Treatment Toxicity Research Articles

Radiotherapy(R) Integration(I) Strategy for Small(S)-Cell Lung Cancer in Extensive(E) Stage (RISE) with up to 10 metastases- a study protocol of a randomized phase II trial

Background The current standard of care (SoC) for patients with extensive-disease small-cell lung cancer (ED-SCLC) is chemo-immunotherapy. The efficacy of radiotherapy (RT) for chest consolidation has been established for patients with ED-SCLC who have responded to chemotherapy. There is a lack of data on incorporating RT as chest consolidation and metastasis-directed therapy for ED-SCLC. The RISE (Radiotherapy for Extensive-Stage Small-Cell Lung Cancer) study aims to evaluate the effectiveness of different RT strategies for residual lesions for patients with ED-SCLC who receive chemo-immunotherapy.MethodsA total of 165 patients with ED-SCLC will be recruited, with 55 patients assigned to each of the three study arms. Patients with stabilization or partial regression, according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, during chemo-immunotherapy will be included.• Arm I will serve as the control group, comprising patients who continue SoC of programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) immunotherapy (durvalumab or atezolizumab) following platinum-based chemo-immunotherapy.• Arm II will receive the SoC with consolidative RT to the chest area and potentially, according to palliative indications to metastatic lesions, delivered in 30 Gy in 3-Gy fractions.• Arm III will receive SoC with RT of 45 Gy in 3-Gy fractions to the chest area and stereotactic body radiotherapy (SBRT) with 24 Gy in 8-Gy fractions to the metastatic lesions.Blood samples for circulating tumor DNA (ctDNA) will be collected before RT, during each week of treatment, and at the time of disease progression.The primary endpoint is progression-free survival (PFS) based on RECIST 1.1 or patient death. 1. Secondary endpoints are OS, treatment toxicity (frequency of G3 toxicity according to CTCAE v.5.0), area of progression (primary tumor localization/new lesions), Overall response rate (ORR), and the response rate in non-irradiated lesions.DiscussionThe study population of patients with ED-SCLC has a poor prognosis. Dose-escalated chest RT and SBRT (for up to 10 metastases) administered with modern techniques offer the possibility to improve OS and PFS.Trial registrationClinicaltrials.gov NCT06529081 (Registered 26th Jul 2024).

Selenomethionine Attenuates Aflatoxin B1-induced Liver Injury by Modulating the Gut Microbiota and Metabolites in Rabbits.

Dietary contamination with aflatoxin B1 (AFB1), which can lead to severe liver damage, poses a great threat to livestock and poultry breeding and has detrimental impacts on food safety. Selenomethionine (SeMet), with anti-inflammatory, antioxidative, and detoxifying effects, is regarded as a beneficial food additive. However, whether SeMet can reduce AFB1-induced liver injury and intestinal microbial disorders in rabbits remains to be revealed. Forty 35-day-old rabbits were randomly divided into a control group, an AFB1 group, and 0.2 mg/kg Se and 0.4 mg/kg Se groups. The SeMet treatment group was fed different doses of the SeMet diet every day for 21 days. On Days 17-21, the AFB1 group, 0.2 mg/kg Se, and 0.4 mg/kg Se groups were intragastrically administered 0.3 mg AFB1/kg b.w. Results showed that SeMet restored alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, alleviating AFB1-induced liver function damage. This was linked to changes in intestinal metabolites and activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway. In this study, the relationships between intestinal microorganisms and their metabolites and AFB1-induced liver injury are investigated, and the potential protective role of SeMet against liver damage induced by AFB1 offers novel insights into strategies for the prevention and treatment of AFB1-related toxicity.

Radioprotective effects of coenzyme Q10 on X-ray radiation-induced intestinal damage via oxidative stress and apoptosis.

