Toxicity of immunotherapy combinations with chemotherapy across tumor indications: Current knowledge and practical recommendations.

Chemotherapy associated with Immune Checkpoint Inhibitors is currently the standard of care in several tumor indications. This combination approach improves progression free survival (PFS), overall survival (OS) and complete pathological response (pCR) in several cancer types both in the early and metastatic approaches. However, the distinct spectrum of toxicities between cytotoxic side effects and immune related adverse events (irAEs) with similar clinical presentations and different management strategies remains a challenge in daily practice for healthcare professionals. This review summarizes the most common toxicities reported in the randomized clinical trials that led to the subsequent FDA approval of these combinations, across tumor indications. We cite in particular: non-small cell lung cancer, small cell lung cancer, triple negative breast cancer, squamous cell carcinoma of the head and neck, gastric carcinoma, esophageal carcinoma, cervical carcinoma and biliary tract carcinoma. We found that the combination of chemotherapy and immunotherapy was associated with an increased incidence of all grade adverse events (RR 1.11 [1.09; 1.12]) without an excess in treatment related mortality when compared to chemotherapy alone. We report also an increase in the incidence of serious adverse events (grade ≥ 3) (RR 1.16 [1.10;1.24]); in particular: high grade diarrhea, dyspnea, fatigue, rash and elevated liver enzymes. Together with the collaboration of our institutional network of organ specialists with expertise in irAEs, we propose practical recommendations for physicians to enhance clinical care and management of patients undergoing treatment with combined ICI immunotherapy and chemotherapy.

Corrigendum: Evaluation of PIK3CA mutations in advanced ER+/HER2-breast cancer in Portugal - U-PIK Project.

[This corrects the article DOI: 10.3389/fmolb.2023.1082915.].

Nitrogen-containing andrographolide derivatives with multidrug resistance reversal effects in cancer cells.

Multidrug resistance (MDR) remains a challenging issue in cancer treatment. Aiming at finding anticancer agents to overcome MDR, the triacetyl derivative (2) of the labdane diterpenoid lactone andrographolide (1) underwent the Michael-type addition reaction followed by elimination, yielding twenty-three new derivatives, bearing nitrogen-containing substituents (3-25). Their structures were assigned, mainly, by 1D and 2D NMR experiments. The MDR reversal potential of compounds 1-25 was assessed, by functional and chemosensitivity assays, using resistant human ABCB1-gene transfected L5178Y mouse lymphoma cells as a model. Several derivatives exhibited remarkable P-glycoprotein (P-gp) inhibitory ability. Compounds 13 and 20, bearing thiosemicarbazide moieties, were the most active exhibiting a strong MDR reversal effect at 2 µM. Some compounds showed selectivity towards the resistant cells, with compound 5 exhibiting a collateral sensitivity effect associated with significant antiproliferative activity (IC50 = 5.47 ± 0.22 µM). Moreover, all selected compounds displayed synergistic interaction with doxorubicin, with compound 3 being the most active. In the ATPase assay, selected compounds exhibited characteristics of P-gp inhibitors.

Maternal obesity increases the risk of hepatocellular carcinoma through the transmission of an altered gut microbiome.

Background & Aims: Emerging evidence suggests that maternal obesity negatively impacts the health of offspring. Additionally, obesity is a risk factor for hepatocellular carcinoma (HCC). Our study aims to investigate the impact of maternal obesity on the risk for HCC development in offspring and elucidate the underlying transmission mechanisms. Methods: Female mice were fed either a high-fat diet (HFD) or a normal diet (ND). All offspring received a ND after weaning. We studied liver histology and tumor load in a N-diethylnitrosamine (DEN)-induced HCC mouse model. Results: Maternal obesity induced a distinguishable shift in gut microbial composition. At 40 weeks, female offspring of HFD-fed mothers (HFD offspring) were more likely to develop steatosis (9.43% vs. 3.09%, p = 0.0023) and fibrosis (3.75% vs. 2.70%, p = 0.039), as well as exhibiting an increased number of inflammatory infiltrates (4.8 vs. 1.0, p = 0.018) and higher expression of genes involved in fibrosis and inflammation, compared to offspring of ND-fed mothers (ND offspring). A higher proportion of HFD offspring developed liver tumors after DEN induction (79.8% vs. 37.5%, p = 0.0084) with a higher mean tumor volume (234 vs. 3 µm3, p = 0.0041). HFD offspring had a significantly less diverse microbiota than ND offspring (Shannon index 2.56 vs. 2.92, p = 0.0089), which was rescued through co-housing. In the principal component analysis, the microbiota profile of co-housed animals clustered together, regardless of maternal diet. Co-housing of HFD offspring with ND offspring normalized their tumor load. Conclusions: Maternal obesity increases female offspring's susceptibility to HCC. The transmission of an altered gut microbiome plays an important role in this predisposition. Impact and implications: The worldwide incidence of obesity is constantly rising, with more and more children born to obese mothers. In this study, we investigate the impact of maternal diet on gut microbiome composition and its role in liver cancer development in offspring. We found that mice born to mothers with a high-fat diet inherited a less diverse gut microbiome, presented chronic liver injury and an increased risk of developing liver cancer. Co-housing offspring from normal diet- and high-fat diet-fed mothers restored the gut microbiome and, remarkably, normalized the risk of developing liver cancer. The implementation of microbial screening and restoration of microbial diversity holds promise in helping to identify and treat individuals at risk to prevent harm for future generations.

