Risk factors associated with high-dose methotrexate induced toxicities.

INTRODUCTION: High-dose methotrexate (HDMTX) therapy poses challenges in various neoplasms due to individualized pharmacokinetics and associated adverse effects. Our purpose is to identify early risk factors associated with HDMTX-induced toxicities, paving the way for personalized treatment. AREAS COVERED: A systematic review of PubMed and Cochrane databases was conducted for articles from inception to July 2023. Eligible studies included reviews, clinical trials, and real-world analyses. Irrelevant studies were excluded, and manual searches and citation reviews were performed. Factors such as MTX exposure, drug interactions, demographics, serum albumin, urine pH, serum calcium, and genetic polymorphisms affecting MTX transport (e.g. SLCO1B1), intracellular folate metabolism (MTHFR), cell development (ARID5B), metabolic pathways (UGT1A1, PNPLA3), as well as epigenetics were identified. EXPERT OPINION: This comprehensive review aids researchers and clinicians in early identification of HDMTX toxicity risk factors. By understanding the multifaceted risk factors associated with hematologic malignancies, personalized treatment approaches can be tailored to optimize therapeutic outcomes.

Colchicine Ameliorates 5-Fluorouracil-Induced Cardiotoxicity in Rats.

Background and Objective. 5-Fluorouracil is one of the most common chemotherapeutic agents used in the treatment of solid tumors. 5-Fluorouracil-associated cardiotoxicity is the second cause of cardiotoxicity induced by chemotherapeutic drugs after anthracyclines. Colchicine is a strong anti-inflammatory drug used to prevent and treat acute gout and treat familial Mediterranean fever. And also, its protective effects on cardiovascular disease have been reported in various studies. The current study is aimed at appraising the effect of colchicine on 5-fluorouracil-induced cardiotoxicity in rats. Methods. Twenty male Wistar rats were divided into four groups as follows: control, 5-fluorouracil, colchicine (5 mg/kg), and 5-fluorouracil+5 mg/kg colchicine. Cardiotoxicity was induced with an intraperitoneal injection of a single dose of 5-fluorouracil (100 mg/kg). The control group received normal saline, and the treatment groups received colchicine with an intraperitoneal injection for 14 days. Findings. 5-Fluorouracil resulted in significant cardiotoxicity represented by an increase in cardiac enzymes, malondialdehyde levels, cyclooxygenase-2 and tumor necrosis factor-alpha expression, cardiac enzymes, and histopathological degenerations. 5-Fluorouracil treatment also decreased body weight, total antioxidant capacity and catalase values, blood cells, and hemoglobin levels. In addition, 5-fluorouracil disrupted electrocardiographic parameters, including increased elevation in the ST segment and increased QRS duration. Treatment with colchicine reduced oxidative stress, cardiac enzymes, histopathological degenerations, and cyclooxygenase-2 expression in cardiac tissue, improved electrocardiographic disorders, and enhanced the number of blood cells and total antioxidant capacity levels. Moreover, body weight loss was hampered after treatment with colchicine. Our results demonstrated that treatment with colchicine significantly improved cardiotoxicity induced by 5-fluorouracil in rats.

Inhibition of NLRP3 inflammasome activation in myeloid-derived suppressor cells by andrographolide sulfonate contributes to 5-FU sensitization in mice.