The World Health Organization reported that cancer was the cause of death for 9.7 million people in 2022, and the numbers continue to rise every day. The present study examines the potential radioprotective effects of ubiquinone against x-ray radiation-induced intestinal damage and offers insight into new near-future methods for the treatment of radiation-induced tissue toxicity. Thirty-two male Sprague-Dawley rats were randomly divided into four groups. Group I (control) received no treatment during the experiment; Group II (IR [a single dose of 2 Gy pelvic/abdominal ionizing radiation]) received radiation only; Group III (a low dose of CoQ10 [30 mg/kg CoQ10 by oral gavage for 7 d] + IR) and Group IV (a high dose of CoQ10 [150 mg/kg CoQ10 by oral gavage for 7 d] + IR). The rats were sacrificed 24 h after x-ray radiation, and tissues were collected from the small intestine and subjected to histochemical analysis. Diffuse villous fusion, enterocyte loss, hemorrhagic areas, inflammation, and fibrosis were observed in the IR group, as well as an increase in apoptotic enterocytes. In contrast, a decrease was observed in the IR+LD-CoQ10 and IR+HD-CoQ10 groups, along with a decrease, especially in villous fusion and enterocyte loss, hemorrhagic areas, inflammation, and fibrosis. CoQ10 was found to reduce duodenal damage, oxidative stress, and apoptosis induced by x-ray radiation exposure and had a radioprotective effect.

The Role of the Microbiome in Cancer Therapies: Current Evidence and Future Directions.

The microbiome is essential for maintaining human health and is also a key factor in the development and progression of various diseases, including cancer. Growing evidence has highlighted the microbiome's significant impact on cancer development, progression, and treatment outcomes. As research continues to unfold, the microbiome and its modulation stand out as a promising frontier in cancer research and therapy. This review highlights current literature on the interplay between various cancer treatment modalities and human microbiotas, focusing on how the microbiome may affect treatment efficacy and toxicity and its potential as a therapeutic target to enhance future outcomes.

Management of inhalation injuries in emergency and critical care: immediate interventions and long-term outcomes

Inhalation injury is respiratory injury caused by inhalation of substances such as toxic gas, fire fumes and chemical products. It can lead to hypoxia, ventilation dysfunction, increased airway resistance, and massive pulmonary edema. Immediate intervention is crucial for inhalation injuries. Current management strategies include endotracheal intubation, tracheostomy, fluid resuscitation, mechanical ventilation, and treatment of systemic toxicity. Many factors can affect the outcomes of inhalation injury such as age, severity of inhalation injury, and total body surface area burned. The following databases were used in systematic research: Medline (PubMed), Web of Science, and Scopus till 22 December 2024. Inclusion criteria is any study that discusses management of inhalation injuries in emergency and critical care and their outcomes and published in peer-reviewed journals was included with the inclusion of full-text articles, abstracts, and case series with the related topics are included. All languages are included. Animal studies, case reports, letters and comments were excluded. Endotracheal intubation, mechanical ventilation, and tracheostomy are considered important interventions in the inhalation injury emergency setting. However, studies reported poor long-term outcomes of these interventions. The objective of this review is to discuss the different approaches of management of inhalation injuries in emergency department and the obtained outcomes.

Design, Synthesis, and SAR of Covalent KIT and PDGFRA Inhibitors─Exploring Their Potential in Targeting GIST.

Gastrointestinal stromal tumors (GIST), driven by KIT and PDGFRA mutations, are the most common mesenchymal tumors of the gastrointestinal tract. Although tyrosine kinase inhibitors (TKIs) have advanced treatment, resistance mutations and off-target toxicity limit their efficacy. This study develops covalent TKIs targeting drug-resistant GIST through structure-based design, synthesis, and biological evaluation. SAR studies provided key insights into mutant KIT and PDGFRA interactions, and the first crystal structure of PDGFRA bound to a covalent inhibitor is reported. These findings highlight the promise of covalent inhibitors for overcoming resistance and advancing safer, more effective therapies for advanced GIST.

Musician's Experience After Breast Cancer Treatment: Defining Musical Toxicity and its Frequency.

