that are currently under research to overcome these resistance alterations in preclinical studies and early phase clinical trials.
Bone sarcomas are a heterogeneous group of rare tumors with a predominance in the young population. Few options of systemic treatment are available once they become unresectable and resistant to ...conventional chemotherapy. A better knowledge of the key role that tyrosine kinase receptors (VEGFR, RET, MET, AXL, PDGFR, KIT, FGFR, IGF-1R) may play in the pathogenesis of these tumors has led to the development of multi-target inhibitors (TKIs) that are progressively being incorporated into our therapeutic arsenal. Osteosarcoma (OS) is the most frequent primary bone tumor and several TKIs have demonstrated clinical benefit in phase II clinical trials (cabozantinib, regorafenib, apatinib, sorafenib, and lenvatinib). Although the development of TKIs for other primary bone tumors is less advanced, preclinical data and early trials have begun to show their potential benefit in advanced Ewing sarcoma (ES) and rarer bone tumors (chondrosarcoma, chordoma, giant cell tumor of bone, and undifferentiated pleomorphic sarcoma). Previous reviews have mainly provided information on TKIs for OS and ES. We aim to summarize the existing knowledge regarding the use of TKIs in all bone sarcomas including the most recent studies as well as the potential synergistic effects of their combination with other systemic therapies.
Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch ...repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of non-small cell lung cancer (NSCLC), either used in monotherapy or in combination with chemotherapy. While some ...patients achieve durable responses, some will not get benefit from this treatment. Early identification of non- responder patients could avoid unnecessary treatment, potentially serious immune-related adverse events and reduce treatment costs. PD-L1 expression using immunohistochemistry is the only approved biomarker for the selection of patients that can benefit from immunotherapy. However, application of PD-L1 as a biomarker of treatment efficacy shows many deficiencies probably due to the complexity of the tumor microenvironment and the technical limitations of the samples. Thus, there is an urgent need to find other biomarkers, ideally blood biomarkers to help us to identify different subgroups of patients in a minimal invasive way. In this review, we summarize the emerging blood-based markers that could help to predict the response to ICIs in NSCLC.
Anti-Ma2 encephalitis is a rare neurological disorder with a predominant involvement of brainstem, limbic and diencephalic structures. Although an unspecific encephalopathy is the usual form of ...presentation, acute-onset neurologic symptoms and other atypical manifestations have been described and account for the challenging diagnosis of this entity. Despite being usually detected as a paraneoplastic syndrome in patients with early-stage tumors or without a previous history of malignancy, a growing concern has arisen from several cases reported in metastatic patients under treatment with immune checkpoint inhibitors. We report what to our knowledge is the first known case of anti-Ma2 encephalitis associated to pembrolizumab and presenting as an acute-onset focal neurological syndrome, consisting on acute global aphasia, right upper limb paresia, hypoacusia, sleep disorder, decreased conscious level and a motor focal status that was refractory to anticonvulsant therapy. A brain MRI scan showed a focal alteration of the cortical-subcortical signal on the left parietal lobe. CSF study found a significant hyperproteinorrhachia and electroencephalography showed lateralized periodic discharges (LPDs), suggestive of a diffuse encephalopathy. A positive result for anti-Ma2 antibodies was obtained both in blood and CSF samples through indirect immune-fluorescence (IFI) and later confirmed by western-blot technique. Our patient obtained a mild response to steroid therapy and a significant improvement after the administration of intravenous immunoglobulins. The hypothesis that checkpoint inhibitors may trigger the expression of previously subclinical paraneoplastic events, through the strengthening of cytotoxic T cells-mediated immune response, is supported by our finding of preexisting anti-Ma2 antibodies in preserved blood samples obtained before the initiation of pembrolizumab in our patient. Further research is needed to reveal if the detection of onconeural antibodies prior to a treatment with checkpoint inhibitors may be used as a predictive biomarker of neurologic immune-related high-grade toxicity.
