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PURPOSE: To evaluate VEGF-C-induced lymphoproliferation in conjunction with 5-fluorouracil (5-FU) antimetabolite treatment in a rabbit glaucoma filtration surgery (GFS) model. METHODS: Thirty-two rabbits underwent GFS and were assigned to four groups (n = 8 each) defined by subconjunctival drug treatment: (a) VEGF-C combined with 5-FU, (b) 5-FU, (c) VEGF-C, (d) and control. Bleb survival, bleb measurements, and IOP were evaluated over 30 days. At the end, histology and anterior segment OCT were performed on some eyes. mRNA was isolated from the remaining eyes for RT-PCR evaluation of vessel-specific markers (lymphatics, podoplanin and LYVE-1; and blood vessels, CD31). RESULTS: Qualitatively and quantitatively, VEGF-C combined with 5-FU resulted in blebs which were posteriorly longer and wider than the other conditions: vs. 5-FU (P = 0.043 for longer, P = 0.046 for wider), vs. VEGF-C (P

Background: Patients with platinum-refractory disease who experience early treatment failure of head and neck squamous cell carcinoma (HNSCC) exhibit a dismal prognosis. Metronomic chemotherapy is a promising treatment schedule in clinical practice for HNSCC. Oral metronomic chemotherapy with methotrexate, celecoxib, and capecitabine regimens was effective because of overcoming drug resistance and antiangiogenesis effects. We aimed to improve treatment outcomes of recurrent, platinum--resistant, and metastatic HNSCC. Method: In this prospective clinical trial, 94 patients diagnosed with advanced/recurrent HNSCC were enrolled. Patients received triple therapy, including capecitabine, methotrexate, and celecoxib. The multidisciplinary team evaluated treatment toxicity, response, progression-free survival (PFS), and overall survival (OS). Kaplan Meier curve was used to show the survival/Wilcoxon signed-rank test. Results: The most common observable toxicity findings were grade 1 plus grade 2 fatigue in 49 (52.1%), oral mucositis in 40 patients (42.5%), and anemia in 37 patients (39.4%) in the absence of notified grade 3 or 4 toxicities. 20 patients out of 94 exhibited complete responses (CRs). One and two-year PFS rates were 16% and 11.7%; and one and two-year OS were 21.3% and 17 %, respectively. Two median years PFS was 4 months, and two median years OS was 8 months (SPSS 16.0 for Windows, Wilcoxon signed-rank test, P value ≤ 0.05 is significant). Conclusion: Capecitabine, methotrexate, and celecoxib combined chemotherapy are effective and tolerable in treating platinum-refractory, recurrent, and metastatic HNSCC with non-inferior clinical outcome results, especially in poor societies. [ABSTRACT FROM AUTHOR]

Simple Summary: Capecitabine (CAP), belonging to the fluoropyrimidines class, is one of the most common drugs used in the treatment of colon cancer. In this study we cover the real-world impact of adverse effects, with focus on cardiotoxicity. The frequency of reports of cardiac toxicity in the EudraVigilance database was studied. Following the analysis, we observed that CAP and 5-FU can cause heart diseases, such as acute myocardial infarction, angina pectoris, heart failure, etc. From a physio-pathological point of view, coronary vasospasm, endothelial dysfunction and oxidative stress are the main factors in the production of cardiotoxicity induced by fluoropyrimidines. Capecitabine (CAP) is one of the most commonly prescribed fluoropyrimidines in oncology, especially in the treatment of colon cancer. Cardiac toxicity is a severe and potentially lethal adverse drug reaction (ADR) against fluoropyrimidines. Cardiac ADRs, such as myocardial infarction (MI), heart failure (HF), arrhythmias, and a number of cardiomyopathies, are reported for these molecules. To have a better understanding of the risk–benefit ratio of colon cancer therapy, a pharmacovigilance study of real-world evidence of the cardiac toxicity of antineoplastic agents is required. Aim: This post-marketing research on CAP aims to assess the risk of cardiac toxicity. Five other antitumor drugs used in colorectal cancer, i.e., 5-fluorouracil (5-FU), irinotecan (IRI), oxaliplatin (OX), bevacizumab (BEV) and panitumumab (PAN), were also studied to create a relative profile of observed cardiotoxicity. Methods: A retrospective study based on reports submitted in the EudraVigilance (EV) database until 28 July 2024 was conducted. Using the aggregated data from EV, a descriptive analysis and disproportionality analysis of cardiac ADRs induced by fluoropyrimidines were performed. To evaluate the disproportionality of the signals, Reporting Odds Ratio (ROR) and 95% confidence interval (95% CI) were calculated by comparison with other drugs used in colorectal cancer: 5-FU, IRI, OX, BEV, and PAN. Results: "Cardiac disorders" represent 3.4% of the total reports for CAP. The value is comparable to 5-FU, but higher than for other drugs. t was observed that there are no significant differences in the occurrence of cardiac ADRs in patients exposed to CAP and 5-FU treatments, and in particular MI and HF. Compared to 5-FU, which could produce cardiac arrythmias with a higher probability than all other drugs, CAP has a higher probability of reporting this ADR only in comparison with IRI (ROR: 1.2971; 95% CI: 1.0196-1.6502). Conclusions: CAP induces adverse cardiovascular reactions, especially MI, HF, and cardiomyopathies. Arrhythmias have been shown to be side effects more frequent associated with 5-FU than with CAP. The results emphasize the need for a rigorous cardiovascular monitoring of patients following treatment with CAP or 5-FU and especially for those with pre-existing cardiac pathology. [ABSTRACT FROM AUTHOR]