Over 50% of households in the United States have at least one musician-many musicians are also breast cancer survivors. This group has not been well studied, and given the level of fine sensory-motor skill required for musicianship, we hypothesized that musicians experience unique manifestations of breast cancer treatment toxicities. A nine-item Musical Toxicity Questionnaire (MTQ) was distributed to patients who had consented to participate in the Mayo Clinic Breast Cancer Registry. The MTQ screened participants by asking if they played a musical instrument or sang in the last 10 years: questions populated for those who answered yes. Respondents were asked if they noticed difficulty with their musical endeavor during or after breast cancer treatment, defined as acute musical toxicity (AMT). The questionnaire asked which side effect and cancer-directed therapy most influenced musical ability, what musical attributes were affected, and the timeline of resolution. Multivariable and classification tree analyses assessed relationships between AMT and treatment characteristics. Of 1,871 survey respondents, 29% (535/1,871) self-identified as musicians. Over a quarter (27%, 144/535) reported AMT, and for 57% (82/144), AMT had not resolved at the time of survey. Of the treatments each participant received, chemotherapy was most often reported as most negatively impactful (63/89 who received chemotherapy, 71%). Decreased endurance was the most common musical difficulty (64% of those with AMT, 92/144), followed by decreased accuracy, trouble playing/singing quickly, and difficulty using proper technique. Multivariable and classification tree analyses revealed that receipt of chemotherapy was most strongly correlated with AMT. These results will help oncology care teams counsel musicians, answer questions about impacts on musicality, and provide a timeline for resolution of musical symptoms.

Proton Beam Therapy for Advanced Periocular Skin Cancer: An Eye-Sparing Approach.

Background/Objectives: The management of periocular skin malignancies presents a unique challenge. Proton beam therapy, due to its sharp dose fall-off, allows for the delivery of a tumoricidal dose to the tumor while sparing adjacent normal tissues. Methods: Thirteen patients with a median age of 76.5 years received protons at our institution to a median dose of 66.6 Gy (RBE). Sixty-four percent of the lesions were basal cell carcinoma, and 22% were squamous cell carcinoma. Eighty-six percent of patients underwent biopsy only or partial resection. Fifty-seven percent of the lesions were located in the medial or lateral canthus. There was orbital invasion in 93% of the cases. Locoregional control probability and overall survival were estimated with the Kaplan-Meier method. Treatment toxicity was scored using the CTCAE 4.0. Results: At a median follow-up of 96 months, there was no local recurrence. The rate of orbital preservation was 100%. Functional vision was maintained in all the patients. There was no acute or late grade 3 or higher toxicity. Conclusions: Protons allow for long-term tumor control with eye preservation in patients with locally advanced periocular skin cancers. Larger prospective multi-institutional trials with standardized ophthalmological assessments are needed to confirm our findings.

Delineating the Potential Therapeutic Effects of Lobaric Acid as a Novel Strategy in the Treatment of Melanoma.

Melanoma is one of the most dangerous and common types of cancer in humans. In order to minimize the toxicity and side effects of melanoma treatment, it is important to identify drug candidates that have strong anti-cancer activity and fewer side effects. Lobaric acid is a small molecule that has been found to have significant anti-cancer effects on various types of cancer cells. The study aimed to investigate the effects of lobaric acid on human melanoma cell lines (A-375, MDA-MB-435, G-361, and WM-115) and normal human epidermal melanocyte cells. The study also examined the regulation of cell cycle and apoptosis, as well as the gene expression level of apoptosis-related genes and regulatory proteins to induce apoptosis in melanoma cells. The study suggests that lobaric acid may have an effect on the proliferation of A-375 melanoma cells, with results indicating a dose- and time-dependent manner. Additionally, the study found that the expression levels of 70 target genes out of 88 apoptosis- related genes in the primary apoptosis library panel were obtained. Out of these, 54 genes showed an increase in expression levels, while 16 genes showed a decrease. Moreover, it has been determined that the levels of apoptosis-related proteins, such as Casp3, Casp7, Casp9, and PARP, were increased. The results suggest that lobaric acid induces apoptosis through the extrinsic pathway by upregulating the expression of Caspases and PARP. The findings of this study provided a strong basis for the use of lobaric acid as a potential therapeutic agent in the treatment of melanoma.

Gender and sex differences in colorectal cancer screening, diagnosis and treatment.

Males have a higher incidence and mortality rate from colorectal cancer (CRC) compared with females. This review examines the reasons for these differences, including risk factors, screening participation, interpretation of screening tests, presentation and tumour types, pathophysiology (particularly the impact of sex hormones on tumour-related gene expression, microsatellite instability, micro-RNA expression, and the tumour microenvironment), and the efficacy and toxicity of treatment. Sex differences in hormones and body composition are responsible for some of the sexual dimorphism in CRC incidence and outcomes, particularly the pathophysiology, CRC presentation, the pharmacokinetics of cytotoxic therapies, and the impact of treatment on outcomes. However, gender differences also play a role, affecting risk factors, access to or participation in screening and treatment, and patients' experience of treatment (e.g. adverse events and sequelae). Sex and gender issues warrant further investigation in CRC to optimise treatment outcomes for patients.

