Efficacy and safety of a combination treatment of immune checkpoint inhibitors in metastatic breast cancer: a systematic review and meta-analysis.

PURPOSE: Immune checkpoint inhibitors (ICIs) in combination with chemotherapy have showed its benefits in clinical studies, and here we conducted a further evaluation on the safety and efficacy of this treatment strategy. METHODS: A systematic literature review was conducted in PubMed, Embase and Cochrane Library to identify clinical studies on ICIs and chemotherapy for metastatic breast cancer. The primary efficacy endpoints were progression-free survival (PFS) and overall survival (OS), and adverse events (AEs) were analyzed. Random or fixed effects models were used to estimate pooled Hazard ratio (HR), odds ratio (OR) and the data of 95% confidence interval (CI) depend on the Heterogeneity. Cochrane risk assessment tool was used to assess risk of bias. We also drew forest plots and funnel plots, respectively. RESULTS: Seven studies with intend-to-treat (ITT) population for 3255 patients were analyzed. ICIs pooled therapy showed clinical benefits compared with chemotherapy alone, improving PFS (HR = 0.81, 95% CI: 0.74-0.90) of patients with metastatic triple negative breast cancer (mTNBC), especially in patients with PD-L1-positive tumors. However, it had no effect on OS (HR = 0.92, 95% CI 0.85-1.01). Besides, mTNBC patients received pooled therapy were less frequently to have AEs (OR = 1.30, 95% CI: 1.09-1.54). In patients with metastatic Human Epidermal Growth Factor Receptor 2 (HER2) negative breast cancer, pooled therapy showed no benefit for PFS (HR = 0.80, 95% CI: 0.50-1.28) and OS (HR = 0.87, 95% CI: 0.48-1.58). CONCLUSION: Pooled therapy had improved PFS in mTNBC patients, especially in patients with PD-L1-positive tumors, and it was less likely to cause grade ≥ 3 AEs.

An analysis pipeline for understanding 6-thioguanine effects on a mouse tumour genome.

Mouse tumour models are extensively used as a pre-clinical research tool in the field of oncology, playing an important role in anticancer drugs discovery. Accordingly, in cancer genomics research, the demand for next-generation sequencing (NGS) is increasing, and consequently, the need for data analysis pipelines is likewise growing. Most NGS data analysis solutions to date do not support mouse data or require highly specific configuration for their use. Here, we present a genome analysis pipeline for mouse tumour NGS data including the whole-genome sequence (WGS) data analysis flow for somatic variant discovery, and the RNA-seq data flow for differential expression, functional analysis and neoantigen prediction. The pipeline is based on standards and best practices and integrates mouse genome references and annotations. In a recent study, the pipeline was applied to demonstrate the efficacy of low dose 6-thioguanine (6TG) treatment on low-mutation melanoma in a pre-clinical mouse model. Here, we further this study and describe in detail the pipeline and the results obtained in terms of tumour mutational burden (TMB) and number of predicted neoantigens, and correlate these with 6TG effects on tumour volume. Our pipeline was expanded to include a neoantigen analysis, resulting in neopeptide prediction and MHC class I antigen presentation evaluation. We observed that the number of predicted neoepitopes were more accurate indicators of tumour immune control than TMB. In conclusion, this study demonstrates the usability of the proposed pipeline, and suggests it could be an essential robust genome analysis platform for future mouse genomic analysis.

Opportunistic Infections and Immune-Related Adverse Events Associated with Administering Immune Checkpoint Inhibitors: A Narrative Review.

Manipulating the immune system by blocking the immune checkpoint receptors is the basis of immunotherapy, a relevant tool in current clinical oncology. The strategy of blocking the immune checkpoints (Immune Checkpoint Inhibitors, ICI) consists of using monoclonal antibodies to inhibit the interaction between ligand and inhibitory receptors from triggering a complete activation of helper and cytotoxic T cells to fight against tumour cells. Immunotherapy has benefited patients with diverse cancers such as stomach, lung, melanoma, and head and neck squamous cell carcinoma, among others. Unfortunately, a growing number of reports have indicated that the ICI treatment also can show a dark side under specific conditions; some of the adverse effects induced by ICI are immunosuppression, opportunistic infections, and organ-specific alterations. This review discusses some immunologic aspects related to these unwanted effects.