5-Fluorouracil (5-FU)-based chemotherapy is the first-line recommended regimen in colorectal cancer (CRC), but resistance limits its clinical application. Andrographolide sulfonate, a traditional Chinese medicine, is mainly used to treat infectious diseases. In the present study, we reported that andrographolide sulfonate could significantly inhibit the growth of transplanted CT26 colon cancer in mice and improve survival when combined with 5-FU. Furthermore, TUNEL assay and immunohistochemistry analysis of proliferating cell nuclear antigen, Ki-67 and p-STAT3 confirmed that co-treatment could inhibit tumor proliferation and promote apoptosis. In tumor tissues of groups that received 5-FU and andrographolide sulfonate, CD4+ and CD8+ T cell infiltration was increased, and the expression of IFN-γ and Granzyme B detected by immunohistochemistry and qPCR was upregulated, reflecting improved antitumor immunity. Finally, we verified that 5-FU significantly activated the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome in myeloid-derived suppressor cells (MDSCs) and that andrographolide sulfonate reversed this process to sensitize cells to 5-FU. In summary, andrographolide sulfonate synergistically enhanced antitumor effects and improved antitumor immunity by inhibiting 5-FU-induced NLRP3 activation in MDSCs. These findings provide a novel strategy to address 5-FU resistance in the treatment of CRC.

Age as a modifier of the effects of chemoradiotherapy with infusional 5-fluorouracil after D2 dissection in gastric cancer.

Adjuvant concurrent chemoradiotherapy (CCRT) is the standard care for patients with resected advanced gastric cancer, but its survival benefits remain undetermined in patients undergoing D2 lymph node dissection (D2 dissection). We evaluated safety and efficacy of adjuvant CCRT with 5-fluorouracil (5-FU) versus chemotherapy alone in 110 gastric cancer patients with D2 dissection treated in Taiwan between January 2009 and January 2013. All the 71 patients receiving adjuvant CCRT were treated with daily infusional 5-FU and radiotherapy. Adjuvant CCRT was associated with higher risks of major hematologic (56.3% vs. 23.8%, p = 0.002) and gastrointestinal (46.9% vs. 14.3%, p = 0.027) toxicities and death (12.5% vs. 0.0%, p = 0.041) in patients above 70 years old, but this was not the case in those ≤70 years of age. Univariate Cox proportional regressions identified adjuvant CCRT as a factor for better overall survival (OS) (hazard ratio [HR]=0.52; 95% confidence interval [CI]: 0.27-0.99) and disease-free survival (DFS) (HR=0.46, 95% CI: 0.24-0.88), but it was not a significant factor for OS or DFS after adjusting for other factors in the multivariate analysis. However, in stratified analyses by age, we found adjuvant CCRT was an independent prognostic factor for better OS (HR=0.07; 95% CI: 0.01-0.38) in patients ≤70 years old, but not in those above 70 years of age. Therefore, it was concluded that age may to be a modifier of the effects of adjuvant CCRT.

Tumor-Specific Delivery of 5-Fluorouracil-Incorporated Epidermal Growth Factor Receptor-Targeted Aptamers as an Efficient Treatment in Pancreatic Ductal Adenocarcinoma Models.

BACKGROUNDS & AIMS: Fluoropyrimidine c (5-fluorouracil [5FU]) increasingly represents the chemotherapeutic backbone for neoadjuvant, adjuvant, and palliative treatment of pancreatic ductal adenocarcinoma (PDAC). Even in combination with other agents, 5FU efficacy remains transient and limited. One explanation for the inadequate response is insufficient and nonspecific delivery of 5FU to the tumor. METHODS: We designed, generated, and characterized 5FU-incorporated systematic evolution of ligands by exponential enrichment (SELEX)-selected epidermal growth factor receptor (EGFR)-targeted aptamers for tumor-specific delivery of 5FU to PDAC cells and tested their therapeutic efficacy in vitro and in vivo. RESULTS: 5FU-EGFR aptamers reduced proliferation in a concentration-dependent manner in mouse and human pancreatic cancer cell lines. Time-lapsed live imaging showed EGFR-specific uptake of aptamers via clathrin-dependent endocytosis. The 5FU-aptamer treatment was equally effective in 5FU-sensitive and 5FU-refractory PDAC cell lines. Biweekly treatment with 5FU-EGFR aptamers reduced tumor burden in a syngeneic orthotopic transplantation model of PDAC, in an autochthonously growing genetically engineered PDAC model (LSL-KrasG12D/+;LSL-Trp53flox/+;Ptf1a-Cre [KPC]), in an orthotopic cell line-derived xenograft model using human PDAC cells in athymic mice (CDX; Crl:NU-Foxn1nu), and in patient-derived organoids. Tumor growth was significantly attenuated during 5FU-EGFR aptamer treatment in the course of follow-up. CONCLUSIONS: Tumor-specific targeted delivery of 5FU using EGFR aptamers as the carrier achieved high target specificity; overcame 5FU resistance; and proved to be effective in a syngeneic orthotopic transplantation model, in KPC mice, in a CDX model, and in patient-derived organoids and, therefore, represents a promising backbone for pancreatic cancer chemotherapy in patients. Furthermore, our approach has the potential to target virtually any cancer entity sensitive to 5FU treatment by incorporating 5FU into cancer cell-targeting aptamers as the delivery platform.