Bidirectional Mendelian Randomization Analysis to Study the Relationship Between Human Skin Microbiota and Radiation-Induced Skin Toxicity.

Radiation-induced skin toxicity, resulting from ionizing or nonionizing radiation, is a common skin disorder. However, the underlying relationship between skin microbiota and radiation-induced skin toxicity remains largely unexplored. Herein, we uncover the microbiota-skin interaction based on a genome-wide association study (GWAS) featuring 150 skin microbiota and three types of skin microenvironment. Summary datasets of human skin microbiota were extracted from the GWAS catalog database, and summary datasets of radiation-induced skin toxicity from the FinnGen biobank. Mendelian Randomization (MR) analysis was leveraged to sort out the causal link between skin microbiota and radiation-induced skin toxicity. We identified 33 causal connections between human skin microbiota and radiation-induced skin toxicity, including 19 positive and 14 negative causative directions. Among these potential associations, the genus Staphylococcus could serve as a common risk factor for radiation-induced skin toxicity, especially for radiodermatitis. And Streptococcus salivarius was identified as a potential protective factor against radiation-induced skin toxicity. Additional analysis indicated no pleiotropy, heterogeneity, or reverse causal relationship in the results. We comprehensively assessed potential associations of skin microbiota with radiation-induced skin toxicity and identified several suggestive links. Our results provide promising targets for the prevention and treatment of radiation-induced skin toxicity.

Methanol Leaf Extract of Voacanga Africana Protects Against Diethylnitrosamine and Carbon Tetrachloride-Induced Hepatotoxicity in Wistar Rats via Antioxidant and Anti-Inflammatory Activities

Background: Hepatotoxicity induced by chemical agents is a common and life-threatening disease that developed from acute or chronic exposure to environmental chemicals. Despite numerous approaches towards the treatment of liver toxicity, no safe and effective therapy exists. This study evaluated the antioxidative and anti-inflammatory effects of methanol leaf extract of Voacanga africana (VA) in diethylnitrosamine (DEN) and carbon tetrachloride (CCL4)-induced hepatotoxicity in rats. The animals were assigned into seven groups: Control, [DEN+CCL4], [DEN+CCL4] with VA (100, 200, 400 mg/kg), [DEN+CCL4] with Sorafenib (SFB), and SFB alone. Rats received DEN (200 mg/kg) once via i.p. and CCL4 (3 mL/kg) via subcutaneous route once in a week for six weeks. VA was administered orally from the second week until the 15th week. GC-FID analyses of VA revealed active components Voacinol, Voacangine, Amataine, and Ibogaine. [DEN+CCL4] caused a 26% increase in liver organo-somatic weight, which was reduced by 18%, 20%, and 9% with VA doses of 100, 200, and 400 mg/kg, respectively. [DEN+CCL4] also significantly increased serum gamma-glutamyl transferase, alanine, and aspartate aminotransferases by 55%, 25%, and 17%, and raised α-fetoprotein and total bilirubin levels by 2.0 and 2.5folds, respectively. Hepatic nitric oxide and myeloperoxidase activities were increased by 52% and 123%, respectively in the intoxicated rats. Additionally, malondialdehyde levels increased by 80% with decrease in glutathione peroxidase, glutathione-s-transferase, catalase and superoxide dismutase by 35%, 34%, 25% and 32%, respectively. Immunohistochemistry showed mild APC and strong Bcl-2 expression, while histology revealed severe hepatic necrosis. VA treatment mitigated oxidative stress, inflammation, and restored liver architecture.

Diagnosis and Management of Skin Toxicities in Systemic Treatment of Genitourinary Cancers.

The landscape of available therapeutic options for treatment of genitourinary (GU) cancers is expanding dramatically. Many of these treatments have distinct, sometimes severe, skin toxicities including morbilliform, bullous, pustular, lichenoid, eczematous, psoriasiform, and palmoplantar eruptions. Pruritus and skin pigmentation changes have also been noted. This review aims to synthesize dermatologic events observed with antibody drug conjugates, poly (ADP-ribose) polymerase (PARP) inhibitors, androgen receptor pathway inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and the combination of these agents used for the treatment of GU cancers. It provides a guide on diagnosis and initial management of these rashes for medical oncologists.