Background Biliary tract cancer (BTC) is a highly malignant tumor, with limited therapy regimens and short response duration. In this study, we aim to assess the efficacy and safety of the combination of camrelizumab, apatinib, and capecitabine as the first- or second-line treatment in patients with advanced BTC. Methods In this phase 2, nonrandomized, prospective study, eligible patients received camrelizumab (200 mg, d1, Q3W), apatinib (250 mg, qd, d1-d21, Q3W), and capecitabine (1000 mg/m², bid, d1-d14, Q3W) until trial discontinued. The primary endpoint was the objective response rate (ORR). The secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and safety. Results From July 2019 to April 2023, we enrolled a total of 28 patients, of whom 14 patients were in the first-line treatment setting and 14 patients were in the second-line setting. At the data cutoff (April 30, 2023), the median follow-up duration was 18.03 months. Eight of 28 patients reached objective response (ORR: 28.57%), with an ORR of 50% and 7.1% for first-line and second-line treatment patients (P  = .033). The median PFS was 6.30 months and the median OS was 12.80 months. Grade 3 or 4 adverse events (AEs) occurred in 9 (32.14%) patients, including elevated transaminase, thrombocytopenia, etc. No serious treatment-related AEs or treatment-related deaths occurred. Conclusions In this trial, the combination of camrelizumab, apatinib, and capecitabine showed promising antitumor activity and manageable toxicity in patients with advanced BTC, especially in the first-line setting. Clinical Trial Registration NCT04720131. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) uses the Leloir pathway to catabolize D-Galactose (Gal) for tumor growth. Selective targeting of the Leloir pathway with Gal-based antimetabolites has potential for the treatment of GBM. Here, we tested the effect of a Gal-based antimetabolite, 4-deoxy-4-fluorogalactose (4DFG) on the viability and metabolism of GBM cells in culture. 4DFG is a good Glut3/Glut14 substrate and acts as a potent glioma chemotherapeutic. GBM cell cultures were used to examine toxicity and alterations in glycan composition. 4DFG is moderately potent against GBM cells in vitro (IC50: 125–300 µM). Glycosylation in GBM was disrupted by 4DFG. The effect of 4DFG on D-glucose (Glc) metabolism in GBM cells was assessed by using 13C NMR-based tracer studies. 13C-NMR-based metabolic flux analysis revealed that both glycolytic and mitochondrial metabolic fluxes of [U-13C]Glc were significantly decreased in the presence of 4DFG in GBM cells. Survival analysis in an intracranial mouse model during treatment with 4DFG (6 × 25 mg/kg of 4DFG, intravenously) showed improved outcomes by three-fold (p < 0.01). 4DFG is metabolized by GBM in vitro and in vivo, and is lethal to GBM tumors, but well tolerated in mice. A functional Gal-scavenging pathway in GBM allows Gal-based antimetabolites to act as chemotherapeutics. Background: Glioblastoma (GBM) uses Glut3 and/or Glut14 and the Leloir pathway to catabolize D-Galactose (Gal). UDP-4-deoxy-4-fluorogalactose (UDP-4DFG) is a potent inhibitor of the two key enzymes, UDP-galactose-4-epimerase (GALE) and UDP-Glucose 6-dehydrogenase (UGDH), involved in Gal metabolism and in glycan synthesis. The Gal antimetabolite 4-deoxy-4-fluorogalactose (4DFG) is a good substrate for Glut3/Glut14 and acts as a potent glioma chemotherapeutic. Methods: Primary GBM cell cultures were used to examine toxicity and alterations in glycan composition via lectin binding in fixed cells and by Western blots. Toxicity/efficacy in vivo data was performed in mouse flank and intracranial models. The effect of 4DFG on D-glucose (Glc) metabolism in GBM cells was assessed by using 13C NMR-based tracer studies. Results: 4DFG is moderately potent against GBM cells (IC50: 125–300 µM). GBM glycosylation is disrupted by 4DFG. Survival analysis in an intracranial mouse model showed that treatment with 4DFG (6 × 25 mg/kg of 4DFG, intravenously) improved outcomes by three-fold (p < 0.01). Metabolic flux analysis revealed that both glycolytic and mitochondrial metabolic fluxes of [U-13C]Glc were significantly decreased in the presence of 4DFG in GBM cells. Conclusion: A functional Gal-scavenging pathway in GBM allows Gal-based antimetabolites to act as chemotherapeutics. 4DFG is metabolized by GBM in vitro and in vivo, is lethal to GBM tumors, and is well tolerated in mice. [ABSTRACT FROM AUTHOR]

Background: Leukocytoclastic vasculitis (LCV) is a vasculitic inflammation against blood vessels. Various anticancer therapies can cause vasculitis, but capecitabine-induced LCV is an unusual entity. Here, we describe an LCV case associated with neoadjuvant capecitabine use for locally advanced rectal cancer (LARC). Case report: A 70-year-old man presented with rectal bleeding. A colonoscopic biopsy revealed rectal adenocarcinoma and he was diagnosed with LARC after imaging studies. Capecitabine plus radiation therapy was started as a neoadjuvant treatment. Management and outcome: Seven days after the first capecitabine dose, the patient was admitted with a rash. The LCV diagnosis was histopathologically proven. Capecitabine was withheld. After the patient's rash began to regress under corticosteroid pressure, capecitabine was started at a lower dose. His treatment was completed successfully with oral corticosteroids plus low-dose capecitabine. Discussion: We aimed to point out a rare and unusual adverse effect of a frequently used drug in oncologic practice. [ABSTRACT FROM AUTHOR]

Objective: Textbook outcome (TO) is widely recognized as a comprehensive prognostic indication for patients with gastric cancer (GC). This study aims to develop a modified TO (mTO) for elderly patients with GC. Methods: Data from the elderly patients (aged ≥ 65 years) in two Chinese tertiary referral hospitals were analyzed. 1389 patients from Fujian Medical University Union Hospital were assigned as the training cohort and 185 patients from Affiliated Hospital of Putian University as the validation cohort. Nomogram was developed by the independent prognostic factors of Overall Survival (OS) based on Cox regression. Results: In the training cohort, laparoscopic surgery was significantly correlated with higher TO rate (P < 0.05). Cox regression analysis revealed that surgical approach was also an independent factor of OS (P < 0.001), distinct from the traditional TO. In light of these findings, TO parameters were enhanced by the inclusion of surgical approach, rendering a modified TO (mTO). Further analysis showed that mTO, tumor size, pTNM staging, and adjuvant chemotherapy were independent prognostic factors associated with OS (all P < 0.05). Additionally, the nomogram incorporating these four indicators accurately predicted 1-, 3-, and 5-year OS in the training cohort, with AUC values of 0.793, 0.814, and 0.807, respectively, and exhibited outstanding predictive performance within the validation cohort. Conclusion: mTO holds a robust association with the prognosis of elderly patients with GC, meriting intensified attention in efforts aimed at enhancing surgical quality. Furthermore, the predictive model incorporating mTO demonstrates excellent predictive performance for elderly patients with GC. [ABSTRACT FROM AUTHOR]

Purpose: The effectiveness of mitomycin C (MMC) in trabeculectomy has long been established. The aim of this review is to evaluate the efficacy and safety of adjunctive agents in tube shunt drainage device surgery for glaucoma or ocular hypertension, since controversy still exists regarding their benefit. Methods: We searched CENTRAL, PubMed, Embase, Web of Science, Scopus, and BASE for RCTs, which have used adjuvant antimetabolites—either MMC or 5-Fluorouracil (5-FU)—and/or anti-vascular endothelial growth factors (anti-VEGF) agents. The main outcome was IOP reduction at 12 months. Results: Ten studies met our inclusion criteria. Nine used the Ahmed Glaucoma Valve (AGV) implant, while the double-plate Molteno implant was used in one study. Four studies used MMC. The remaining six studies used an anti-VEGF drug – either bevacizumab, ranibizumab or conbercept. Only one MMC-study reported a significant difference in the IOP reduction between groups at 12 months, favouring the MMC group (55% and 51%; p < 0.01). A significant difference was also reported by two out of five bevacizumab-studies, both favouring the bevacizumab group (55% and 51%, p < 0.05; 58% and 27%, p < 0.05), with the highest benefit seen in neovascular glaucoma cases, especially when panretinal photocoagulation (PRP) was also used. Neither ranibizumab nor conbercept were found to produce significant differences between groups regarding IOP reduction. Conclusion: There is no high-quality evidence to support the use of MMC in tube shunt surgery. As for anti-VEGF agents, specifically bevacizumab, significant benefit seems to exist in neovascular glaucoma patients, especially if combined with PRP. [ABSTRACT FROM AUTHOR]

Background: The prevalence of multi-drug-resistant E. coli isolates is on the increase around the world. This study was designed to evaluate the antimicrobial activity of Tetrapleura tetraptera (Uyayak) fruit bioactive compounds against E. coli using an in silico approach. Methods: Gas chromatography coupled to mass spectrophotometry (GC-MS) was used to identify the bioactive compounds in our sample T. tetraptera. The resulting bioactive compounds from GC-MS were converted into canonical strings and used for target and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties predictions using the pkCSM and SWISSADME tools, respectively. Bioactive compounds that met Lipinski's rule of five (ROF) were docked against the dihydropteroate synthase of E. coli using the AutoDock Vina tool, and the resulting interactions were visualized in 2-D using Biovia Discovery Studio 21. Results: The GC-MS analysis returned a total of twenty-eight (28) bioactive compounds, out of which 13 did not violate Lipinski's ROF. ADMET analysis of the screened bioactive compounds showed better absorption (intestinal and water solubility) and toxicity (AMES and hepatoxicity) profiles than trimethoprim, the control drug. Molecular docking gave docking scores that ranged from −4.0 to −5.3 kcal/mol for the bioactive compounds while that of trimethoprim was −6.5 kcal/mol. Target prediction showed that all the bioactive compounds are capable of reaching various targets, with the nuclear receptor being the most abundant target. Conclusion: The bioactive compounds of T. tetraptera fruits examined showed favorable docking scores and pharmacokinetics, suggesting the need for further studies to validate their potential as antimetabolites. [ABSTRACT FROM AUTHOR]