Frequency and clinical characteristics of hypophysitis and hypopituitarism in patients undergoing immunotherapy - A systematic review.

Objective: To describe the frequency of hypophysitis and hypopituitarism in cancer patients who are undergoing antineoplastic treatment with immunotherapy, as well as to describe the clinical, epidemiological, and demographic characteristics of these patients. Methods: A systematic search of the literature in PubMed, Embase, Web of Science, ClinicalTrials.gov and Cochrane Controlled Register of Trials took place on May 8 and 9, 2020. Randomized and nonrandomized clinical trials, cohort studies, case-control studies, case series and case reports were included. Results: A total of 239 articles were obtained, in which 963 cases of hypophysitis and 128 cases of hypopituitarism were found in a treated population of 30,014 individuals (3.20% and 0.42% of the evaluated population, respectively). In the cohort studies, the incidence of hypophysitis and hypopituitarism ranged from 0% to 27.59% and from 0% to 17.86%, respectively. In the non-randomized clinical trials, the incidence of hypophysitis and hypopituitarism ranged from 0% to 25% and from 0% to 14.67%, and in randomized clinical trials from 0% to 16.2% and from 0% to 33.33%. The most common hormonal changes were in the corticotrophic, thyrotrophic and gonadotrophic axes. The main magnetic resonance imaging (MRI) findings were enlargement of the pituitary gland and enhanced contrast uptake. The main symptoms presented by patients with hypophysitis were fatigue and headache. Conclusion: The present review reported a frequency of hypophysitis and hypopituitarism of 3.20% and 0.42%, respectively, in the evaluated population. The clinical-epidemiological characteristics of patients affected by hypophysitis were also described. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42020175864.

Carrier Diversity Incorporation to Low-Complexity Near-ML Detection for Multicarrier Systems over V2V Radio Channel.

Inter-carrier interference (ICI) in vehicle to vehicle (V2V) orthogonal frequency division multiplexing (OFDM) systems is a common problem that makes the process of detecting data a demanding task. Mitigation of the ICI in V2V systems has been addressed with linear and non-linear iterative receivers in the past; however, the former requires a high number of iterations to achieve good performance, while the latter does not exploit the channel's frequency diversity. In this paper, a transmission and reception scheme for low complexity data detection in doubly selective highly time varying channels is proposed. The technique couples the discrete Fourier transform spreading with non-linear detection in order to collect the available channel frequency diversity and successfully achieving performance close to the optimal maximum likelihood (ML) detector. When compared with the iterative LMMSE detection, the proposed system achieves a higher performance in terms of bit error rate (BER), reducing the computational cost by a third-part when using 48 subcarriers, while in an OFDM system with 512 subcarriers, the computational cost is reduced by two orders of magnitude.

Comprehensive assessment of multiple tryptophan metabolites as potential biomarkers for immune checkpoint inhibitors in patients with non-small cell lung cancer.

PURPOSE: Tryptophan metabolites have immunomodulatory functions, suggesting possible roles in cancer immunity. METHODS: Plasma tryptophan metabolites were measured using liquid chromatography/mass spectrometry before immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC). RESULTS: The 19 patients with NSCLC had significantly lower levels of tryptophan (p = 0.002) and xanthurenic acid (p = 0.032), and a significantly higher level of 3-hydroxyanthranilic acid (3-HAA) (p = 0.028) compared with the 10 healthy volunteers. The patients achieving objective responses had significantly lower levels of 3-HAA than those who did not (p = 0.045). Receiver operating characteristic analyses determined that the cutoff value of 3-HAA for objective response was 35.4 pmol/mL (sensitivity: 87.5% and specificity: 83.3%). The patients with 3-HAA < 35.4 pmol/mL had significantly longer median progression-free survival (7.0 months) than those without (1.6 months, p = 0.022). CONCLUSIONS: Tryptophan metabolites may have a potential for predicting the efficacy of ICIs. REGISTRATION NUMBER: University Hospital Medical Information Network Clinical Trial Registry 000026140.