Cірководень: механізм токсичної дії, клінічні прояви гострого отруєння, патогістологічні ознаки та стратегія лікування

Hydrogen sulphide (H2S) is a highly toxic gas. Among this group of poisonous substances – causes of death – it is second only to carbon monoxide. The mechanism of its toxicity has not been sufficiently studied and there is currently no specific antidote therapy. This gas is a high-priority chemical threat in industry, as well as a potential terrorist weapon of mass destruction, especially in wartime. Aim. Based on literary data and own researches, to summarize the current concepts of its toxicity mechanisms, clinical manifestations, treatment strategies and pathohistological signs of acute hydrogen sulphide poisoning. Materials and Мethods. Open sources of public information and scientific literature on the research topic were analysed. An analytical review of the publications of scientific online libraries PubMed, Medline, Elsevier was carried out. A retrospective analysis of the medical documentation of two cases with acute poisoning with H2S in combination with other toxic gases was carried out. The first case of acute poisoning with H2S and other sewage gases is in a patient who died in the conditions of a medical institution in the Kyiv region, who fell ill after a 15-minute stay in a household sewage septic tank. In the victim, the data of sectional and microscopic studies of lung tissue were also studied. The second case of acute H2S poisoning in combination with other gases of putrefaction is represented by three victims hospitalized at the clinic of the Research Centre of Preventive Toxicology, Food and Chemical Safety named after L.I. Medved, Ministry of Healthcare of Ukraine after cleaning a deep tank with the remains of rotten sauerkraut. One of the victims died after 6 hours. The methods of system comparative and content analysis were applied. Results. Modern ideas about the mechanism of the toxic effect of H2S indicate that it is a rapidly metabolizing systemic toxicant that affects mitochondria, is the basis for the formation of tissue hypoxia, activation of oxidative stress, inflammatory reactions, and apoptosis. Under the acute effects of H2S, the main target organs are the nervous, bronchopulmonary and cardiovascular systems. Until now, there are no specific antidotes for the treatment of H2S poisoning, so it includes oxygen, symptomatic and supportive therapy. New therapeutic agents – potential antidotes are at the stage of preclinical research, most of which are aimed at binding H2S. There is an urgent need for the development of new therapeutic agents – absorbents (scavengers) of H2S for the prevention and treatment of poisoning, reducing morbidity and mortality. Keywords: hydrogen sulphide, toxicity, acute poisoning, treatment, pathohistological signs.

Hypericin-Mediated Photodynamic Therapy for Head and Neck Cancers: A Systematic Review.

Background: Conventional treatments for cancers of the head and neck region are often associated with high recurrence rates and impaired quality of life. Photodynamic therapy (PDT) has emerged as a promising alternative, leveraging photosensitizers such as hypericin to selectively target tumour cells with minimal damage to surrounding healthy tissues. Objectives: We aimed to evaluate the efficacy and underlying mechanisms of hypericin-mediated PDT (HY-PDT) in treating head and neck cancers. Methods: Adhering to PRISMA 2020 guidelines, a systematic search was conducted across PubMed/Medline, Embase, Scopus, and the Cochrane Library for studies published between January 2000 and December 2024. Inclusion criteria encompassed preclinical in vitro and in vivo studies and clinical trials focusing on HY-PDT for head and neck malignancies and its subtypes. Results: A total of 13 studies met the inclusion criteria, comprising both in vitro and in vivo investigations. HY-PDT consistently demonstrated significant cytotoxicity against squamous cell carcinoma cells through apoptotic and necrotic pathways, primarily mediated by ROS generation. Hypericin exhibited selective uptake in cancer cells over normal keratinocytes. Additionally, HY-PDT modulated the tumour microenvironment by altering cytokine profiles, such as by increasing IL-20 and sIL-6R levels, which may enhance antitumor immunity and reduce metastasis. Conclusions: HY-PDT emerges as a highly promising and minimally toxic treatment modality for head and neck cancers, demonstrating efficacy in inducing selective tumour cell death and modulating the immune microenvironment. Despite the encouraging preclinical evidence, significant methodological variability and limited clinical data necessitate further large-scale, standardized and randomized controlled trials.