Objectives: As the world population ages, the incidence of gastric cancer is increasing. This study aimed to compare the efficacy and adverse events of 5-Fluorouracil (5-FU)- and capecitabine-containing regimens in geriatric gastric cancer patients. Methods: Our study included 258 geriatric patients with relapsed or metastatic gastric cancer at the time of diagnosis who were treated with 5-FU-or capecitabine-containing regimens in the oncology clinic of Van Yüzüncü Yıl University Faculty of Medicine between January 2006-December 2019. The patients were divided into two groups: patients receiving 5-FU-containing regimens and those receiving capecitabine-containing regimens. Medical records of the patients (demographical and clinical characteristics) were analyzed using appropriate statistical methods. Results: A total of 258 patients (181 men and 77 women) were enrolled in the study. 96 patients were treated with capecitabine and 162 patients were treated with 5-FU-containing regimens. There was no statistically significant difference in median OS and PFS between the 5-FU and capecitabine groups (p>0,05). Grade 3-4 neutropenia, grade 3-4 anemia, grade 3-4 thrombocytopenia, and febrile neutropenia were more frequent in the 5-FU group (p<0.05). Conclusion: Capecitabine was as effective as 5-FU. It is also more tolerable in terms of side effects than 5-FU containing regimens. [ABSTRACT FROM AUTHOR]

PURPOSE: High-dose methotrexate (HD-MTX) is the backbone of curative therapy for CNS lymphoma. Because of toxicity, MTX is administered in the inpatient setting along with hyperhydration and monitoring until MTX clearance is documented (3-5 days). Frequent hospitalizations result in patient time away from work, home, and exposure to potential iatrogenic/nosocomial complications. Here, we aim to demonstrate feasibility of HD-MTX administration in the outpatient setting with low-dose glucarpidase facilitating clearance. METHODS: This is a prospective nonrandomized study of outpatient HD-MTX followed by glucarpidase 2000u (ClinicalTrials.gov identifier: NCT03684980). Eligible patients had CNS lymphoma, creatinine <1.3 mg/dL, and previously tolerated HD-MTX. Patients were enrolled between May 2020 December 2021 for one HD-MTX treatment. Patients could re-enroll for subsequent doses of HD-MTX as eligibility and slots permitted. MTX 3.5 g/m2 was administered once over 2 hours, preceded by standard hydration and followed by an additional 2 hours of dextrose 5% in water with NaHCO3 75 mEq at 150 cc/h. Glucarpidase 2000u was administered once in the clinic 24 hours later. The primary end point was MTX level 48 hours after HD-MTX. RESULTS: Twenty doses of outpatient HD-MTX with glucarpidase were administered to seven patients. After 20 of 20 (100%) treatments, serum MTX levels were reduced to <100 nmol/L. Treatments were well-tolerated, and no admissions were required. One patient received additional outpatient hydration for elevated creatinine. Development of antiglucarpidase antibody was rare and did not affect treatment. CONCLUSION: Outpatient HD-MTX with glucarpidase is safe and well-tolerated and has the potential to alter standard treatment for CNS lymphoma. CNS lymphoma patients received glucarpidase to avoid hospitalization for MTX therapy. [ABSTRACT FROM AUTHOR]

Summary: Obstacles facing chemotherapeutic drugs for cancers led scientists to load Gemcitabine (GEM) into nanocarriers like liposomes, known for their nontoxicity profile and targeting capacity. The liposomal nanostructures containing GEM were coated with Fucoidan (FU) due to its anti-tumor properties by targeting cancer cells. Thus four different cationic liposomes formulations were prepared by thin-film hydration method in optimal conditions: DOTAP (formulation A); DPPC/DOTAP (4:1 molar ratio, formulation B), DPPC/DMPC/DOTAP (4:1:1 molar ratio, formulation C) and DPPC/DMPC/DOTAP/DSPE-mPEG2000 (4:1:1:0.1 molar ratio, formulation D). They were studied to identify lipid-compositions offering effective GEM-entrapment and successful coating of FU on the liposome surface. Additional qualitative characteristics, such as particle size, polydispersity index, zeta potential, stability and in vitro drug release were then evaluated. Formulation C gave the best GEM-entrapment efficiency (EE) but formed aggregates when coated with FU, giving non-homogenous large size particles then not suitable for effective delivery. It was the same situation with formulation A and B. Only the formulation D showed a good GEM-EE (> 80%) and affinity by successful coating FU from three different algae species. The PEGylated formulation D coated of FU, with regard to storage stability and drug release studies, revealed to be a promising approach on design of optimal drug delivery system. [ABSTRACT FROM AUTHOR]

Background: The cost-effectiveness of NALIRIFOX as a potential new standard of care for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) has yet to be established. Our objective was to evaluate the cost-effectiveness of NALIRIFOX vs. nab-paclitaxel and gemcitabine in this indication from the perspective of U.S. public payers. Methods: A partitioned survival model was constructed from the perspective of U.S. public payers, drawing on baseline patient characteristics and vital clinical data from the NAPOLI-3 trial. Costs and utilities were sourced from publicly accessible databases and literature. A lifetime horizon was applied, with an annual discount rate of 3%. We calculated and compared cumulative costs, life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER). To evaluate the model's robustness, sensitivity analyses, scenario analyses, and subgroup analyses were carried out. Additionally, a price simulation for the costly liposomal irinotecan was conducted to inform the pricing strategy at the given willingness to pay (WTP) threshold. Results: In the base-case analysis, NALIRIFOX provided an additional 0.29 QALYs with an ICER of $206,340.69 /QALY compared to nab-paclitaxel and gemcitabine, indicating it is not cost-effective at a $150,000/QALY threshold. Sensitivity analysis showed the model was most sensitive to the costs of liposomal irinotecan, capecitabine, and post-progression care. Probabilistic sensitivity analysis indicated a 17.66% probability of NALIRIFOX being cost-effective at $150,000/QALY, rising to 47.48% at $200,000/QALY. Pricing simulations suggested NALIRIFOX could become cost-effective at $150,000/QALY if the price of irinotecan liposome drops to $53.24/mg (a 14.8% reduction). Conclusions: NALIRIFOX may not be cost-effective at its current price as a first-line treatment for patients with mPDAC in the long term. The cost of liposomal irinotecan has the greatest impact. It may become cost-effective only if its cost is reduced by 14.8%, with a WTP threshold of $150,000 /QALY. [ABSTRACT FROM AUTHOR]

Introduction: Fluorouracil (5FU) and capecitabine are metabolised by dihydropyrimidine dehydrogenase (DPD). Up to 9% of people have low levels of a working DPD enzyme and are at risk of severe toxicity from 5FU/capecitabine. In April 2020, the EMEA recommended patients undergo prospective screening for DPD deficiency before starting treatment, and this was introduced in our hospital. Methods: We retrospectively reviewed records of all patients receiving 5FU/capecitabine in a tertiary Irish cancer centre from May 2020 to April 2021 (n = 197), and those starting first-line treatment in May 2019–April 2020 (n = 97). Our primary outcome was to estimate the prevalence of DPYD variant genes by prospective genotypic screening, with secondary outcomes including variant prevalence by prospective and reactive screening in patients receiving first-line treatment, and 5FU toxicity/tolerability in those with detected variants. Results: In those treated 2020–2021, cancer subtypes included colorectal (n = 120, 61%), breast (n = 34, 17%), and biliary/pancreatic cancers (n = 21, 11%). Median patient age was 62 (range 25–86 years); 40% (n = 79) of patients were screened overall, with a prospective-screening deficiency prevalence of 6.8% (n = 3 of 44). Three patients had pathogenic DPYD-variants detected by prospective screening and tolerated treatment with 50% up-front dose reduction of 5FU, two had variants of uncertain significance detected by reactive screening. Discussion: Other Irish studies estimated prevalence at 11–12%. As the number of variants detected was small, and screening rates were incomplete, our study may have underestimated prevalence. Conclusions: Approximately 6.8% of Irish patients may carry DPD deficiencies, prospective screening is essential to reduce the risk of life-threatening toxicity in these patients. [ABSTRACT FROM AUTHOR]