Uracil-tegafur vs fluorouracil as postoperative adjuvant chemotherapy in Stage II and III colon cancer: A nationwide cohort study and meta-analysis.

ABSTRACT: We conducted a population-based cohort study enrolling patients with Stage II and III colon cancer receiving postoperative adjuvant chemotherapy with uracil and tegafur (UFT) or fluorouracil (5-FU) from the Taiwan National Health Insurance Research Database from 2000 to 2015. The outcomes of the current study were disease-free survival (DFS) and overall survival (OS). Hazard ratios (HRs) were calculated by multivariate Cox proportional hazard regression models. We compared our effectiveness results from the literature by meta-analysis, which provided the best evidence. Severe adverse events were compared in meta-analysis of reported clinical trials. In the nationwide cohort study, UFT (14,486 patients) showed DFS similar to postoperative adjuvant chemotherapy (adjusted HR 1.037; 95% confidence interval [CI] 0.954-1.126; P = .397) and OS (adjusted HR 0.964; 95% CI 0.891-1.041; P = .349) compared with the 5-FU (866 patients). Our meta-analysis confirmed the similarity of effectiveness and found the incidence of leucopaenia was statistically significantly reduced in UFT (risk ratio 0.12; 95% CI 0.02-0.67; I2 = 0%). Through our analysis, we have confirmed that UFT is a well-tolerated adjuvant therapy choice, and has similar treatment efficacy as 5-FU in terms of DFS and OS in patients with Stage II and III colon cancer.

Risk factors for high-dose methotrexate-induced nephrotoxicity.

High-dose methotrexate (MTX) is widely used for the treatment of hematological malignancies. Despite the application of routine supportive care measures, such as intensive fluid hydration and urine alkalinization, nephrotoxicity is still a problem. The present study aimed to evaluate the risk factors for MTX-induced nephrotoxicity. We retrospectively reviewed 88 patients who received a regimen consisting of high-dose MTX (1000 mg/m2) and cytosine arabinoside between 2006 and 2018. Nephrotoxicity (≥ grade 2) was observed in 11 patients. Nephrotoxicity was observed only in patients with a high MTX concentration. Other than the MTX concentration, the serum uric acid level and urine pH at day 1 were associated with nephrotoxicity. A multivariate analysis revealed that urine pH was an independent risk factor for MTX-induced nephrotoxicity. Urine pH < 7.0 at day 1 was a significant risk factor for nephrotoxicity (odds ratio, 8.05; 95% confidence interval 1.95-33.3) and was also a predictor of delayed MTX elimination at 72 h after injection. Among pre-treatment factors, a low serum calcium level predicted urine pH < 7.0 at day 1. In conclusion, the present study suggests that low urine pH at day 1 is an independent risk factor for MTX-induced nephrotoxicity.

Ambulatory high-dose methotrexate administration as central nervous system prophylaxis in patients with aggressive lymphoma.