BackgroundImmune checkpoint inhibitors (ICIs) have become a revolution in the treatment of many tumoral diseases, resulting in a significant increase in terms of life expectancy and quality of ...life.Despite these outstanding advances in long-life survival, a new spectrum of adverse events has been developed and is known to be one of the biggest challenges in clinical practice nowadays.Immune-mediated neurotoxicity stands out as a rather unusual complication, but its potentially lethal consequences make the characterization and right management of this adverse event a crucial issue in this field.MethodsThis is a retrospective study including all the cancer patients that have developed any neurological adverse event related to ICIs treatment, in a period of 4 years (from 2017 to 2020).Results13 patients were included in the study (8 were treated with antiPD-1/PD-L1 immunotherapy, 1 with antiCTLA-4 and 4 with the combination of both strategies). 4 patients developed generalized myasthenia gravis (GMG), 4 immune-mediated encephalitis (IME), 3 immune-related encephalopathy without radiological/analytical evidence of encephalitis, 1 mixed-polyneuropathy, and 1 polymyositis.3 patients with GMG were seropositive, 3 developed the clinical feature within the first 21 days of immunotherapy treatment and all of them received anti-PD-1/PD-L1 treatment. All patients with IME showed pleocytosis in cerebrospinal fluid, without any data in brain MRI.12 patients suspended ICIs treatment after the event and were treated with high doses of intravenous corticosteroids. Half of them required treatment with intravenous immunoglobulins. 10 showed total or partial resolution as clinical outcome. However, 4 patients passed away due to toxicity (2 with GMG). In severe cases that precise ICU admission, 4 out of 6 patients (66%) showed a spectacular clinical improvement with complete recovery after early treatment with high doses of methylprednisolone and intravenous immunoglobulins.ICIs withdrawal was sustained indefinitely in all patients, showing a progression-free survival at six-months of 50%. In patients with tumoral diseases that have an indication of treatment with ICIs, the PFS at 6 and 12 months stands at 66%.ConclusionsIn this series, the majority of neurotoxicity was related to anti-PD1/PD-L1 treatment, appearing in the first 21 days within the treatment. Most of the patients showed a favourable clinical outcome. In severe cases, an improvement in clinical features was objective after an early onset of treatment with high doses of intravenous corticosteroids and immunoglobulins.ICIs withdrawal did not suppose harm in terms of PFS in patients with tumoral types where ICIs are already indicated.
Background
Catheter ablation of premature ventricular complexes from aortic sinus cusps (ASC‐PVC) is a complex procedure that conventionally requires coronary catheterization (CC) to localize ...coronary artery ostium (CAO). Little published information is available on the mapping and ablation with zero‐fluoroscopy (ZF) of ASC‐PVC. The aim of the study was to determine the efficacy and safety of ASC‐PVC ablation with a ZF approach guided by 3D intracardiac echocardiography integration in the electroanatomical mapping system (ICE 3D‐EAM).
Methods
This observational study included one patient cohort treated conventionally and another treated with ICE 3D‐EAM‐guided ZF ablation. Clinical, efficacy, and safety outcomes were evaluated acutely and at 3 months follow‐up.
Results
The study included 21 patients with ASC‐PVC: 10 in the ZF group (age 49 ± 16 years, 60% males) and 11 in the control group (age 47 ± 15 years, 27% males). Fluoroscopy was not required for any patient in the ZF group. Acute success was obtained in 80% of the ZF group vs 55% of the control group (P = .36). The recurrence rate was 30% in the ZF group vs 27% in the control group (P = 1). One nonsevere complication was observed in the ZF group (P = .48).
Conclusions
ZF catheter ablation of ASC‐PVC guided by ICE 3D‐EAM is feasible, effective, and safe.
The graphical shows the workflow for ZF ablation approach of ASC‐PVC using ICE 3D‐EAM. The key point is the ICE 3D‐EAM reconstruction which allows to assess the distance of the ablation catheter tip to CAO. Note that if the distance is at least >5 mm from earliest LVAT to CAO, the ablation is started. On the other hand, with a distance <5 mm respect to CAO, the ablation is not performed and another safe adjacent site is searched. ZF: zero‐fluoroscopy. ASC: Aortic sinus cusp. PVC: Premature ventricular complex. LV: Left ventricle. RV: Right ventricle. CAO: Coronary artery ostium. LVAT: Local ventricular activation time. ICE 3D‐EAM: Electroanatomic reconstruction guided by intracardiac echocardiography.
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