Combined mTOR and MEK inhibition, critical components of the RAS effector pathway underlying the pathogenesis of NF1 related tumors caused regression in a malignant peripheral nerve sheath tumor (MPNST) transgenic mouse model. The primary objective was to determine the clinical benefit rate in patients with unresectable/metastatic MPNST. The study design was a multi-institutional open label Simon 2 stage phase 2 study of the MEK inhibitor selumetinib and mTOR inhibitor sirolimus. Patients ≥12 years with histologically confirmed MPNST received selumetinib 50mg twice daily and sirolimus 4mg once daily, in continuous 28-day cycles. Correlative studies evaluated patient-reported pain, immune signature in peripheral blood, and cell-free DNA (cfDNA). 21 heavily pretreated patients (7F; median age 41 y (range 16-72), 14 with NF1) with advanced disease enrolled at 5 participating sites. Clinical benefit was observed in only 1/7 in stage 1 and 1/14 in stage 2. The median number of cycles was 2 (range 1-6). Most common adverse events (AEs) were grade ≤2 gastrointestinal toxicity, acneiform rash, hypertriglyceridemia, mucositis, and transaminase elevation. Unlike the preclinical model, early 18FDG-PET scan performed during cycle 1 demonstrated partial metabolic responses in 5 patients (24%) but did not correlate with objective responses post cycle 2. cfDNA was able to detect MPNST with the potential to be a biomarker of response. The combination was safe with manageable and expected AEs, but did not meet study parameters for further evaluation in MPNST. Correlative studies were informative and may guide future therapeutic trials of MPNST.

Chemotherapeutic agents exert antineoplastic effects by damaging the DNA of cancer cells, leading to cell death. However, this effect is not specific, and may affect healthy cells and cause several adverse events such as myelosuppression and gastrointestinal mucositis. The term gastrointestinal mucositis refers to lesions in the mucosa, which include the oral cavity, pharynx, larynx, stomach, and intestine. The focus of this chapter will be the chemotherapy-induced intestinal damage, which can lead to weight loss, diarrhea, constipation, and increased predisposition to infections. Despite its severity, there is no treatment available for mucositis, and the pathophysiology of the disease has not been fully elucidated so far. This highlights the relevance of studying the mechanism of the disease and possible intervention strategies in intestinal mucositis. Here, we provide a detailed description of the main methodologies involved in the evaluation of changes induced by chemotherapy in a murine model, namely, 5-Fluorouracil (5-FU)-induced mucositis. These parameters include (i) assessment of body weight, (ii) stool consistency, (iii) fecal occult blood, and (iv) intestinal permeability. In addition, we describe a protocol to model opportunistic infection after chemotherapy, by exposing mice treated with 5-FU to Candida albicans in the drinking water.

Targeted deletion of Cyp24a1 in the intestine reduces mucosal injury and preserves epithelial proliferation after 5-fluorouracil treatment.

Abstract Febrile neutropenia is one of the major complications in patients receiving chemotherapy. In terms of the burden of disease, including mortality, hospital admissions, intensive care unit (ICU) admissions, and financial burden, febrile neutropenia plays a major role in patients receiving chemotherapy. The study aimed to evaluate the role of procalcitonin (PCT), Quick Sequential Organ Failure Assessment score, and the Multinational Association of Supportive Care in Cancer (MASCC) score in predicting mortality and ICU admission. A prospective observational study was performed at two tertiary oncology centers. Forty-seven adult patients diagnosed with chemotherapy-induced febrile neutropenia were enrolled over 12 months. Demographic, clinical, and laboratory data were collected for each patient. Admission risk scores (qSOFA, MASCC, and Clinical Index of Stable Febrile Neutropenia [CISNE]) as well as PCT levels were collected. Statistical analyses were conducted using SPSS v 26 and a p-value <0.05 was considered statistically significant. The majority of the cohort had solid malignancies (n = 30, 63.8%). Among culture-positive cases, 75% were infected with gram-negative organisms, followed by 25% with gram-positive organisms. The low and high risk scores for MASCC were found to be 57.4 and 42.6%, respectively. Respiratory rate, granulocyte colony-stimulating factor, systolic blood pressure, qSOFA, MASCC score, CISNE, oral mucositis, and gastrointestinal tract mucositis were significantly associated with mortality. Patients with PCT >1 ng/mL exhibited higher qSOFA and CISNE scores with p-values of 0.004 and 0.001, respectively, and lower MASCC scores (p = 0.005). PCT, qSOFA score, and MASCC score were effective in predicting mortality in patients with febrile neutropenia.