High-dose methotrexate (HD-MTX) at 3 g/m2 is one of the strategies for central nervous system (CNS) prophylaxis in the first-line treatment of aggressive lymphomas, especially in diffuse large B cell lymphoma patients with high-risk CNS-International Prognostic Index. The objective of our study was to retrospectively analyze the safety of 2 cycles of systemic HD-MTX administered as an ambulatory regimen. Between January 2013 and December 2016, 103 patients were carefully selected on 6 criteria, including age < 60, albumin > 34, performance status 0 or 1, normal renal and hepatic functions, good understanding of practical medical guidance, and no loss of weight. Strict procedures of HD-MTX infusion were observed including alkalinization, urine pH monitoring, and leucovorin rescue. Renal and hepatic functions were monitored at days 2 and 7. MTX clearance was not monitored. Toxicities and grades of toxicity were collected according to the NCI-CTCAE (version 4.0). Among the 103 selected patients, 92 (89%) patients successfully completed the planned 2 cycles of HD-MTX on an outpatient basis. Eleven patients completed only 1 cycle, 3 because of lymphoma progression and 8 because of toxicity including 3 grade II hepatotoxicity, 2 grade I/II renal toxicity, 1 grade III neutropenia, 1 active herpetic infection, and 1 grade III ileus reflex. Reported adverse events (AE) included 92 (84%) grade I/II and 18 (16%) grade III/IV. Grade III hepatotoxicity, mostly cytolysis, was the most frequent AE observed with 8 (8%) events. Grade III/IV hematologic toxicities concerned 9 patients with 8 grade III/IV neutropenia and 1 thrombocytopenia. Renal toxicity was rare, mild, and transient, observed with 4 (4%) grade I/II events. Ambulatory administration of HD-MTX at 3 g/m2 without MTX clearance monitoring is safe with strict medical guidance. It requires careful selection of patients before administration, and a renal and hepatic monitoring after the administration.

Significant interaction between high-dose methotrexate and high-dose piperacillin-tazobactam causing reversible neurotoxicity and renal failure in an osteosarcoma patient.

INTRODUCTION: Pharmacokinetic interaction of high-dose methotrexate (MTX) and other concomitantly administered renally secreted medicinal products may lead to insufficient methotrexate serum level decrease and significant MTX toxicity. CASE REPORT: We report the case of an 18-year-old male patient treated with high-dose MTX for an osteosarcoma and with high-dose piperacillin-tazobactam at the same time. MTX serum levels were severely elevated 24 hours after the MTX infusion and did not decrease in accordance with the specific calcium folinate rescue protocol. The patient experienced renal failure accompanied by neurological symptoms, most consistent with MTX-related renal and CNS toxicity.Management and outcome: After discontinuation of piperacillin-tazobactam, intensified calcium folinate rescue therapy, and IV hydration, the MTX serum levels decreased appropriately, and toxicity symptoms resolved. DISCUSSION: Severe MTX-related toxicity, caused by drug-drug interaction, suggests that the concomitant use of high-dose MTX and high-dose piperacillin-tazobactam should be avoided generally.

Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper.

BACKGROUND: 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2-1.0%. SUMMARY: Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. Key Messages: (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitoring.

The evaluation of red blood cell folate and methotrexate levels during protocol M in childhood acute lymphoblastic leukemia.