Background: Despite common global usage, fluoropyrimidine (FP; 5‐flurouracil and capecitabine)‐related chemotherapy toxicity is poorly reported in the literature, with serious toxicity ranging from 10% to 40% and early toxicity (within 60 days of exposure) quoted at 14%. Data reflecting the incidence of Grades 3–5 FP‐related toxicity in Australian cancer patients is scant, despite the significant impact of toxicity on patients (hospitalisations, intensive care unit (ICU) admissions and even death). Aims: This retrospective audit evaluated Grades 3–5 toxicities in a contemporaneous cohort of 500 patients receiving FP chemotherapies within the Hunter‐New England Local Health District from June 2020 to June 2022. Data were extracted from public hospital records and oncology‐specific e‐records to determine rates of toxicity and associated hospitalisations, intensive care admissions and deaths that occurred within 60 days of first exposure to FP chemotherapy‐containing regimens. Results: One hundred and fifty incidents of Grades 3–4 toxicity in the first 60 days led to 87 patients presenting to hospital (87/500, 17.4%). The most common serious toxicities were diarrhoea (39.3%), nausea and vomiting (22.7%) and febrile neutropaenia (10%). Four patients were admitted to the ICU, and four patients died of toxicity. Within the first 60 days, 22.2% of patients required treatment delays, 21.4% required dose reductions, and 7.8% of patients ceased treatment because of toxicities. Discussion and Conclusion: Our experience reflects international reports and is likely generalisable to the Australian population. These data are a basis to understand the potential benefits of precision medicine strategies such as pharmacogenomic screening to improve patient tolerability and the cost‐effectiveness of FP chemotherapy prescribing. [ABSTRACT FROM AUTHOR]

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Objective To review how different classes of immunosuppressants affect wound healing. Data Sources A literature search was conducted in PubMed, Google Scholar, and the University of Calgary Health Sciences Library. Study Selection The researchers initially screened article titles using key words such as "immunosuppressive medication," "wound healing," and "immunosuppression." Articles in which the title and/or abstract contained these key words, that addressed wound healing related to immunosuppressant medications, and were published after 2000 were included in the review. When human data were not available for an immunosuppressant (class), animal studies were included. Data Extraction The 61 included articles underwent full text review and summarization. Data Synthesis: All included studies were summarized descriptively including immunosuppressive mechanism of action, study participants or subjects, and evidence of effects on wound healing. Conclusions Corticosteroids and mechanistic target of rapamycin inhibitors most consistently demonstrate detrimental effects on wound healing. For other classes of immunosuppressants, evidence is limited with varying effects on wound healing described. Larger, high-quality studies are required to better understand the effects of immunosuppressants, including those with new mechanisms of action, to identify those with the most impact on wound healing. [ABSTRACT FROM AUTHOR]

Little has been written about the challenges in wound healing presented by rare cases of dermatomyositis (DM) complicated by glucocorticoid use. The authors explore the clinical presentation of a 60-year-old female patient with end-stage DM, chronic steroid use and delayed wound healing, requiring surgical debridement of wounds and extensive calcification removal. Her atypical presentation—lacking some of the characteristic dermal and antibody findings—is described, while also highlighting calcification and wound trials that complicated management. The underlying pathophysiology of effects on capillary networks is discussed, as well as the effectiveness of various treatment modalities, including steroids, antimetabolites and biologics, some of which were used. The report concludes with opportunities for future study on the disease's complex mechanisms. [ABSTRACT FROM AUTHOR]

Simple Summary: Pseudocirrhosis is a nodularity in the liver that it is typically associated with breast cancer liver metastases, and may occur as a response to chemotherapy and other systemic anticancer treatments. The types of patients who develop pseudocirrhosis, the treatments that they have received, and their outcomes are not well known. This study reviewed 170 patients with a diagnosis of pseudocirrhosis. A variety of different anticancer treatments were received, with taxanes (74.7%) and capecitabine (67.1%) being the most common. The median time between diagnosis of liver metastases and diagnosis of pseudocirrhosis was 17.1 months. The median overall survival once diagnosed with pseudocirrhosis was 7.6 months and patients with HER2+ disease had a statistically significant longer overall survival. To our knowledge, this is the largest dataset of pseudocirrhotic patients that has been published. It provides information to patients and clinicians on risk factors to develop pseudocirrhosis, and prognosis in different subtypes. Pseudocirrhosis is a diffuse nodularity of the liver that radiologically mimics cirrhosis but is a distinct pathological process. It is seen almost exclusively in patients with liver metastases and may represent a response to systemic treatment. Data on the risk factors for pseudocirrhosis and outcomes are limited. In total, 170 patients with a diagnosis of breast cancer and pseudocirrhosis in a 10-year period were identified and retrospectively analysed. Data were collected on baseline patient characteristics, treatments received, and outcomes. Median time between diagnosis of liver metastases and diagnosis of pseudocirrhosis was 17.1 months (range, 0–149 months). In total, 89.4% of patients received chemotherapy between their diagnosis of breast cancer liver metastases and their diagnosis of pseudocirrhosis, most commonly a taxane (74.7%) or capecitabine (67.1%), and the median treatment lines received was 3. Median OS from first diagnosis of pseudocirrhosis was 7.6 months (95% CI: 6.1–9.6 months) and was longer in patients with HER2+ disease at 16.7 months (95% CI: 6.4–32.9 months), which was statistically significant. In our study, pseudocirrhosis occurred in the presence of liver metastases and was associated with a poor prognosis. HER2+ patients with pseudocirrhosis had a better prognosis than other subtypes, but we did not identify other significant predictors of survival. Chemotherapy was not a prerequisite for pseudocirrhosis development, although the majority of patients had received at least one line of chemotherapy before pseudocirrhosis was diagnosed. [ABSTRACT FROM AUTHOR]

Introduction: This is the first report of a patient who developed cardiogenic shock after receiving oral chemotherapy with capecitabine and was treated with venoarterial extracorporeal membrane oxygenation combined with continuous renal replacement therapy. Clinical Findings: A 58-year-old man developed an arrhythmia that rapidly progressed to cardiogenic shock and cardiac arrest after receiving oral capecitabine tablets to treat a rectal malignancy. Interventions: The patient was treated with venoarterial extracorporeal membrane oxygenation in combination with continuous renal replacement therapy. Outcome: The patient made a full recovery and was discharged from the hospital. Conclusion: The use of comprehensive supportive treatments such as extracorporeal membrane oxygenation combined with continuous renal replacement therapy in patients with capecitabine-induced cardiac arrest can rapidly reduce drug concentrations, eliminate harmful substances, and improve the prognosis. [ABSTRACT FROM AUTHOR]