Adenosine receptors are the on-and-off switch of astrocytic cannabinoid type 1 (CB1) receptor effect upon synaptic plasticity in the medial prefrontal cortex.

The medial prefrontal cortex (mPFC) is involved in cognitive functions such as working memory. Astrocytic cannabinoid type 1 receptor (CB1R) induces cytosolic calcium (Ca2+) concentration changes with an impact on neuronal function. mPFC astrocytes also express adenosine A1 and A2A receptors (A1R, A2AR), being unknown the crosstalk between CB1R and adenosine receptors in these cells. We show here that a further level of regulation of astrocyte Ca2+ signaling occurs through CB1R-A2AR or CB1R-A1R heteromers that ultimately impact mPFC synaptic plasticity. CB1R-mediated Ca2+ transients increased and decreased when A1R and A2AR were activated, respectively, unveiling adenosine receptors as modulators of astrocytic CB1R. CB1R activation leads to an enhancement of long-term potentiation (LTP) in the mPFC, under the control of A1R but not of A2AR. Notably, in IP3R2KO mice, that do not show astrocytic Ca2+ level elevations, CB1R activation decreases LTP, which is not modified by A1R or A2AR. The present work suggests that CB1R has a homeostatic role on mPFC LTP, under the control of A1R, probably due to physical crosstalk between these receptors in astrocytes that ultimately alters CB1R Ca2+ signaling.

Communication defects with astroglia contribute to early impairments in the motor cortex plasticity of SOD1G93A mice.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, involving the selective degeneration of cortical upper synapses in the primary motor cortex (M1). Excitotoxicity in ALS occurs due to an imbalance between excitation and inhibition, closely linked to the loss/gain of astrocytic function. Using the ALS SOD1G93A mice, we investigated the astrocytic contribution for the electrophysiological alterations observed in the M1 of SOD1G93A mice, throughout disease progression. Results showed that astrocytes are involved in synaptic dysfunction observed in presymptomatic SOD1G93A mice, since astrocytic glutamate transport currents are diminished and pharmacological inhibition of astrocytes only impaired long-term potentiation and basal transmission in wild-type mice. Proteomic analysis revealed major differences in neuronal transmission, metabolism, and immune system in upper synapses, confirming early communication deficits between neurons and astroglia. These results provide valuable insights into the early impact of upper synapses in ALS and the lack of supportive functions of cortical astrocytes, highlighting the possibility of manipulating astrocytes to improve synaptic function.

Petrosamine isolated from marine sponge Petrosia sp. demonstrates protection against neurotoxicity in vitro and in vivo.

According to The World Alzheimer Report 2023 by Alzheimer's Disease International (ADI) estimates that 33 to 38.5 million people worldwide suffer from Alzheimer's Disease (AD). A crucial hallmark associated with this disease is associated with the deficiency of the brain neurotransmitter acetylcholine, due to an affected acetylcholinesterase (AChE) activity. Marine organisms synthesize several classes of compounds, some of which exhibit significant AChE inhibition, such as petrosamine, a coloured pyridoacridine alkaloid. The aim of this work was to characterize the activity of petrosamine isolated for the first time from a Brazilian marine sponge, using two neurotoxicity models with aluminium chloride, as exposure to aluminium is associated with the development of neurodegenerative diseases. The in vitro model was based in a neuroblastoma cell line and the in vivo model exploited the potential of zebrafish (Danio rerio) embryos in mimicking hallmarks of AD. To our knowledge, this is the first report on petrosamine's activity over these parameters, either in vitro or in vivo, in order to characterize its full potential for tackling neurotoxicity.