Phase II Study of Nanoliposomal Irinotecan (Nal-IRI) with 5-Fluorouracil and Leucovorin in Refractory Advanced High-Grade Neuroendocrine Cancer of Gastroenteropancreatic (GEP) or Unknown Origin.

Neuroendocrine carcinomas (NECs) are treated with a frontline platinum-etoposide combination with no standard second-line therapies. We explored a novel combination of nanoliposomal irinotecan (Nal-IRI), 5-fluorouracil (5-FU), and leucovorin (LV) in advanced refractory NECs and investigated the impact of UGT1A1*28 polymorphism on treatment outcomes and toxicity. We conducted an open-label, single-arm, multi-center Phase 2 trial in advanced NEC patients of gastroenteropancreatic (GEP) or unknown origin with progression or intolerance to first-line therapy. Eligible patients received nal-IRI 70 mg/m2 and leucovorin 400 mg/m2, followed by 5-FU 2400 mg/m2 biweekly till disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Next-generation sequencing (NGS) was performed on blood/tissue samples at baseline and during treatment. Eleven patients were enrolled, with nine evaluable for the primary endpoint. Seven were male, the median age was 66.7 years, and the median Ki-67 was 90%. We observed partial response in one patient, stable disease in six patients, and progressive disease in two patients. The median OS was 9.4 months (95% CI 2.9-29.3), and the median PFS was 4.4 months (95% CI 1.7-6.7). The most common adverse events were diarrhea (45%), nausea (45%), vomiting (45%), and fatigue (45%). The most common genetic mutations on NGS were TP53 (88.9%), CHEK2 (88.9%), and APC (33.3%). Patients with CHEK2 and APC mutation had longer PFS (p = 0.005 and p = 0.013, respectively). UGT1A1*28 polymorphism was not associated with OS, PFS, or toxicity. Nal-IRI with 5-FU/LV is a safe and effective treatment for refractory high-grade NECs of GEP or unknown origin. Future studies should explore novel combinations with Nal-IRI in high-grade NECs both in frontline and refractory settings.

Long-term Outcomes of Definitive Chemoradiation with Proton Therapy for Treatment of Carcinoma of the Anal Canal: Combined Analysis of Two Prospective Trials.

While definitive chemoradiation (CRT) with 5-FU/MMC remains the standard of care for localized anal cancer, treatment is associated with significant acute and late toxicity. Proton radiation therapy (RT) may potentially reduce such toxicity. Here, we assess the long-term outcomes of anal cancer patients treated with CRT using proton RT in two prospective pilot studies. Patients with stage I-III anal cancer treated with proton RT (pencil beam scanning or intensity modulated proton therapy) per RTOG 0529 dose schema with concurrent 5-FU/MMC (2 cycles) in two prospective, single-arm trials were followed. Loco-regional failure (LRF), distant metastases (DM), colostomy-free survival (CFS), disease free survival (DFS), and overall survival (OS) were assessed. Physician-graded late toxicity (>90 days from CRT) was assessed per CTCAE v4.0. Late toxicities were compared with RTOG 0529 via Fisher's exact test. Patient-reported outcomes (PROs) were analyzed. Between 2013-2020, 39 patients were treated. 37 (95%) patients completed treatment per protocol. Median follow-up was 63 months. 5-year LRF, DM, CFS, DFS, and OS were 21%, 19%, 72%, 69%, and 75%, respectively. Worst late treatment toxicities were G1 in 38%, G2 in 24%, G3 in 19%, G4 in 3%, and no G5. Compared to RTOG 0529, rates of overall G2+ late toxicities were significantly lower (46% vs 75%, p=0.01), attributed to lower dermatologic toxicities (0% vs 25%, p<0.01), but there was no significant difference in overall G3+ toxicities (22% vs 20%, p=1.00). No statistically significant correlations between organ-at-risk dosimetry and late toxicities were noted. Available PROs demonstrated significant proportion of patients had persistent gastrointestinal symptoms at long-term. Definitive CRT with proton RT with concurrent 5-FU/MMC for the treatment of anal cancer resulted in comparable long-term disease control and grade 3+ late toxicities compared to RTOG 0529. Future studies should evaluate additional measures to minimizing treatment toxicity and subsets of patients who are most likely to benefit from proton RT.