BACKGROUND: After High-Dose Methotrexate (HD-MTX), folinic acid rescue therapy (Leucovorin) is administered to reduce side effects in pediatric acute lymphoblastic leukemia (ALL) patients. Leucovorin and MTX are structural analogues, possibly competing for cellular transport and intracellular metabolism. We hypothesize that Leucovorin accumulates during consecutive courses, which might result in a lower MTX uptake. METHODS: We prospectively measured red blood cell (RBC) folate and MTX levels during four HD-MTX and Leucovorin courses in 43 patients treated according the DCOG ALL-11 protocol with 2-weekly HD-MTX (5 g/m2/dose) and Leucovorin (15 mg/m2/dose) using LC-MS/MS. We estimated a linear mixed model to assess the relationship between these variables over time. RESULTS: Both RBC MTX-PG and folate levels increased significantly during protocol M. MTX-PG2-5 levels increased most substantially after the first two HD-MTX courses (until median 113.0 nmol/L, IQR 76.8-165.2) after which levels plateaued during the 3d and 4th course (until median 141.3 nmol/L, IQR 100.2-190.2). In parallel, folate levels increased most substantially after the first two HD-MTX courses (until median 401.6 nmol/L, IQR 163.3-594.2) after which levels plateaued during the 3d and 4th course (until median 411.5 nmol/L, IQR 240.3-665.6). The ratio folate/MTX-PG decreased significantly over time, which was mostly due to the relatively higher increase (delta) of MTX-PG. CONCLUSION: These results suggest that the increase in RBC folate levels does not seem to have a large effect on RBC MTX levels. Future studies, assessing competition of Leucovorin and MTX on other cellular mechanisms which might negatively affect treatment efficacy, are necessary.

Synthesis and characterization of thermo/pH-sensitive pectin-graft-poly(dimethylaminoethyl methacrylate) coated magnetic nanoparticles.

Herein, thermo- and pH-sensitive pectin-graft-poly(dimethylaminoethyl methacrylate) copolymer-coated magnetic nanoparticles were synthesized via a green and rapid synthetic approach based on microwave irradiation. Firstly, a novel thermo- and pH-sensitive pectin-graft-poly(dimethylaminoethyl methacrylate) copolymer (Pec-g-PolyDMAEMA) was synthesized and then, Pec-g-PolyDMAEMA based magnetic nanoparticles (Pec-g-PolyDMAEMA@Fe3O4) were produced via microwave-assisted co-precipitation method. The thermo/pH/magnetic field multi-sensitive hybrid nanoparticle was characterized by techniques like TEM, VSM, FT-IR, and TGA/DSC. In vitro release studies of 5-Fluorouracil (FL) were carried out by altering the temperature (37 and 44°C), pH (5.5 and 7.4) and presence of an AMF. The FL release of Pec-g-PolyDMAEMA@Fe3O4@FL exhibited pH-sensitive behavior. They showed thermo/pH-sensitive FL release features with the greatest release of FL at 37°C (56%) than at 44°C (40%) and at pH of 7.4 (63%) than at pH of 5.5 (45%) within 48h. The FL release was also significantly increased (100%) with the presence of a 50 mT magnetic field. These results indicate that the developed Pec-g-PolyDMAEMA@Fe3O4 nanoparticles are promising in the application of multi-stimuli-sensitive delivery of drugs.

An injectable, self-healing hydrogel system from oxidized pectin/chitosan/γ-Fe2O3.

Injectable hydrogels with self-healing ability present great potential for drug delivery. They could be facilely implanted in vivo and maintained structural and functional integrity till the hydrogel arriving at target sites. Herein, a series of injectable and self-healing composite hydrogel were developed as delivery vehicles for anti-cancer drug. The hydrogels were obtained with varying ratios of oxidized pectin/chitosan to nano γ-Fe2O3, which present excellent injectable, self-healing, magnetic, high biocompatible, and anti-cancer properties. The nano γ-Fe2O3 with particle size of about 0.25 µm loaded on the surface of hydrogel. Magnetic hysteresis loops of the hydrogel presented S-shape over the applied magnetics and the MS value was 4.86 emu/g. When pH dropped from 7.4 to 6.5 or temperature increased form 36 °C to 37 °C, the percentage increase in the swelling rate of OP4-400 reached to 35.89% and 25.13%, respectively. The composite hydrogels could continuously release water-soluble 5-FU for more than 12 h. In addition, the drug delivery systems indicated acceptable anti-cancer property though trace amounts of 5-FU were added in the hydrogel systems. The addition of γ-Fe2O3 could not only be beneficial to the targeting but also collectively enhance the anti-cancer property.