In this study, we retrospectively analysed the efficacy and safety of three treatment models, namely, short-course radiotherapy sequential XELOX chemotherapy, neoadjuvant mFOLFOX6 concurrent radiotherapy and long-course concurrent radiotherapy with total mesorectal excision (TME) after treatment of locally advanced rectal cancer with high-risk factors. We collected clinical data on 177 patients with locally advanced rectal cancer (cT3-4 and/or cN+) who were treated at the Department of Abdominal Oncology of the Affiliated Cancer Hospital of Guizhou Medical University from December 2017 to December 2022. All patients were associated with 2-3 risk factors [T4b, N2, Extramural Vascular Invasion (EMVI), Mesorectal Fascia (MRF) positivity], positive lateral lymph nodes. Among them, there were 45 cases in the short course radiotherapy sequential XELOX chemotherapy group (RT + XELOX group); 64 cases in the neoadjuvant mFOLFOX6 concurrent radiotherapy group (mFOLFOX6 + CRT group); and 68 cases in the long course concurrent radiotherapy group (CRT group). The RT + XELOX group and mFOLFOX6 + CRT group completed radiotherapy and 4 cycles of neoadjuvant chemotherapy, respectively, and then rested for 1-2 weeks before TME surgery; the CRT group completed concurrent radiotherapy and then rested for 6-8 weeks before TME surgery.Adjuvant chemotherapy was conducted after surgery in each of the three groups: 2 cycles of adjuvant chemotherapy with XELOX regimen in the RT + XELOX group, 4-6 cycles of adjuvant chemotherapy with mFOLFOX6 in the mFOLFOX6 + CRT group, and 8-12 cycles of adjuvant chemotherapy with mFOLFOX6 in the CRT group.The pathological complete response rate (pCR rate), tumour downstage rate, tumour complete resection rate (R0 resection rate), local recurrence rate, distant metastasis rate, overall survival rate, incidence of adverse reactions, surgical complications and completion rate of perioperative systemic chemotherapy were compared among patients in the three groups of cases after TME. The pCR rate (21.95% vs 17.24% vs 5.00%, p = 0.034) and and tumour downstage rate (78.05% vs 68.97% vs 53.33%, p = 0.029) were higher in the RT + XELOX group and mFOLFOX6 + CRT group compared to the CRT group. The RT + XELOX group had a lower 3-year distant metastasis rate (14.63% vs 36.67%, p = 0.048) and improved 3-year overall survival (76.57% vs 48.56%, p < 0.001) compared to the CRT group. There was no significant reduction in the 3-year distant metastasis rate in the mFOLFOX6 + CRT group versus the CRT group (27.59% vs 36.67%, p = 0.719), and the 3-year overall survival was similar (51.23% vs 48.56%, p = 0.35). Multi-logistic regression analysis and stratified analysis showed that patients in the RT + XELOX group and mFOLFOX6 + CRT group were more likely to achieve pCR than the CRT group (RT + XELOX group: OR 7.3, 95% CI [2.6-20.8], p < 0.001; mFOLFOX6 + CRT group OR 2.9, 95% CI [1.1-7.9], p = 0.036). The completion rates of perioperative systemic chemotherapy in the RT + XELOX, mFOLFOX6 + CRT, and CRT groups were 82.93% vs. 84.48% vs. 61.67% (χ2=9.95, p = 0.007), respectively. And there were significant differences in grade 3-4 leukopenia and thrombocytopenia (incidence of leukopenia: 15.50% vs. 7.81% vs. 1.47%, p = 0.045; incidence of thrombocytopenia: 13.33% vs 7.81% vs 1.47%, p = 0.027). There was no significant difference in the incidence of intraoperative and postoperative complications among the three groups (p > 0.05). RT + XELOX group and mFOLFOX6 + CRT group significantly improved the near-term outcome (e.g., pCR rate) in patients with locally advanced rectal cancer with high-risk factors compared with CRT group. The RT + XELOX group also reduced the 3-year distant metastasis rate, increased the 3-year overall survival rate, and did not increase the incidence of perioperative surgical complications. It provides an effective means for the comprehensive treatment of locally advanced rectal cancer and has important clinical guidance and application value. [ABSTRACT FROM AUTHOR]

PURPOSE: Several allelic variants of the gene DPYD encoding dihydropyrimidine dehydrogenase (DPD) are associated with impaired metabolism of the systemic fluoropyrimidine fluorouracil (5FU) and its oral prodrug, capecitabine, which elevates the risk for severe toxicity. Following a patient death related to capecitabine toxicity in which DPD deficiency was suspected, a multidisciplinary advisory panel was convened to develop an institution-wide approach to future patients planned for a systemic fluoropyrimidine. METHODS: The panel selected an opt-out testing strategy which focused on developing reliable processes to collect and report test results and targeted education. An electronic health record–based automated reminder was designed to activate when a 5FU- or capecitabine-containing chemotherapy regimen was ordered for a patient without prior exposure to either agent and without a prior DPYD sequencing test result. DPYD testing was standardized across all sites of care, and a closed loop reporting system for abnormal test results was created. Before implementation, targeted education was provided to providers, pharmacists, and nurses, and a failure mode and effects analysis was performed. Program rollout was staged over a 6-month period. RESULTS: At 10 months, the rate of preemptive testing increased from a baseline of 26% to a sustained rate of >90%. In the six network sites, the testing rate increased from 9% to 96%. A total of 1,043 patients have been tested preemptively; allelic variants have been identified in 43 (4.1%). Among 25 evaluable patients, dose reduction or change to a non–fluoropyrimidine-based regimen was accomplished in 96%. CONCLUSION: Preemptive DPYD testing is feasible, and high rates of testing can be achieved using an opt-out, reminder-based program. We provide the details of the implementation and encourage others to emulate it. [ABSTRACT FROM AUTHOR]

Chemotherapeutic drugs have demonstrated effectiveness in treating various neoplastic conditions; however, they can also have detrimental effects on male gonadal function and fertility. Consequently, interest has grown in identifying novel approaches that can mitigate chemotherapy-induced testicular damage. Thymoquinone (TQ), the chief active component of the volatile oil of Nigella sativa (NS), has a wide range of therapeutic properties, including antioxidant, anti-inflammatory and anti-apoptotic effects. The aim of this systematic review was to identify experimental animal studies that have evaluated the protective effects of TQ against testicular complications associated with chemotherapy. In accordance with the preferred reporting items for systematic review and meta-analyses (PRISMA) guidelines, a thorough search was performed across several databases (PubMed, EBSCOhost, Sage and Scopus) to identify experimental studies published from 2010 to May 2022 that focused on rodent models and compared the effects of TQ versus other chemotherapeutic drugs. Eight studies met the inclusion criteria, comparing TQ with methotrexate (MTX), 6-mercaptopurine (6-MP), cyclophosphamide (CPA), bleomycin (BL), doxorubicin (DOX) or busulfan (BUS). The results of these studies consistently demonstrated that TQ significantly improved sperm parameters, the levels of oxidative stress (OS) markers, apoptosis markers, and hormones and testicular histopathology, indicating that TQ has protective effects against chemotherapy-induced damage. TQ mitigated chemotherapy-induced testicular toxicity by decreasing lipid peroxidation and enhancing the activity of antioxidant enzymes within chemotherapy-treated testes. These findings highlight the potential of TQ as a therapeutic agent that can ameliorate testicular complications associated with chemotherapy, thereby providing a basis for further research and potential therapeutic applications. [ABSTRACT FROM AUTHOR]