Central Nervous System Demyelination Associated With Immune Checkpoint Inhibitors: Review of the Literature.

Immune checkpoint inhibitors (ICI) are a novel class of antineoplastic treatment that enhances immunity against tumors. They are associated with immune adverse events, and several neurological syndromes have been described, including multiple sclerosis and atypical demyelination. We performed a systematic literature review of case reports with neurological immune adverse events that presented with central nervous system demyelination, up to December 2019. We found 23 cases: seven with myelitis, four isolated optic neuritis, one neuromyelitis optica spectrum disorder, five multiple sclerosis, and six with atypical demyelination. Ipilimumab was the most frequently used ICI (11/23). The median time to develop symptoms from the onset of ICI was 6.5 weeks [range 1.0-43.0], and from last ICI dose was 14 days [range 0-161]. Anatomopathological examination was performed in four cases, with the finding of a T-cell mediated immune response. Outcomes were generally favorable after immunosuppression: 18 patients had improvement or a full recovery, three patients did not respond to treatment, three patients died, and in one, treatment was not reported. We describe the patients' clinical presentation, treatment administered, and outcomes. We further speculate on possible pathophysiological mechanisms and discuss potential treatments that may be worth investigating.

Beta-Adrenergic Blockade Decreases the Neuroimmune Changes in Mice Induced by Cohabitation with an Ehrlich Tumor-Bearing Cage Mate.

OBJECTIVES: Cohabitation with Ehrlich tumor-bearing (ETB) mice induced behavioral, neurochemical, hormonal, and immune effects in the conspecifics as a consequence of stress-induced activation of the sympathetic nervous system (SNS) with catecholamine release. In the current study, the nonspecific ß-AR blocker d,l-propranolol and the specific ß2-AR blocker ICI-118.551 were employed as pharmacological tools to assess the extent to which catecholamines participated in the effects induced by cohabitation with ETB mice. METHODS: Two experiments were performed, 1 with d,l-propranolol treatment and the other with ICI-118.551. One mouse in the experimental group was called the "companion of the sick partner" (CSP) since it was forced to live in the same cage with 2 (experiment 1) or 1 (experiment 2) cage mate that had been i.p. injected with 5 × 106 Ehrlich tumor cells. RESULTS: The d,l-propranolol treatment, but not the ICI-118.551 treatment, attenuated the effects of cohabitation with 2 ETB mice on both open-field behavior and the hypothalamic levels and turnover rate of norepinephrine. The 2 ß-AR blockers were unable to change the serum corticosterone levels and adrenal weights of the CSP mice; however, these drugs abrogated the effects of cohabitation on neutrophil oxidative burst and phagocytosis. Finally, an increase in the 5-HT turnover rate was observed in the olfactory bulb of CSP mice compared to their respective controls, an effect that was not modified by ß-AR blockade. CONCLUSION: These results confirm and strengthen our hypothesis that the SNS is involved in the effects induced by cohabitation with ETB mice and point towards ß2-AR participation in the immune effects analyzed.

Functional ß2-adrenoceptors in rat left atria: effect of foot-shock stress.

Altered sensitivity to the chronotropic effect of catecholamines and a reduction in the ß1/ß2-adrenoceptor ratio have previously been reported in right atria of stressed rats, human failing heart, and aging. In this report, we investigated whether left atrial inotropism was affected by foot-shock stress. Male rats were submitted to 3 foot-shock sessions and the left atrial inotropic response, adenylyl cyclase activity, and ß-adrenoceptor expression were investigated. Left atria of stressed rats were supersensitive to isoprenaline when compared with control rats and this effect was abolished by ICI118,551, a selective ß2-receptor antagonist. Schild plot slopes for the antagonism between CGP20712A (a selective ß1-receptor antagonist) and isoprenaline differed from unity in atria of stressed but not control rats. Atrial sensitivity to norepinephrine, as well as basal and forskolin- or isoprenaline-stimulated adenylyl cyclase activities were not altered by stress. The effect of isoprenaline on adenylyl cyclase stimulation was partially blocked by ICI118,551 in atrial membranes of stressed rats. These findings indicate that foot-shock stress equally affects inotropism and chronotropism and that ß2-adrenoceptor upregulation contributes to the enhanced inotropic response to isoprenaline.