Respect - A multicenter retrospective study on preoperative chemotherapy in locally advanced and borderline resectable pancreatic cancer.

BACKGROUND: Neoadjuvant chemotherapy has become a powerful tool to convert borderline resectable (BRPC) and locally advanced pancreatic cancers (LAPC) into a resectable scenario. However, data analyzing the optimal type of therapy are scarce. In the present multicenter retrospective study, we evaluated the influence of FOLFIRINOX (FFX) and gemcitabine (GEM)-based neoadjuvant therapy on patient prognosis. METHODS: Data on 239 patients from 7 centers across Europe was gathered using an online database. Patients having received their first cycle of chemotherapy for BRPC/LAPC before 06/2017, with a minimum follow-up of 12 months, were included in the intention-to-treat analysis. RESULTS: Patients treated with neoadjuvant FFX (n = 135) or gemcitabine + nab-paclitaxel (GNP) (n = 38) had significantly improved radiological response according to RECIST criteria as compared to single-agent GEM (n = 16), with a partial/complete response of 59.3%, 55.3% and 6.25% respectively (p = 0.001). Treatment with FFX (n = 135) and GNP (n = 38) resulted in higher resection rates compared to GEM (73.3%, 81.6% and 43.8%; p = 0.01 and p = 0.005). Regardless of regimen, patients who were resected had significantly prolonged overall survival compared to non-resected patients (p < 0.01). Complete pathological responses (ypT0 ypN0) were predominantly observed with FFX (p = 0.01). Adjuvant GNP in addition to successful neoadjuvant therapy and surgery resulted in a trend towards improved median survival as compared to postoperative observation (47.0 vs. 30.1 months, p = 0.06). CONCLUSIONS: Representing one of the largest studies published so far, our results reveal that patients with BRPC/LAPC should be offered either FFX or GNP to improve chances of resection and with this also survival.

Langerhans Cell Histiocytosis Involving Second Cervical Vertebra and the Hypothalamus and Pituitary in an Adult.

BACKGROUND: Adult-onset Langerhans cell histiocytosis (LCH) with simultaneous involvement of the high cervical spine and the hypothalamus is rare. CASE DESCRIPTION: We have reported a case of adult-onset LCH in the second cervical vertebra with bony destruction and subsequent diabetes insipidus due to simultaneous involvement of the hypothalamus and pituitary stalk. Magnetic resonance imaging of the hypothalamus and pituitary lesion and immunohistochemistry of the cervical lesion revealed LCH. Posterior fusion of the cervical spine (first, third, and fourth cervical vertebrae) was performed, followed by systemic chemotherapy. The cervical fusion was well maintained, and the patient achieved clinical remission. No new LCH lesion was found during the follow-up of >2 years. CONCLUSIONS: Patients with known LCH of the spine showing new symptoms of diabetes insipidus should be examined for infiltrating lesions of the pituitary stalk or hypothalamus. In cases of severe instability of the spine, surgical treatment should be performed. If multiple and systemic LCH lesions are found, systemic chemotherapy should be administered.

Pyrotinib in the treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer: A case report.

RATIONALE: Pyrotinib is a novel dual pan-ErbB receptor tyrosine kinase inhibitor, approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, there was still limited information regarding specific effect of pyrotinib on HER2-positive MBC patients with phosphoinositol-3 kinase mutation. PATIENT CONCERNS: A 63-year-old woman accidentally discovered a left breast lesion. The breast cancer was diagnosed by biopsy of breast lesion and postoperative pathological examination in March, 2017. The patient was presented with HER2-positive (3+), invasive carcinoma of the left breast with lymph nodes and lung nodules metastasis, and the clinical stage was T4N2M1. However, the lesion continued to aggressive disease progression with the treatment of trastuzumab plus multiple chemotherapy regimens and traditional Chinese medicine. DIAGNOSES: The woman was diagnosed with invasive carcinoma of the left breast and lymph nodes and lung nodules metastasis. INTERVENTIONS: The patient received 6 cycles of pyrotinib in combination with capecitabine regularly. OUTCOMES: Progression free survival was more than 6 months, and the patient's efficacy evaluation was partial remission. LESSONS: Our clinical observations demonstrated that pyrotinib may be an effective treatment for patients with HER2-positive MBC.