Guanidines Conjugated with Cell-Penetrating Peptides: A New Approach for the Development of Antileishmanial Molecules.

Leishmaniasis is a neglected tropical disease caused by a protozoan of the genus Leishmania, which has visceral and cutaneous forms. The symptoms of leishmaniasis include high fever and weakness, and the cutaneous infection also causes lesions under the skin. The drugs used to treat leishmaniasis have become less effective due to the resistance mechanisms of the protozoa. In addition, the current compounds have low selectivity for the pathogen, leading to various side effects, which results in lower adherence to treatment. Various strategies were developed to solve this problem. The bioconjugation between natural compounds with antimicrobial activity and cell-penetrating peptides could alleviate the resistance and toxicity of current treatments. This work aims to conjugate the cell penetration peptide TAT to the guanidine GVL1. The GVL1-TAT bioconjugate exhibited leishmanicidal activity against Leishmania amazonensis and Leishmania infantum with a high selectivity index. In addition, the bioconjugate was more active against the intracellular enzyme CPP than the individual compounds. This target is very important for the viability and virulence of the parasite within the host cell. Docking studies confirmed the higher interaction of the conjugate with CPP and suggested that other proteins, such as trypanothione reductase, could be targeted. Thus, the data indicated that guanidines conjugated with cell-penetrating peptides could be a good approach for developing antileishmanial molecules.

Applied pharmacogenetics to predict response to treatment of first psychotic episode: study protocol.

The application of personalized medicine in patients with first-episode psychosis (FEP) requires tools for classifying patients according to their response to treatment, considering both treatment efficacy and toxicity. However, several limitations have hindered its translation into clinical practice. Here, we describe the rationale, aims and methodology of Applied Pharmacogenetics to Predict Response to Treatment of First Psychotic Episode (the FarmaPRED-PEP project), which aims to develop and validate predictive algorithms to classify FEP patients according to their response to antipsychotics, thereby allowing the most appropriate treatment strategy to be selected. These predictors will integrate, through machine learning techniques, pharmacogenetic (measured as polygenic risk scores) and epigenetic data together with clinical, sociodemographic, environmental, and neuroanatomical data. To do this, the FarmaPRED-PEP project will use data from two already recruited cohorts: the PEPS cohort from the "Genotype-Phenotype Interaction and Environment. Application to a Predictive Model in First Psychotic Episodes" study (the PEPs study from the Spanish abbreviation) (N=335) and the PAFIP cohort from "Clinical Program on Early Phases of Psychosis" (PAFIP from the Spanish abbreviation) (N = 350). These cohorts will be used to create the predictor, which will then be validated in a new cohort, the FarmaPRED cohort (N = 300). The FarmaPRED-PEP project has been designed to overcome several of the limitations identified in pharmacogenetic studies in psychiatry: (1) the sample size; (2) the phenotype heterogeneity and its definition; (3) the complexity of the phenotype and (4) the gender perspective. The global reach of the FarmaPRED-PEP project is to facilitate the effective deployment of precision medicine in national health systems.

Successful Management of Acetamiprid Intoxication in a Captive Eurasian Goshawk (Accipiter gentilis).

A captive, 1-year-old, male Eurasian goshawk (Accipiter gentilis) weighing 0.85 kg and owned by a falconer was presented with a history of acute onset of weakness, dyspnea, diarrhea, and regurgitation of a fresh-thawed pigeon contaminated with acetamiprid, an insecticide used in the raptor enclosure. The raptor had eaten the contaminated pigeon approximately 10-12 hours earlier. Two-view (lateral and ventrodorsal) full-body survey radiographs were taken, and no abnormalities were noted. A complete blood count and serum biochemistry panel showed increased concentrations of hematocrit, uric acid concentrations, and creatine kinase activity. Intravenous isotonic crystalloid fluids, oxygen supplementation, active warming, and assist feeding by oral syringe were provided. The bird rapidly improved approximately 12 hours after initiating supportive care. Complete resolution of clinical signs and return of normal appetite occurred within 2 days of hospitalization. No recurrence of clinical signs was reported in the raptor presented on 2 months' follow-up. The outcome of this case suggests that supportive treatment of acetamiprid toxicity in captive goshawks can be successful with early intervention.