Treatments for fibrosis of the corpora cavernosa.

INTRODUCTION: Corporal fibrosis usually occurs after explantation of an infected penile prosthesis, severe penile trauma, refractory low-flow priapism, Peyronie's disease, or the chronic intracavernous injection of vasoactive drugs. METHODS: We analysed current treatmentss for penile fibrosis. We searched PubMed using the keywords 'penile corporal fibrosis', 'treatment' and 'penile fibrosis', resulting in 63 matches, of which 19 articles met the inclusion criteria. RESULTS AND CONCLUSIONS: This review covers conservative medical therapy for corporal fibrosis and surgical therapeutic methods. The roles of phosphodiesterase- 5 inhibitors and pentoxifylline are analysed. Surgical therapy includes implantation of a penile prosthesis and corporal reconstruction, and these are reviewed. Corporal fibrosis is a major problem for patients, and is associated with severe erectile dysfunction. Conservative treatment options can be applicable in the early phase, but simultaneous corporal reconstruction procedures with concomitant implantation of a penile prosthesis should be attempted in severe cases of corporal fibrosis.

Apotransferrin-induced recovery after hypoxic/ischaemic injury on myelination.

We have previously demonstrated that aTf (apotransferrin) accelerates maturation of OLs (oligodendrocytes) in vitro as well as in vivo. The purpose of this study is to determine whether aTf plays a functional role in a model of H/I (hypoxia/ischaemia) in the neonatal brain. Twenty-four hours after H/I insult, neonatal rats were intracranially injected with aTf and the effects of this treatment were evaluated in the CC (corpus callosum) as well as the SVZ (subventricular zone) at different time points. Similar to previous studies, the H/I event produced severe demyelination in the CC. Demyelination was accompanied by microglial activation, astrogliosis and iron deposition. Ferritin levels increased together with lipid peroxidation and apoptotic cell death. Histological examination after the H/I event in brain tissue of aTf-treated animals (H/I aTF) revealed a great number of mature OLs repopulating the CC compared with saline-treated animals (H/I S). ApoTf treatment induced a gradual increase in MBP (myelin basic protein) and myelin lipid staining in the CC reaching normal levels after 15 days. Furthermore, significant increase in the number of OPCs (oligodendroglial progenitor cells) was found in the SVZ of aTf-treated brains compared with H/I S. Specifically, there was a rise in cells positive for OPC markers, i.e. PDGFRα and SHH(+) cells, with a decrease in cleaved-caspase-3(+) cells compared with H/I S. Additionally, neurospheres from aTf-treated rats were bigger in size and produced more O4/MBP(+) cells. Our findings indicate a role for aTf as a potential inducer of OLs in neonatal rat brain in acute demyelination caused by H/I and a contribution to the differentiation/maturation of OLs and survival/migration of SVZ progenitors after demyelination in vivo.

Effect of the ionophore ICI 139603 on growth rate and feed conversion in Zebu / Efeito do ionóforo ICI 139603 no desempenho e conversão alimentar de novilhos zebu alimentados com gramíneas tropicais

The effect of the ICI 139603 ionophore on the performance of Zebu steers was evaluated on this trial utilizing two treatments: A) control and B) 0.1 mg/kg LW of ICI 139603. Fifty four 27 month old Nellore steers were grouped based on live weight and weight gain on a 3 week pre-trial period. The basal diet consisted of chopped Guinea grass ad libitum plus 0.5 kg of soybean meal and ground corn (0.37% of the live weight). The ICI 139603 additive was mixed with the ground corn on treatment B. Dry matter intake was not affected by the additive (P >0.05), but daily weight gain was greater (P 0.01) for the animals receiving it (0.585 and 0.655 kg for treatments A and B, respectivelly). Consequently, feed conversion was improved (P 0.01) by the additive (in the same order above, 14.66 and 13.12 kg DM/kg LWG). The concentration of propionic acid in the ruminal liquid was increased by the additive. The improvement of feed conversion was 10.5% and the weight gain 12.2% higher than the control group of cattle.