Clinical predictors of NEDA-3 one year after diagnosis of pediatric multiple sclerosis: an exploratory single-center study.

Introduction: Multiple sclerosis (MS) is an inflammatory and demyelinating disorder of central nervous system that can be diagnosed in pediatric age (<18 years) in 3-5% of the cases. This early onset is associated with higher relapse rates and earlier progression to neurological disability. By using NEDA-3 (No Evidence of Disease Activity-3) criteria, we aimed to identify clinical predictors associated with absence of disease activity and control of disease progression 12 months after the diagnosis, in a cohort of pediatric-onset MS (POMS) patients regularly followed-up in our center. Methods: We analyzed demographic, clinical, laboratorial and imaging variables of patients with POMS identified in our center, between 2010 and 2021, in two moments: at the diagnosis and 12 months after it. Statistical tests were applied to compare the distribution of those variables between groups defined by NEDA-3 status and by each one of its three variable components. Results: We included 27 patients in the study (18 female), with a mean age of 14.8 years (± 2.8), being all diagnosed with relapsing-remitting MS and with a median score of 1.5 at the Expanded Disability Status Scale (EDSS). The use of natalizumab (p = 0.017) and the negativity for anti-EBV IgG antibodies (p = 0.018) at diagnosis were associated with a higher achievement of NEDA-3 status 12 months after, in our cohort. Prescribed treatment was also associated with statistically significant differences in the "absence of MRI activity" component of NEDA-3 (p = 0.006): patients under treatment with natalizumab had a higher probability of achieving this status, and the opposite was observed in glatiramer acetate-treated children. Discussion and conclusion: Our exploratory results underline the pivotal importance that an early and more effective therapeutical approach may have in the control of disease activity, in POMS. Additionally, they also seem to suggest that the presence of anti-EBV antibodies is not innocent, as it can be related to a less favorable evolution of the disease, even at a very early stage. Further studies are needed to confirm the applicability of these variables as prognostic and personalized tools in this clinical setting.

Combined Oxidative Phosphorylation Deficiency Type-13 with Perinatal Presentation: A Case Report.

INTRODUCTION: Polynucleotide phosphorylase is involved in RNA processing in mitochondria. Biallelic variants in PNPT1 cause mitochondrial RNA import protein deficiency and heterogeneous clinical manifestations. CASE REPORT: The patiest was the first child of remote consanguineous parents, born at 35 weeks by caesarean section due to fetal growth restriction. Apgar index was 9/10/10. Birth weight, length and head circumference were at 3rd, <3rd and 10th percentiles, respectively. In the first hours of life, respiratory distress, hypoglycaemia and seizures ensued. She started invasive mechanic ventilation, phenobarbital and was transferred to ICU. Physical examination showed minor facial dysmorphisms, brief eye-opening, hypotonia and hyporeflexia. Electroencephalogram showed immature pattern and multifocal paroxysmal activity. MRI at D8 of life showed severe reduced brain volume. Normal aminoacid screen was also observed. Expanded newborn screening was negative. Mitochondrial organic aciduria was seen. WES showed a homozygotic likely pathogenic variant in the PNPT1 gene. MRI at 6-months showed brain atrophy, thin corpus callosum, reduced brainstem volume. Bilateral and symmetrical lesions in globi pallidi, compatible with Leigh síndrome were observed. Currently, at 14 months, no neurodevelopment progress, dystonia, visual deficit, sensorineural deafness, hypertrophic cardiomyopathy and microcephaly are observed. CONCLUSION: The early and severe Leigh-like presentation of our patient expands the phenotype spectrum of this disease. As far as we know, this is the first reported case of PNPT1 mutation with onset in the perinatal period. Moreover, hypertrophic cardiomyopathy has not yet been described in association with mutation of the PNPT1 gene. WES was the key for early diagnosis in this patient. It should be done in all children with severe clinical presentation of unknown origin.

Hyperbaric oxygen therapy as a complementary treatment in neuroblastoma - a narrative review.