PURPOSE: Limited evidence exists regarding methotrexate (MTX) resumption after patients with lymphoma receive glucarpidase for toxic MTX levels and acute kidney injury (AKI). METHODS: This retrospective review included adults with lymphoma treated with glucarpidase after MTX at Mayo Clinic between January 31, 2020, and October 10, 2022. Descriptive statistics summarize patient characteristics and clinical outcomes. RESULTS: Of 11 patients treated with glucarpidase after MTX, seven (64%) were rechallenged with MTX. Indications for MTX rechallenge included confirmed CNS disease (n = 6, 86%) and intravascular lymphoma (n = 1, 14%). Compared with the nonrechallenged subgroup, before receiving MTX that required glucarpidase rescue, the rechallenged patients had lower median pretreatment serum creatinine (Scr; 0.7 v 1.2 mg/dL), and none had AKI with previous MTX doses, n = 0 (0%) versus n = 2 (50%). During the MTX dose requiring glucarpidase rescue, the rechallenged group had lower median peak Scr (1.26 v 3.32 mg/dL) and lower incidence of AKI stage III (n = 1 [14%] v n = 3 [75%]), and none of the rechallenged patients required renal replacement therapy (RRT; n = 0 [0%] v n = 1 [25%]). At the first rechallenge after glucarpidase administration, the median MTX dose reduction was 56% (range, 46%-75%), and the lowest used dose when prescribed according to each treatment protocol schedule was 1.5 g/m2. Two (29%) patients experienced AKI (n = 1 stage I, n = 1 stage II) after MTX rechallenge. Zero patients required RRT, and zero required another glucarpidase administration. Six (86%) patients completed all recommended MTX doses. CONCLUSION: In selected adults with lymphoma who required glucarpidase for toxic MTX levels after administration of high-dose MTX, resumption of MTX therapy at lower doses is safe. Patients selected for MTX resumption had experienced less severe AKI during the previous cycle compared with those not selected for MTX resumption. [ABSTRACT FROM AUTHOR]

Background In male patients with cancer treated with antineoplastic drug, hypogonadism is a neglected cause of diminished quality of life. This condition may be cancer related as well as toxicity related. The role of antineoplastic drug in causing hypogonadism is poorly understood. The aim of this systematic review was to establish the prevalence, nature (primary/secondary), and impact of hypogonadism on quality of life in male patients with cancer on antineoplastic therapy. Methods The search strategy used PubMed, Embase, and Cochrane databases to select articles in English language that described hypogonadism in male patients with cancer. The search period was from January 1, 1945 to February 28, 2023. We included observational studies, case reports or case series and excluded studies concerning hematological malignancies, prostate cancer, female patients, and survivors. Findings Of 4488 records identified, 28 studies met inclusion criteria (17 observational studies, 11 case reports or case series). Anti-angiogenic drugs and crizotinib were found to have a role in the development of hypogonadism. Patients treated with immune checkpoint-inhibitors developed secondary hypogonadism due to immune-related hypophysitis or orchitis. As for active chemotherapy, platinum salts were often associated with hypogonadism, followed by antimetabolites and taxanes. Selected studies were heterogeneous for populations, interventions, and outcomes assessments. Thus, a generalization is difficult. Moreover, the role of concurrent etiologies cannot be excluded in most studies. Conclusion Our research emphasizes the importance of evaluating the gonadal axis before treatment in patients considered at risk and testing it at regular intervals or in case of clinical suspicion. [ABSTRACT FROM AUTHOR]

PurposeTo characterize and pharmacologically influence subconjunctival lymphatics in rabbit and mouse eyes.MethodsRabbits received subconjunctival injections of trypan blue or fixable fluorescent dextrans. Bleb-related outflow pathways were quantified. Immunofluorescence for vessel-specific markers (lymphatics [podoplanin and LYVE-1] and blood vessels [CD31]) were performed in native rabbit conjunctiva and after fixable fluorescent dextran injection. Vascular endothelial cell growth factor-C (VEGFC) was injected subconjunctivally in rabbits. mRNA and protein were assessed for the above markers using RT-PCR and Western blot. Alternatively, mouse studies used Prox1-tdTomato transgenic reporter mice. Subconjunctival injection conditions included: no injection, balanced salt solution (BSS), VEGFC, 5-fluorouracil (5FU) and two concentrations of mitomycin-C (MMC). Two mouse injection protocols (short and long) with different follow-up times and number of injections were performed. Mouse eyes were enucleated, flat mounts created, and subconjunctival branching and length assessed.ResultsRabbit eyes demonstrated clear bleb-related subconjunctival outflow pathways that were distinct from blood vessels and were without nasal/temporal predilection. Immunofluorescence against vessel-specific markers showed lymphatics and blood vessels in rabbit conjunctiva, and these lymphatics overlapped with bleb-related subconjunctival outflow pathways. Subconjunctival VEGFC increased lymphatic (P = 0.004-0.04) but not blood vessel (P = 0.77-0.84) mRNA or protein in rabbits. Prox1-tdTomato transgenic reporter mice demonstrated natively fluorescent lymphatics. Subconjunctival VEGFC increased murine lymphatic branching and length (P ≤ 0.001-0.004) while antimetabolites (P ≤ 0.001-0.043) did the opposite for the long protocol.DiscussionSubconjunctival lymphatics are pharmacologically responsive to both VEGFC and antimetabolites in two animal models studied using different methodologies. These results may be important for bleb-forming glaucoma surgeries or ocular drug delivery.

To evaluate how changes in visual acuity are associated with changes in quality of life (QoL) among patients with non-infectious uveitis taking antimetabolites. This secondary analysis of the multicenter First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial involves 216 participants randomized to methotrexate or mycophenolate mofetil. Vision-related (NEI-VFQ and IND-VFQ) and health-related (PCS and MCS SF-36v2) QoL and visual acuity were measured at baseline and 6-month primary endpoint. Visual acuity was significantly associated and correlated with all QoL measures (Spearman correlation coefficients = 0.5, 0.5, 0.3, and 0.4 for NEI-VFQ, IND-VFQ, SF-36v2 MCS and PCS, respectively). All observed changes in QoL met or exceeded the minimal clinically important difference definition on each scale. Treatment group was not significantly associated with any QoL measure. By adding insight beyond visual acuity, QoL provides a more comprehensive picture of the patient experience during uveitis treatment. Abbreviations and Acronyms: QoL = quality of life; VR-QoL = vision-related quality of life; HR-QoL = health-related quality of life; FAST = First-line Antimetabolites as Corticosteroid Sparing Treatment; NEI-VFQ = National Eye Institute Visual Functioning Questionnaire; IND-VFQ = Indian Visual Functioning Questionnaire; SF-36v2 = Medical Outcomes Study 36-Item Short Form Survey; PCS = physical component score; MCS = mental component score; 95% CI = 95% confidence interval; MCID = minimal clinically important difference [ABSTRACT FROM AUTHOR]

Simple Summary: The vaginal microbiome may play a role in racial disparities in ovarian cancer; there is evidence suggesting that it differs according to race and contributes to inflammation by producing or consuming compounds that can shape how ovarian cancer progresses. Our cross-sectional study aimed to investigate the extent to which chemical compounds, or metabolites, from vaginal fluid, also differ by race, and whether these metabolites are linked to systemic inflammation. Our study of 20 White and 16 Black patients identified 1 out of 99 metabolites, arachidonoylcarnitine (C20:4), as occurring at lower levels in Black and higher levels in White patients with ovarian cancer. More than one-third of vaginal fluid metabolites considered showed correlations with biomarkers of systemic inflammation. Our findings suggest that vaginal fluid metabolites likely differ by race, and may play an important role in inflammatory processes, which may be relevant to racial differences in ovarian cancer outcomes. These pilot findings have the potential to improve our understanding of biological mechanisms underlying racial disparities in ovarian cancer but need verification with larger sample sizes. The vaginal microbiome differs by race and contributes to inflammation by directly producing or consuming metabolites or by indirectly inducing host immune response, but its potential contributions to ovarian cancer (OC) disparities remain unclear. In this exploratory cross-sectional study, we examine whether vaginal fluid metabolites differ by race among patients with OC, if they are associated with systemic inflammation, and if such associations differ by race. Study participants were recruited from the Ovarian Cancer Epidemiology, Healthcare Access, and Disparities Study between March 2021 and September 2022. Our study included 36 study participants with ovarian cancer who provided biospecimens; 20 randomly selected White patients and all 16 eligible Black patients, aged 50–70 years. Acylcarnitines (n = 45 species), sphingomyelins (n = 34), and ceramides (n = 21) were assayed on cervicovaginal fluid, while four cytokines (IL-1β, IL-10, TNF-α, and IL-6) were assayed on saliva. Seven metabolites showed >2-fold differences, two showed significant differences using the Wilcoxon rank-sum test (p < 0.05; False Discovery Rate > 0.05), and 30 metabolites had coefficients > ±0.1 in a Penalized Discriminant Analysis that achieved two distinct clusters by race. Arachidonoylcarnitine, the carnitine adduct of arachidonic acid, appeared to be consistently different by race. Thirty-eight vaginal fluid metabolites were significantly correlated with systemic inflammation biomarkers, irrespective of race. These findings suggest that vaginal fluid metabolites may differ by race, are linked with systemic inflammation, and hint at a potential role for mitochondrial dysfunction and sphingolipid metabolism in OC disparities. Larger studies are needed to verify these findings and further establish specific biological mechanisms that may link the vaginal microbiome with OC racial disparities. [ABSTRACT FROM AUTHOR]