Background/Objectives: Despite significant advancements in cancer treatment outcomes, side effects, such as gastrointestinal mucositis (GIM), continue to impair patients’ quality of life. The recent literature suggests L-citrulline as a novel treatment for GIM. However, no in vitro model to study the potential for L-citrulline as a treatment for GIM is currently available, and the effect of L-citrulline on the gut microbiota remains unclear. This study aims to propose a suitable in vitro model to study the effect of L-citrulline on the gut microbiota and to determine whether it can mitigate GIM. Methods: The CaCo-2 and T84 cell lines were cultured using cell impedance assays and treated with different doses of methotrexate and melphalan to select an appropriate model for L-citrulline research. The selected model was further used to investigate the impact of L-citrulline on gut microbiota cultured using microbial culture assays containing YCFAG. Results: Neither CaCo-2 nor T84 cells treated with methotrexate were suitable models for our study due to varying responses to treatment. T84 cells treated with 100 μg/mL melphalan demonstrated a consistent response, making them a suitable model for in vitro research on treatments for GIM. The use of L-citrulline demonstrated potential protective effects, as melphalan-treated enterocytes showed less cellular damage in its presence and slightly reduced enteroaggregative E. coli growth. Conclusions: L-Citrulline supplementation reduced epithelial cell injury due to melphalan, suggesting therapeutic potential. Further testing is required to determine its efficacy in vivo and clarify the mechanisms underlying this potential benefit.

Exploration of key targets and mechanisms in radiotherapy-induced gastrointestinal mucositis: A systematic literature review

IntroductionMany chemotherapy agents used to treat advanced cancer are inherently mucotoxic, causing breakdown of the gastrointestinal mucosa (gastrointestinal mucositis (GI-M)) and lead to a constellation of secondary complications including diarrhoea,...

Acute Lymphoblastic Leukemia (ALL) is the most common pediatric malignancy, with survival rates exceeding 90% due to advancements in chemotherapy, including high-dose methotrexate (HD-MTX). However, gastrointestinal (GI) mucositis remains a significant complication, impairing treatment continuity and quality of life. Citrulline, a biomarker synthesized in enterocytes, reflects intestinal integrity and offers a non-invasive alternative for monitoring mucosal damage. This study aimed to evaluate citrulline dynamics in children with ALL undergoing HD-MTX chemotherapy during the consolidation phase. This cross-sectional study included 34 pediatric ALL patients in consolidation phase. Serum citrulline levels were measured pre- and post-HD-MTX chemotherapy using high-performance liquid chromatography. Mucositis severity was assessed using the National Cancer Institute Common Terminology Criteria. Data analysis involved paired t-tests and subgroup comparisons by risk stratification (Standard Risk [SR], High Risk [HR]) and mucositis grades. Overall, no significant changes in serum citrulline levels were observed post-chemotherapy. SR patients exhibited a significant decline in citrulline levels, consistent with mucosal injury. Conversely, HR patients demonstrated an unexpected increase in citrulline, potentially due to compensatory enterocyte responses or altered metabolism. Grade 1 mucositis patients showed increased citrulline levels, indicating early recovery, while grade 2 mucositis patients showed no significant changes, reflecting sustained injury. Citrulline is a promising biomarker for monitoring chemotherapy-induced GI mucositis in pediatric ALL patients. Its non-invasive measurement and correlation with mucosal health highlight its potential for improving personalized care. Further validation in diverse populations is required to optimize its clinical application.

Purpose: Gastrointestinal mucositis (GI-M) is the most common adverse effect of methotrexate (MTX). Gallic acid (GA) is a polyphenolic component rich in green tea, gall nuts, hops, grapes, and oak bark and has anti-inflammatory and antioxidant properties. The aim was to investigate the impact of GA on proinflammatory cytokines, expression level of hepatocyte growth factor (HGF) and C-met genes, and histopathological alterations of MTX-induced GI-M in rats. Methods: Twenty-four male Wistar rats were randomly divided into four groups: control, GA, MTX, and MTX + GA. Mucositis was induced in the experimental groups (MTX and MTX + GA) through three intradermal injections (the third to fifth days) of 2.5 mg/kg MTX in the suprascapular region. The GA group received 100 mg/kg GA via gavage, while the control group received normal saline by gavage (7 continuous days) and via intradermal injection (the third to fifth days) in the suprascapular region. The intestinal jejunal tissue and serum were analyzed for HGF and C-met mRNA expression, as well as levels of tumor necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β). In addition, a histopathological study was to eperformedvaluate the villi of mucosa and fibrosis of submucosal layers. Results: Decreased levels of HGF and C-met gene expression in the MTX group were significantly increased by GA administration (p < 0.05). GA administration decreased the elevated levels of TNF-α and IL-1β (p < 0.001) in the MTX group. Histopathological findings showed an adverse effect of MTX in mucosa which was relatively ameliorated in the MTX + GA ones. Conclusion: GA could increase HGF and C-met expression, decrease inflammatory cytokines, and improve histological injuries, affected by MTX, indicating a beneficial role for GA following GI-M.