MRI T2-weighted sequences-based texture analysis (TA) as a predictor of response to neoadjuvant chemo-radiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC).

PURPOSE: To determine whether MRI T2-weighted sequences-based texture analysis (TA) can predict histopathological tumor regression grade (TRG) in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemo-radiotherapy (nCRT). METHODS: Data on patients undergoing curative-intent surgery for LARC were collected. Patients with a complete pathological response, or TRG1 according to Mandard's system were classified as responders, while patients with TRG ≥ 2 were classified as non-responders. Tumor TA was performed on each patient's paraxial T2w MRI in both pre- and post-nCRT scans, in order to extract histograms, gray-level co-occurrence matrix (GLCM) and run-length matrix (RLM) texture parameters. For features that showed a significant difference between the two groups, a receiver operating characteristic (ROC) curve was drawn. RESULTS: Overall, 62 patients with LARC, treated with nCRT and resective surgery at our institution between 2013 and 2019 were identified. Only post-nCRT GLCM maximum probability showed a significant difference between the two groups (2909 ± 4479 in responders vs. 6515 ± 8990 in non- responders; p = 0.039); at the ROC curve, Youden index showed a sensitivity of 14% and a specificity of 100% for this parameter. CONCLUSIONS: MRI T2-weighted sequences-based TA was not effective in predicting pathological complete response to nCRT in patients with LARC. Further studies are needed to thoroughly investigate the potential of MRI TA in this setting.

Development of Gemcitabine Loaded PLGA/Lecithin Nanoparticles for Non-Small Cell Lung Cancer Therapy.

BACKGROUND: Compared to polymeric nanoparticles prepared using non-lipid surfactants, lecithin addition forms larger nanoparticles and exhibits higher drug loading and the stability of nanoparticles can be conferred by adding Vitamin E Polyethylene Glycol Succinate (TPGS) into the formulation. AIM: The aim of this study is to prepare Gemcitabine (Gem) loaded lecithin/PLGA nanoparticles. Moreover, the effect of TPGS and sodium cholate (SK) on the preparation of lecithin/PLGA nanoparticles was compared. METHODS: It was found that while PC addition into PLGATPGS nanoparticles formed larger particles (251.3± 6.0 nm for Gem-PLGATPGS NPs and 516,9 ± 3.9 nm for Gem-PLGA-PCTPGS NPs), the particle size of PLGASK nanoparticles was not affected by lecithin addition (p>0.05;). RESULTS: In cytotoxicity studies, it was found that the SK-MES-1 cell inhibition rates of Gem-PLGATPGS NPs, Gem-PLGA-PCTPGS NPs, Gem-PLGASK NPs, Gem-PLGA-PCSK NPs were similar with free Gem (p>0.05;). In cytotoxicity studies, it was found that the encapsulation into nanoparticles did not change the cytotoxicity of the drug. However, higher cellular uptake has been observed when the lecithin was used in the preparation of PLGA nanoparticles. CONCLUSION: Compared with free Gem, the Gem-loaded nanoparticles enhanced the uptake of the drug by SK-MES-1 cells which can increase the effect of gemcitabine for non-small cell lung cancer therapy.

Kanglaite injection plus fluorouracil-based chemotherapy on the reduction of adverse effects and improvement of clinical effectiveness in patients with advanced malignant tumors of the digestive tract: A meta-analysis of 20 RCTs following the PRISMA guidelines.