Introduction: Mercaptopurine (6MP) and methotrexate (MTX) are commonly used for maintenance chemotherapy for acute lymphoblastic leukemia (ALL). These medications have been associated with various side effects such as myelosuppression, colitis, and thyroiditis in addition to numerous cutaneous adverse events. Cutaneous side-effects most reported include mucositis, alopecia, xerosis, and pruritus. We report an interesting case of hand–foot syndrome to 6MP in a child on maintenance therapy for B-cell ALL from an alteration in medication metabolism. Case: We report a 10-year-old male on maintenance chemotherapy for pre-Bcell ALL who presented to the hospital with worsening oral lesions and erythematous, fissured plaques on the palms and soles. Maintenance therapy consisted of IV vincristine and 5-day pulse of steroids every 12 weeks, daily 6MP, and weekly MTX, which were increased to ≥ 150% of standard dosing due to persistent absolute neutrophil counts > 1500. Metabolites obtained on admission demonstrated elevated 6MMP metabolites at 35,761 (normal < 5700). TPMT and NUDT15 enzyme activity were normal and no alterations in genotyping were discovered. Outcome: Patient's oral chemotherapy, including both 6MP and MTX, were stopped and allopurinol 100 mg daily was initiated, which lead to overall improvement. Discussion: Clinical findings of acute mucositis and worsening of hand–foot syndrome, in the setting of inadequate myelosuppression in a child on maintenance therapy for ALL should raise concerns to consider altered metabolism pathway leading to toxic metabolite buildup. Allopurinol can play in improving cutaneous manifestation and chemotherapeutic dosing in patients with altered metabolism. [ABSTRACT FROM AUTHOR]

Drug‐induced thrombocytopenia (DIT) deserves both clinical and research attention for the serious clinical consequences and high prevalence of the condition. The current study aimed to perform a comprehensive pharmacovigilance analysis of DIT reported in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, with a particular focus on drugs associated with thrombocytopenia events. A disproportionality analysis of DIT was conducted using reports submitted to FARES from January 2004 to December 2022. Both the information component (IC) and reporting odds ratio (ROR) algorithms were applied to identify an association between target drugs and DIT events. A total of 15,940,383 cases were gathered in FAERS, 168,657 of which were related to DIT events. The top 50 drugs ranked by number of cases and ranked by signal strength were documented. The top 5 drugs ranked by number of cases were lenalidomide (10,601 cases), niraparib (3726 cases), ruxolitinib (3624 cases), eltrombopag (3483 cases), and heparin (3478 cases). The top 5 drugs ranked by signal strength were danaparoid (ROR 37.61, 95%CI 30.46‐46.45), eptifibatide (ROR 34.75, 95%CI 30.65‐39.4), inotersen (ROR 34.00, 95%CI 29.47‐39.23), niraparib (ROR 30.53, 95%CI 29.42‐31.69), and heparin (ROR 28.84, 95%CI 27.76‐29.97). The top 3 involved drug groups were protein kinase inhibitors, antimetabolites, and monoclonal antibodies and antibody‐drug conjugates. The current comprehensive pharmacovigilance study identified more drugs associated with thrombocytopenia. Although the mechanisms of DIT have been elucidated for some drugs, others still require further investigation. [ABSTRACT FROM AUTHOR]

Purpose: To present the surgical options and surgical outcomes of juvenile open-angle glaucoma (JOAG). Methods: A retrospective review of the case series with JOAG that had undergone surgical treatment was undertaken. Surgical techniques, patient characteristics, and surgical outcomes were analyzed. Results: Thirteen eyes from eight patients with the diagnosis of JOAG were included in the study. The mean age was 26.77 ± 9.83 years. Five (62.5%) of the patients were male. The distribution of the operations was as follows: deep sclerectomy and external suture trabeculotomy in one eye (8%); Ahmed glaucoma valve implantation in one eye (8%); trabeculectomy with antimetabolite augmentation in five eyes (38%); and gonioscopy-assisted transluminal trabeculotomy (GATT) in six eyes (46%). The preoperative mean intraocular pressure (IOP) was 27.62 ± 7.17 mmHg, which decreased to 17.62 ± 13.06 mmHg at the last follow-up visit (36.21% decrease, P = 0.023, Wilcoxon rank test). IOP control was achieved without any additional surgical intervention in 10 (76.9%) eyes over the mean of 15.62 ± 12.17 months of the follow-up period. Further glaucoma surgery was required in three eyes, of which two had undergone GATT and one had undergone trabeculectomy as the primary surgery. Conclusion: The surgical treatment of JOAG results in IOP reduction, and more than one surgery may be required in some cases. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) is responsible for 10–20% cases of breast cancer and is resulting in rising healthcare costs. Thus, health-economic evaluations are needed to relate clinical outcomes and costs of treatment options and to provide recommendations of action from a health-economic perspective. Methods: We investigated the cost-benefit-ratio of approved treatment options in metastatic TNBC in Germany by applying the efficiency frontier approach. These included sacituzumab-govitecan (SG), eribulin, vinorelbine, and capecitabine. Clinical benefit was measured as (i) median overall survival (mOS) and (ii) health-related quality of life (HRQoL) in terms of time to symptom worsening (TSW). To assess medical benefits, literature was systematically reviewed in PubMed for (i) and (ii), respectively. Treatment costs were calculated considering annual direct outpatient treatment costs from a statutory healthcare payer perspective. It was intended that both, (i) and (ii), yield an efficiency frontier. Results: Annual direct outpatient treatment costs amounted to EUR 176,415.21 (SG), EUR 47,414.14 (eribulin), EUR 13,711.35 (vinorelbine), and EUR 3,718.84 (capecitabine). Systematic literature review of (i) and statistical analysis resulted in OS values of 14.3, 9.56, 9.44, and 7.46 months, respectively. Capecitabine, vinorelbine, and SG are part of the efficiency frontier including OS. The highest additional benefit per additional cost was determined for vinorelbine, followed by SG. Systematic review of (ii) revealed that no TSW data of TNBC patients receiving vinorelbine were available, preventing the presentation of an efficiency frontier including HRQoL. Conclusions: Vinorelbine is most cost-effective, followed by SG. Health-economic evaluations support decision-makers to assess treatment options within one indication area. In Germany, the efficiency frontier can provide decision support for the pricing of innovative interventions. Results of our analysis may thus guide reimbursement determination. [ABSTRACT FROM AUTHOR]