The efficacy and safety of total marrow irradiation (TMI) plus a reduced dose of melphalan as autologous stem cell transplantation (ASCT) preconditioning for multiple myeloma (MM) patients were evaluated. The 11 patients with MM had a median age of 57 (range: 46–75) years; six of them were at standard risk and five of them were at high risk based on the Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART) standard risk factors. Before ASCT, three patients achieved stringent complete response (sCR), two patients achieved complete remission (CR), and the rest of the patients had either partial response (PR) or progressive disease. Most of the 11 patients were pretreated with melphalan 120–140 mg/m2 and TMI 12 Gy. The intravenous infusion median mononuclear cell count (MNC) was 8.13 (4.16–11.84) × 108/kg, and the median CD34+ count was 4.74 (2.51–21.98) × 106/kg. The minimal residual disease (MRD) in the grafts as determined by flow cytometry (FCM) and fluorescence in situ hybridization (FISH) were negative in 10 patients but positive in the progressive patient. All patients stopped maintenance therapy after transplantation, and further observation focused on the efficacy and tolerability of the transplantation. The neutropenic and thrombocytopenia durations were 11 (7–28) and 14 (8–70) days, respectively. The primary acute non-hematological toxicities were mild oral and gastrointestinal mucositis; there were no transplant-related deaths or serious complications. Of the eight patients who did not achieve sCR before transplantation, seven converted to sCR and one converted to VGPR after transplantation. The median follow-up period was 24 (10–57.5) months. Only one patient relapsed, and the progression-free survival (PFS) was 90.9%, while the overall survival (OS) was 100%. Our preliminary results suggest that melphalan 120–140 mg/m2 plus TMI 12 Gy/6f as a conditioning regimen is safe and efficient for patients with MM.

BackgroundThis study investigated the protective effects of verbascoside (VER) against 5-fluorouracil (5-FU)-induced gastrointestinal mucositis in Wistar albino rats.Methods and resultsThe study involved 30 female rats that were equally divided into five groups as follows: Control group, 5-FU group (400 mg/kg, IP), VER-only group (0.2 mg/kg, IP), 5-FU (400 mg/kg, IP) + VER (0.2 mg/kg, IP) group, and 5-FU (400 mg/kg, IP) + VER (0.4 mg/kg, IP) group. All animals were euthanized four days after 5-FU administration. Gastrointestinal tissues (esophagus, stomach, duodenum, jejunum, ileum, and colon) and blood sera were collected for histopathological and biochemical analyses. Tissue and sera analyses showed that 5-FU caused significant alterations marked by increases in matrix metalloproteinases (MMP-1, -2, -8), alkaline phosphatase (ALP), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) levels and decreases in tissue inhibitor of metalloproteinases-1 (TIMP-1), albumin, and total protein levels. VER treatment effectively attenuated these 5-FU-induced changes, with trends toward improved histological outcomes at higher doses.ConclusionThe findings strongly suggest that VER offers significant protection, and these results warrant further investigation into its potential clinical application as an adjunct therapy to mitigate gastrointestinal and other toxicities associated with 5-FU chemotherapy.

Introduction. Monitoring infectious complications during the programmed therapy of hematological malignancies remains a critical issue in modern hematology. Aim. To examine the frequency and nature of infectious complications in patients with multiple myeloma (MM) treated at the Irkutsk Regional Clinical Hospital from 2016 to 2023. Materials and methods. A total of 450 medical records of MM patients who underwent programmed chemotherapy (CT) from 2016 to 2023 were analyzed. Among these, 213 patients (47%) were diagnosed with various infectious complications. These patients were divided into two groups: Group 1 consisted of 100 patients who received CT from 2016 to 2019, while Group 2 included 113 patients treated from 2020 to 2023. Results. The most common infectious complications associated with MM were bacterial pneumonia (41% in 2016-2019 and 18% in 2020-2023), fever of unknown origin (20% in 2016-2019 and 22% in 2020-2023), urinary tract infections (20% in 2016-2019 and 8.8% in 2020-2023), cytomegalovirus (CMV) infection (9% in 2016-2019 and 18.5% in 2020-2023), and in 2020-2023, the emergence of novel coronavirus infection (observed in 17% of MM patients). The majority of infectious complications occurred during the remission induction phase. A significant decrease in bacterial pneumonia (p&lt;0.001) and urinary tract infections (p=0.020) was observed in 2020-2023 compared to 2016-2019, while an increase in CMV infection was noted (p=0.045). Other infectious complications, including gastrointestinal infections, mucositis, herpes infections, and skin and ENT infections, were infrequently reported during the study period. Conclusion. The study revealed new data that can be used to predict the development of infectious complications at various stages of programmed therapy for MM and to formulate effective preventive measures in clinical practice.