Neuroblastoma is the most frequently diagnosed cancer during the first year of life. This neoplasm originates from neural crest cells derived from the sympathetic nervous system, adrenal medulla, or paraspinal ganglia. The clinical presentation can vary from an asymptomatic mass to symptoms resulting from local invasion and/or spread of distant disease spread. The natural history of neuroblastoma is highly variable, ranging from relatively indolent biological behavior to a high-risk clinical phenotype with a dismal prognosis. Age, stage, and biological features are important prognostic risk stratification and treatment assignment prognostic factors. The multimodal therapy approach includes myeloablative chemotherapy, radiotherapy, immunotherapy, and aggressive surgical resection. Hyperbaric oxygen therapy (HBOT) has been proposed as a complementary measure to overcome tumor hypoxia, which is considered one of the hallmarks of this cancer treatment resistance. This article aims to review the relevant literature on the neuroblastoma pathophysiology, clinical presentation, and different biological and genetic profiles, and to discuss its management, focusing on HBOT.

The first Portuguese Open Dialogue pilot project intervention.

Introduction: In 2020, the Directorate General of Health (DGS), a central service of the Ministry of Health in Portugal, approved and co-financed the first Open Dialogue program in the country. The present report aims to demonstrate the preliminary results of the first year of the project, implemented in the northern interior region of Alentejo. Methods: Seven people at the Center of Concern (PCC) and 21 family members/social networks received care through Open Dialogue; four external social workers and psychologists were also involved in the project as members of the support network. A total of 160 network meetings were undertaken, reaching as many as 27 per month in the busiest periods. Based on a previous Italian Research Protocol, developed by Pocobello et al. (non-published manuscript), quantitative and qualitative data were collected in and after the clinical meetings involving PCC and their family/social network, through a multi-method approach: clinical history interview (e.g., generic research on sociodemographic data, duration of untreated symptoms, reasons for requesting help, possible hospitalizations, and/or treatments/therapies) and the following scales applied every five sessions (e.g., CORE-OM, BSI, GAF, and LSNS-6). Results: The preliminary results indicate an improvement in global functioning and the enlargement of social network size/support, a decrease in symptoms, and a negative correlation between the number of sessions and the LSNS6. Medication use remained largely unchanged at the end of the project. Discussion: In general, even with a small sample, the results are considered satisfactory and seem to be aligned with the vast majority of Open Dialogue studies, which for several decades have consistently pointed toward better recovery rates than treatment as usual as well as increased client satisfaction. We expect that the results presented can boost further research and help strengthen the OD approach.

Unusual Vulvar, Perineal, and Uterine Leiomyomas: A Case Report.

Vulvar leiomyomas are extremely rare smooth muscle tumors that are easily mistaken for other lesions, as the differential diagnosis must consider a wide spectrum of benign and malignant lesions. We present the case of a 52-year-old woman with a three-year history of progressive abdominal distension and pain and an enlarging vulvar mass distorting the labia majora and causing gait disturbance. Imaging confirmed an enormous pelvic mass originating in the uterus, compatible with a leiomyoma/sarcoma, and large perineal and vulvar masses with similar characteristics. Histopathology after surgical removal revealed benign abdominal, vulvar, and perineal leiomyomas. This case highlights the rarity and diagnostic challenges of extra-uterine leiomyomas, particularly those in the vulvar region.

X-Linked Myotubular Myopathy: A Novel Mutation Expanding the Genotypic Spectrum of a Phenotypically Heterogeneous Myopathy.

X-linked myotubular myopathy (XLMTM), a centronuclear congenital myopathy secondary to pathogenic variants in the MTM1 gene encoding myotubularin, is typically recognized for its classic and severe phenotype which includes neonatal hypotonia, severe muscle weakness, long-term ventilator dependence, markedly delayed gross motor milestones with inability to independently ambulate, and a high neonatal and childhood mortality. However, milder congenital forms of the condition and other phenotypes are recognized. We describe a 6-year-old boy with a mild XLMTM phenotype with independent gait and no respiratory insufficiency even in the neonatal period. The child has a hemizygous novel splice site variant in the MTM1 gene (c.232-25A > T) whose pathogenicity was confirmed by cDNA studies (exon 5 skipping) and muscle biopsy findings. We also compared the phenotype of our patient with the few reported cases that presented a mild XLMTM phenotype and no respiratory distress at birth, and discussed the potential mechanisms underlying this phenotype such as the presence of residual expression of the normal myotubularin transcript.