Objective: We retrospectively analyzed breast cancer patients who received adjuvant radiotherapy to determine the incidence of lymphocytopenia and its risk factors. Methods: We reviewed 812 patients with breast cancer who received postoperative radiotherapy. Patients were divided into two groups based on the use of chemotherapy, and a generalized linear regression model was used to explore predictive factors for grade 2 or higher lymphocytopenia. We also examined the effect of lymphocytopenia on overall survival. Results: Grade 2 or higher lymphocytopenia was observed in 19.4% of patients who did not receive chemotherapy and 45.1% of patients who received chemotherapy. In multivariate analysis, bilateral disease, regional lymph node irradiation, and baseline lymphocytopenia were associated with lymphocytopenia in patients who did not receive cytotoxic chemotherapy. Regional lymph node irradiation, baseline lymphocytopenia, use of antimetabolites, and use of molecular‐targeted agents were associated with lymphocytopenia in patients treated with chemotherapy. In the survival analysis, lymphocytopenia was associated with worse overall survival only in patients treated with cytotoxic chemotherapy (p = 0.039), and not in patients who did not receive chemotherapy (p = 0.77). Conclusion: The analysis revealed the incidence and risk factors of lymphocytopenia after postoperative radiotherapy in patients with breast cancer. [ABSTRACT FROM AUTHOR]

Analogues of N,N-dimethyladenine exploiting both thieno-and isothiazolo-pyrimidine cores were modified with 3-subsituted azetidines to yield visibly emissive and responsive fluorophores. The emission quantum yields, among the highest seen for purine analogues (0.64 and 0.77 in water and dioxane respectively), correlated with the Hammett inductive constants of the substituents on the azetidine ring. Ribosylation of the difluoroazetidino-modified nucleobase yielded an emissive nucleoside that displayed a substantially lower emission quantum yield in water, compared to the precursor nucleobase. Importantly, high emission quantum yield was restored in deuterium oxide, which highlights the potential impact of the sugar moiety on the photophysical features of fluorescent nucleosides, a functionality usually considered non-chromophoric and photophysically benign.

A new fluorescent ribonucleoside alphabet (mth N) consisting of pyrimidine and purine analogues, all derived from methylthieno[3,4-d]pyrimidine as the heterocyclic core, is described. Large bathochromic shifts and high microenvironmental susceptibility of their emission relative to previous alphabets derived from thieno[3,4-d]pyrimidine (th N) and isothiazole[4,3-d]pyrimidine (tz N) scaffolds are observed. Subjecting the purine analogues to adenosine deaminase, guanine deaminase and T7 RNA polymerase indicate that, while varying, all but one enzyme tolerate the corresponding mth N/mth NTP substrates. The robust emission quantum yields, high photophysical responsiveness and enzymatic accommodation suggest that the mth N alphabet is a biophysically viable tool and can be used to probe the tolerance of nucleoside/tide-processing enzymes to structural perturbations of their substrates.

The article comments on a study by J. O. Jacobson and colleagues on a method to integrate dihydropyrimidine dehydrogenase (DPYD) test into the clinics at the Dana Farber Cancer Institute. Topics mentioned include the role of pharmacogenetics in enhancing care and reducing medical care cost, the effectiveness of 5-fluorouracil and fluoropyrimidine prodrug capecitabine in combination with oxaliplatin for the management of colon and rectal cancers and the complexity of DPYD genetics.

PurposeSub-analysis of the FAST Trial comparing change in CD4 (∆CD4) from baseline through 12 months in uveitis patients treated with mycophenolate mofetil (MMF) and methotrexate (MTX).MethodsPatients were randomly allocated to 1.5 g twice daily MMF or 25 mg weekly MTX. Individuals with CD4 counts at baseline, 6 months (or treatment failure prior), and 12 months (or treatment failure between 6 and 12 months) were included. The association between treatment and ∆CD4 (cells/μL) was analyzed using multivariable linear regression.ResultsThere was no significant difference in ∆CD4 between MMF and MTX at 6 months (-31.7 cells/μL for MMF compared to MTX; 95% CI: -358.2 to 294.8, P = .85) and 12 months (-78.3 cells/μL for MMF compared to MTX; 95% CI: -468.0 to 311.3; P = .69).ConclusionThere was no significant difference in ∆CD4 between MMF and MTX from baseline to 12 months, suggesting that MMF does not confer additional risk of CD4 lymphopenia in uveitic patients.ClinicalTrials.gov Identifier: NCT01829295.

Abstract Chemotherapy resistance is considered one of the main causes of tumor relapse, still challenging researchers for the identification of the molecular mechanisms sustaining its emergence. Here, we setup and characterized chemotherapy-resistant models of Medulloblastoma (MB), one of the most lethal pediatric brain tumors, to uncover targetable vulnerabilities associated to their resistant phenotype. Integration of proteomic, transcriptomic and kinomic data revealed a significant deregulation of several pathways in resistant MB cells, converging to cell metabolism, RNA/protein homeostasis, and immune response, eventually impacting on patient outcome. Moreover, resistant MB cell response to a large library of compounds through a high-throughput screening (HTS), highlighted nucleoside metabolism as a relevant vulnerability of chemotolerant cells, with peculiar antimetabolites demonstrating increased efficacy against them and even synergism with conventional chemotherapeutics. Our results suggest that drug-resistant cells significantly rewire multiple cellular processes, allowing their adaptation to a chemotoxic environment, nevertheless exposing alternative actionable susceptibilities for their specific targeting.

The review presents data on studies of the role of mycoplasmas as infectious agents in carcinogenesis, as well as their participation in cancer drug therapy and the impact on the outcome of treatment. Mycoplasmas are of particular interest because they have unique abilities to readily attach to and enter eukaryotic cells, modulate their functional state, and induce chronic inflammation while evading the host’s immune system. The review will highlight the data confirming the increased colonization of tumor tissue by mycoplasmas compared to healthy ones, describe the molecular mechanisms by which mycoplasmas activate the expression of oncogenes and growth factors, inactivate tumor suppressors, promote NF-κB-dependent migration of cancer cells and modulate apoptosis, which results in abnormal growth and transformation of host cells. The review also presents data on the effectiveness of anticancer drugs in mycoplasmal infections.

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a hematologic tumor, characterized by several genetic alterations, that constitutes 15% of pediatric and 25% of adult ALL. While with current therapeutic protocols children and adults’ overall survival (OS) rates reach 85–90% and 40–50%, respectively, the outcome for both pediatric and adult T-ALL patients that relapse or are refractory to induction therapy, remains extremely poor, achieving around 25% OS for both patient groups. About 60% of T-ALL patients show increased NOTCH1 activity, due to activating NOTCH1 mutations or alterations in its ubiquitin ligase FBXW7. NOTCH signaling has been shown to contribute to chemotherapy resistance in some tumor models. Hence, targeting the NOTCH1 signaling pathway may be an effective option to overcome relapsed and refractory T-ALL. Here, we focused on the therapeutic activity of the NOTCH1-specific monoclonal antibody OMP-52M51 in combination either with drugs used during the induction, consolidation, or maintenance phase in mice xenografts established from pediatric and adult relapsed NOTCH1 mutated T-ALL samples. Interestingly, from RNAseq data we observed that anti-NOTCH1 treatment in vivo affects the purine metabolic pathway. In agreement, both in vitro and in vivo, the greatest effect on leukemia growth reduction was achieved by anti-NOTCH1 therapy in combination with antimetabolite drugs. This result was further corroborated by the longer life span of mice treated with the anti-NOTCH1 in combination with antimetabolites, indicating a novel Notch-targeted therapeutic approach that could ameliorate pediatric and adult T-ALL patients outcome with relapse disease for whom so far, no other therapeutic options are available.