BACKGROUND: The digestive tract malignancies are a series of malignant tumor with high morbidity and mortality. Traditional Chinese medicine (TCM) combined with chemotherapy drugs interventions have been applied for the treatment of malignant tumors in Asian countries for dacades. This study aimed to assess the effectiveness and safety on the combination of Kanglaite injection and fluorouracil-based chemotherapy for treating digestive tract malignancies. PURPOSE: To assess the effectiveness and safety on the combination of Kanglaite injection and fluorouracil-based chemotherapy for digestive tract malignancies. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed when conducting the meta-analysis. Randomized controlled trials (RCTs) of Kanglaite injection combined with fluorouracil-based chemotherapy in the treatment of digestive tract malignant tumors were selected and assessed for inclusion. RevMan 5.3 software (Cochrane Collaboration, Oxford, UK) was used for meta-analysis. The objective response rate (ORR) was defined as the primary endpoint, and the disease control rate (DCR), quality of life (QoL), and toxicities were the secondary outcomes. RESULTS: 20 RCTs enrolling 1339 patients with advanced digestive tract malignancies were included. The methodological quality of most included trials was low to moderate. Compared with fluorouracil-based chemotherapy alone, Kanglaite injection plus fluorouracil-based chemotherapy can improve DCR (risk ratio (RR) = 1.18, 95% confidence interval (CI) 1.11-1.25, P < .00001), ORR (RR = 1.35, 95% CI 1.18-1.54, P < .00001), QoL (RR = 1.58, 95% CI 1.35-1.85, P < .00001), and can reduce adverse drug reactions (ADRs) such as myelosuppression (RR = 0.33, 95% CI 0.25-0.43, P < .00001), leukopenia (RR = 0.31, 95% CI 0.22-0.43, P < .00001), thrombocytopenia (RR = 0.6, 95% CI 0.38-0.49, P = .03), neutropenia (RR = 0.26, 95% CI 0.12-0.55, P = .0005), anemia (RR = 0.41, 95% CI 0.23-0.75, P = .004), gastrointestinal reaction (RR = 0.35, 95% CI 0.27-0.46, P < .00001), nausea/vomiting (RR = 0.41, 95% CI 0.28-0.61, P < .00001), diarrhea (RR = 0.34, 95% CI 0.18-0.62, P = .0004), hepatotoxicity (RR = 0.28, 95% CI 0.17-0.47, P < .00001), neurotoxicity (RR = 0.58, 95% CI 0.41-0.82, P = .002), mucositis (RR = 0.59, 95% CI 0.29-1.21, P = .15). CONCLUSION: Kanglaite injection combined with fluorouracil-based chemotherapy could remarkably improve the clinical effectiveness and reduce the adverse effects in patients with advanced malignant tumors of the digestive tract which may provide evidence to judge whether TCM is an effective and safe intervention for the digestive tract malignancies.

FOLFOX and capecitabine-induced hepatic granuloma mimicking metastasis in a rectal cancer patient.

A 49-year-old male carcinoma rectum patient was treated with neoadjuvant FOLFOX (folinic acid, fluorouracil (5-FU) and oxaliplatin) chemotherapy, chemoradiotherapy with capecitabine, surgery and adjuvant FOLFOX. On follow-up, the patient developed a metabolically active liver lesion mimicking metastasis. Liver biopsy and histopathology showed sinusoidal dilatation with non-caseating granulomas. Follow-up fluorodeoxyglucose positron-emission tomography CT scan demonstrated increase in size of the lesion with metabolic activity suspicious of metastasis. The patient underwent segmental liver resection and histopathology showed non-necrotising granuloma with no evidence of malignancy. It is crucial to consider potential side effects of chemotherapeutic agents and have an unbiased approach when evaluating new liver lesions during post treatment follow-up of colorectal cancer. A multidisciplinary tumour board approach comprising of gastroenterologists, medical oncologists, pathologists, radiologists and surgeons is suggested in the management of such patients. The patient is currently doing well and on regular follow-up.