Pralatrexate injection combined with oral leucovorin for mucositis management in the treatment of peripheral and cutaneous T-cell lymphomas: results from a multicenter phase 2 trial

IntroductionCancer treatment with high-dose chemotherapy damages the mucosal barrier of the gastrointestinal (GI) tract and is associated with severe toxicity involving mucositis, severe inflammation and organ dysfunction. Currently, there is...

Management of chemotherapy-induced mucosal barrier damage and oral/anal mucositis in leukemia is challenging. The aim of this study was to investigate the effect of mucositis care training given to children receiving leukemia treatment and their caregivers on caregiver knowledge and skills, the development of gastrointestinal mucositis in children, the mean oral mucositis area in children, and the mucosal barrier injury laboratory-confirmed bloodstream infection in the clinic. A stepped-wedge, quasi-experimental, unpaired control group design was used. The participants in the control group were given routine training, and the intervention group members were given mucositis care training in accordance with the guideline recommendations. No significant difference was found between groups in developing anal mucositis, but a significant difference in developing oral mucositis was documented, with the mean mucositis area of children being 8.36 ± 3.97 cm 2 in the control group and 4.66 ± 2.90 cm 2 in the intervention group. The mucosal barrier injury laboratory-confirmed bloodstream infection ratio was 4 per 1000 catheter days in the control group and 3 per 1000 catheter days in the intervention group. Mucositis care training had a significant positive effect on caregivers' knowledge and skills, the development of oral mucositis, and the mean oral mucositis area in children. However, the training had no effect on the development of anal mucositis or the infection rate in the clinic. Nurses might increase the knowledge and skill levels of caregivers with training on mucositis care, prevent the development of mucositis, and reduce the mean mucositis area. Training might also contribute to the reduction in the infection rate of the clinic.

Selected phytocannabinoids inhibit SN-38- and cytokine-evoked increases in epithelial permeability and improve intestinal barrier function in vitro

Guidance on mucositis assessment from the MASCC Mucositis Study Group and ISOO: an international Delphi study

This focused, narrative review mostly describes our team's investigations into the potential inflammatory mechanisms that contribute to the development of cancer-related gastrointestinal (GI) mucositis and its associated symptoms. This review summarizes details of our clinical and preclinical findings to test the role of inflammation in the development and occurrence of these cancer-related conditions. GI mucositis (GIM) is a common, distressing condition reported by cancer patients. GIM is often clustered with other behaviors including fatigue, pain, anorexia, depression, and diarrhea. It is hypothesized that there is a common biologic mechanism underpinning this symptom cluster. Our multi-platform investigations revealed that GIM and its associated cluster of behaviors may be triggered by local inflammation spreading systemically causing pro-inflammatory-mediated toxicities, leading to alterations in immune, metabolic, and nervous system functions and activities. For example, behavioral toxicities related to local irradiation for non-metastatic cancer may be triggered by mGluR5 activation influencing prolonged T cell as well as NF-κB transcription factor activities. Thus, interventions targeting inflammation and associated pathways may be a reasonable strategy to alleviate GIM and its symptom cluster. GIM may be a sign of a broader systemic inflammatory response triggered by cancer or its treatment. Addressing GIM and its associated symptoms primarily involves supportive care strategies focused on relieving symptoms, promoting healing, and preventing complications.

Novel insights into gut health: Cilostazol strengthens gut integrity by adjusting TLR-2/NF-κB/IL-23 and CD44/AKT/GSK-3β/cyclin-D1 trajectories in methotrexate-induced mucositis model

Gastrointestinal mucositis (GIM) is a significant complication of cancer therapy. Whilst inflammation is a central feature of GIM, studies attempting to mitigate mucosal damage via this mechanism are scarce. This review describes the relation between GIM, local and systemic inflammation, and the microbiome and its metabolites, and explores recent research on therapeutics that target this relationship. Recent literature underscores the pivotal role of inflammation in GIM, elucidating its bidirectional relation with disturbance of the gut microbiota composition and intestinal permeability. These events cause a heightened risk of bloodstream infections and lead to systemic inflammation. While studies investigating risk prediction models or therapeutics targeting GIM-related inflammation remain scarce, results have shown promise in finding biomarkers and alleviating GIM and its accompanying clinical symptoms. The findings underscore the important role of inflammation and the microbiome in GIM. Understanding the inflammatory pathways driving GIM is crucial for developing effective treatments. Further research is needed using genomics, epigenomics, and microbiomics to explore better risk prediction models or therapeutic strategies aimed at mitigating GIM-related inflammation.