O efeito do ionóforo ICI 139603 no desempenho de novilhos azebuados foi avaliado num experimento conduzido em Nova Odessa, SP. O experimento consistia de dois tratamentos: A- controle e B- ionóforo (0,lmg do composto ativo por kg de peso vivo). Foram selecionados 54 novilhos nelore com 27 meses de idade e agrupados com base no peso vivo e no ganho de peso durante período pré-experimental de 3 semanas. A dieta basal era constituída de capim colonião picado, à vontade, 0,5 kg de farelo de soja e quirera de milho à base de aproximadamente 0,37% do peso vivo. No tratamento B, o milho foi utilizado como veículo para o ionóforo. A ingestão de matéria seca não foi afetada pela adição de ionóforo na dieta (P> 0,05). Por outro lado, o ganho de peso diário foi maior (P 0,01) para os animais que receberam o ionóforo (0,585 e 0,655 kg/cab/dia, para os tratamentos A e B, respectivamente). O grupo tratado, apresentou uma conversão alimentar melhor (P 0,01) (na mesma ordem, 14,66 e 13,12 kg MS/kg ganho). A concentração e a proporção de ácido propiônico no fluido ruminal também foram aumentadas pela utilização do ionóforo. O aumento médio no ganho de peso e melhora na conversão alimentar ocasionados pelo tratamento foram de 12,2% e 10,5% respectivamente.

Effect of the ionophore ICI 139603 on growth rate and feed conversion in Zebu / Efeito do ionóforo ICI 139603 no desempenho e conversão alimentar de novilhos zebu alimentados com gramíneas tropicais

The effect of the ICI 139603 ionophore on the performance of Zebu steers was evaluated on this trial utilizing two treatments: A) control and B) 0.1 mg/kg LW of ICI 139603. Fifty four 27 month old Nellore steers were grouped based on live weight and weight gain on a 3 week pre-trial period. The basal diet consisted of chopped Guinea grass ad libitum plus 0.5 kg of soybean meal and ground corn (0.37% of the live weight). The ICI 139603 additive was mixed with the ground corn on treatment B. Dry matter intake was not affected by the additive (P >0.05), but daily weight gain was greater (P 0.01) for the animals receiving it (0.585 and 0.655 kg for treatments A and B, respectivelly). Consequently, feed conversion was improved (P 0.01) by the additive (in the same order above, 14.66 and 13.12 kg DM/kg LWG). The concentration of propionic acid in the ruminal liquid was increased by the additive. The improvement of feed conversion was 10.5% and the weight gain 12.2% higher than the control group of cattle.

O efeito do ionóforo ICI 139603 no desempenho de novilhos azebuados foi avaliado num experimento conduzido em Nova Odessa, SP. O experimento consistia de dois tratamentos: A- controle e B- ionóforo (0,lmg do composto ativo por kg de peso vivo). Foram selecionados 54 novilhos nelore com 27 meses de idade e agrupados com base no peso vivo e no ganho de peso durante período pré-experimental de 3 semanas. A dieta basal era constituída de capim colonião picado, à vontade, 0,5 kg de farelo de soja e quirera de milho à base de aproximadamente 0,37% do peso vivo. No tratamento B, o milho foi utilizado como veículo para o ionóforo. A ingestão de matéria seca não foi afetada pela adição de ionóforo na dieta (P> 0,05). Por outro lado, o ganho de peso diário foi maior (P 0,01) para os animais que receberam o ionóforo (0,585 e 0,655 kg/cab/dia, para os tratamentos A e B, respectivamente). O grupo tratado, apresentou uma conversão alimentar melhor (P 0,01) (na mesma ordem, 14,66 e 13,12 kg MS/kg ganho). A concentração e a proporção de ácido propiônico no fluido ruminal também foram aumentadas pela utilização do ionóforo. O aumento médio no ganho de peso e melhora na conversão alimentar ocasionados pelo tratamento foram de 12,2% e 10,5% respectivamente.